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Malignant pleural mesothelioma (MPM) is an aggressive cancer most commonly caused by prior exposure to asbestos. Median survival is 12–18 months, since surgery is ineffective and chemotherapy offers minimal benefit. Preclinical models that faithfully recapitulate the genomic and histopathological features of cancer are critical for the development of new treatments. The most commonly used models of MPM are two-dimensional cell lines established from primary tumours or pleural fluid. While these have provided some important insights into MPM biology, these cell models have significant limitations. In order to address some of these limitations, spheroids and microfluidic chips have more recently been used to investigate the role of the three-dimensional environment in MPM. Efforts have also been made to develop animal models of MPM, including asbestos-induced murine tumour models, MPM-prone genetically modified mice and patient-derived xenografts. Here, we discuss the available in vitro and in vivo models of MPM and highlight their strengths and limitations. We discuss how newer technologies, such as the tumour-derived organoids, might allow us to address the limitations of existing models and aid in the identification of effective treatments for this challenging-to-treat disease.

Neutrophils play an important role in the lung tumour microenvironment. We hypothesised that radiolabelled neutrophils coupled to single-photon emission CT (SPECT) may non-invasively quantify neutrophil uptake in tumours from patients with non-small cell lung cancer. We demonstrated increased uptake of radiolabelled neutrophils from the blood into tumours compared with non-specific uptake using radiolabelled transferrin. Moreover, indium-111-neutrophil activity in the tumour biopsies also correlated with myeloperoxidase (MPO)-positive neutrophils. Our data support the utility of imaging with In-111-labelled neutrophils and SPECT-CT to quantify neutrophil uptake in lung cancer.

IntroductionMesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left.Methods and analysisThe MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery—(extended) pleurectomy decortication—versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment.Ethics and disseminationResearch ethics approval was granted by London – Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal.Trial registration numbersISRCTN—ISRCTN44351742 and ClinicalTrials.gov—NCT02040272.

In the ASTER study, mediastinal staging was more accurate for patients randomised to combined endobronchial and endoscopic ultrasound, followed by surgical staging if endoscopy was negative, versus surgical staging alone. Here, we report survival, quality of life and cost effectiveness up to 6 months, for the UK, The Netherlands and Belgium, separately. Survival in the two arms of the study was similar. In all three countries, the endosonography strategy had slightly higher quality-adjusted life years over 6 months, and was cheaper. Therefore, based on clinical accuracy and cost effectiveness, we conclude that mediastinal staging should commence with endosonography.

BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial.METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction.RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569).CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction.TRIAL REGISTRATION: ISRCTN 78513845.

Diagnosis of mediastinal/hilar lymph nodes and peribronchial masses | || | Conventional transbronchial fine needle aspiration (TBNA) | | B | | | √ | | | Endobronchial ultrasound-guided transbronchial fine needle aspiration (EBUS-TBNA) | | B | | | D | | | √ | | | Therapeutic procedures for malignant disease | | Malignant airway obstruction | | 1. Endobronchial debulking of tumours | | D | | | √ | | | 2. Endobronchial electrocautery or diathermy | | D | | | √ |

Background Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as an important tool for the diagnosis and staging of lung cancer but its role in the diagnosis of tuberculous intrathoracic lymphadenopathy has not been established. The aim of this study was to describe the diagnostic utility of EBUS-TBNA in patients with intrathoracic lymphadenopathy due to tuberculosis (TB). Methods 156 consecutive patients with isolated intrathoracic TB lymphadenitis were studied across four centres over a 2-year period. Only patients with a confirmed diagnosis or unequivocal clinical and radiological response to antituberculous treatment during follow-up for a minimum of 6 months were included. All patients underwent routine clinical assessment and a CT scan prior to EBUS-TBNA. Demographic data, HIV status, pathological findings and microbiological results were recorded. Results EBUS-TBNA was diagnostic of TB in 146 patients (94%; 95% CI 88% to 97%). Pathological findings were consistent with TB in 134 patients (86%). Microbiological investigations yielded a positive culture of TB in 74 patients (47%) with a median time to positive culture of 16 days (range 3–84) and identified eight drug-resistant cases (5%). Ten patients (6%) did not have a specific diagnosis following EBUS; four underwent mediastinoscopy which confirmed the diagnosis of TB while six responded to empirical antituberculous therapy. There was one complication requiring an inpatient admission. Conclusions EBUS-TBNA is a safe and effective first-line investigation in patients with tuberculous intrathoracic lymphadenopathy.

Linear endobronchial ultrasound was first described in 2003. Since then the technique has spread rapidly and has now become an established practice in many centres as the first-line mediastinal investigation for the diagnosis and staging of lung cancer. In combination with endoscopic ultrasound, the majority of the mediastinum can be assessed and this approach has been shown to have equivalent accuracy to surgical staging. This strategy is also cost-effective. New tissue processing techniques using liquid-based thin-layer cytology and cell blocks have increased diagnostic yield using immunohistochemical staining and molecular diagnostics. Several meta-analyses of case series and, more recently, randomised controlled trials have provided high-level evidence of efficacy leading to incorporation into national lung cancer staging guidelines. In addition, linear endobronchial ultrasound is increasingly used in the investigation of mediastinal lymphadenopathy for suspected sarcoidosis, tuberculosis and lymphoma. While undoubtedly endobronchial/endoscopic ultrasound has reduced the need for surgical staging in lung cancer, the latter still has an important role to play in certain scenarios. The challenge now facing clinicians is to learn to apply the appropriate test or sequence of tests in each patient while ensuring that operators are appropriately trained in order to ensure optimal outcomes.

Screening for the early detection of lung cancers should increase the percentage of operable tumours, thus improving cure rates. A large randomised US trial showed that CT screening moderate/heavy smokers is effective but expensive, with a high false-positive rate. We designed LungSEARCH in 2006 to target screening in higher-risk subjects. Because most tumours in the UK were of squamous-histology, we hypothesised that sputum cytology plus cytometry would be an effective initial screen, only offering more intensive/expensive tests to those with abnormal sputum. Eligibility criteria were: current/former smokers (≥20 pack-years and/or smoked ≥20 years), GOLD-defined COPD, no prior cancer. Subjects were randomised to surveillance or a control group, and each followed for 5 years. Screened subjects provided sputum for central assessment, and those with abnormal results (cytology: low/high-grade squamous intraepithelial lesions, and/or cytometry: abnormal ploidy) were referred for annual low-dose CT and autofluorescence bronchoscopy (AFB) for the remainder of the trial, with diagnostic investigations when cancer suspected by abnormal CT/AFB. Sputum-negatives provided annual sputum samples only. Control subjects had a chest X-ray when they reached 5 years. Primary objective: to show a higher proportion of early stage cancers using surveillance than controls. 1568 subjects were recruited (target 1300) from GPs or chest clinics around 10 UK centres (August 2007–March 2011): 785 screened, 783 controls. Mean age 63 years; males 52%; current (56%), former (44%) smokers; mild (25%), moderate (75%) COPD; from GPs (79%). >90% screened subjects provided sputum samples in their first year. After 5 years, the overall sputum-positive rate is 33%; 30% (236/785) had a CT scan and 25% (193/785) had an AFB at any time. Of those who had a CT scan 19% (45/236) were abnormal (lung nodule(s) ≥9 mm); and of those who had AFB 3% (5/193) had severe dysplasia or worse. 79 lung cancers have been identified to date via the centres/national registry: 43 surveillance and 36 control. But awaiting staging details for 6 surveillance and 14 control cases. Preliminary results are promising: 57% (surveillance) versus 41% (controls) of cancers were diagnosed with stage I/II non-small-cell-lung cancer or limited disease small-cell-lung cancer. Final data available later in 2016.

INTRODUCTION: Solitary pulmonary nodules (SPNs) are common on CT. The most cost-effective investigation algorithm is still to be determined. Dynamic contrast-enhanced CT (DCE-CT) is an established diagnostic test not widely available in the UK currently.METHODS AND ANALYSIS: The SPUtNIk study will assess the diagnostic accuracy, clinical utility and cost-effectiveness of DCE-CT, alongside the current CT and 18-flurodeoxyglucose-positron emission tomography) ((18)FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for (18)FDG-PET-CT and DCE-CT will follow a standardised protocol with central review of 10% to ensure quality assurance. Decision analytic modelling will assess the likely costs and health outcomes resulting from incorporation of DCE-CT into management strategies for patients with SPNs.ETHICS AND DISSEMINATION: Approval has been granted by the South West Research Ethics Committee. Ethics reference number 12/SW/0206. The results of the trial will be presented at national and international meetings and published in an Health Technology Assessment (HTA) Monograph and in peer-reviewed journals.TRIAL REGISTRATION NUMBER: ISRCTN30784948; Pre-results.

Introduction and objectives Improving the early detection and chemoprevention of lung cancer are key to improving outcomes. The pathobiology of early squamous lung cancer is poorly understood. We have shown in a previous publication that amplification of SOX2 is an early and consistent event in the pathogenesis of this disease but its functional oncogenic potential remains uncertain. We aimed to test the impact of deregulated SOX2 expression in a novel organotypic system that recreates both the molecular and microenvironmental context in which squamous carcinogenesis occurs. Our objectives are: To develop a 3D in vitro model of bronchial dysplasia that recapitulates key molecular and phenotypic characteristics of the human disease. To test the hypothesis that SOX2 deregulation is a key initiating event in the pathogenesis of bronchial dysplasia. Methods We use lentiviral transduction to facilitate the inducible activation of SOX2 in immortalised bronchial epithelial cells iBECs. We use lentiviral shRNA and cutting edge CRISPR genome editing technology to introduce specific defects in key tumour suppressor pathways in order to recapitulate the molecular context seen in vivo . We incorporate the genetically manipulated iBECs at the air-liquid interface in a 3-dimensional tissue culture system that also comprises a stromal equivalent with embedded pulmonary fibroblasts and carefully defined media to build an organotypic model of bronchial dysplasia. Results We develop a model that recapitulates human bronchial dysplasia. SOX2 deregulation does not cause an obvious phenotype in standard tissue culture conditions, but can initiate the dysplastic phenotype in 3D culture systems. Loss of TP53 and PTEN are co-operating genetic events that potentiate the dysplastic phenotype. The alterations in cell signalling pathways recapitulate signatures seen in invasive squamous cell lung cancer. Conclusions In the appropriate molecular and microenvironmental context acute deregulation of SOX2 expression initiates and drives bronchial dysplasia. This confirms it’s oncogenic potential in human cells. This model can be used to test the impact of therapeutic agents aimed at chemoprevention and the potential for co-operating genetic lesions to drive disease progression.

We thank Dhooria et al 1 for their complimentary comments on our review article about linear endobronchial ultrasound.2 We congratulate them on their carefully performed randomised controlled trial comparing endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in conjunction with transbronchial lung biopsies (TBLB) and endobronchial biopsies (EBB) with conventional non-ultrasound-guided transbronchial needle aspiration (cTBNA) in conjunction with TBLB and EBB for the diagnosis …

Introduction MDT meetings are now an essential and integral part of lung cancer services but no formal measurement of the variability of decisions made by these teams has been studied. Variation in decision making may be an important factor influencing the UK-wide differences in lung cancer outcomes and survival.1 Aim The aim of this pilot study was to develop and trial a tool for measuring variation in decision making within MDTs. Method Seven anonymised clinical cases were provided for discussion with accompanying radiology and histology to 12 MDTs in two regional lung cancer networks. MDTs were asked to provide a comprehensive plan for further investigation (if necessary) and treatment for each case. They were encouraged to specify modality of treatment. Treatment decisions were compared across the participating MDTs and a simple scoring system devised to rate concordance. 10 MDTs provided enough data for analysis. Straight-forward cases were considered by the investigators to have only one clear preferred treatment. Complex cases were less clear cut and selected to pose more of a challenge to MDTs. Nevertheless, each of these cases had a pre-defined preferred treatment option. Results The three cases rated straight-forward produced good agreement between MDTs, (Abstract P153 table 1) for radical vs palliative treatment. More complex cases resulted in less agreement between MDTs. One case (number 5) was excluded from analysis as it was clearly too ambiguous for MDTs to properly assess. Conclusions We conclude this method to compare decision making by MDTs is a feasible tool. A roll-out is now planned to a further 50 MDTs to document more clearly the variation in decision making UK-wide. Even with this small sample of MDTs for just two Networks, complex cases clearly produce greater variation in the proportion of patients offered radical treatment.

This new guideline covers the rapidly advancing field of interventional bronchoscopy using flexible bronchoscopy. It includes the use of more complex diagnostic procedures such as endobronchial ultrasound, interventions for the relief of central airway obstruction due to malignancy and the recent development of endobronchial therapies for chronic obstructive pulmonary disease and asthma. The guideline aims to help all those who undertake flexible bronchoscopy to understand more about this important area. It also aims to inform respiratory physicians and other specialists dealing with lung cancer of the procedures possible in the management and palliation of central airway obstruction. The guideline covers transbronchial needle aspiration and endobronchial ultrasound-guided transbronchial needle aspiration, electrocautery/diathermy, argon plasma coagulation and thermal laser, cryotherapy, cryoextraction, photodynamic therapy, brachytherapy, tracheobronchial stenting, electromagnetic navigation bronchoscopy, endobronchial valves for emphysema and bronchial thermoplasty for asthma.

Introduction Small Cell Lung Cancer (SCLC) typically responds well to initial chemotherapy with Etoposide and a platinum-containing agent. However survival is poor due to invariable relapse with chemoresistant disease. We used a unique series of SCLC cell lines (GLC-14, 16, 19), derived from a single patient at various time-points during her treatment, to identify genes involved in Etoposide resistance. We then attempted to determine their functional role and validate their importance using patient specimens. Methods The relationship of the cell lines to each other was confirmed using genomic methods. Genes whose expression pattern could explain the relative response of the cell lines to treatment with Etoposide were identified using cDNA microarray. These candidate Etoposide response genes were cloned from the cell line in which they were expressed at the highest level and transiently over-expressed in the cell line in which they were naturally expressed at the lowest level to determine whether this altered Etoposide resistance. Using immunohistochemistry, expression of the most promising candidates was examined using a tissue microarray (TMA). Results The two most promising candidate genes were identified as DNA Polymerase β, a DNA repair enzyme and NKX2.2, a neuroendocrine transcription factor. Specific inhibition of DNA Polymerase β with Pamoic Acid reduced the numbers of cells surviving treatment with Etoposide (p=0.029) and increased the amount of DNA damage in the cells (p Conclusion Using a biologically plausible model of in vivo acquired resistance to Etopoide we have identified two novel Etoposide resistance factors—DNA Polymerase β and NKX2.2. Our in vitro data, in conjunction with the TMA results, provide justification for further prospective work to confirm the roles of these molecules in chemotherapy resistance in SCLC.

Background We recently published clinical results of ASTER, a randomised controlled trial in which endosonography, a strategy of combined endoscopic (EUS) and endobronchial (EBUS) ultrasound (followed by surgical staging if these tests were negative for malignancy), had significantly higher sensitivity and negative predictive value than surgical staging alone for mediastinal staging in NSCLC. Here we present ASTER quality of life (QoL) and cost-effectiveness outcomes. Methods EuroQoL EQ-5D questionnaire was performed at baseline, end of staging, 2 and 6 months post randomisation. The UK EQ-5D social tariff was applied to calculate utility values. Quality-adjusted survival was estimated using the area under the utility curve. Full resource use information was recorded for all patients and NHS 2008–2009 Reference Costs were applied. Total expected costs over 6 months were estimated by summing the resource use multiplied by its unit cost and taking the sample average for each group. Results Of 241 randomised patients, 144 (60%) provided EQ-5D data at baseline; of these 139 (97%) were followed up at the end of staging, 132 (92%) at 2 months and 124 (86%) at 6 months. At the end of staging, those randomised to endosonography had significantly better QoL than those randomised to surgical staging (utility difference=0.11, 95%CI 0.02 to 0.19). At all other time points, there was little difference between the groups, so that quality adjusted survival over the 6 months was similar (4.1 vs 4.0 months respectively). Complete resource use data were available for 172/214 (71%) patients. Other than the number of thoracotomies performed (66% of patients in the surgical staging arm and 53% in the endosonography arm) resource use did not differ between the two groups. The endosonography group had a non-significant cost saving of £746 per patient compared to the surgical staging group. Conclusions Given that (a) the sensitivity of endosonography was significantly higher than that of the surgical staging arm; (b) QoL post-staging was higher in the endosonography arm and (c) there is no difference in cost between the two strategies, mediastinal staging should commence with endosonography proceeding to surgical staging if there is no evidence of malignancy.

Introduction Squamous cell carcinoma is believed to develop in a step-wise fashion from squamous metaplasia (SqMet), through low- and high-grade dysplasia (LGDys; HGDys) and carcinoma-in-situ (CIS) to invasive disease (InvSCC). Epithelial mesenchymal transition (EMT) is an important process by which epithelial cells shed their differentiated characteristics and acquire mesenchymal, fibroblast-like properties including increased motility and invasiveness. There is now convincing phenotypic, genetic and functional evidence that EMT plays a central role in carcinogenesis. To date, EMT is believed to occur during transition from pre-invasive disease to invasive disease. A hallmark of EMT is the down-regulation of E-cadherin, a cell adhesion molecule present in the plasma membrane of epithelial cells. We have examined the role of EMT during the progression of bronchial dysplasia. Methods Using immunohistochemistry, 170 formalin-fixed paraffin-embedded blocks from lung cancer biopsies and resection specimens were stained for epithelial markers E-cadherin and MNF116 and the mesenchymal marker S100A4. In each sample, areas of SqMet, LGDys, HGDys (incorporating CIS) and InvSCC were identified. Up to three representative areas were assessed for each lesion type present and an aggregate score assigned which took into account strength and extent of staining. Specimens were also stained for β-catenin which translocates from the membrane to the nucleus during EMT. One hundred cells per high power field were counted and the proportion of membranous, cytoplasmic and nuclear staining calculated. Results There was a progressive loss of epithelial markers and a concurrent gain in S100A4 with increasing dysplasia. The switch from expression of epithelial to mesenchymal markers began as early as SqMet and reached significance for all three markers between LGDys and HGDys. Likewise, β-catenin showed translocation from membranous to cytoplasmic expression; this also reached significance between LGDys and HGDys. The difference in nuclear expression between groups did not reach significance. Conclusions In order to improve lung cancer survival there is increasing interest in identifying early stage disease. The mechanisms underlying progression of bronchial dysplasia are poorly understood. Our results suggest that EMT is occurring much earlier in bronchial dysplasia than previously appreciated and this may have implications for the surveillance and treatment of pre-invasive disease.

Background For many years the standard approach to staging of the mediastinum in non-small cell lung cancer (NSCLC) has been surgical using cervical mediastinoscopy, left anterior mediastinotomy or video assisted thoracoscopic surgery (VATS). More recently endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) have been reported. We conducted a randomised phase III trial to compare surgical staging versus endoscopic staging. The primary endpoint was detection of mediastinal nodal metastasis (N2/3); secondary endpoints were complication and futile thoracotomy rates. Methods Consecutive patients with potentially resectable (suspected) NSCLC in whom invasive mediastinal staging was indicated based on CT or PET-CT findings were randomly assigned to either Arm A, surgical staging or Arm B, combined EBUS/EUS (followed by surgical staging if endoscopic findings were negative for malignancy). Surgical staging involved mediastinoscopy and/or mediastinotomy and/or VATS. Subsequently, in the absence of mediastinal disease, thoracotomy with systematic lymph node sampling was performed. 240 pts were required to show a 20% increase in sensitivity (power 80% and α=0.05) to detect mediastinal nodal disease with a prevalence of 50%. Results 118 patients were randomised to Arm A and 123 to Arm B. The sensitivity for detection of mediastinal metastases by surgical staging in Arm A was 80% (95% CI, 68 to 89) vs 94% (95% CI, 85 to 98) for endoscopic (± surgical) staging in Arm B (p=0.04). Nodal metastases were found in 41 (35%) of surgically staged patients in Arm A and 62 patients (50%) (56 by EBUS/EUS + 6 by subsequent surgical staging) in Arm B (p=0.019). Overall, the prevalence of mediastinal disease in each arm was similar (p=0.24). Thoracotomy was considered futile in 21 (18%) in those staged in Arm A vs 8 patients (7%) in Arm B (p=0.009). Complication rate was similar in both arms (6 vs 7 patients, p=0.8); however, 12 of 13 complications were due to surgical staging procedures. Conclusions Mediastinal staging for NSCLC should commence with combined EBUS/EUS (followed by surgical staging if endoscopic findings are negative for malignancy) as this improves the detection of nodal metastases and reduces futile thoracotomies compared to surgical staging alone.

Introduction Bcl-2 is an anti-apoptotic protein that has previously been associated with increased cell survival in Small Cell Lung Cancer (SCLC) in vitro . However, several immunohistochemical studies of Bcl-2 expression and survival using patient samples have produced conflicting results. We aimed to determine if Bcl-2 expression has prognostic relevance in SCLC using a unique dedicated SCLC tissue microarray (TMA). Methods The TMA was constructed using formal in fixed, paraffin embedded diagnostic biopsy samples (endobronchial biopsies, TBNA, CT-guided needle biopsies) from 203 patients diagnosed at Papworth Hospital (Cambridge, UK) between 1998 and 2005. 189 cases had cores of tissue on the completed TMA. There was some attrition due to the small size of individual biopsies. The TMA was stained for Bcl-2 using a standard antibody (DAKO clone 124) and the slides were scored by two readers for both extent and intensity of tumour cell staining. Data from the TMA were then correlated with clinical data. The results obtained were combined with those of previous studies in a meta-analysis. Results 140 cases had tumour tissue on the TMA that could be evaluated for Bcl-2 staining. Patients with low intensity staining had better overall survival than those with high intensity staining in a Cox regression analysis (HR 0.55, 95% CI 0.33 to 0.94, p=0.03, n=117). The meta-analysis included 510 deaths in 673 cases and showed no significant effect of Bcl-2 on survival (HR 0.91, 95% CI 0.74 to 1.09). Conclusion This study equals the largest published study of Bcl-2 expression in SCLC. Our data showed improved survival in SCLC patients with lower Bcl-2 expression, consistent with in vitro data and the rationale behind current on-going trials of Bcl-2 antagonists in SCLC. However, our meta-analysis showed no overall effect and this may be due to differences in staining and scoring methods between the studies.