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.

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.

Interactions between hypoxia and epidermal growth factor receptor in non-small-cell-lung cancer

Tumor hypoxia has been recognized to confer resistance to anticancer therapy since the early 20th century. More recently, its fundamental role in tumorigenesis has been established. Hypoxia-inducible factor (HIF)-1 has been identified as an important transcription factor that mediates the cellular response to hypoxia, promoting both cellular survival and apoptosis under different conditions. Increased tumor cell expression of this transcription factor promotes tumor growth In vivo and is associated with a worse prognosis in patients with non-small-cell lung cancer (NSCLC) undergoing tumor resection. The epidermal growth factor receptor (EGFR) promotes tumor cell proliferation and anglogenesis and inhibits apoptosis. Epidermal growth factor receptor expression increases in a stepwise manner during tumorigenesis and is overexpressed in > 50% of NSCLC tumors. This review discusses the reciprocal relationship between tumor cell hypoxia and EGFR. Recent studies suggest that hypoxia induces expression of EGFR and its ligands. In return, EGFR might enhance the cellular response to hypoxia by increasing expression of HIF-1α, and so act as a survival factor for hypoxic cancer cells. Immunohistochemical studies on a series of resected NSCLC tumors add weight to this contention by demonstrating a close association between expression of EGFR, HIF-1α, and:1 of HIF-1's target proteins, carbonic anhydrase IX. In this article we discuss emerging treatment strategies for NSCLC that target HIF-1, HIF-1 transcriptional targets, and EGFR.

The Tarim picrite-basalt-rhyolite suite, a Permian flood basalt from Northwest China with contrasting rhyolites produced by fractional crystallization and anatexis

We report major and trace element composition, Sr–Nd isotopic and seismological data for a picrite–basalt–rhyolite suite from the northern Tarim uplift (NTU), northwest China. The samples were recovered from 13 boreholes at depths between 5,166 and 6,333 m. The picritic samples have high MgO (14.5–16.8 wt%, volatiles included) enriched in incompatible element and have high 87Sr/86Sr and low 143Nd/144Nd isotopic ratios (εNd (t) = −5.3; Sri = 0.707), resembling the Karoo high-Ti picrites. All the basaltic samples are enriched in TiO2 (2.1–3.2 wt%, volatiles free), have high FeOt abundances (11.27–15.75 wt%, volatiles free), are enriched in incompatible elements and have high Sr and low Nd isotopic ratios (Sri = 0.7049–0.7065; εNd (t) = −4.1 to −0.4). High Nb/La ratios (0.91–1.34) of basalts attest that they are mantle-derived magma with negligible crustal contamination. The rhyolite samples can be subdivided into two coeval groups with overlapping U–Pb zircon ages between 291 ± 4 and 272 ± 2 Ma. Group 1 rhyolites are enriched in Nb and Ta, have similar Nb/La, Nb/U, and Sr–Nd isotopic compositions to the associated basalts, implying that they are formed by fractional crystallization of the basalts. Group 2 rhyolites are depleted in Nb and Ta, have low Nb/La ratios, and have very high Sr and low Nd isotopic ratios, implying that crustal materials have been extensively, if not exclusively, involved in their source. The picrite–basalt–rhyolite suite from the NTU, together with Permian volcanic rocks from elsewhere Tarim basin, constitute a Large Igneous Province (LIP) that is characterized by large areal extent, rapid eruption, OIB-type chemical composition, and eruption of high temperature picritic magma. The Early Permian magmatism, which covered an area >300,000 km2, is therefore named the Tarim Flood Basalt.

The enemy of music : modeling the behavior of a cultural industry in crisis

The purpose of this explorative study is to contribute to the understanding of current music industry dynamics. The situation is undeniably quite dramatic: Since the turn of the millennium, the global music industry has declined by $ US 6.2 billion in value—a fall of 16.3% in constant dollar terms. IFPI, the trade organization representing the international recording industry, identifies a number of exogenous factors as the main drivers of the downturn. This article suggests that other factors, in addition to those identified by IFPI, may have contributed to the current difficulties. A model is presented which indicates that business strategies which were designed to cope with the challenging business environment have reduced product diversity, damaged profitability, and contributed to the problem they were intended to solve.

A randomized controlled trial of a 10 percent CPP-ACP cream to reduce mutans streptococci colonization

Purpose The purpose of this study was to investigate the effectiveness of a 10 percent casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) cream to reduce mutans streptococci (MS) colonization and prevent early childhood caries. Methods The cohort was randomized at mean age of 11 days old to receive once-daily CPP-ACP cream (n=102) or no product (comparison group; n=89) from the time of first tooth eruption. All mothers were contacted by telephone at six, 12, and 18 months and advised to brush their children's teeth twice daily with low-dose fluoride toothpaste. At 24 months, all children were examined at a community clinic. Results At 24 months old, one out of 65 (2 percent) children in the CPP-ACP group had caries vs. four out of 58 (seven percent) in the comparison group (difference not statistically significant). There were fewer MS-positive children in the CPP-ACP group (26 percent) vs. the comparison group (47 percent; P=.02). A dose-response effect of CPP-ACP usage on MS was observed, where MS was present in eight percent of regular CPP-ACP users, 28 percent of irregular users, and 47 percent of non-users (P<.02). Conclusions CPP-ACP reduced the percentages of mutans streptococci-positive 24-month-old children, although it did not reduce caries prevalence.

The transformation of Sweden from a haven for online pirates to the hope of the digital music industry [Musikbranschens föregångsland]

1974 was the year when the Swedish pop group ABBA won the Eurovision Song Contest in Brighton and when Blue Swede reached number one on the Billboard Hot 100 in the US. Although Swedish pop music gained some international success even prior to 1974, this year is often considered as the beginning of an era in which Swedish pop music had great success around the world. With brands such as ABBA, Europe, Roxette, The Cardigans, Ace of Base, In Flames, Robyn, Avicii, Swedish House Mafia and music producers Stig Andersson, Ola Håkansson, Dag Volle, Max Martin, Andreas Carlsson, Jorgen Elofsson and several others have the myth of the Swedish music miracle kept alive for nearly more than four decades. Swedish music looks to continue reap success around the world, but since the millennium, Sweden's relationship with music has been more focused on relatively controversial Internet-based services for music distribution developed by Swedish entrepreneurs and engineers rather than on successful musicians and composers. This chapter focusses on the music industry in Sweden. The chapter will discuss the development of the Internet services mentioned above and their impact on the production, distribution and consumption of recorded music. Ample space will be given in particular to Spotify, the music service that quickly has fundamentally changed the music industry in Sweden. The chapter will also present how the music industry's three sectors - recorded music, music licensing and live music - interact and evolve in Sweden.

An ICT Implementation Strategy for Primary Schools in Fiji

Information and Communication Technology (ICT) has been embraced with hope and optimism in both developing and developed countries. While in the developed countries most citizens have access to one or many of the devices which utilize this technology (e.g. desktop, laptop, tablet, mobile phone), in developing countries this “luxury” can only be afforded by a privileged few. The use of these technologies in primary schools in developing countries is low. This is due to the fact that there are other bigger issues that some of these countries have to grapple with such as meeting the basic health and education needs of its citizens. Quality primary education and global development partnerships are two of the eight Millennium Development Goals of the United Nations (UNDP, 2012). Many Governments, NGO’s, service organizations, and individuals in developing countries are always looking at ways in which the disparity (not just in terms of ICT) can be narrowed. There has to be a greater collaboration between stakeholders in developing and developed countries (Mutonyi & Norton, 2007). How do stakeholders from developed countries engage with partners in developing countries to deliver meaningful and relevant outcomes for primary school students using ICT? As a first step getting the key stakeholders on side is critical. In the Fijian context, schools are managed and run by committees who are members of the community. Therefore, getting the committee on side together with the head-teachers and teachers is critical. Conversations about teaching and learning with technology can then follow with greater ease. The sustainability of any innovative approaches is also an essential element of this equation. Through this lens, this chapter investigates how ICT can be implemented in primary schools in Fiji. It proposes a three-layered approach which focuses on: (1) the community, school leadership, and teachers; (2) content, pedagogy, and technology, and (3) sustainability.

Archimedes, aid/watch, constitutional levers and where we now stand

Archimedes is reported as famously saying: 'Give me a place to stand and I will move the earth.' He was referring to the power of levers. His point was that a person of ordinary capacity with a place to stand, a fulcrum and a level could change the path of planets. This principle of physics is a metaphor for how the common law has moved over the last millennium. Courts have found a stable foundation on which to stand, such as the constitutional bedrock or well-grounded precedent, and, using cases as fulcrums and legal principles as levers, the have moved the law. Australia is at a critical juncture in the development of the law of charities. The High Court of Australia has held that political purposes can be charitable in certain circumstances. The Parliament of Australia has not only enshrined this in a statutory definition of charity but has done so with a preamble to the legislation which affirms the basis for this development in residing in the 'unique nature and diversity of charities and the distinctive and important role that they play in Australia'.

Restructuring arts and cultural funding in Tanzania : expectations and impasses

In 1984, the Tanzanian government established the Tanzania Culture Trust Fund (TCTF) – well known as ‘Mfuko’ – with the support of the Swedish government. The focus of Mfuko was to enable the arts and cultural sector to strengthen its position through grant allocations. However, rural artists have limited opportunity to access financial support to strengthen their works. The challenge remains: how to restructure arts and cultural funding in line with cutting dependence on foreign aid. This article reports on the research findings of a case study based on ‘Strategies for youth employment in Tanzania: A creative industries approach’. The study was undertaken in Dar-Es-Salaam, Bagamoyo, Dodoma, Lindi and Morogoro from July to October, 2012. This study employed mixed me thods incorporating questionnaires, interviews, and focus groups. This paper argues that lack of deliberate initiatives to restructure arts and cultural funding (in line with cutting dependence on foreign assistance) have prevented artists from fulfilling their desire for better lives. Hence, the severe lack of financial support to the artists remains a challenge to meeting the Millennium Development Goals and Tanzania Development Vision 2025. Although this discussion is specific to Tanzania, the significance and contribution of this case may apply to other developing countries.

Late Pleistocene stratigraphy of IODP Site U1396 and compiled chronology offshore of south and south west Montserrat, Lesser Antilles

Marine sediments around volcanic islands contain an archive of volcaniclastic deposits, which can be used to reconstruct the volcanic history of an area. Such records hold many advantages over often incomplete terrestrial datasets. This includes the potential for precise and continuous dating of intervening sediment packages, which allow a correlatable and temporally-constrained stratigraphic framework to be constructed across multiple marine sediment cores. Here, we discuss a marine record of eruptive and mass-wasting events spanning ~250 ka offshore of Montserrat, using new data from IODP Expedition 340, as well as previously collected cores. By using a combination of high-resolution oxygen isotope stratigraphy, AMS radiocarbon dating, biostratigraphy of foraminifera and calcareous nannofossils and clast componentry, we identify five major events at Soufriere Hills volcano since 250 ka. Lateral correlation of these events across sediment cores collected offshore of the south and south west of Montserrat, have improved our understanding of the timing, extent and associations between events in this area. Correlations reveal that powerful and potentially erosive density-currents travelled at least 33 km offshore, and demonstrate that marine deposits, produced by eruption-fed and mass-wasting events on volcanic islands, are heterogeneous in their spatial distribution. Thus, multiple drilling/coring sites are needed to reconstruct the full chronostratigraphy of volcanic islands. This multidisciplinary study will be vital to interpreting the chaotic records of submarine landslides at other sites drilled during Expedition 340 and provides a framework that can be applied to the stratigraphic analysis of sediments surrounding other volcanic islands.

The SEA-CALIPSO volcano imaging experiment at Montserrat : plans, campaigns at sea and on land, scientific results, and lessons learned

Since 1995 the eruption of the andesitic Soufrière Hills Volcano (SHV), Montserrat, has been studied in substantial detail. As an important contribution to this effort, the Seismic Experiment with Airgunsource-Caribbean Andesitic Lava Island Precision Seismo-geodetic Observatory (SEA-CALIPSO) experiment was devised to image the arc crust underlying Montserrat, and, if possible, the magma system at SHV using tomography and reflection seismology. Field operations were carried out in October–December 2007, with deployment of 238 seismometers on land supplementing seven volcano observatory stations, and with an array of 10 ocean-bottom seismometers deployed offshore. The RRS James Cook on NERC cruise JC19 towed a tuned airgun array plus a digital 48-channel streamer on encircling and radial tracks for 77 h about Montserrat during December 2007, firing 4414 airgun shots and yielding about 47 Gb of data. The main objecctives of the experiment were achieved. Preliminary analyses of these data published in 2010 generated images of heterogeneous high-velocity bodies representing the cores of volcanoes and subjacent intrusions, and shallow areas of low velocity on the flanks of the island that reflect volcaniclastic deposits and hydrothermal alteration. The resolution of this preliminary work did not extend beyond 5 km depth. An improved three-dimensional (3D) seismic velocity model was then obtained by inversion of 181 665 first-arrival travel times from a more-complete sampling of the dataset, yielding clear images to 7.5 km depth of a low-velocity volume that was interpreted as the magma chamber which feeds the current eruption, with an estimated volume 13 km3. Coupled thermal and seismic modelling revealed properties of the partly crystallized magma. Seismic reflection analyses aimed at imaging structures under southern Montserrat had limited success, and suggest subhorizontal layering interpreted as sills at a depth of between 6 and 19 km. Seismic reflection profiles collected offshore reveal deep fans of volcaniclastic debris and fault offsets, leading to new tectonic interpretations. This chapter presents the project goals and planning concepts, describes in detail the campaigns at sea and on land, summarizes the major results, and identifies the key lessons learned.

UNICEF, Jakarta, Indonesia : Review of Satap Schools

A. Background and context 1. Education, particularly basic education (grades1-9), has been considered critical to promoting national economic growth and social well being1. Three factors that con-tribute to the above are: (i) Education increases human capital inherent in a labor force and thus increases productivity. It also increases capacity for working with others and builds community consensus to support national development. (ii) Education can in-crease the innovative capacity of a community to support social and economic growth—use of new technologies, products and services to promote growth and wellbeing. (iii) Education can facilitate knowledge transfer needed to understand the social and eco-nomic innovations and new processes, practices and values. Cognizant of the above benefits of education, the Millennium Development Goals (MDG) and the Education for All (EFA) declarations advocating universal basic education were formulated and ratified by UN member countries. 2. Achieving universal primary education (grade 6) may not be sufficient to maxim-ize the above noted socio-economic and cultural benefits. There is general consensus that basic literacy and numeracy up to grade 9 are essential foundational blocks for any good education system to support national development. Basic Education provides an educational achievement threshold that ensures the learning is retained. To achieve this, the donor partner led interventions and the UN declarations such as the MDG goals have sought universal access to basic education (grades 1-9). As many countries progress towards achieving the universal access targets, recent research evidence suggests that we need more than just access to basic education to impact on the na-tional development. Measuring basic education completion cycle, gross enrolment rate (GER) and participation rate etc., has to now include a focus on quality and relevance of the education2. 3. While the above research finding is generally accepted by the Government of In-donesia (GoI), unlike many other developing countries, Indonesia is geographically and linguistically complex and has the fourth largest education sector in the world. It has over 3000 islands, 17,000 ethnic groups and it takes as long as 7 hours to travel from east to west of the country and has multiple time differences. The education system has six years of primary education (grades 1-6), 3 years of junior secondary education (grades 7-9) and three years of senior secondary education (grades 10-12). Therefore, applying the findings of the above cited research in a country like Indonesia is a chal-lenge. Nevertheless, since the adoption of the National Education Law (2003)3 the GoI has made significant progress in improving access to and quality of basic education (grades 1-9). The 2011/12 national education statistics show the primary education (grades 1-6) completion rate was 99.3%, the net enrolment rate (NER) was 95.4% and the GER was 115.4%. This is a significant achievement considering the complexities faced within Indonesia. This increase in the primary education sub-sector, however, has not flowed onto the Junior Secondary School (JSS) education. The transition from pri-mary to JSS is still short of the GoI targets. In 2012, there were 146,826 primary schools feeding into 33,668 junior secondary schools. The transition rate from primary to secondary in 2011/12 was 78%. When considering district or sub-district level data the transition in poor districts could be less than the aggregated national rate. Poverty and lack of parents’ education, confounded by opportunity cost, are major obstacles to transitioning to JSS4. 4. Table 1 presents a summary of GoI initiatives to accelerate the transition to JSS. GoI, with assistance from the donor community, has built 2465 new regular JSS, mak-ing the total number of regular JSS 33,668. In addition, 57,825 new classrooms have been added to existing regular JSS. Also, in rural and remote areas 4136 Satu-Atap5 (SATAP) schools were built to increase access to JSS. These SATAP schools are the focus of this study as they provide education opportunities to the most marginalized, ru-ral, remote children who otherwise would not have access to JSS and consequently not complete basic education.

Construction of volcanic records from marine sediment cores : a review and case study (Montserrat, West Indies)

Detailed knowledge of the past history of an active volcano is crucial for the prediction of the timing, frequency and style of future eruptions, and for the identification of potentially at-risk areas. Subaerial volcanic stratigraphies are often incomplete, due to a lack of exposure, or burial and erosion from subsequent eruptions. However, many volcanic eruptions produce widely-dispersed explosive products that are frequently deposited as tephra layers in the sea. Cores of marine sediment therefore have the potential to provide more complete volcanic stratigraphies, at least for explosive eruptions. Nevertheless, problems such as bioturbation and dispersal by currents affect the preservation and subsequent detection of marine tephra deposits. Consequently, cryptotephras, in which tephra grains are not sufficiently concentrated to form layers that are visible to the naked eye, may be the only record of many explosive eruptions. Additionally, thin, reworked deposits of volcanic clasts transported by floods and landslides, or during pyroclastic density currents may be incorrectly interpreted as tephra fallout layers, leading to the construction of inaccurate records of volcanism. This work uses samples from the volcanic island of Montserrat as a case study to test different techniques for generating volcanic eruption records from marine sediment cores, with a particular relevance to cores sampled in relatively proximal settings (i.e. tens of kilometres from the volcanic source) where volcaniclastic material may form a pervasive component of the sedimentary sequence. Visible volcaniclastic deposits identified by sedimentological logging were used to test the effectiveness of potential alternative volcaniclastic-deposit detection techniques, including point counting of grain types (component analysis), glass or mineral chemistry, colour spectrophotometry, grain size measurements, XRF core scanning, magnetic susceptibility and X-radiography. This study demonstrates that a set of time-efficient, non-destructive and high-spatial-resolution analyses (e.g. XRF core-scanning and magnetic susceptibility) can be used effectively to detect potential cryptotephra horizons in marine sediment cores. Once these horizons have been sampled, microscope image analysis of volcaniclastic grains can be used successfully to discriminate between tephra fallout deposits and other volcaniclastic deposits, by using specific criteria related to clast morphology and sorting. Standard practice should be employed when analysing marine sediment cores to accurately identify both visible tephra and cryptotephra deposits, and to distinguish fallout deposits from other volcaniclastic deposits.

Implications of differences in technical efficiency of fishing boats for capacity measurement and reduction

Capacity measurement and reduction is a major international issue to emerge in the new millennium. However, there has been limited assessment of the success of capacity reduction schemes (CRS). In this paper, the success of a CRS is assessed for a European fishery characterised by differences in efficiency levels of individual boats. In such a fishery, given it is assumed that the least efficient producers are the first to exit through a CRS, the reduction in harvesting capacity is less than the nominal reduction in physical fleet capacity. Further, there is potential for harvesting capacity to increase if remaining vessels improve their efficiency.