EUELC project : a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration

The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular - pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARβ genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes. Copyright©ERS Journals Ltd 2009.

Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study

Background: A recent study by Dhillon et al. [12], identified both angioinvasion and mTOR as prognostic biomarkers for poor survival in early stage NSCLC. The aim of this study was to verify the above study by examining the angioinvasion and mTOR expression profile in a cohort of early stage NSCLC patients and correlate the results to patient clinico-pathological data and survival. Methods: Angioinvasion was routinely recorded by the pathologist at the initial assessment of the tumor following resection. mTOR was evaluated in 141 early stage (IA-IIB) NSCLC patients (67 - squamous; 60 - adenocarcinoma; 14 - others) using immunohistochemistry (IHC) analysis with an immunohistochemical score (IHS) calculated (% positive cells × staining intensity). Intensity was scored as follows: 0 (negative); 1+ (weak); 2+ (moderate); 3+ (strong). The range of scores was 0-300. Based on the previous study a cut-off score of 30 was used to define positive versus negative patients. The impact of angioinvasion and mTOR expression on prognosis was then evaluated. Results: 101 of the 141 tumors studied expressed mTOR. There was no difference in mTOR expression between squamous cell carcinoma and adenocarcinoma. Angioinvasion (p= 0.024) and mTOR staining (p= 0.048) were significant univariate predictors of poor survival. Both remained significant after multivariate analysis (p= 0.037 and p= 0.020, respectively). Conclusions: Our findings verify angioinvasion and mTOR expression as new biomarkers for poor outcome in patients with early stage NSCLC. mTOR expressing patients may benefit from novel therapies targeting the mTOR survival pathway. © 2011 Elsevier Ireland Ltd.

Defining target volumes for stereotactic ablative radiotherapy of early-stage lung tumours: a comparison of three-dimensional 18F-fluorodeoxyglucose positron emission tomography and four-dimensional computed tomography.:PETCT versus 4DCT for SABR in Early Stage NSCLC

AIMS: High local control rates are achieved in stage I lung cancer using
stereotactic ablative radiotherapy. Target delineation is commonly based on
four-dimensional computed tomography (CT) scans. Target volumes defined by
positron emission tomography/computed tomography (PET/CT) are compared with those defined by four-dimensional CT and conventional ('three-dimensional')
(18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT.

MATERIALS AND METHODS: For 16 stage I non-small cell lung cancer tumours, six
approaches for deriving PET target volumes were evaluated: manual contouring,
standardised uptake value (SUV) absolute threshold of 2.5, 35% of maximum SUV
(35%SUV(MAX)), 41% of SUV(MAX) (41%SUV(MAX)) and two different source to
background ratio techniques (SBR-1 and SBR-2). PET-derived target volumes were compared with the internal target volume (ITV) from the modified maximum
intensity projection (MIP(MOD) ITV). Volumetric and positional correlation was
assessed using the Dice similarity coefficient (DSC).

RESULTS: PET-based target volumes did not correspond to four-dimensional CT-based target volumes. The mean DSC relative to MIP(MOD) ITV were: PET manual = 0.64, SUV2.5 = 0.64, 35%SUV(MAX) = 0.63, 41%SUV(MAX) = 0.57. SBR-1 = 0.52, SBR-2 =0.49. PET-based target volumes were smaller than corresponding MIP ITVs.

CONCLUSIONS: Conventional three-dimensional (18)F-FDG PET-derived target volumes for lung stereotactic ablative radiotherapy did not correspond well with those derived from four-dimensional CT, including those in routine clinical use
(MIP(MOD) ITV). Caution is required in using three-dimensional PET for motion
encompassing target volume delineation.

Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer.

Background:Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC.Methods:FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I-II. The FISH results were correlated with clinico-pathological features and overall survival (OS).Results:The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC.Conclusions:FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation.

A comparison between accelerated hypofractionation and stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC): Results of a propensity score-matched analysis

BACKGROUND AND PURPOSE: Stereotactic ablative radiotherapy (SABR) has become standard for inoperable early-stage non-small cell lung cancer (NSCLC). However, there is no randomized evidence demonstrating benefit over more fractionated radiotherapy. We compared accelerated hypofractionation (AH) and SABR using a propensity score-matched analysis.

MATERIALS AND METHODS: From 1997-2007, 119 patients (T1-3N0M0 NSCLC) were treated with AH (48-60Gy, 12-15 fractions). Prior to SABR, this represented our institutional standard. From 2008-2012, 192 patients (T1-3N0M0 NSCLC) were treated with SABR (48-52Gy, 4-5 fractions). A total of 114 patients (57 per cohort) were matched (1:1 ratio, caliper: 0.10) using propensity scores.

RESULTS: Median follow-up (range) for the AH cohort was 36.3 (2.5-109.1) months, while that for the SABR group was 32.5 (0.3-62.6)months. Three-year overall survival (OS) and local control (LC) rates were 49.5% vs. 72.4% [p=0.024; hazard ratio (HR): 2.33 (1.28, 4.23), p=0.006] and 71.9% vs. 89.3% [p=0.077; HR: 5.56 (1.53, 20.2), p=0.009], respectively. On multivariable analysis, tumour diameter and PET staging were predictive for OS, while the only predictive factor for LC was treatment cohort.

CONCLUSIONS: OS and LC were improved with SABR, although OS is more closely related to non-treatment factors. This represents one of the few studies comparing AH to SABR for early-stage lung cancer.

An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers

Background: To directly assess tumor oxygenation in resectable non - small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes. Methods: Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes. Results: The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO 2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001). Conclusions: Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors. © 2006 American Association for Cancer Research.

2nd ESMO consensus conference on lung cancer : early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, earlystage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Gene Expression Meta-Analysis Identifies VDAC1 as a Predictor of Poor Outcome in Early Stage Non-Small Cell Lung Cancer

Background: The bioenergetic status of non-small cell lung cancer correlates with tumour aggressiveness. The voltage dependent anion channel type 1 (VDAC1) is a component of the mitochondrial permeability transition pore, regulates mitochondrial ATP/ADP exchange suggesting that its over-expression could be associated with energy dependent processes including increased proliferation and invasiveness. To test this hypothesis, we conducted an in vivo gene-expression meta-analysis of surgically resected non-small cell lung cancer (NSCLC) using 602 individual expression profiles, to examine the impact of VDAC1 on survival.

User-designer collaboration during the early stage of the product development process

As an understanding of users' tacit knowledge and latent needs embedded in user experience has played a critical role in product development, users’ direct involvement in design has become a necessary part of the design process. Various ways of accessing users' tacit knowledge and latent needs have been explored in the field of user-centred design, participatory design, and design for experiencing. User-designer collaboration has been used unconsciously by traditional designers to facilitate the transfer of users' tacit knowledge and to elicit new knowledge. However, what makes user-designer collaboration an effective strategy has rarely been reported on or explored. Therefore, interaction patterns between the users and the designers in three industry-supported user involvement cases were studied. In order to develop a coding system, collaboration was defined as a set of coordinated and joint problem solving activities, measured by the elicitation of new knowledge from collaboration. The analysis of interaction patterns in the user involvement cases revealed that allowing users to challenge or modify their contextual experiences facilitates the transfer of knowledge and new knowledge generation. It was concluded that users can be more effectively integrated into the product development process by employing collaboration strategies to intensify the depth of user involvement.

Building for competitive advantage in early stage start-ups : the role of entrepreneurial capabilities

Recent theoretical work has suggested “entrepreneurial capabilities” themselves may provide the resource foundations to deliver competitive advantage for entrepreneurial firms. This paper empirically examines how start-ups use such entrepreneurial capabilities to build competitive advantage. We investigate the effects of technological and marketing expertise, knowledge of market trends, flexibility and networking on the ability to obtain a cost leadership or differentiation advantage. Using a large dataset of 1,108 start-ups obtained after random sampling of over 30,193 households, we find that differentiation strategies benefit from most resource advantages. Cost leadership strategies, however, seem only to benefit from technological expertise and flexibility and not related to market-based advantages. By doing so, this study contributes to both entrepreneurship and RBV-theories by showing how entrepreneurial capabilities lead to competitive advantages in nascent and early-stage start-ups.

User-designer collaboration during the early stage of the design process

As user involvement becomes a necessary part of the product development process, various ways of accessing users' latent needs have been developed and studied. Reviews of literatures in user involvement and product development have revealed that accessing users' latent needs and transferring them into design process could be facilitated by effectively implementing user-designer collaboration during the early stage of the design process. In this paper, various types of user-designer collaboration were observed and then distinct characteristics of user-designer collaboration were classified into three categories. 1) Passive objectivity, 2) workplace democratisation, and 3) shared contexts were observed as strategies for better user-designer collaboration, which have been employed in the area of user-centred design, user participatory design and design for experiencing. Based on the literature review, this paper proposed a basic collaboration mechanism between the users and the designers during the early stage of the design process and then discussed how its mechanism will help to describe the interactions between the users and the designers during the user involvement sessions.

Delirium in early-stage Alzheimer's disease : enhancing cognitive reserve as a possible preventive measure

Delirium is a disorder of acute onset with fluctuating symptoms and is characterized by inattention, disorganized thinking, and altered levels of consciousness. The risk for delirium is greatest in individuals with dementia, and the incidence of both is increasing worldwide because of the aging of our population. Although several clinical trials have tested interventions for delirium prevention in individuals without dementia, little is known about the mechanisms for the prevention of delirium in early-stage Alzheimer’s disease (AD). The purpose of this article is to explore ways of preventing delirium and slowing the rate of cognitive decline in early-stage AD by enhancing cognitive reserve. An agenda for future research on interventions to prevent delirium in individuals with early-stage AD is also presented.

Effectiveness of community-based nonpharmacological interventions for early-stage dementia : conclusions and recommendations

In 2007, a comprehensive review of the extant research on nonpharmacological interventions for persons with early-stage dementia was conducted. More than 150 research reports, centered on six major domains, were included: early-stage support groups, cognitive training and enhancement programs, exercise programs, exemplar programs, health promotion programs, and “other” programs not fitting into previous categories. Theories of neural regeneration and plasticity were most often used to support the tested interventions. Recommendations for practice, research, and health policy are outlined, including evidence-based, nonpharmacological treatment protocols for persons with mild cognitive impairment and early-stage dementia. A tested, community-based, multimodal treatment program is also described. Overall, findings identify well-supported nonpharmacological treatments for persons with early-stage dementia and implications for a national health care agenda to optimize outcomes for this growing population of older adults.