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David Baldwin,1 Jonathan Carmichael,2 Gordon Cook,3 Neal Navani,4,5 James Peach,6 Ruth Slater,7 Pete Wheatstone,8 Julia Wilkins,7 Nicola Allen-Delingpole,9 Cicely EP Kerr,10 Khalid Siddiqui11 1Department of Respiratory Medicine, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; 2Department of Oncology, The National Institute for Health Research Leeds In Vitro Diagnostics Co-Operative (NIHR Leeds MIC), Leeds, UK; 3Cancer Research UK Trials Unit, LICTR, University of Leeds & NIHR (Leeds) IVD MIC, Leeds, UK; 4Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK; 5Department of Thoracic Medicine, University College London Hospital, London, UK; 6Human Centric Drug Discovery, Wood Centre for Innovation, Oxford, UK; 7Health Economics Unit, London, UK; 8Patient and Public Involvement and Engagement Group, DATA-CAN, London, UK; 9The Association of the British Pharmaceutical Industry, London, UK; 10Research Data Scotland, Bayes Centre, Edinburgh, UK; 11Janssen-Cilag Ltd, High Wycombe, UKCorrespondence: James Peach, Human Centric Drug Discovery, Wood Centre for Innovation, Quarry Road, Oxford, OX3 8SB, UK, Email james@humancentricdd.comAbstract: Duration of overall survival in patients with cancer has lengthened due to earlier detection and improved treatments. However, these improvements have created challenges in assessing the impact of newer treatments, particularly those used early in the treatment pathway. As overall survival remains most decision-makers’ preferred primary endpoint, therapeutic innovations may take a long time to be introduced into clinical practice. Moreover, it is difficult to extrapolate findings to heterogeneous populations and address the concerns of patients wishing to evaluate everyday quality and extension of life. There is growing interest in the use of surrogate or interim endpoints to demonstrate robust treatment effects sooner than is possible with measurement of overall survival. It is hoped that they could speed up patients’ access to new drugs, combinations, and sequences, and inform treatment decision-making. However, while surrogate endpoints have been used by regulators for drug approvals, this has occurred on a case-by-case basis. Evidence standards are yet to be clearly defined for acceptability in health technology appraisals or to shape clinical practice. This article considers the relevance of the use of surrogate endpoints in cancer in the UK context, and explores whether collection and analysis of real-world UK data and evidence might contribute to validation.Keywords: cancer, surrogate endpoints, real-world data, multiple myeloma, lung cancer, quality of life

Lung cancer screening has come a long way since the early studies with chest X-ray. Advancing technology and progress in the processing of images have enabled low dose CT to be tried and tested, and evidence suggests its use can result in a significant mortality benefit. There are several issues that need refining in order to successfully implement screening in the UK and elsewhere. Some countries have started patchy implementation of screening and there is increased recognition that the appropriate management of pulmonary nodules is crucial to optimise benefits of early detection, while reducing harm caused by inappropriate medical intervention. This review summarises and differentiates the many recent guidelines on pulmonary nodule management, discusses screening activity in other countries and exposes the present barriers to implementation in the UK. [ABSTRACT FROM AUTHOR]

Rationale: Patients with isolated mediastinal lymphadenopathy (IML) are a common presentation to physicians, and mediastinoscopy is traditionally considered the "gold standard" investigation when a pathological diagnosis is required. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as an alternative to mediastinoscopy in patients with lung cancer.Objective: To determine the efficacy and health care costs of EBUS-TBNA as an alternative initial investigation to mediastinoscopy in patients with isolated IML.Methods: Prospective multicenter single-arm clinical trial of 77 consecutive patients with IML from 5 centers between April 2009 and March 2011. All patients underwent EBUS-TBNA. If EBUS-TBNA did not provide a diagnosis, then participants underwent mediastinoscopy.Measurements and Main Results: EBUS-TBNA prevented 87% of mediastinoscopies (95% confidence interval [CI], 77-94%; P < 0.001) but failed to provide a diagnosis in 10 patients (13%), all of whom underwent mediastinoscopy. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML were 92% (95% CI, 83-95%) and 40% (95% CI, 12-74%), respectively. One patient developed a lower respiratory tract infection after EBUS-TBNA, requiring inpatient admission. The cost of the EBUS-TBNA procedure per patient was £1,382 ($2,190). The mean cost of the EBUS-TBNA strategy was £1,892 ($2,998) per patient, whereas a strategy of mediastinoscopy alone was significantly more costly at £3,228 ($5,115) per patient (P < 0.001). The EBUS-TBNA strategy is less costly than mediastinoscopy if the cost per EBUS-TBNA procedure is less than £2,718 ($4,307) per patient.Conclusions: EBUS-TBNA is a safe, highly sensitive, and cost-saving initial investigation in patients with IML. Clinical trial registered with ClinicalTrials.gov (NCT00932854). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cancers are a heterogeneous mix of cells, some of which exhibit cancer stem cell-like characteristics including ATP-dependent drug efflux and elevated tumorigenic potential. To determine whether aerodigestive squamous cell carcinomas (SCCs) contain a subpopulation of cancer stem cell-like cells, we performed Hoechst dye efflux assays using four independent cell lines. Results revealed the presence of a rare, drug effluxing stem cell-like side population (SP) of cells within all cell lines tested (SCC-SP cells). These cells resembled previously characterised epithelial stem cells, and SCC-SP cell abundance was positively correlated with overall cellular density and individual cell quiescence. Serial SCC-SP fractionation and passaging increased their relative abundance within the total cell population. Purified SCC-SP cells also exhibited increased clonogenic potential in secondary cultures and enhanced tumorigenicity in vivo. Despite this, SCC-SP cells remained chemotherapeutically sensitive upon ATP-dependent transporter inhibition. Overall, these findings suggest that the existence of ATP transporter-dependent cancer stem-like cells may be relatively common, particularly within established tumours. Future chemotherapeutic strategies should therefore consider coupling identification and targeting of this potential stem cell-like population with standard treatment methodologies. [ABSTRACT FROM AUTHOR]

Introduction Isolated mediastinal lymphadenopathy (IML) is a common presentation to respiratory physicians and mediastinoscopy is traditionally considered the gold-standard investigation when a pathological diagnosis is required. EBUS-TBNA is established as an alternative to mediastinoscopy in patients with lung cancer. However, the utility and healthcare costs of EBUS-TBNA in patients with IML is unknown. Methods This prospective clinical trial recruited 77 consecutive patients with IML who were referred for mediastinoscopy from five centres between April 2009 and March 2011. All patients underwent EBUS-TBNA. If the results from EBUS-TBNA were not conclusive, patients underwent mediastinoscopy. The co-primary endpoints were the proportion of mediastinoscopies saved and NHS costs. The Bonferroni correction was applied to the type 1 error to account for multiple significance testing. Economic evaluation of the EBUS-TBNA strategy (where negative EBUS-TBNA is followed by mediastinoscopy) vs mediastinoscopy alone from an NHS perspective was carried out using a decision tree model and univariate threshold sensitivity analysis. Results EBUS-TBNA prevented 87% of mediastinoscopies (97.5% CI 78 to 96%, p<0.001) but failed to provide a diagnosis in 10 patients, all of whom underwent mediastinoscopy (Abstract S56 figure 1). Mediastinoscopy provided a specific diagnosis in 6 cases while the remaining four patients had clinical and radiological follow-up of at least 6 months duration. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML was 92% (95% CI 83 to 95) and 40% (95% CI 12% to 74%) respectively. No significant complications of EBUS-TBNA or mediastinoscopy were observed. The patients included in the trial were similar to a historical control group of 68 patients with IML undergoing mediastinoscopy in 2008. The cost of the EBUS-TBNA strategy was £1871 per patient while a strategy of mediastinoscopy alone was £3268 per patient (p<0.001). Threshold sensitivity analysis demonstrated that the EBUS-TBNA strategy was less costly than mediastinoscopy if the cost per EBUS-TBNA procedure was <£2828. Conclusions EBUS-TBNA is a safe, highly sensitive and cost-saving initial investigation in patients with IML being referred for mediastinoscopy. The low negative predictive value of EBUS-TBNA in this setting indicates that mediastinoscopy should be performed in cases of negative EBUS-TBNA. Trial registration clinicaltrials.gov NCT00932854. [ABSTRACT FROM AUTHOR]

Background Patients with bronchial pre-invasive lesions represent a significant management challenge due to the risk of lung cancer both at the site of known dysplasia and at remote sites within their lungs. The role of combined positron emission tomography/CT (PET/CT) in those patients is unknown. Aims To evaluate the diagnostic and clinical utility of 18F-FDG PET/CT in a surveillance programme for patients with pre-invasive endobronchial lesions. This was defined as the ability of abnormal 18F-FDG uptake to detect invasive bronchial carcinomas adjacent to known pre-invasive lesions or at remote sites in the lung. The prognostic value of 18F-FDG uptake at dysplasia sites was also assessed with surveillance. Can 18F-FDG uptake predict progression of pre-invasive lesions or cancer elsewhere? Methods 39 patients with pre-invasive endobronchial lesions underwent 18F-FDG PET/CTexamination prior to autofluorescence bronchoscopy. Pre-invasive lesions were classified as either high-grade (carcinoma in situ or severe dysplasia) or low grade (mild to moderate dysplasia). The degree of uptake of 18F-FDG was analysed without knowledge of the bronchoscopic or other clinical findings. Results 8/39 patients (all with high grade dysplasia) had increased 18F-FDG uptake at known dysplasia sites. Of these 8 patients 1 had surgical resection of invasive carcinoma and two patients were diagnosed and treated as invasive cancer based on imaging and follow-up. Eight patients had 18F-FDG uptake at sites remote from known dysplasia; 2/8 patients had synchronous invasive lung carcinoma (pT1N0M0), 2/8 recurrent cancer in hilar and mediastinal nodes, and 4/8 patients had inflammatory uptake in lung, mediastinal or hilar nodes. During surveillance of up to 3 years, 3/5 patients with positive 18F-FDG uptake developed biopsy proven invasive cancer at site of dysplasia. 3/31 patients with negative 18F-FDG uptake developed invasive cancer at high grade dysplasia sites during surveillance. No low grade lesion showed 18F-FDG uptake or progressed to invasive cancer during surveillance. Conclusions PET/CT was able to detect early synchronous cancers in patients with pre-invasive endobronchial lesions. PET/CT was also able to detect 18F-FDG uptake in a proportion of patients at known dysplasia sites suggesting adjacent or underlying occult invasive carcinoma. [ABSTRACT FROM AUTHOR]

The article reports that the use of endobronchial ultrasound-guided transbronchial needle aspiration was able to halved time needed to come up with treatment decisions for patients with suspected lung cancer, which was concluded by researchers from six British centres involved in the Lung-BOOST trial.

People exposed to chickens on Dutch poultry farms affected by H7N7 influenza A virus were asked to report signs of conjunctivitis or influenza like illness from February to June 2003. Of the estimated 3410 or more at risk, 453 had health complaints, 349 conjunctivitis, 90 influenza like illness and 67 others. Laboratory confirmation from eye and nose and throat swabs was by RT-PCR or viral culture and typing. Influenza like symptoms were reported less often in those who were A/H7 positive than in those in whom viruses could not be detected.

Purpose: Recent clinical trials and meta-analyses have shown that both CHART (continuous hyperfractionated accelerated radiation therapy) and induction chemotherapy offer a survival advantage over conventional radical radiotherapy for patients with inoperable non-small cell-lung cancer (NSCLC). This multicenter randomized controlled trial (INCH) was set up to assess the value of giving induction chemotherapy before CHART.Methods and Materials: Patients with histologically confirmed, inoperable, Stage I-III NSCLC were randomized to induction chemotherapy (ICT) (three cycles of cisplatin-based chemotherapy followed by CHART) or CHART alone.Results: Forty-six patients were randomized (23 in each treatment arm) from 9 UK centers. As a result of poor accrual, the trial was closed in December 2007. Twenty-eight patients were male, 28 had squamous cell histology, 34 were Stage IIIA or IIIB, and all baseline characteristics were well balanced between the two treatment arms. Seventeen (74%) of the 23 ICT patients completed the three cycles of chemotherapy. All 42 (22 CHART + 20 ICT) patients who received CHART completed the prescribed treatment. Median survival was 17 months in the CHART arm and 25 months in the ICT arm (hazard ratio of 0.60 [95% CI 0.31-1.16], p = 0.127). Grade 3 or 4 adverse events (mainly fatigue, dysphagia, breathlessness, and anorexia) were reported for 13 (57%) CHART and 13 (65%) ICT patients.Conclusions: This small randomized trial indicates that ICT followed by CHART is feasible and well tolerated. Despite closing early because of poor accrual, and so failing to show clear evidence of a survival benefit for the additional chemotherapy, the results suggest that CHART, and ICT before CHART, remain important options for the treatment of inoperable NSCLC and deserve further study. [ABSTRACT FROM AUTHOR]