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Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

Introduction: Dementia and Imagination is a multidisciplinary research collaboration bringing together arts and science to address current evidence limitations around the benefits of visual art activities in dementia care. The research questions ask: Can art improve quality of life and well-being? If it does make a difference, how does it do this - and why? Does it have wider social and community benefits? Methods and analysis: This mixed-methods study recruits participants from residential care homes, National Health Service (NHS) wards and communities in England and Wales. A visual art intervention is developed and delivered as 1×2-hour weekly group session for 3 months in care and community settings to N=100 people living with dementia. Quantitative and qualitative data are collected at 3 time points to examine the impact on their quality of life, and the perceptions of those who care for them (N=100 family and professional carers). Repeated-measures systematic observations of well-being are obtained during the intervention (intervention vs control condition). The health economics component conducts a social return on investment evaluation of the intervention. Qualitative data are collected at 3 time points (n=35 carers/staff and n=35 people living with dementia) to explore changes in social connectedness. Self-reported outcomes of the intervention delivery are obtained (n=100). Focus groups with intervention participants (n=40) explore perceptions of impact. Social network analysis of quantitative and qualitative data from arts and healthcare professionals (N=100) examines changes in perceptions and practice. Ethics and dissemination: The study is approved by North Wales Research Ethics Committee - West. A range of activities will share the research findings, including international and national academic conferences, quarterly newsletters and the project website. Public engagement projects will target a broad range of stakeholders. Policy and practice summaries

© 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.This paper analyses how the methodological approach for a major Arts and Humanities Research Council and Economic and Social Research Council-funded project entitled Dementia and Imagination1 was formulated. This multidisciplinary project brings together the arts and humanities with the social sciences with their different epistemological philosophies and subsequent understandings of research methods. The main objective was to determine how visual arts activities may change, sustain and catalyse community cultures, beliefs, attitudes and behaviours to create dementia-friendly communities. This project involves 6 different UK universities, 14 researchers, 10 formal partners, 7 project artists, 3 research artists and a large number of civil society organisations. The analysis presents a series of themes that have been identified as influencing the approach taken to develop methods which aimed to speak to different audiences in the social sciences, arts and humanities, policy/practice and public domains. It is concluded that a research project of this type needs to embrace a wide variety of epistemological positions if it is to successfully achieve its objectives. This paper contributes to knowledge about how the methodology of large-scale multidisciplinary projects may be constructed which will be of value to those building research consortia across different universities and between universities and community partners.

BACKGROUND Many testicular germ cell cancers are curable despite metastatic disease, but about 10-15% of patients fail cisplatin-based first-line treatment. Immunotherapy is considered as additional treatment approach for these patients. Inhibition of the interaction between Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) enhances T-cell responses in vitro and mediates clinical antitumour activity. We analysed the expression of PD-L1 in testicular germ cell tumours to evaluate its potential as target for immunotherapeutic strategies. METHODS Immunohistochemistry was performed in 479 formalin-fixed paraffin-embedded specimens using a rabbit monoclonal antibody (E1L3N). The tissue microarray consisted of 208 pure seminomas, 121 non-seminomas, 20 intratubular germ cell neoplasia unclassified (IGCNU) and 20 specimens of non-neoplastic testicular tissue. RESULTS Programmed Death Receptor Ligand-1 expression was found in 73% of all seminomas and in 64% of all non-seminomas. None of 20 IGCNU and none of 20 normal tissue specimens exhibited PD-L1 expression. PD-L1 positive stromal cells were only detected in seminomas, but not in non-seminomas. The anti PD-L1 antibody showed a pre-dominantly membranous staining pattern in testicular tumour cells, as well as expression in stromal cells. CONCLUSIONS This frequent expression of PD-L1 in human testicular germ cell tumours suggests that patients with testicular germ cell tumours could profit from immunotherapeutic strategies using anti-PD1 and anti-PDL1 antibodies.

OBJECTIVES: Restaging of patients with locally advanced non-small-cell lung cancer (NSCLC) is of paramount importance, since only patients with down-staging after induction therapy will benefit from surgery. In this study, we assessed the aetiology of new (18)fluoro-2-deoxy-d-glucose (FDG)-positive focal abnormalities on restaging positron emission tomography/computed tomography (PET/CT) in patients with a good response after induction chemotherapy in the primary tumour and lymph nodes. METHODS: Between 2004 and 2008, 31 patients with histological proven stage III NSCLC had a PET/CT prior and after induction chemotherapy. Their medical charts were retrospectively reviewed. RESULTS: Restaging PET/CT revealed a new FDG-positive lesion in 6 of 31 (20%) patients. The initial clinical stage of the disease was IIIA N2 in four and IIIB T4 in two patients. The maximal standard uptake value in the primary tumour (P = 0.043) and in the initially involved mediastinal nodes (P = 0.068) decreased after induction treatment in all patients. The new PET/CT findings were located in an ipsilateral cervical lymph node in two patients, a contralateral mediastinal in one patient and an ipsilateral mammary internal lymph node in one patient. Two other patients had a lesion on the contralateral lung. Malignant lymph node infiltrations were excluded following fine-needle puncture, intraoperative biopsy or follow-up PET/CT. Contralateral pulmonary lesions were diagnosed as benign following mini thoracotomy and pulmonary wedge resection.CONCLUSIONS: New solitary FDG-positive lesions on restaging PET/CT after induction chemotherapy for NSCLC are not rare in good responders to chemotherapy. In our experience, all these lesions were not associated with malignancy.

Background: The L1 cell adhesion molecule (L1CAM) is potentially involved in epithelial-mesenchymal transition (EMT). EMT marker expression is of prognostic significance in non-small cell lung cancer (NSCLC). The relevance of L1CAM for NSCLC is unclear. We investigated the protein expression of L1CAM in a cohort of NSCLC patients. L1CAM protein expression was correlated with clinico-pathological parameters including survival and markers of epithelial-mesenchymal transition. Results: L1CAM protein expression was found in 25% of squamous cell carcinomas and 24% of adenocarcinomas and correlated with blood vessel invasion and metastasis (p < 0.05). L1CAM was an independent predictor of survival in a multivariate analysis including pT, pN, and pM category, and tumor differentiation grade. L1CAM expression positively correlated with vimentin, beta-catenin, and slug, but inversely with E-cadherin (all p-values < 0.05). E-cadherin expression was higher in the tumor center than in the tumor periphery, whereas L1CAM and vimentin were expressed at the tumor-stroma interface. In L1CAM-negative A549 cells the L1CAM expression was upregulated and matrigel invasion was increased after stimulation with TGF-beta1. In L1CAM-positive SK-LU-1 and SK-LC-LL cells matrigel invasion was decreased after L1CAM siRNA knockdown. Conclusions: A subset of NSCLCs with vessel tropism and increased metastasis aberrantly expresses L1CAM. L1CAM is a novel prognostic marker for NSCLCs that is upregulated by EMT induction and appears to be instrumental for enhanced cell invasion.

BACKGROUND: Expression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far. METHODS: Here, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93) and a test cohort (n = 325). Metastatic prostate cancers (n = 20), hormone refractory prostate cancers (n = 19) and benign prostatic tissues (n = 38) were also analyzed. RESULTS: In total, strong epithelial periostin expression was detectable in 142 of 418 (34.0%) of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%). Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p < 0.01) and advanced tumour stage (p < 0.05) in the test cohort. Whereas periostin expression was weak or absent in the stroma around normal prostate glands, strong periostin expression in tumour stroma was found in most primary and metastatic prostate cancers. High stromal periostin expression was associated with higher Gleason scores (p < 0.001). There was a relationship between stromal periostin expression and shortened PSA relapse free survival times in the training cohort (p < 0.05). CONCLUSIONS: Our data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer.

Acquired chromosomal aberrations play an important role in tumour development and progression. Such genetic alterations occur in a significant proportion of non-small cell lung carcinomas (NSCLCs) and include amplification of 14q13.3, which contains the TTF1 gene. We asked whether TTF1 amplification is associated with increased TTF1 protein expression in NSCLCs, and whether TTF1 is associated with clinicopathological features, including patient survival. We used a FISH assay and quantitative immunohistochemical staining to interrogate a population-based cohort of 538 NSCLCs from Swiss patients for TTF1 amplification and protein expression. We found TTF1 amplification in ???13% of adenocarcinomas (ACs) and in ???9% of squamous cell carcinomas (SCCs) and TTF1 amplification was associated with increased TTF1 protein expression. High-level TTF1 expression was significantly associated with smaller tumour size, female gender and longer overall survival only among ACs (median survival 82 versus 28 months; p = 0.002). On multivariate analysis, high TTF1 expression was an independent predictor of favourable prognosis in patients with AC [hazard ratio, 0.56 (95% CI 0.38???0.83); p = 0.008]. We conclude that TTF1 amplification is a mechanism of high-level TTF1 expression in a subset of NSCLCs. When expressed at high levels, this routinely used diagnostic marker is also an independent biomarker of favourable prognosis in AC. Copyright ?? 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A method is developed which allows to use the flexible behaviour of aircraft structures to enhance aerodynamic derivatives. A vertical tail analytical model was used to show these effects and by exploiting the aeroelastic deflections it is possible to reduce the area of this sunface up to thirty percent. Numerous applications are possible including fighter and transport airplanes. Since composite structues are involved it is absolutely necessary to use a multidisciplinary optimisation program code such as the US-Airforce ASTROS-code., Presented at the Specialists' Meeting of the RTO Applied Vehicle Technology Panel (AVT) held in Ottawa, Canada, 18-20 Oct 1999. This article is from ADA388195 Structural Aspects of Flexible Aircraft Control (les Aspects structuraux du controle actif et flexible des aeronefs)