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.

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.

Co-morbidity of depression and anxiety in common age-related eye diseases : a population-based study of 662 adults

This study examined the prevalence of co-morbid age-related eye disease and symptoms of depression and anxiety in late life, and the relative roles of visual function and disease in explaining symptoms of depression and anxiety. A community-based sample of 662 individuals aged over 70 years was recruited through the electoral roll. Vision was measured using a battery of tests including high and low contrast visual acuity, contrast sensitivity, motion sensitivity, stereoacuity, Useful Field of View, and visual fields. Depression and anxiety symptoms were measured using the Goldberg scales. The prevalence of self-reported eye disease [cataract, glaucoma, or age-related macular degeneration (AMD)] in the sample was 43.4%, with 7.7% reporting more than one form of ocular pathology. Of those with no eye disease, 3.7% had clinically significant depressive symptoms. This rate was 6.7% among cataract patients, 4.3% among those with glaucoma, and 10.5% for AMD. Generalized linear models adjusting for demographics, general health, treatment, and disability examined self-reported eye disease and visual function as correlates of depression and anxiety. Depressive symptoms were associated with cataract only, AMD, comorbid eye diseases and reduced low contrast visual acuity. Anxiety was significantly associated with self-reported cataract, and reduced low contrast visual acuity, motion sensitivity and contrast sensitivity. We found no evidence for elevated rates of depressive or anxiety symptoms associated with self-reported glaucoma. The results support previous findings of high rates of depression and anxiety in cataract and AMD, and in addition show that mood and anxiety are associated with objective measures of visual function independently of self-reported eye disease. The findings have implications for the assessment and treatment of mental health in the context of late-life visual impairment...

What further benefit, if any, might Australia get from the ALI-III Transnational Insolvency: Global Principles for Cooperation in International Insolvency Cases?

In 2006, the American Law Institute (ALI) and the International Insolvency Institute (III) established a Transnational Insolvency Project and appointed Professor Ian Fletcher (United Kingdom) and Professor Bob Wessels (Netherlands) as Joint Reporters. The objective was to investigate whether the essential provisions of the ALI Principles of Cooperation among the NAFTA Countries (ALI-NAFTA Principles) and the annexed Guidelines Applicable to Court-to-Court Communication in Cross-border Cases (ALI-NAFTA Guidelines) may, with certain necessary modifications, be acceptable for use by jurisdictions across the world. In 2012, Professor Fletcher and Professor Wessels presented the report Transnational Insolvency: Global Principles for Cooperation in International Insolvency Cases (“ALI-III Report”) to the Annual Meetings of the American Law Institute and the International Insolvency Institute. In 2013, the Australian Academy of Law (AAL) provided support to the authors to undertake research on the possible benefits for Australia of courts and insolvency administrators of referring to the ALI-III Report when addressing international insolvency cases. This AAL project was at the request of the Council of Chief Justices of Australia and New Zealand. This research Report compares the Global Principles for Cooperation in International Insolvency Cases with the Cross-border Insolvency Act 2008 and the UNCITRAL Model Law as it has been adopted and has force of law in Australia. Further, it examines the Global Guidelines for Court-to-Court Communications in International Insolvency Cases in light of Australian cross-border insolvency and procedural law. Finally, it makes brief reference to and commentary on the Global Rules on Conflict–of-Laws Matters in International Insolvency Cases annexed to the ALI-III Report from the perspective of Australian choice of law rules.

Status of the world's remaining closed forests : an assessment using satellite data and policy options

Historically, it appears that some of the WRCF have survived because i) they lack sufficient quantity of commercially valuable species; ii) they are located in remote or inaccessible areas; or iii) they have been protected as national parks and sanctuaries. Forests will be protected when people who are deciding the fate of forests conclude than the conservation of forests is more beneficial, e.g. generates higher incomes or has cultural or social values, than their clearance. If this is not the case, forests will continue to be cleared and converted. In the future, the WRCF may be protected only by focused attention. The future policy options may include strategies for strong protection measures, the raising of public awareness about the value of forests, and concerted actions for reducing pressure on forest lands by providing alternatives to forest exploitation to meet the growing demands of forest products. Many areas with low population densities offer an opportunity for conservation if appropriate steps are taken now by the national governments and international community. This opportunity must be founded upon the increased public and government awareness that forests have vast importance to the welfare of humans and ecosystems' services such as biodiversity, watershed protection, and carbon balance. Also paramount to this opportunity is the increased scientific understanding of forest dynamics and technical capability to install global observation and assessment systems. High-resolution satellite data such as Landsat 7 and other technologically advanced satellite programs will provide unprecedented monitoring options for governing authorities. Technological innovation can contribute to the way forests are protected. The use of satellite imagery for regular monitoring and Internet for information dissemination provide effective tools for raising worldwide awareness about the significance of forests and intrinsic value of nature.

Influence of different nitrogen rates and DMPP nitrification inhibitor on annual N2O emissions from a subtropical wheat–maize cropping system

Global cereal production will need to increase by 50% to 70% to feed a world population of about 9 billion by 2050. This intensification is forecast to occur mostly in subtropical regions, where warm and humid conditions can promote high N2O losses from cropped soils. To secure high crop production without exacerbating N2O emissions, new nitrogen (N) fertiliser management strategies are necessary. This one-year study evaluated the efficacy of a nitrification inhibitor (3,4-dimethylpyrazole phosphate—DMPP) and different N fertiliser rates to reduce N2O emissions in a wheat–maize rotation in subtropical Australia. Annual N2O emissions were monitored using a fully automated greenhouse gas measuring system. Four treatments were fertilized with different rates of urea, including a control (40 kg-N ha−1 year−1), a conventional N fertiliser rate adjusted on estimated residual soil N (120 kg-N ha−1 year−1), a conventional N fertiliser rate (240 kg-N ha−1 year−1) and a conventional N fertiliser rate (240 kg-N ha−1 year−1) with nitrification inhibitor (DMPP) applied at top dressing. The maize season was by far the main contributor to annual N2O emissions due to the high soil moisture and temperature conditions, as well as the elevated N rates applied. Annual N2O emissions in the four treatments amounted to 0.49, 0.84, 2.02 and 0.74 kg N2O–N ha−1 year−1, respectively, and corresponded to emission factors of 0.29%, 0.39%, 0.69% and 0.16% of total N applied. Halving the annual conventional N fertiliser rate in the adjusted N treatment led to N2O emissions comparable to the DMPP treatment but extensively penalised maize yield. The application of DMPP produced a significant reduction in N2O emissions only in the maize season. The use of DMPP with urea at the conventional N rate reduced annual N2O emissions by more than 60% but did not affect crop yields. The results of this study indicate that: (i) future strategies aimed at securing subtropical cereal production without increasing N2O emissions should focus on the fertilisation of the summer crop; (ii) adjusting conventional N fertiliser rates on estimated residual soil N is an effective practice to reduce N2O emissions but can lead to substantial yield losses if the residual soil N is not assessed correctly; (iii) the application of DMPP is a feasible strategy to reduce annual N2O emissions from sub-tropical wheat–maize rotations. However, at the N rates tested in this study DMPP urea did not increase crop yields, making it impossible to recoup extra costs associated with this fertiliser. The findings of this study will support farmers and policy makers to define effective fertilisation strategies to reduce N2O emissions from subtropical cereal cropping systems while maintaining high crop productivity. More research is needed to assess the use of DMPP urea in terms of reducing conventional N fertiliser rates and subsequently enable a decrease of fertilisation costs and a further abatement of fertiliser-induced N2O emissions.

Developing sustainable fish farming in the Western Pacific : a viewpoint on potential reasons for why many attempts failed

Capture fisheries and aquaculture have been a major source of food and providers of economic benefits to many communities around the world for a very long time. While the history of aquaculture or fish farming can be traced back for more than 2000 years in some corners of the globe, notably in China, Japan and the Mediterranean, this is not true everywhere, where in general, fish farming is a relatively new industry. Rapid human population growth and increasing urbanisation over the last 20 to 40 years has meant that while fish consumption has doubled globally, returns from capture fisheries have remained static or have declined due to overexploitation and rising pollution levels, with some fisheries either closing or becoming economically unviable. Data from studies suggest that this trend is unlikely to be reversed unless appropriate fisheries management allows depleted wild stocks to rebuild. This has occurred during a time when demand for fish products has grown, in part due to improved purchasing power in some developing countries and changing dietary habits where fish are now considered to have a positive impact on health. Based on the projected population growth over the next two decades, Food and Agricultural Organization (FAO) estimates that at least an additional 40 million tonnes of aquatic food will be required to maintain the current per capita consumption (FAO 2006).

A comparison of MiL‐Lx and Hybrid‐III responses in seated and standing postures with blast mats in simulated under‐vehicle explosions

Blast mats that can be retrofitted to the floor of military vehicles are considered to reduce the risk of injury from under‐vehicle explosions. Anthropometric test devices (ATDs) are validated for use only in the seated position. The aim of this study was to use a traumatic injury simulator fitted with 3 different blast mats in order to assess the ability of 2 ATD designs to evaluate the protective capacity of the mats in 2 occupant postures under 2 severities. Tests were performed for each combination of mat design, ATD, severity and posture using an antivehicle under‐belly injury simulator. The differences between mitigation systems were larger under the H‐III compared to the MiL‐Lx. There was little difference in how the 2 ATDs and how posture ranked the mitigation systems. Results from this study suggest that conclusions obtained by testing in the seated position can be extrapolated to the standing. However, the different percentage reductions observed in the 2 ATDs suggests different levels of protection. It is therefore unclear which ATD should be used to assess such mitigation systems. A correlation between cadavers and ATDs on the protection offered by blast mats is required in order to elucidate this issue.

An R2R3 MYB transcription factor determines red petal colour in an Actinidia (kiwifruit) hybrid population

Background Red colour in kiwifruit results from the presence of anthocyanin pigments. Their expression, however, is complex, and varies among genotypes, species, tissues and environments. An understanding of the biosynthesis, physiology and genetics of the anthocyanins involved, and the control of their expression in different tissues, is required. A complex, the MBW complex, consisting of R2R3-MYB and bHLH transcription factors together with a WD-repeat protein, activates anthocyanin 3-O-galactosyltransferase (F3GT1) to produce anthocyanins. We examined the expression and genetic control of anthocyanins in flowers of Actinidia hybrid families segregating for red and white petal colour. Results Four inter-related backcross families between Actinidia chinensis Planch. var. chinensis and Actinidia eriantha Benth. were identified that segregated 1:1 for red or white petal colour. Flower pigments consisted of five known anthocyanins (two delphinidin-based and three cyanidin-based) and three unknowns. Intensity and hue differed in red petals from pale pink to deep magenta, and while intensity of colour increased with total concentration of anthocyanin, no association was found between any particular anthocyanin data and hue. Real time qPCR demonstrated that an R2R3 MYB, MYB110a, was expressed at significant levels in red-petalled progeny, but not in individuals with white petals. A microsatellite marker was developed that identified alleles that segregated with red petal colour, but not with ovary, stamen filament, or fruit flesh colour in these families. The marker mapped to chromosome 10 in Actinidia. The white petal phenotype was complemented by syringing Agrobacterium tumefaciens carrying Actinidia 35S::MYB110a into the petal tissue. Red pigments developed in white petals both with, and without, co-transformation with Actinidia bHLH partners. MYB110a was shown to directly activate Actinidia F3GT1 in transient assays. Conclusions The transcription factor, MYB110a, regulates anthocyanin production in petals in this hybrid population, but not in other flower tissues or mature fruit. The identification of delphinidin-based anthocyanins in these flowers provides candidates for colour enhancement in novel fruits.

Test-retest reliability of four physical activity measures used in population surveys

Accurate monitoring of prevalence and trends in population levels of physical activity (PA) is a fundamental public health need. Test-retest reliability (repeatability) was assessed in population samples for four self-report PA measures: the Active Australia survey (AA, N=356), the short International Physical Activity Questionnaire (IPAQ, N=104), the physical activity items in the Behavioral Risk Factor Surveillance System (BRFSS, N=127) and in the Australian National Health Survey (NHS, N=122). Percent agreement and Kappa statistics were used to assess reliability of classification of activity status as 'active', 'insufficiently active' or 'sedentary'. Intraclass correlations (ICCs) were used to assess agreement on minutes of activity reported for each item of each survey and for total minutes. Percent agreement scores for activity status were very good on all four instruments, ranging from 60% for the NHS to 79% for the IPAQ. Corresponding Kappa statistics ranged from 0.40 (NHS) to 0.52 (AA). For individual items, ICCs were highest for walking (0.45 to 0.78) and vigorous activity (0.22 to 0.64) and lowest for the moderate questions (0.16 to 0.44). All four measures provide acceptable levels of test-retest reliability for assessing both activity status and sedentariness, and moderate reliability for assessing total minutes of activity.

Physical activity and population health outcomes

SMA members Neville Owen, Adrian Bauman, Wendy Brown and Stewart Trost have recently been awarded two NHMRC grants for research which will focus on understanding and influencing physical activity to improve population health outcomes. They were awarded under the Capital Building for Population Health scheme and the Program Grants scheme. The total value of the grants is 86.5 million over five years. The new grants will allow the researchers to conduct rigorous behavioural and epidemiological research which will inform the development of innovative primary and secondary prevention initiatives and determine their effectiveness. This is important, because physical activity is significantly implicated in the prevention and management of established chronic health problems such as cardiovascular disease, type 2 diabetes, osteoporosis and some forms of cancer. It also has a key role to play in addressing the growing epidemic of childhood and adult obesity, and in the maintenance of functional well-being with age. However, in recent years, physical activity levels in Australia have declined, indicating that the net sum of all our efforts to encourage physical activity participation require renewed and innovative efforts. The proposed research programs will be based on the researchers' cross-disciplinary backgrounds in exercise physiology, psychology, health promotion and epidemiology, and will be integrated across four main domains:..