Matthew Conron

Does Lung Adenocarcinoma Subtype Predict Patient Survival?: A Clinicopathologic Study Based on the New International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification

Introduction: Lung adenocarcinoma is a heterogeneous group of tumors with a highly variable prognosis, not well predicted by the current pathologic classification system. The 2004 World Health Organization classification results in virtually all tumors encountered in clinical practice being allocated to the adenocarcinoma of mixed subtype category. A new classification developed by an international multidisciplinary expert panel sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society, is based on histomorphologic subtype and has recently been validated in a North American series of 514 stage I lung adenocarcinomas. We investigated the relationship between the new classification and patient survival in a series of Australian patients with stages I, II, and III lung adenocarcinoma. Methods: We identified 210 patients from a surgical database who underwent resection of lung adenocarcinoma from 1996 to 2009. Two pathologists, blinded to patient outcome, independently performed histopathologic subtyping according to the new classification. Kaplan-Meier curves were used to calculate 5-year survival for each separate histopathologic subtype/variant. Univariate and multivariate analyses were undertaken to control for validated prognostic factors. Results: We confirmed that the new subtypes of adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic-predominant adenocarcinoma had a 5-year survival approaching 100%, whereas micropapillary-predominant and solid with mucin-predominant adenocarcinomas were associated with particularly poor survival. Papillary-predominant and acinar-predominant adenocarcinomas had an intermediate prognosis. This effect persisted after controlling for stage. Conclusions: Classification of lung adenocarcinoma according to the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification correlated with 5-year survival. These relationships persisted after controlling for known prognostic patient and tumor characteristics. The new classification has advantages not only for individual patient care but also for better selection and stratification for clinical trials and molecular studies.

High resolution melting analysis for the rapid and sensitive detection of mutations in clinical samples: KRAS codon 12 and 13 mutations in non-small cell lung cancer

BackgroundThe development of targeted therapies has created a pressing clinical need for the rapid and robust molecular characterisation of cancers. We describe here the application of high-resolution melting analysis (HRM) to screen for KRAS mutations in clinical cancer samples. In non-small cell lung cancer, KRAS mutations have been shown to identify a group of patients that do not respond to EGFR targeted therapies and the identification of these mutations is thus clinically important.MethodsWe developed a high-resolution melting (HRM) assay to detect somatic mutations in exon 2, notably codons 12 and 13 of the KRAS gene using the intercalating dye SYTO 9. We tested 3 different cell lines with known KRAS mutations and then examined the sensitivity of mutation detection with the cell lines using 189 bp and 92 bp amplicons spanning codons 12 and 13. We then screened for KRAS mutations in 30 non-small cell lung cancer biopsies that had been previously sequenced for mutations in EGFR exons 18–21.ResultsKnown KRAS mutations in cell lines (A549, HCT116 and RPMI8226) were readily detectable using HRM. The shorter 92 bp amplicon was more sensitive in detecting mutations than the 189 bp amplicon and was able to reliably detect as little as 5–6% of each cell line DNA diluted in normal DNA. Nine of the 30 non-small cell lung cancer biopsies had KRAS mutations detected by HRM analysis. The results were confirmed by standard sequencing. Mutations in KRAS and EGFR were mutually exclusive.ConclusionHRM is a sensitive in-tube methodology to screen for mutations in clinical samples. HRM will enable high-throughput screening of gene mutations to allow appropriate therapeutic choices for patients and accelerate research aimed at identifying novel mutations in human cancer.

Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease

Background: Interstitial lung disease (ILD) is characterised by exertional dyspnoea, exercise limitation and reduced quality of life. The role of exercise training in this diverse patient group is unclear. The aims of this study were to establish the safety of exercise training in ILD; its effects on exercise capacity, dyspnoea and quality of life; and whether patients with idiopathic pulmonary fibrosis (IPF) had similar responses to those with other types of ILD. Methods: 57 subjects with ILD (34 IPF) were randomised to receive 8 weeks of supervised exercise training or weekly telephone support. The 6 min walk distance (6MWD), incremental exercise test, modified Medical Research Council (MRC) dyspnoea score and Chronic Respiratory Disease Questionnaire (CRDQ) were performed at baseline, following intervention and at 6 months. Results: 80% of subjects completed the exercise programme and no adverse events were recorded. The 6MWD increased following training (mean difference to control 35 m, 95% CI 6 to 64 m). A significant reduction in MRC score was observed (0.7 points, 95% CI 0.1 to 1.3) along with improvements in dyspnoea (p = 0.04) and fatigue (p<0.01) on the CRDQ. There was no change in peak oxygen uptake; however, exercise training reduced heart rate at maximum isoworkload (p = 0.01). There were no significant differences in response between those with and without IPF. After 6 months there were no differences between the training and control group for any outcome variable. Conclusions: Exercise training improves exercise capacity and symptoms in patients with ILD, but these benefits are not sustained 6 months following intervention. Trial registration number: NCT00168285

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for the Evaluation of Suspected Lymphoma

Background: Evidence regarding the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the assessment of isolated mediastinal lymphadenopathy (IMLN) is evolving. Its diagnostic accuracy in the evaluation of suspected lymphoma remains uncertain. Methods: We reviewed a prospectively recorded database of consecutive patients with suspected lymphoma who underwent EBUS-TBNA to evaluate IMLN. Patients in whom EBUS-TBNA was nondiagnostic subsequently underwent surgical biopsy or a minimum of 6 months radiologic surveillance. Results: Ninety-eight patients underwent EBUS-TBNA for evaluation of IMLN. Clinicoradiologic features suggested sarcoidosis as the likely diagnosis in 43 patients. In the remaining 55 patients, EBUS-TBNA achieved definitive diagnosis in 42 patients (76%; 95% confidence interval [CI] 55–90). Lymphoma was ultimately diagnosed in 21 of 55 patients (38%). EBUS-TBNA demonstrated lymphoma in 16 (76%) patients; however, four patients required further surgical biopsy to completely characterize lymphoma subtypes. Surgical biopsy was required to diagnose specific lymphoma subtypes not readily amenable to diagnosis with low volume specimens. Sensitivity and specificity for definitive diagnosis of lymphoma were 57% (95% CI 37–76) and 100% (95% CI 91–100), respectively. Conclusions: Although the diagnostic accuracy of EBUS-TBNA for lymphoma is lower than that for the lung cancer staging, the procedure is an appropriate investigative technique for the patients with IMLN because of the low incidence of lymphoma in this population, and the significant proportion of such patients (76%) in whom surgical biopsy is obviated.

Small changes in six-minute walk distance are important in diffuse parenchymal lung disease

UNLABELLED The aim of this study was to determine the minimal important difference for the six-minute walk distance in people with diffuse parenchymal lung disease. METHODS Forty-eight subjects (24 idiopathic pulmonary fibrosis) undertook the six-minute walk test before and after an 8-week exercise program. The minimal important difference was calculated using a distribution-based and an anchor-based method. A global rating of change scale was used as the external criterion to judge patients as clinically unchanged or changed. RESULTS The mean change in six-minute walk distance in improved subjects was 50.0 m, compared to 4.0 m in unchanged subjects and a reduction of 64.3 m in those classified as worse (p<0.001). The receiver operating characteristic curve indicated a cut-off value for meaningful change of 30.5 m (area under the curve 0.89, 95% confidence interval 0.81-0.98) whilst the standard error of the mean method indicated a value of 33 m. Similar values were obtained when only subjects with idiopathic pulmonary fibrosis were included (29 and 34 m, respectively). CONCLUSIONS Small differences in six-minute walk distance, in the range 29-34 m, may be clinically significant for people with diffuse parenchymal lung disease.

Correlation of Mutation Status and Survival with Predominant Histologic Subtype According to the New IASLC/ATS/ERS Lung Adenocarcinoma Classification in Stage III (N2) Patients

Introduction: We investigated the relationship between predominant subtype, according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification; mutation status; and patient outcome in stage III (N2) lung adenocarcinoma. Methods: We identified 69 patients with stage III (N2) lung adenocarcinoma operated on with curative intent between 1993 and 2011 who had adequate tumor tissue for molecular analysis and adequate follow-up time for survival analysis. DNA was isolated and tested for mutations using Sequenom’s OncoCarta Panel (v1.0; Sequenom, San Diego, CA). Results: The majority of tumors were acinar (26 of 69 tumors; 38%), solid (24 of 69 tumors; 35%), and micropapillary predominant (13 of 69 tumors; 19%) subtypes. EGFR and KRAS mutations were identified in 17 of 59 tumors (29%) and 13 of 59 tumors (22%), respectively. EGFR mutations occurred most often in acinar (11 of 25 tumors; 44%) and micropapillary predominant tumors (five of 13 tumors; 38%) (p = 0.009), whereas KRAS mutations occurred most often in solid predominant tumors (nine of 21 tumors; 43%) (p = 0.016). Patients with acinar predominant tumors had significantly improved overall survival compared with those with non-acinar predominant tumors (hazard ratio: 0.45; 95% confidence interval: 0.22–0.91; p = 0.026), which remained significant after adjustment for EGFR status, T-stage, sex, and age. Patients with EGFR-mutant micropapillary predominant tumors had similar survival to those with EGFR-mutant acinar predominant tumors. The predominant subtype in the primary tumor was most often seen in the N2 node in micropapillary and solid predominant tumors but not in acinar predominant tumors. Conclusions: The predominant subtype in the primary tumor was associated with overall survival in resected stage III (N2) lung adenocarcinoma and was independent of mutation status. Histologic subtyping provides important prognostic information and potentially molecular correlates.

Analysis of multidisciplinary lung cancer practice.

Background: The aim of this study was to describe the activity of a lung cancer multidisciplinary clinic (MDC) and examine whether this model of clinical practice results in adherence to best‐practice guidelines.

Cost-benefit of minimally invasive staging of non-small cell lung cancer: a decision tree sensitivity analysis.

Background: Accurate staging of non-small cell lung cancer (NSCLC) is critical for optimal management. Minimally invasive pathologic assessment of mediastinal lymphadenopathy is increasingly being performed. The cost-benefit (minimization of health care costs) of such approaches, in comparison with traditional surgical methods, is yet to be established. Methods: Decision-tree analysis was applied to compare downstream costs of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), conventional TBNA, and surgical mediastinoscopy. Calculations were based on real costs derived from actual patient data at a major teaching hospital in Melbourne, Australia. One- and two-way sensitivity analyses were undertaken to account for potential variation in input parameter values. Results: For the base-case analysis, initial evaluation with EBUS-TBNA (with negative results being surgically confirmed) was the most cost-beneficial approach (AU

The accuracy of EUS-FNA in assessing mediastinal lymphadenopathy and staging patients with NSCLC

2961) in comparison with EBUS-TBNA (negative results not surgically confirmed) (

Fibrosing alveolitis in systemic sclerosis: the need for early screening and treatment

3344), conventional TBNA (