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1.  The Impact of Thymoma Histotype on Prognosis in a Worldwide Database 
Journal of Thoracic Oncology  2015;10(2):367-372.
Introduction:
The rarity of thymomas and lack of multi-institutional studies have hampered therapeutic progress for decades. To overcome this, the members of the International Thymic Malignancy Interest Group created a worldwide retrospective database. This database was analyzed regarding the demographic and geographic distribution of thymomas and the impact of different variables on survival and recurrence.
Methods:
This study analyzed 4221 thymomas diagnosed between 1983 and 2012 with World Health Organization histotype information from the International Thymic Malignancy Interest Group database. Associations to survival and recurrence were studied by univariate and multivariate analyses.
Results:
Type B2 thymoma is the most common (28%) and type A the least common (12%) histotypes. They are significantly more frequent in Europe and the United States than Asia. Type A and AB occur at significantly higher age than other thymomas (64 and 57 years, respectively). There are no differences in gender distribution. Stage is lower in type A (90% in stages I–II) and AB than B1 to B3 thymomas (38% of type B3 in stage III). In univariate analysis, recurrence is significantly less frequent among stage I/II tumors, in type A and AB (recurrence rates, 1–2%) than B1 to B3 thymomas (2–7%). Multivariate analysis reveals an impact of age, stage, and resection status on survival and recurrence, whereas for histology there is only a significant impact on recurrence.
Conclusion:
New findings are (1) geographic differences such as a lower incidence of type A and B2 thymoma in Asia; and (2) impact of stage and histology, the latter partially limited to early stage disease, on recurrence.
doi:10.1097/JTO.0000000000000393
PMCID: PMC4318643  PMID: 25616178
Thymoma; International Thymic Malignancy Interest Group; World Health Organization histotype; Prognosis; Epidemiology
2.  A Comparison of Immunohistochemical Assays and FISH in Detecting the ALK Translocation in Diagnostic Histological and Cytological Lung Tumor Material 
Journal of Thoracic Oncology  2014;9(6):769-774.
Introduction:
Detection of the ALK rearrangement in a solid tumor gives these patients the option of crizotinib as an oral form of anticancer treatment. The current test of choice is fluorescence in situ hybridization (FISH), but various cheaper and more convenient immunohistochemical (IHC) assays have been proposed as alternatives.
Methods:
Fifteen FISH-positive cases from patients, seven with data on crizotinib therapy and clinical response, were evaluated for the presence of ALK protein using three different commercially available antibodies: D5F3, using the proprietary automated system (Ventana), ALK1 (Dako), and 5A4 (Abcam). A further 14 FISH-negative and three uncertain (<15% rearrangement detected) cases were also retrieved. Of the total 32 specimens, 17 were excisions and 15 were computed tomography-guided biopsies or cytological specimens. All three antibodies were applied to all cases. Antibodies were semiquantitatively scored on intensity, and the proportion of malignant cells stained was documented. Cutoffs were set by receiver operating curve analysis for positivity to optimize correct classification.
Results:
All three IHC assays were 100% specific but sensitivity did vary: D5F3 86%, ALK 79%, 5A4 71%. Intensity was the most discriminating measure overall, with a combination of proportion and intensity not improving the test. No FISH-negative IHC-positive cases were seen. Two FISH-positive cases were negative with all three IHC assays. One of these had been treated with crizotinib and had failed to show clinical response. The other harbored a second driving mutation in the EGFR gene.
Conclusions:
IHC with all three antibodies is especially highly specific (100%) although variably sensitive (71%-86%), specifically in cases with scanty material. D5F3 assay was most sensitive in these latter cases. Occasional cases are IHC-positive but FISH-negative, suggesting either inaccuracy of one assay or occasional tumors with ALK rearrangement that do not express high levels of ALK protein.
doi:10.1097/JTO.0000000000000157
PMCID: PMC4132045  PMID: 24787965
Pulmonary adenocarcinoma; ALK; Immunohistochemistry; Fluorescence in situ hybridization; Crizotinib
3.  Evidence of mycobacterial disease in COPD patients with lung volume reduction surgery; the importance of histological assessment of specimens: a cohort study 
BMC Pulmonary Medicine  2014;14:124.
Background
Patients with COPD are at risk of non-tuberculous mycobacterial infection (NTM). This study examined the histology of lung tissue from COPD patients following lung volume reduction with particular focus on evidence of mycobacterial infection.
Methods
Retrospective histological study of 142 consecutive lung volume reduction surgical specimens (126 separate patients) at Royal Brompton Hospital between 2000 – 2013, with prospectively collected preoperative data on exacerbation rate, lung function and body mass index.
Results
92% of patients had at least one other histological diagnosis in addition to emphysema. 10% of specimens had histological evidence of mycobacterial infection, one with co-existent aspergilloma. Mycobacteria were only identified in those patients with granulomas that were necrotising. These patients had higher exacerbation rates, lower TLCO and FEV1.
Conclusion
A proportion of severe COPD patients will have evidence of mycobacterial infection despite lack of clinical and radiological suspicion. This may have implications for long-term management of these patients.
doi:10.1186/1471-2466-14-124
PMCID: PMC4125594  PMID: 25086862
COPD; Mycobacterium; Non tuberculous mycobacterium (NTM); Lung volume reduction surgery (LVRS)
4.  Pure bronchoplastic resections of the bronchus without pulmonary resection for endobronchial carcinoid tumours† 
OBJECTIVES
Bronchopulmonary carcinoid tumours are relatively uncommon primary lung neoplasms. A small proportion of these lesions are predominantly endobronchial and do not extend beyond the bronchial wall. Endoscopic resection can be performed, but carries around a one in three risk of local recurrence and, therefore, mandates long-term surveillance. An alternative is complete surgical resection via bronchoplastic resection. We present our experience of surgical resection in patients with endobronchial carcinoids.
METHODS
From 2000 to 2010, 13 patients (age 45 ± 16 years, 10 males) underwent pure bronchoplastic resection, including systematic nodal dissection, for endobronchial carcinoid tumours, without the resection of lung parenchyma.
RESULTS
There was no significant operative morbidity or mortality. This is a retrospective review of a consecutive case series. The last follow-up for all patients was obtained in 2011. The mean maximum tumour size was 18 ± 8 mm. No lymph node invasion was observed. The median follow-up was 6.3 ± 3.3 years, with no regional recurrence. In 1 case, a tumourlet was identified at 5 years in the contralateral airway and viewed as a metachronous new lesion.
CONCLUSIONS
Bronchial sleeve resection is a safe procedure for suitably located endobronchial carcinoid tumours. Endoscopic resection should be reserved for patients who decline, or are unfit, for surgery.
doi:10.1093/icvts/ivt154
PMCID: PMC3715171  PMID: 23628650
Carcinoid; Bronchoplastic resection; Sleeve resection; Endobronchial
5.  Evidence for a functional TSLP signalling axis in fibrotic lung disease 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(9):10.4049/jimmunol.1300588.
Thymic stromal lymphopoietin (TSLP) has recently emerged as a key cytokine in the development of type 2 immune responses. Although traditionally associated with allergic inflammation, type 2 responses are also recognised to contribute to the pathogenesis of tissue fibrosis. However, the role of TSLP in the development of non-allergen driven diseases, characterised by pro-fibrotic type 2 immune phenotypes and excessive fibroblast activation, remains underexplored. Fibroblasts represent the key effector cells responsible for extracellular matrix production, but additionally play important immunoregulatory roles, including choreographing immune cell recruitment through chemokine regulation. The aim of this study was to examine whether TSLP may be involved in the pathogenesis of a proto-typical fibrotic disease, idiopathic pulmonary fibrosis (IPF). We combined the immunohistochemical analysis of human IPF biopsy material with signalling studies employing cultured primary human lung fibroblasts (pHLFs) and report for the first time that TSLP and its receptor (TSLPR) are highly upregulated in IPF. We further show that lung fibroblasts represent both a novel cellular source and target of TSLP and that TSLP induces fibroblast CCL2 release (via STAT3) and subsequent monocyte chemotaxis. These studies extend our understanding of TSLP as a master regulator of type 2 immune responses beyond that of allergic inflammatory conditions and suggest a novel role for TSLP in the context of chronic fibrotic lung disease.
doi:10.4049/jimmunol.1300588
PMCID: PMC3836180  PMID: 24081992
6.  Airway remodelling in children with cystic fibrosis 
Thorax  2007;62(12):1074-1080.
Background
The relationship between airway structural changes and inflammation is unclear in early cystic fibrosis (CF) lung disease. A study was undertaken to determine changes in airway remodelling in children with CF compared with appropriate disease and healthy controls.
Methods
Bronchoalveolar lavage and endobronchial biopsy were performed in a cross‐sectional study of 43 children with CF (aged 0.3–16.8 years), 7 children with primary ciliary dyskinesia (PCD), 26 with chronic respiratory symptoms (CRS) investigated for recurrent infection and/or cough and 7 control children with no lower airway symptoms. Inflammatory cells, cytokines, proteases and matrix constituents were measured in bronchoalveolar lavage fluid (BALF). Reticular basement membrane (RBM) thickness was measured on biopsy specimens using light microscopy.
Results
Increased concentrations of elastin, glycosaminoglycans and collagen were found in BALF from children with CF compared with the CRS group and controls, each correlating positively with age, neutrophil count and proteases (elastase activity and matrix metalloproteinase‐9 (MMP‐9) concentration). There were significant negative correlations between certain of these and pulmonary function (forced expiratory volume in 1 s) in the CF group (elastin: r = −0.45, p<0.05; MMP‐9:TIMP‐1 ratio: r = −0.47, p<0.05). Median RBM thickness was greater in the CF group than in the controls (5.9 μm vs 4.0 μm, p<0.01) and correlated positively with levels of transforming growth factor‐β1 (TGF‐β1; r = 0.53, p = 0.01), although not with other inflammatory markers or pulmonary function.
Conclusions
This study provides evidence for two forms of airway remodelling in children with CF: (1) matrix breakdown, related to inflammation, proteolysis and impaired pulmonary function, and (2) RBM thickening, related to TGF‐β1 concentration but independent of other markers of inflammation.
doi:10.1136/thx.2006.074641
PMCID: PMC2094274  PMID: 17526676
7.  Microarray profiling reveals suppressed interferon stimulated gene program in fibroblasts from scleroderma-associated interstitial lung disease 
Respiratory Research  2013;14(1):80.
Background
Interstitial lung disease is a major cause of morbidity and mortality in systemic sclerosis (SSc), with insufficiently effective treatment options. Progression of pulmonary fibrosis involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of SSc lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from SSc lung biopsies at the time of diagnosis, compared with those from control lungs.
Methods
We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with pulmonary fibrosis associated with SSc (SSc-ILD), with those from control lung tissue peripheral to resected cancer (n=10). Fibroblast cultures from 3 patients with idiopathic pulmonary fibrosis (IPF) were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis.
Results
A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from SSc-ILD and/or IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-β response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group.
Conclusions
This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in pulmonary fibrosis that requires further investigation.
doi:10.1186/1465-9921-14-80
PMCID: PMC3750263  PMID: 23915349
SSc-ILD; IPF; Pulmonary fibroblasts; Interferon regulated genes
8.  Challenges in pulmonary fibrosis · 4: Smoking‐induced diffuse interstitial lung diseases 
Thorax  2007;62(10):904-910.
Smoking‐induced diffuse interstitial lung processes include respiratory bronchiolitis, respiratory bronchiolitis‐associated interstitial lung disease (RBILD), desquamative interstitial pneumonia (DIP) and Langerhans' cell histiocytosis. The histological, radiological and clinical features of respiratory bronchiolitis, RBILD and DIP are reviewed, with particular reference to management issues; Langerhans' cell histiocytosis is covered elsewhere in this series of articles. Possible relationships between smoking and other diffuse lung diseases are explored briefly.
doi:10.1136/thx.2004.031021
PMCID: PMC2094243  PMID: 17909189
9.  Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under‐recognised spectrum of disease 
Thorax  2006;62(3):248-252.
Aims and Methods
A review was undertaken of 19 patients diagnosed with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) between 1992 and 2006.
Results
Most patients were women (n = 15) and non‐smokers (n = 16). Clinical presentation was either with symptomatic pulmonary disease (group 1; n = 9) or as an incidental finding during investigation for another disorder, most frequently malignant disease (group 2; n = 10). In group 1, cough and dyspnoea were the most frequent symptoms, with an average duration of 8.6 years before diagnosis. Both groups showed mainly stable disease without treatment, although one patient progressed to severe airflow obstruction and one was diagnosed at single lung transplantation. Mosaicism with nodule(s) was the typical pattern of DIPNECH on high‐resolution computed tomography, but one case had normal imaging despite airflow obstruction. Lung function tests showed obstructive (n = 8), mixed (n = 3) or normal (n = 5, all group 2) physiology. Two patients underwent a bronchoalveolar lavage and showed a lymphocytosis (30%) with mild chronic bronchiolitis being seen in all biopsies. Tumourlets and associated typical carcinoids (n = 9) showed weak positivity for thyroid transcription factor‐1. Three patients had atypical carcinoids, one with multiple endocrine neoplasia type 1 syndrome.
Conclusions
DIPNECH is being increasingly recognised, probably because of an increase in the usage and accuracy of investigative imaging and increased awareness of the entity. Most cases remain stable over many years independent of the mode of presentation, although a few patients progress to severe airflow obstruction.
doi:10.1136/thx.2006.063065
PMCID: PMC2117154  PMID: 17099078
10.  Surveillance for the detection of early lung cancer in patients with bronchial dysplasia 
Thorax  2006;62(1):43-50.
Background
The natural history of bronchial preinvasive lesions and the risk of developing lung cancer in patients with these lesions are not clear. Previous studies have treated severe dysplasia and carcinoma in situ (CIS) on the assumption that most will progress to invasive carcinoma.
Aims
To define the natural history of preinvasive lesions and assess lung cancer risk in patients with these lesions.
Hypothesis
Most preinvasive lesions will not progress to invasive carcinoma but patients with these lesions will be at high risk.
Methods
A cohort of patients with preinvasive lesions underwent fluorescence bronchoscopy every 4–12 months and computed tomography of the chest annually. The main end point was the development of invasive carcinoma.
Results
22 patients with 53 lesions were followed up for 12–85 months. 11 cancers were diagnosed in 9 patients. Of the 36 high‐grade lesions (severe dysplasia and CIS), 6 progressed to invasive cancers. 5 separate cancers developed at remote sites in patients with high‐grade lesions. All cancers were N0M0 and curative treatment was given to 8 of the 9 patients. The cumulative risk of developing lung cancer in a patient with a high‐grade lesion was 33% and 54% at 1 and 2 years, respectively. Of the 17 low‐grade lesions, none progressed to invasive carcinoma.
Conclusions
Although the risk of malignant progression of individual preinvasive lesions is relatively small, patients with high‐grade lesions are at high risk of lung cancer. Surveillance facilitated early detection and treatment with curative intent in most patients.
doi:10.1136/thx.2005.052191
PMCID: PMC2111271  PMID: 16825337
11.  A Patient Presenting with Bilateral Lung Lesions, Pleural Effusion, and Proteinuria 
Case Reports in Medicine  2013;2013:489362.
Diagnosis and management of a systemic vasculitis are among the most demanding challenges in clinical medicine. A patient with a past history of cryptogenic organizing pneumonia presents with new bilateral lung lesions, unilateral pleural effusion, and significant proteinuria. The patient tested p-ANCA and anti-MPO positive but c-ANCA negative. A diagnosis of granulomatosis with polyangiitis GPA was reached after performing both renal and lung biopsies. Step-by-step differential diagnosis and management are discussed.
doi:10.1155/2013/489362
PMCID: PMC3665212  PMID: 23762073
12.  Suitability of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration Specimens for Subtyping and Genotyping of Non–Small Cell Lung Cancer 
Rationale: The current management of advanced non–small cell lung cancer (NSCLC) requires differentiation between squamous and nonsquamous subtypes as well as epidermal growth factor receptor (EGFR) mutation status. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used for the diagnosis and staging of lung cancer. However, it is unclear whether cytology specimens obtained with EBUS-TBNA are suitable for the subclassification and genotyping of NSCLC.
Objectives: To determine whether cytology specimens obtained from EBUS-TBNA in routine practice are suitable for phenotyping and genotyping of NSCLC.
Methods: Cytological diagnoses from EBUS-TBNA were recorded from 774 patients with known or suspected lung cancer across five centers in the United Kingdom between 2009 and 2011.
Measurements and Main Results: The proportion of patients with a final diagnosis by EBUS-TBNA in whom subtype was classified was 77% (95% confidence interval [CI], 73–80). The rate of NSCLC not otherwise specified (NSCLC-NOS) was significantly reduced in patients who underwent immunohistochemistry (adjusted odds ratio, 0.50; 95% CI, 0.28–0.82; P = 0.016). EGFR mutation analysis was possible in 107 (90%) of the 119 patients in whom mutation analysis was requested. The sensitivity, negative predictive value, and diagnostic accuracy of EBUS-TBNA in patients with NSCLC were 88% (95% CI, 86–91), 72% (95% CI, 66–77), and 91% (95% CI, 89–93), respectively.
Conclusions: This large, multicenter, pragmatic study demonstrates that cytology samples obtained from EBUS-TBNA in routine practice are suitable for subtyping of NSCLC and EGFR mutation analysis and that the use of immunohistochemistry reduces the rate of NSCLC-NOS.
doi:10.1164/rccm.201202-0294OC
PMCID: PMC3378660  PMID: 22505743
endobronchial ultrasound; non–small cell lung cancer; adenocarcinoma; EGFR mutation; NSCLC-NOS
13.  β-Catenin determines upper airway progenitor cell fate and preinvasive squamous lung cancer progression by modulating epithelial–mesenchymal transition 
The Journal of pathology  2012;226(4):575-587.
Human lung cancers, including squamous cell carcinoma (SCC) are a leading cause of death and, whilst evidence suggests that basal stem cells drive SCC initiation and progression, the mechanisms regulating these processes remain unknown. In this study we show that β-catenin signalling regulates basal progenitor cell fate and subsequent SCC progression. In a cohort of preinvasive SCCs we established that elevated basal cell β-catenin signalling is positively associated with increased disease severity, epithelial proliferation and reduced intercellular adhesiveness. We demonstrate that transgene-mediated β-catenin inhibition within keratin 14-expressing basal cells delayed normal airway repair while basal cell-specific β-catenin activation increased cell proliferation, directed differentiation and promoted elements of early epithelial-mesenchymal transition (EMT), including increased Snail transcription and reduced E-cadherin expression. These observations are recapitulated in normal human bronchial epithelial cells in vitro following both pharmacological β-catenin activation and E-cadherin inhibition, and mirrored our findings in preinvasive SCCs. Overall, the data show that airway basal cell β-catenin determines cell fate and its mis-expression is associated with the development of human lung cancer.
doi:10.1002/path.3962
PMCID: PMC3434372  PMID: 22081448
β-catenin; E-cadherin; Snail; airway; stem cell; pre-invasive; lung cancer; squamous
14.  A Key Role for the Endothelium in NOD1 Mediated Vascular Inflammation: Comparison to TLR4 Responses 
PLoS ONE  2012;7(8):e42386.
Understanding the mechanisms by which pathogens induce vascular inflammation and dysfunction may reveal novel therapeutic targets in sepsis and related conditions. The intracellular receptor NOD1 recognises peptidoglycan which features in the cell wall of Gram negative and some Gram positive bacteria. NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. We have previously shown that stimulation of NOD1 directly activates blood vessels and causes experimental shock in vivo. In this study we have used an ex vivo vessel-organ culture model to characterise the relative contribution of the endothelium in the response of blood vessels to NOD1 agonists. In addition we present the novel finding that NOD1 directly activates human blood vessels. Using human cultured cells we confirm that endothelial cells respond more avidly to NOD1 agonists than vascular smooth muscle cells. Accordingly we have sought to pharmacologically differentiate NOD1 and TLR4 mediated signalling pathways in human endothelial cells, focussing on TAK1, NFκB and p38 MAPK. In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This paper is the first to demonstrate activation of whole human artery by NOD1 stimulation and the relative importance of the endothelium in the sensing of NOD1 ligands by vessels. This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock.
doi:10.1371/journal.pone.0042386
PMCID: PMC3411636  PMID: 22870324
15.  Peri-operative chemotherapy in the management of resectable colorectal cancer pulmonary metastases 
BMC Cancer  2012;12:326.
Background
Surgery is often advocated in patients with resectable pulmonary metastases from colorectal cancer (CRC). Our study aims to evaluate peri-operative chemotherapy in patients with metastastic CRC undergoing pulmonary metastasectomy.
Methods
Patients treated for CRC who underwent pulmonary metastasectomy by a single surgeon were identified. Outcome measures included survival, peri-operative complications, radiological and histological evidence of chemotherapy-induced lung toxicities.
Results
Between 1997 and 2009, 51 eligible patients were identified undergoing a total of 72 pulmonary resections. Thirty-eight patients received peri-operative chemotherapy, of whom 9 received an additional biological agent. Five-year overall survival rate was 72% in the whole cohort - 74% and 68% in those who received peri-operative chemotherapy (CS) and those who underwent surgery alone (S) respectively. Five-year relapse free survival rate was 31% in the whole cohort - 38% and ≤18% in CS and S groups respectively. Only 8% had disease progression during neoadjuvant chemotherapy. There were no post-operative deaths. Surgical complications occurred in only 4% of patients who received pre-operative chemotherapy. There was neither radiological nor histological evidence of lung toxicity in resected surgical specimens.
Conclusions
Peri-operative chemotherapy can be safely delivered to CRC patients undergoing pulmonary metastasectomy. Survival in this selected group of patients was favourable.
doi:10.1186/1471-2407-12-326
PMCID: PMC3541252  PMID: 22849559
Colorectal cancer; lung resection; peri-operative chemotherapy
16.  Suitability of EBUS-TBNA Specimens for Subtyping and Genotyping of NSCLC: A Multi-Centre Study of 774 Patients 
Rationale
The current management of advanced non-small cell lung cancer (NSCLC) requires differentiation between squamous and non-squamous sub-types as well as epidermal growth factor receptor (EGFR) mutation status. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used for the diagnosis and staging of lung cancer. However, it is unclear whether cytology specimens obtained with EBUS-TBNA are suitable for the sub-classification and genotyping of NSCLC.
Objectives
To determine whether cytology specimens obtained from EBUS-TBNA in routine practice are suitable for phenotyping and genotyping of NSCLC.
Methods
Cytological diagnoses from EBUS-TBNA were recorded from 774 patients with known or suspected lung cancer across 5 centres in the United Kingdom between 2009 and 2011.
Measurements and Main Results
The proportion of patients with a final diagnosis by EBUS-TBNA in whom subtype was classified was 77% (95% CI 73% - 80%). The rate of NSCLC not otherwise specified (NSCLC-NOS) was significantly reduced in patients who underwent immunohistochemistry (adjusted OR 0.50 95% CI 0.28 – 0.82, P=0.016). EGFR mutation analysis was possible in 107 (90%) of the 119 patients in whom mutation analysis was requested. The sensitivity, negative predictive value and diagnostic accuracy of EBUS-TBNA in patients with NSCLC was 88% (95% CI 86% - 91%), 72% (95% CI 66% - 77%) and 91% (95% CI 89% - 93%) respectively.
Conclusions
This large multi-centre pragmatic study demonstrates that cytology samples obtained from EBUS-TBNA in routine practice are suitable for sub-typing of NSCLC and EGFR mutation analysis and that use of immunohistochemistry reduces the rate of NSCLC-NOS.
doi:10.1164/rccm.201202-0294OC
PMCID: PMC3378660  PMID: 22505743
Endobronchial ultrasound; non-small cell lung cancer; adenocarcinoma; EGFR mutation; squamous cell carcinoma; NSCLC-NOS
17.  Data-driven information retrieval in heterogeneous collections of transcriptomics data links SIM2s to malignant pleural mesothelioma 
Bioinformatics  2011;28(2):246-253.
Motivation: Genome-wide measurement of transcript levels is an ubiquitous tool in biomedical research. As experimental data continues to be deposited in public databases, it is becoming important to develop search engines that enable the retrieval of relevant studies given a query study. While retrieval systems based on meta-data already exist, data-driven approaches that retrieve studies based on similarities in the expression data itself have a greater potential of uncovering novel biological insights.
Results: We propose an information retrieval method based on differential expression. Our method deals with arbitrary experimental designs and performs competitively with alternative approaches, while making the search results interpretable in terms of differential expression patterns. We show that our model yields meaningful connections between biological conditions from different studies. Finally, we validate a previously unknown connection between malignant pleural mesothelioma and SIM2s suggested by our method, via real-time polymerase chain reaction in an independent set of mesothelioma samples.
Availability: Supplementary data and source code are available from http://www.ebi.ac.uk/fg/research/rex.
Contact: samuel.kaski@aalto.fi
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr634
PMCID: PMC3259436  PMID: 22106335
18.  Diminished Prostaglandin E2 Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis 
Rationale: Patients with idiopathic pulmonary fibrosis (IPF), a progressive disease with a dismal prognosis, exhibit an unexplained disparity of increased alveolar epithelial cell (AEC) apoptosis but reduced fibroblast apoptosis.
Objectives: To examine whether the failure of patients with IPF to up-regulate cyclooxygenase (COX)-2, and thus the antifibrotic mediator prostaglandin (PG)E2, accounts for this imbalance.
Methods: Fibroblasts and primary type II AECs were isolated from control and fibrotic human lung tissue. The effects of COX-2 inhibition and exogenous PGE2 on fibroblast and AEC sensitivity to Fas ligand (FasL)-induced apoptosis were assessed.
Measurements and Main Results: IPF lung fibroblasts are resistant to FasL-induced apoptosis compared with control lung fibroblasts. Inhibition of COX-2 in control lung fibroblasts resulted in an apoptosis-resistant phenotype. Administration of PGE2 almost doubled the rate of FasL-induced apoptosis in fibrotic lung fibroblasts compared with FasL alone. Conversely, in primary fibrotic lung type II AECs, PGE2 protected against FasL-induced apoptosis. In human control and, to a greater extent, fibrotic lung fibroblasts, PGE2 inhibits the phosphorylation of Akt, suggesting that regulation of this prosurvival protein kinase is an important mechanism by which PGE2 modulates cellular apoptotic responses.
Conclusions: The observation that PGE2 deficiency results in increased AEC but reduced fibroblast sensitivity to apoptosis provides a novel pathogenic insight into the mechanisms driving persistent fibroproliferation in IPF.
doi:10.1164/rccm.200905-0674OC
PMCID: PMC2902759  PMID: 20203246
alveolar epithelial cell; fibroblast; pathogenesis; Fas ligand; Akt
19.  Pulmonary fibrosis associated with psychotropic drug therapy: a case report 
Introduction
Sertraline and Risperidone are commonly used psychotropic drugs. Sertraline has previously been associated with eosinopilic pneumonia. Neither drug is recognised as a cause of diffuse fibrotic lung disease. Our report represents the first such case.
Case Presentation
We describe the case of a 33 year old Asian male with chronic schizophrenia who had been treated for three years with sertraline and risperidone. He presented to hospital in respiratory failure following a six month history of progressive breathlessness. High resolution CT scan demonstrated diffuse pulmonary fibrosis admixed with patchy areas of consolidation. Because the aetiology of this man's diffuse parenchymal lung disease remained unclear a surgical lung biopsy was undertaken. Histological assessment disclosed widespread fibrosis with marked eosinophillic infiltration and associated organising pneumonia - features all highly suggestive of drug induced lung disease. Following withdrawal of both sertraline and risperidone and initiation of corticosteroid therapy the patient's respiratory failure resolved and three years later he remains well albeit limited by breathlessness on heavy exertion.
Conclusion
Drug induced lung disease can be rapidly progressive and if drug exposure continues may result in respiratory failure and death. Prompt recognition is critical as drug withdrawal may result in marked resolution of disease. This case highlights sertraline and risperidone as drugs that may, in susceptible individuals, cause diffuse pulmonary fibrosis.
doi:10.1186/1752-1947-3-126
PMCID: PMC2803800  PMID: 20062766
20.  Lung function in idiopathic pulmonary fibrosis - extended analyses of the IFIGENIA trial 
Respiratory Research  2009;10(1):101.
Background
The randomized placebo-controlled IFIGENIA-trial demonstrated that therapy with high-dose N-acetylcysteine (NAC) given for one year, added to prednisone and azathioprine, significantly ameliorates (i.e. slows down) disease progression in terms of vital capacity (VC) (+9%) and diffusing capacity (DLco) (+24%) in idiopathic pulmonary fibrosis (IPF). To better understand the clinical implications of these findings we performed additional, explorative analyses of the IFGENIA data set.
Methods
We analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients.
Results
In trial completers the functional indices did not change significantly with NAC, whereas most indices deteriorated with placebo; in non-completers the majority of indices worsened but decline was generally less pronounced in most indices with NAC than with placebo. Most categorical analyses of VC, DLco and CPI also showed favourable changes with NAC. The effects of NAC on VC, DLco and CPI were significantly better if the baseline CPI was 50 points or lower.
Conclusion
This descriptive analysis confirms and extends the favourable effects of NAC on lung function in IPF and emphasizes the usefulness of VC, DLco, and the CPI for the evaluation of a therapeutic effect. Most importantly, less progressed disease as indicated by a CPI of 50 points or lower at baseline was more responsive to therapy in this study.
Trial Registration
Registered at http://www.ClinicalTrials.gov; number NCT00639496.
doi:10.1186/1465-9921-10-101
PMCID: PMC2774307  PMID: 19860915
21.  Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury 
The Journal of Clinical Investigation  2009;119(9):2550-2563.
Uncontrolled activation of the coagulation cascade contributes to the pathophysiology of several conditions, including acute and chronic lung diseases. Coagulation zymogens are considered to be largely derived from the circulation and locally activated in response to tissue injury and microvascular leak. Here we report that expression of coagulation factor X (FX) is locally increased in human and murine fibrotic lung tissue, with marked immunostaining associated with bronchial and alveolar epithelia. FXa was a potent inducer of the myofibroblast differentiation program in cultured primary human adult lung fibroblasts via TGF-β activation that was mediated by proteinase-activated receptor–1 (PAR1) and integrin αvβ5. PAR1, αvβ5, and α-SMA colocalized to fibrotic foci in lung biopsy specimens from individuals with idiopathic pulmonary fibrosis. Moreover, we demonstrated a causal link between FXa and fibrosis development by showing that a direct FXa inhibitor attenuated bleomycin-induced pulmonary fibrosis in mice. These data support what we believe to be a novel pathogenetic mechanism by which FXa, a central proteinase of the coagulation cascade, is locally expressed and drives the fibrotic response to lung injury. These findings herald a shift in our understanding of the origins of excessive procoagulant activity and place PAR1 central to the cross-talk between local procoagulant signaling and tissue remodeling.
doi:10.1172/JCI33288
PMCID: PMC2735922  PMID: 19652365
22.  Patterns of somatic mutation in human cancer genomes 
Nature  2007;446(7132):153-158.
Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be ‘passengers’ that do not contribute to oncogenesis. However, there was evidence for ‘driver’ mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
doi:10.1038/nature05610
PMCID: PMC2712719  PMID: 17344846
23.  Non-specific interstitial pneumonia in cigarette smokers: a CT study 
European Radiology  2009;19(7):1679-1685.
The goal of this study was to seek indirect evidence that smoking is an aetiological factor in some patients with non-specific interstitial pneumonia (NSIP). Ten current and eight ex-smokers with NSIP were compared to controls including 137 current smokers with no known interstitial lung disease and 11 non-smokers with NSIP. Prevalence and extent of emphysema in 18 smokers with NSIP were compared with subjects meeting GOLD criteria for chronic obstructive pulmonary disease (COPD; group A; n = 34) and healthy smokers (normal FEV1; group B; n = 103), respectively. Emphysema was present in 14/18 (77.8%) smokers with NSIP. Emphysema did not differ in prevalence between NSIP patients and group A controls (25/34, 73.5%), but was strikingly more prevalent in NSIP patients than in group B controls (18/103, 17.5%, P < 0.0005). On multiple logistic regression, the likelihood of emphysema increased when NSIP was present (OR = 18.8; 95% CI = 5.3–66.3; P < 0.0005) and with increasing age (OR = 1.04; 95% CI = 0.99–1.11; P = 0.08). Emphysema is as prevalent in smokers with NSIP as in smokers with COPD, and is strikingly more prevalent in these two groups than in healthy smoking controls. The association between NSIP and emphysema provides indirect support for a smoking pathogenesis hypothesis in some NSIP patients.
doi:10.1007/s00330-009-1308-7
PMCID: PMC2691530  PMID: 19214521
Nonspecific interstitial pneumonia; Pulmonary fibrosis; Emphysema; Cigarette smoking
24.  Certified causes of death in patients with mesothelioma in South East England 
BMC Cancer  2009;9:28.
Background
Mesothelioma is a highly fatal cancer that is caused by exposure to asbestos fibres. In many populations, the occurrence of mesothelioma is monitored with the use of mortality data from death certification. We examine certified causes of death of patients who have been diagnosed with mesothelioma, and assess the validity of death certification data as a proxy for mesothelioma incidence.
Methods
We extracted mesothelioma registrations in the South East of England area between 2000 and 2004 from the Thames Cancer Registry database. We retained for analysis 2200 patients who had died at the time of analysis, after having excluded seven dead cases where the causes of death were not known to the cancer registry. The 2200 deaths were classified hierarchically to identify (1) mesothelioma deaths, (2) deaths certified as lung cancer deaths or (3) deaths from unspecified cancer, and (4) deaths from other causes.
Results
87% of the patients had mesothelioma mentioned on the death certificate. 6% had no mention of mesothelioma but included lung cancer as a cause of death. Another 6% had no mention of mesothelioma or lung cancer, but included an unspecified cancer as a cause of death. Lastly, 2% had other causes of death specified on the death certificate.
Conclusion
This analysis suggests that official mortality data may underestimate the true occurrence of mesothelioma by around 10%.
doi:10.1186/1471-2407-9-28
PMCID: PMC2639607  PMID: 19166594
25.  Idiopathic Interstitial Pneumonia 
Rationale: Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult.
Objectives: Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers.
Methods: Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days.
Measurements and Main Results: Each observer's diagnosis was coded into one of eight categories. A κ statistic allowing for multiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (κ = 0.55–0.71) than within community centers (κ = 0.32–0.44). Clinically significant disagreement was present between academic and community-based physicians (κ = 0.11–0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians.
Conclusions: Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options.
doi:10.1164/rccm.200606-833OC
PMCID: PMC1899268  PMID: 17255566
academic; community; diagnosis; nonspecific interstitial pneumonia; usual interstitial pneumonia

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