Lung Unit

Marsden, United Kingdom

Lung Unit

Marsden, United Kingdom

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Marco F.,Respiratory Unit | Marco F.,University of Milan | Papa G.F.S.,Respiratory Unit | Papa G.F.S.,University of Milan | And 4 more authors.
Clinical and Molecular Allergy | Year: 2017

Background: Bronchial asthma is a heterogeneous respiratory condition which can be mimicked by a wide range of pathologies including upper airways stenosis. The accurate diagnosis of asthma, as with other conditions, may be influenced by fixation errors, which are common in medicine and occur when a physician concentrates on only one element of a clinical case without considering other relevant aspects. Here we report a challenging case characterized by the contemporaneous presence of a common disease, asthma, together with a rare respiratory disease, idiopathic tracheal stenosis. Case presentation: The 56-year-old female patient, a former smoker, was referred to our outpatient clinic for exertional dyspnea and persistent wheezing. There were no other respiratory or systemic symptoms over the past three months, and a psychological component was suspected. Spirometry with flow-volume evaluation and bronchoscopy were the key elements to establish the diagnoses and provide treatments. Once the diagnosis of asthma was confirmed, the combination of the anti-inflammatory corticosteroid fluticasone and the rapid-acting bronchodilator formoterol in a single inhaler effectively controlled the patient's symptoms, confirming the favorable efficacy and safety profile which are reflected in the recommendations of the international guidelines. Conclusions: In this paper we describe the clinical investigations and interventions that eventually confirmed a diagnosis of asthma complicated by an idiopathic tracheal stenosis and led to effective treatment of the patient. Awareness of fixation error may avoid misdiagnosis in patients with respiratory disease and a complicated history at presentation. © 2017 The Author(s).


Pearson A.,Institute of Cancer Research | Smyth E.,Royal Marsden Hospital | Babina I.S.,Institute of Cancer Research | Herrera-Abreu M.T.,Institute of Cancer Research | And 22 more authors.
Cancer Discovery | Year: 2016

FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy. SIGNIFICANCE: Robust single-agent response to FGFR inhibition is seen only in high-level FGFRamplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. © 2016 American Association for Cancer Research.


Guckenberger M.,University of Würzburg | Guckenberger M.,Oncology and Radiotherapy Institute | Guckenberger M.,Lung Unit | Richter A.,University of Würzburg | And 3 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: To evaluate doses to the microscopic disease (MD) in adaptive radiotherapy (ART) for locally advanced non-small-cell lung cancer (NSCLC) and to model tumor control probability (TCP). Methods and Materials: In a retrospective planning study, three-dimensional conformal treatment plans for 13 patients with locally advanced NSCLC were adapted to shape and volume changes of the gross tumor volume (GTV) once or twice during conventionally fractionated radiotherapy with total doses of 66 Gy; doses in the ART plans were escalated using an iso-mean lung dose (MLD) approach compared to non-adapted treatment. Dose distributions to the volumes of suspect MD were simulated for a scenario with synchronous shrinkage of the MD and GTV and for a scenario of a stationary MD despite GTV shrinkage; simulations were performed using deformable image registration. TCP calculations considering doses to the GTV and MD were performed using three different models. Results: Coverage of the MD at 50 Gy was not compromised by ART. Coverage at 60 Gy in the scenario of a stationary MD was significantly reduced from 92% ± 10% to 73% ± 19% using ART; however, the coverage was restored by iso-MLD dose escalation. Dose distributions in the MD were sufficient to achieve a TCP >80% on average in all simulation experiments, with the clonogenic cell density the major factor influencing TCP. The combined TCP for the GTV and MD was 19.9% averaged over all patients and TCP models in non-adaptive treatment with 66 Gy. Iso-MLD dose escalation achieved by ART increased the overall TCP by absolute 6% (adapting plan once) and by 8.7% (adapting plan twice) on average. Absolute TCP values were significantly different between the TCP models; however, all TCP models suggested very similar TCP increase by using ART. Conclusions: Adaptation of radiotherapy to the shrinking GTV did not compromise dose coverage of volumes of suspect microscopic disease and has the potential to increase TCP by >40% compared with radiotherapy planning without ART. © 2011 Elsevier Inc.


Puglisi M.,Institute of Cancer Research and Royal Marsden NHS Foundation Trust | Puglisi M.,Lung Unit | Thavasu P.,Institute of Cancer Research and Royal Marsden NHS Foundation Trust | Stewart A.,Institute of Cancer Research and Royal Marsden NHS Foundation Trust | And 5 more authors.
Lung Cancer | Year: 2014

Objectives: EGFR inhibitors are ineffective against most EGFR wild-type non-small cell lung cancer, for which novel treatment strategies are needed. AKT signalling is essential for mediating EGFR survival signals in NSCLC. We evaluated the combination of gefitinib and two different AKT inhibitors, the allosteric inhibitor AKTi-1/2 and the ATP-competitive pan-AKT inhibitor AZD5363, in EGFR-mutant (HCC-827 and PC-9) and -wild-type (NCI-H522, NCI-H1651), non-small cell lung cancer cell lines. Materials and methods: Drug interaction was studied in two EGFR mutant and two EGFR wild-type non-small cell lung cancer cell lines by calculating combination index (CI) using median effect analysis. The effects on p-EGFR, p-ERK, p-AKT, p-S6 and apoptosis were studied by Western blot analysis. Results: The combination of gefitinib and AKTi-1/2 or AZD5363 showed synergistic growth inhibition in all cell lines. CI values for the combination of gefitinib and AKTi-1/2 were 0.35 (p= 0.0048), 0.56 (p= 0.036), 0.75 (p= 0.13) and 0.64 (p= 0.0003) in NCI-H522, NCI-H1651, HCC-827 and PC-9 cell lines, respectively; CI values of 0.45 (p= 0.0087) and 0.22 (p< 0.0001) were observed in NCI-H522 and PC-9 cells, respectively, when gefitinib was combined with AZD5363. Additive inhibition of signalling output through AKT and key downstream proteins (S6) and increased apoptosis were demonstrated. Conclusion: Dual inhibition of EGFR and AKT may be a useful up-front strategy for patients with EGFR-mutant and -wild-type non-small cell lung cancer. © 2014 Elsevier Ireland Ltd.


Cook G.J.R.,King's College London | O'Brien M.E.,Lung Unit | Siddique M.,King's College London | Chicklore S.,King's College London | And 6 more authors.
Radiology | Year: 2015

Purpose: To determine if first-order and high-order textural features on fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) images of non-small cell lung cancer (NSCLC) (a) at baseline, (b) at 6 weeks, or (c) the percentage change between baseline and 6 weeks can predict response or survival in patients treated with erlotinib. Materials and Methods: Institutional review board approval was obtained for post hoc analysis of data from a prospective single-center study for which informed consent was obtained. The study included 47 patients with NSCLC who underwent 18F-FDG PET/computed tomography (CT) at baseline (n = 47) and 6 weeks (n = 40) after commencing treatment with erlotinib. First-order and high-order primary tumor texture features reflecting image heterogeneity, standardized uptake values, metabolic tumor volume, and total lesion glycolysis were measured for all 18F-FDG PET studies. Response to erlotinib was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) on CT images obtained at 12 weeks (n = 32). Associations between PET parameters, overall survival (OS), and RECIST-based treatment response were tested by Cox and logistic regression analyses, respectively. Results: Median OS was 14.1 months. According to CT RECIST at 12 weeks, there were 21 nonresponders and 11 responders. Response to erlotinib was associated with reduced heterogeneity (first-order standard deviation, P = .01; entropy, P = .001; uniformity, P = .001). At multivariable analysis, high-order contrast at 6 weeks (P = .002) and percentage change in first-order entropy (P = .03) were independently associated with survival. Percentage change in first-order entropy was also independently associated with treatment response (P = .01). Conclusion: Response to erlotinib is associated with reduced heterogeneity at 18F-FDG PET. Changes in first-order entropy are independently associated with OS and treatment response. Copyright © 2015 Radiological Society of North America.


PubMed | Lung Unit, The Newcastle upon Tyne Hospitals NHS Foundation Trust, The Royal Surrey County Hospital NHS Foundation Trust, Royal Marsden Hospital and 5 more.
Type: Journal Article | Journal: Cancer discovery | Year: 2016

FGFR1 and FGFR2 are amplified in many tumor types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial, we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy.Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumor DNA may present a viable strategy to screen patients. Cancer Discov; 6(8); 838-51. 2016 AACR.This article is highlighted in the In This Issue feature, p. 803.

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