Five-Year Survival After Endosonography vs Mediastinoscopy for Mediastinal Nodal Staging of Lung Cancer.

Lung cancer accounts for the highest cancer-related mortality rate worldwide.1 Accurate mediastinal nodal staging is crucial in the management of non–small cell lung cancer (NSCLC) because it directs therapy and has prognostic value.2,

Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial

Copyright @ Queen’s Printer and Controller of HMSO 2012. This work was produced by Sharples et al. under the terms of a commissioning contract issued by the Secretary of State for Health.Objective: To assess the clinical effectiveness and cost-effectiveness of endosonography (followed by surgical staging if endosonography was negative), compared with standard surgical staging alone, in patients with non-small cell lung cancer (NSCLC) who are otherwise candidates for surgery with curative intent. Design: A prospective, international, open-label, randomised controlled study, with a trialbased economic analysis. Setting: Four centres: Ghent University Hospital, Belgium; Leuven University Hospitals,Belgium; Leiden University Medical Centre, the Netherlands; and Papworth Hospital, UK. Participants: Inclusion criteria: known/suspected NSCLC, with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for endosonography and surgery; and no evidence of metastatic disease. Exclusion criteria: previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; and not suitable for surgical staging. Interventions: Study patients were randomised to either surgical staging alone (n = 118) or endosonography followed by surgical staging if endosonography was negative (n = 123). Endosonography diagnostic strategy used endoscopic ultrasound-guided fine-needle aspiration combined with endobronchial ultrasound-guided transbronchial needle aspiration, followed by surgical staging if these tests were negative. Patients with no evidence of mediastinal metastases or tumour invasion were referred for surgery with curative intent. If evidence of malignancy was found, patients were referred for chemoradiotherapy. Main outcome measures: The main clinical outcomes were sensitivity (positive diagnostic test/nodal involvement during any diagnostic test or thoracotomy) and negative predictive value (NPV) of each diagnostic strategy for the detection of N2/N3 metastases, unnecessary thoracotomy and complication rates. The primary economic outcome was cost–utility of the endosonography strategy compared with surgical staging alone, up to 6 months after randomisation, from a UK NHS perspective. Results: Clinical and resource-use data were available for all 241 patients, and complete utilities were available for 144. Sensitivity for detecting N2/N3 metastases was 79% [41/52; 95% confidence interval (CI) 66% to 88%] for the surgical arm compared with 94% (62/66; 95% CI 85% to 98%) for the endosonography strategy (p = 0.02). Corresponding NPVs were 86% (66/77; 95% CI 76% to 92%) and 93% (57/61; 95% CI 84% to 97%; p = 0.26). There were 21/118 (18%) unnecessary thoracotomies in the surgical arm compared with 9/123 (7%) in the endosonography arm (p = 0.02). Complications occurred in 7/118 (6%) in the surgical arm and 6/123 (5%) in the endosonography arm (p = 0.78): one pneumothorax related to endosonography and 12 complications related to surgical staging. Patients in the endosonography arm had greater EQ-5D (European Quality of Life-5 Dimensions) utility at the end of staging (0.117; 95% CI 0.042 to 0.192; p = 0.003). There were no other significant differences in utility. The main difference in resource use was the number of thoracotomies: 66% patients in the surgical arm compared with 53% in the endosonography arm. Resource use was similar between the groups in all other items. The 6-month cost of the endosonography strategy was £9713 (95% CI £7209 to £13,307) per patient versus £10,459 (£7732 to £13,890) for the surgical arm, mean difference £746 (95% CI –£756 to £2494). The mean difference in quality-adjusted life-year was 0.015 (95% CI –0.023 to 0.052) in favour of endosonography, so this strategy was cheaper and more effective. Conclusions: Endosonography (followed by surgical staging if negative) had higher sensitivity and NPVs, resulted in fewer unnecessary thoracotomies and better quality of life during staging, and was slightly more effective and less expensive than surgical staging alone. Future work could investigate the need for confirmatory mediastinoscopy following negative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the diagnostic accuracy of EUS-FNA or EBUS-TBNA separately and the delivery of both EUSFNA or EBUS-TBNA by suitably trained chest physicians.This project was funded by the NIHR Health Technology Assessment programm

Lymphocyte subsets and the role of Th1/Th2 balance in stressed chronic pain patients

Background: The complex regional pain syndrome (CRPS) and fibromyalgia (FM) are chronic pain syndromes occurring in highly stressed individuals. Despite the known connection between the nervous system and immune cells, information on distribution of lymphocyte subsets under stress and pain conditions is limited. Methods: We performed a comparative study in 15 patients with CRPS type I, 22 patients with FM and 37 age- and sex-matched healthy controls and investigated the influence of pain and stress on lymphocyte number, subpopulations and the Th1/Th2 cytokine ratio in T lymphocytes. Results: Lymphocyte numbers did not differ between groups. Quantitative analyses of lymphocyte subpopulations showed a significant reduction of cytotoxic CD8+ lymphocytes in both CRPS (p < 0.01) and FM (p < 0.05) patients as compared with healthy controls. Additionally, CRPS patients were characterized by a lower percentage of IL-2-producing T cell subpopulations reflecting a diminished Th1 response in contrast to no changes in the Th2 cytokine profile. Conclusions: Future studies are warranted to answer whether such immunological changes play a pathogenetic role in CRPS and FM or merely reflect the consequences of a pain-induced neurohumoral stress response, and whether they contribute to immunosuppression in stressed chronic pain patients. Copyright (c) 2008 S. Karger AG, Basel

What have transgenic and knockout animals taught us about respiratory disease?

Over the past decade there has been a significant shift to the use of murine models for investigations into the molecular basis of respiratory diseases, including asthma and chronic obstructive pulmonary disease. These models offer the exciting prospect of dissecting the complex interaction between cytokines, chemokines and growth related peptides in disease pathogenesis. Furthermore, the receptors and the intracellular signalling pathways that are subsequently activated are amenable for study because of the availability of monoclonal antibodies and techniques for targeted gene disruption and gene incorporation for individual mediators, receptors and proteins. However, it is clear that extrapolation from these models to the human condition is not straightforward, as reflected by some recent clinical disappointments. This is not necessarily a problem with the use of mice itself, but results from our continued ignorance of the disease process and how to improve the modelling of complex interactions between different inflammatory mediators that underlie clinical pathology. This review highlights some of the strengths and weaknesses of murine models of respiratory disease

Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways

BACKGROUND: The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR. METHODS: The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01–3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR. RESULTS: Dexamethasone reduced BAL and lung tissue eosinophilia (ED(50 )values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED(50 )of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia. CONCLUSION: This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma

The Leydig cell biomarker INSL3 as a predictor of age-related morbidity: Findings from the EMAS cohort

Background: Insulin-like peptide 3 (INSL3) is a constitutive hormone secreted in men by the mature Leydig cells of the testes. It is an accurate biomarker for Leydig cell functional capacity, reflecting their total cell number and differentiation status. Objectives: To determine the ability of INSL3 to predict hypogonadism and age-related morbidity using the EMAS cohort of older community-dwelling men. Materials & methods: Circulating INSL3 was assessed in the EMAS cohort and its cross-sectional and longitudinal relationships to hypogonadism, here defined by testosterone (T) <10.5nmol/l, and a range of age-related morbidities determined by correlation and regression analysis. Results & discussion: While INSL3 is an accurate measure of primary hypogonadism, secondary and compensated hypogonadism also indicate reduced levels of INSL3, implying that testicular hypogonadism does not improve even when LH levels are increased, and that ageing-related hypogonadism may combine both primary and secondary features. Unadjusted, serum INSL3, like calculated free testosterone (cFT), LH, or the T/LH ratio reflects hypogonadal status and is associated with reduced sexual function, bone mineral density, and physical activity, as well as increased occurrence of hypertension, cardiovascular disease, cancer, and diabetes. Using multiple regression analysis to adjust for a range of hormonal, anthropometric, and lifestyle factors, this relationship is lost for all morbidities, except for reduced bone mineral density, implying that INSL3 and/or its specific receptor, RXFP2, may be causally involved in promoting healthy bone metabolism. Elevated INSL3 also associates with hypertension and cardiovascular disease. When unadjusted, INSL3 in phase 1 of the EMAS study was assessed for its association with morbidity in phase 2 (mean 4.3 years later); INSL3 significantly predicts 7 out of 9 morbidity categories, behaving as well as cFT in this regard. In contrast, total T was predictive in only 3 of the 9 categories. Conclusion: Together with its low within-individual variance, these findings suggest that assessing INSL3 in men could offer important insight into the later development of disease in the elderly

Ag85B DNA vaccine suppresses airway inflammation in a murine model of asthma

<p>Abstract</p> <p>Background</p> <p>In allergic asthma, Th2 lymphocytes are believed to play important roles in orchestrating airway eosinophilia and inflammation. Resetting the Th1/Th2 imbalance may have a therapeutic role in asthma. The mycobacterium tuberculosis 30-kilodalton major secretory protein (antigen 85B, Ag85B) can protect animals from M. tuberculosis infection by inducing a Th1-dominant response.</p> <p>Methods</p> <p>In this study, the Ag85B gene was cloned into pMG plasmids to yield the pMG-Ag85B plasmid. The expression of Ag85B gene in murine bronchial epithelia cells was detected by Western blotting and immunohistochemical staining after intranasal immunization with reconstructed pMG-Ag85B plasmids. The protective effect of pMG-Ag85B plasmids immunization in airway inflammation was evaluated by histological examination and bronchoalveolar lavage (BAL). IL-4 and IFN-γ levels in the BAL and supernatant from splenocyte culture were determined using ELISA kits.</p> <p>Results</p> <p>The Ag85B gene was successfully expressed in murine bronchial epithelia cells by intranasal immunization with reconstructed pMG-Ag85B plasmids. Using a murine model of asthma induced by ovalbumin (OVA), pMG-Ag85B immunization significantly inhibited cellular infiltration across the airway epithelium with a 37% decrease in the total number of cells (9.6 ± 2.6 × 10⁵/ml vs. 15.2 ± 3.0 × 10⁵/ml, p < 0.05) and a 74% decrease in the number of eosinophils (1.4 ± 0.2 × 10⁵/ml vs. 5.4 ± 1.1 × 10⁵/ml, p < 0.01) compared with the OVA-sensitized control group. There was no difference in the number of neutrophils in BAL fluid between the pMG-Ag85B group, the OVA-sensitized control group and the empty pMG group. IL-4 production was significantly decreased in the BAL fluid (32.0 ± 7.6 pg/ml vs. 130.8 ± 32.6 pg/ml, p < 0.01) and in the splenocyte supernatant (5.1 ± 1.6 pg/ml vs. 10.1 ± 2.3 pg/ml, p < 0.05) in the pMG-Ag85B group compared with the OVA-sensitized control group, while IFN-γ production was increased in the BAL fluid (137.9 ± 25.6 pg/ml vs. 68.4 ± 15.3 pg/ml, p < 0.05) and in the splenocyte supernatant (20.1 ± 5.4 pg/ml vs. 11.3 ± 3.2 pg/ml, p < 0.05).</p> <p>Conclusion</p> <p>In a murine model of asthma induced by OVA, intranasal immunization with pMG-Ag85B significantly reduced allergic airway inflammation with less eosinophil infiltration. This protective effect was associated with decreased IL-4 and increased IFN-γ production in the BAL fluid and in the supernatant of cultured splenocytes.</p