Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma : results from the European Thoracic Oncology Platform Lungscape Project

PURPOSE: The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage non-small-cell lung cancer (NSCLC) varies by population examined and detection method used. The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population. METHODS: Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank. Positive patients were matched with negative patients in a 1:2 ratio, both for IHC and for FISH testing. Testing was performed in 16 participating centers, using the same protocol after passing external quality assessment. RESULTS: Positive ALK IHC staining was present in 80 patients (prevalence of 6.2%; 95% CI, 4.9% to 7.6%). Of these, 28 patients were ALK FISH positive, corresponding to a lower bound for the prevalence of FISH positivity of 2.2%. FISH specificity was 100%, and FISH sensitivity was 35.0% (95% CI, 24.7% to 46.5%), with a sensitivity value of 81.3% (95% CI, 63.6% to 92.8%) for IHC 2+/3+ patients. The hazard of death for FISH-positive patients was lower than for IHC-negative patients (P = .022). Multivariable models, adjusted for patient, tumor, and treatment characteristics, and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better overall survival (OS). CONCLUSION: In this large cohort of surgically resected lung adenocarcinomas, the prevalence of ALK positivity was 6.2% using IHC and at least 2.2% using FISH. A screening strategy based on IHC or H-score could be envisaged. ALK positivity (by either IHC or FISH) was related to better OS.

Examination of EXOSC4 as a new prognostic marker and a novel therapeutic avenue in lung adenocarcinoma

Although prevention and early detection of the disease greatly improved over the past few years, lung cancer remains the leading cause of cancer deaths. In order to be able to treat a larger population, we are in urgent need for novel treatments. While it is known that DNA repair genes play a major role in the oncogenic transformation, they also represent a weakness of cancers that constitute a therapeutic opportunity. To identify novel DNA repair genes implicated in Lung cancers, we conducted an in silico investigation to identify genes co-regulated with two DNA repair factors, BRCA2 and hSSB1. This approach allowed for the identification of EXOSC4, a component of the RNA Exosome machinery, as a potential factor involved in the maintenance of genome stability and that is deregulated in lung cancer.

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.

HER2 positive gastric and gastroesophageal adenocarcinoma; An Irish tertiary center experience

Background: Trastuzumab has been approved for patients with human epidermal growth factor receptor 2 (HER2) over expression and gene amplification metastatic gastric cancer. Here we present the prevalence of HER2 positive gastric cancer in an Irish population, the use of Trastuzumab in first line and beyond progression. Methods: The study was conducted in St James's Hospital, Dublin. A retrospective analysis of the date of patients with HER2 positive gastric cancer over a period of 3 years was carried out. Her2 positive was defined as immunohistochemistry (IHC) score of +3, of IHC score of +2 and increased gene copy number by fluorescence in situ hybridization (FISH). Overall survival was calculated from the day of initiation of treatment with Trastuzumab until death. Results: During the study period 140 patients with gastric and gastro-esophageal junction adenocarcinoma were treated. Out of those, 30 (21.4%) had HER2 positive disease. Among HER2 positive disease patients 18 (12.8%) were treated with first line Trastuzumab containing regimen with a median overall survival of 13 months. Nine (50%) developed progressive disease while on Trastuzumab and of those, 4 (22.2%) patients continued on Trastuzumab beyond progression, two (11.1%) of whom achieved stable disease and a prolonged survival. Conclusion: HER2 positivity rate in an Irish population with advanced gastric and gastro-esophageal junction adenocarcinoma is 21.4%. Treatment with Trastuzumab in the first line in combination with chemotherapy is a reasonable approach. Continuation of Trastuzumab beyond progression is a feasible strategy that requires further exploration.

Application of the analytic hierarchy process (AHP) in multi-criteria analysis of the selection of intelligent building systems

The availability of innumerable intelligent building (IB) products, and the current dearth of inclusive building component selection methods suggest that decision makers might be confronted with the quandary of forming a particular combination of components to suit the needs of a specific IB project. Despite this problem, few empirical studies have so far been undertaken to analyse the selection of the IB systems, and to identify key selection criteria for major IB systems. This study is designed to fill these research gaps. Two surveys: a general survey and the analytic hierarchy process (AHP) survey are proposed to achieve these objectives. The first general survey aims to collect general views from IB experts and practitioners to identify the perceived critical selection criteria, while the AHP survey was conducted to prioritize and assign the important weightings for the perceived criteria in the general survey. Results generally suggest that each IB system was determined by a disparate set of selection criteria with different weightings. ‘Work efficiency’ is perceived to be most important core selection criterion for various IB systems, while ‘user comfort’, ‘safety’ and ‘cost effectiveness’ are also considered to be significant. Two sub-criteria, ‘reliability’ and ‘operating and maintenance costs’, are regarded as prime factors to be considered in selecting IB systems. The current study contributes to the industry and IB research in at least two aspects. First, it widens the understanding of the selection criteria, as well as their degree of importance, of the IB systems. It also adopts a multi-criteria AHP approach which is a new method to analyse and select the building systems in IB. Further research would investigate the inter-relationship amongst the selection criteria.

The appeal of the International Baccalaureate in Australia’s educational market: A curriculum of choice for mobile futures

In Australia there is growing interest in a national curriculum to replace the variety of matriculation credentials managed by State Education departments, ostensibly to address increasing population mobility. Meanwhile, the International Baccalaureate (IB) is attracting increasing interest and enrolments in State and private schools in Australia, and has been considered as one possible model for a proposed Australian Certificate of Education. This paper will review the construction of this curriculum in Australian public discourse as an alternative frame for producing citizens, and ask why this design appeals now, to whom, and how the phenomenon of its growing appeal might inform national curricular debates. The IB’s emergence is understood with reference to the larger context of neo-liberal marketization policies, neo-conservative claims on the curriculum and middle class strategy. The paper draws on public domain documents from the IB Organisation and newspaper reportage to demonstrate how the IB is constructed for public consumption in Australia.

Student perceptions of the impact of online discussion forum participation on learning outcomes

Choosing the “right” type of technology, either synchronous or asynchronous, to facilitate learning outcomes is a new challenge as the pace of emerging technologies increases and diversifies. Teachers are encouraged to design courses that require collaboration in online learning communities to facilitate the development of higher order thinking skills for life long learning. It is therefore important to gather evidence of the kinds of opportunities afforded to students and whether the students themselves endorse collaborative online tools as a legitimate method of assisting in their learning. This paper outlines the way in which one secondary school has used an online discussion forum to support students in the International Baccalaureate (IB) Diploma Program in enhancing research skills and skills for lifelong learning. The paper considers whether online collaborative tools are perceived by students as a positive way to improve learning outcomes.

Towards developing an integrated model of information behaviour

This paper presents the results from a study of information behaviors in the context of people's everyday lives undertaken in order to develop an integrated model of information behavior (IB). 34 participants from across 6 countries maintained a daily information journal or diary – mainly through a secure web log – for two weeks, to an aggregate of 468 participant days over five months. The text-rich diary data was analyzed using a multi-method qualitative-quantitative analysis in the following order: Grounded Theory analysis with manual coding, automated concept analysis using thesaurus-based visualization, and finally a statistical analysis of the coding data. The findings indicate that people engage in several information behaviors simultaneously throughout their everyday lives (including home and work life) and that sense-making is entangled in all aspects of them. Participants engaged in many of the information behaviors in a parallel, distributed, and concurrent fashion: many information behaviors for one information problem, one information behavior across many information problems, and many information behaviors concurrently across many information problems. Findings indicate also that information avoidance – both active and passive avoidance – is a common phenomenon and that information organizing behaviors or the lack thereof caused the most problems for participants. An integrated model of information behaviors is presented based on the findings.

Quality of life after total laparoscopic hysterectomy versus total abdominal hysterectomy for stage I endometrial cancer (LACE) : a randomised trial

Background: The two-stage Total Laparoscopic Hysterectomy (TLH) versus Total Abdominal Hysterectomy (TAH) for stage I endometrial cancer (LACE) randomised controlled trial was initiated in 2005. The primary objective of stage 1 was to assess whether TLH results in equivalent or improved QoL up to 6 months after surgery compared to TAH. The primary objective of stage 2 was to test the hypothesis that disease-free survival at 4.5 years is equivalent for TLH and TAH. Results addressing the primary objective of stage 1 of the LACE trial are presented here. Methods: The first 361 LACE participants (TAH n= 142, TLH n=190) were enrolled in the QoL substudy at 19 centres across Australia, New Zealand and Hong Kong, and 332 completed the QoL analysis. Randomisation was performed centrally and independently from other study procedures via a computer generated, web-based system (providing concealment of the next assigned treatment) using stratified permuted blocks of 3 and 6, and assigned patients with histologically confirmed stage 1 endometrioid endometrial adenocarcinoma and ECOG performance status <2 to TLH or TAH stratified by histological grade and study centre. No blinding of patients or study personnel was attempted. QoL was measured at baseline, 1 and 4 weeks (early), and 3 and 6 months (late) after surgery using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. The primary endpoint was the difference between the groups in QoL change from baseline at early and late time points (a 5% difference was considered clinically significant). Analysis was performed according to the intention-to-treat principle using generalized estimating equations on differences from baseline for the early and late QoL recovery. The LACE trial is registered with clinicaltrials.gov (NCT00096408) and the Australian New Zealand Clinical Trials Registry (CTRN12606000261516). Patients for both stages of the trial have now been recruited and are being followed up for disease-specific outcomes. Findings: The proportion of missing values at the 5%, 10% 15% and 20% differences in the FACT-G scale was 6% (12/190) in the TLH and 14% (20/142) in the TAH group. There were 8/332 conversions (2.4%, 7 of which were from TLH to TAH). In the early phase of recovery, patients undergoing TLH reported significantly greater improvement of QoL from baseline compared to TAH in all subscales except the emotional and social well-being subscales. Improvements in QoL up to 6 months post-surgery continued to favour TLH except for the emotional and social well-being of the FACT and the visual analogue scale of the EuroQoL five dimensions (EuroQoL-VAS). Length of operating time was significantly longer in the TLH group (138±43 mins), than in the TAH group at (109±34 mins; p=0.001). While the proportion of intraoperative adverse events was similar between the treatment groups (TAH 8/142, 5.6%; TLH 14/190, 7.4%; p=0.55), postoperatively, twice as many patients in the TAH group experienced adverse events of CTC grade 3+ than in the TLH group (33/142, 23.2% and 22/190, 11.6%, respectively; p=0.004). Postoperative serious adverse events occurred more frequently in patients who had a TAH (27/142, 19.0%) than a TLH (15/190, 7.9%) (p=0.002). Interpretation: QoL improvements from baseline during early and later phases of recovery, and the adverse event profile significantly favour TLH compared to TAH for patients treated for Stage I endometrial cancer.

Down the rabbit hole and through the looking glass: A conception of information seeking and searching through a diary study.

Information behaviour (IB) is an area within Library and Information Science that studies the totality of human behaviour in relation to information, both active and passive, along with the explicit and the tacit mental states related to information. This study reports on a recently completed dissertation research that integrates the different models of information behaviours using a diary study where 34 participants maintained a daily journal for two weeks through a web log or paper diary. This resulted in thick descriptions of IB, which were manually analysed using the Grounded Theory method of inquiry, and then cross-referenced through both text-analysis and statistical analysis programs. Among the many key findings of this study, one is the focus this paper: how participants express their feelings of the information seeking process and their mental and affective states related specifically to the sense-making component which co-occurs with almost every other aspect of information behaviour. The paper title – Down the Rabbit Hole and Through the Looking Glass – refers to an observation that some of the participants made in their journals when they searched for, or avoided information, and wrote that they felt like they have fallen into a rabbit hole where nothing made sense, and reported both positive feelings of surprise and amazement, and negative feelings of confusion, puzzlement, apprehensiveness, frustration, stress, ambiguity, and fatigue. The study situates this sense-making aspects of IB within an overarching model of information behaviour that includes IB concepts like monitoring information, encountering information, information seeking and searching, flow, multitasking, information grounds, information horizons, and more, and proposes an integrated model of information behaviour illuminating how these different concepts are interleaved and inter-connected with each other, along with it's implications for information services.

Spatiotemporal investigations of DNA damage repair using microbeams

Cellular response to radiation damage is made by a complex network of pathways and feedback loops whose spatiotemporal organisation is still unclear despite its decisive role in determining the fate of the damaged cell. Revealing the dynamic sequence of the repair proteins is therefore critical in understanding how the DNA repair mechanisms work. There are also still open questions regarding the possible movement of damaged chromatin domains and its role as trigger for lesion recognition and signalling in the DNA repair context. The single-cell approach and the high spatial resolution offered by microbeams provide the perfect tool to study and quantify the dynamic processes associated with the induction and repair of DNA damage. We have followed the development of radiation-induced foci for three DNA damage markers (i.e. γ-H2AX, 53BP1 and hSSB1) using normal fibroblasts (AG01522), human breast adenocarcinoma cells (MCF7) and human fibrosarcoma cells (HT1080) stably transfected with yellow fluorescent protein fusion proteins following irradiation with the QUB X-ray microbeam (carbon X-rays <2 µm spot). The size and intensity of the foci has been analysed as a function of dose and time post-irradiation to investigate the dynamics of the above-mentioned DNA repair processes and monitor the remodelling of chromatin structure that the cell undergoes to deal with DNA damage.

Global Business Today 2nd edition

Global Business Today is focused on the fundamentals of international business. Not only does this text provide coverage of the strategic imperatives of operating IB out of a small, dependent economy but it also builds a thorough worldwide orientation. In this edition, international business Graduate Attributes have been integrated throughout and there is topical discussion of issues such as the Doha round of trade negotiation, climate change and the rise of China and India. The authors recognise that case studies reinforce relevance and have therefore included either entirely new or significantly revised cases in every chapter. With a concise treatment of the crucial elements of an IB course, Global Business Today is the ideal text for a first subject in international busines

The role of information avoidance in everyday-life information behaviors

This paper presents the results from a study of information behaviors in the context of people's everyday lives as part of a larger study of information behaviors (IB). 34 participants from across 6 countries maintained a daily information journal or diary – mainly through a secure web log – for two weeks, to an aggregate of 468 participant days over five months. The text-rich diary data was analyzed using Grounded Theory analysis. The findings indicate that information avoidance is a common phenomenon in everyday life and consisted of both passive avoidance and active avoidance. This has implications for several aspects of peoples' lives including health, finance, and personal relationships.

Turbulence characteristics of a small subtropical estuary during and after some moderate rainfall

In natural estuaries, scalar diffusion and dispersion are driven by turbulence. In the present study, detailed turbulence measurements were conducted in a small subtropical estuary with semi-diurnal tides under neap tide conditions. Three acoustic Doppler velocimeters were installed mid-estuary at fixed locations close together. The units were sampled simultaneously and continuously at relatively high frequency for 50 h. The results illustrated the influence of tidal forcing in the small estuary, although low frequency longitudinal velocity oscillations were observed and believed to be induced by external resonance. The boundary shear stress data implied that the turbulent shear in the lower flow region was one order of magnitude larger than the boundary shear itself. The observation differed from turbulence data in a laboratory channel, but a key feature of natural estuary flow was the significant three dimensional effects associated with strong secondary currents including transverse shear events. The velocity covariances and triple correlations, as well as the backscatter intensity and covariances, were calculated for the entire field study. The covariances of the longitudinal velocity component showed some tidal trend, while the covariances of the transverse horizontal velocity component exhibited trends that reflected changes in secondary current patterns between ebb and flood tides. The triple correlation data tended to show some differences between ebb and flood tides. The acoustic backscatter intensity data were characterised by large fluctuations during the entire study, with dimensionless fluctuation intensity I0b =Ib between 0.46 and 0.54. An unusual feature of the field study was some moderate rainfall prior to and during the first part of the sampling period. Visual observations showed some surface scars and marked channels, while some mini transient fronts were observed.

Optimising meritocratic advantage with the International Baccalaureate Diploma in Australian schools

This paper explores two of the tensions Tarc (2009) identifies in the history of the International Baccalaureate (IB) Diploma: firstly between its design for meritocratic competition and its internationalist vision; and secondly between the IB as a global commodity and its localised interpretations. Using data from three case studies of Australian schools offering both the IB Diploma and the local government curriculum, and student responses to an online survey across 26 such schools, the analysis shows how choices behind the IB’s growing popularity foreground strategies for optimising meritocratic competition. Framed through Bourdieu’s concepts of field and ‘rules of the game’, the analysis shows how students act on their own comparative analyses of each curriculum to optimise their chances to access desirable university pathways within the local rules of the game for university placement. Schools are shown to offer the IB Diploma to recruit and retain academically ambitious students by pooling their relative advantage in different local ecologies. Students are shown to carefully evaluate the benefits and costs of the IB choice. The conclusion reflects on how the choice of the IB Diploma for meritocratic advantage by some might change conditions for others not choosing it.