Multi-observer concordance and accuracy of the British Thoracic Society scale and other visual assessment qualitative criteria for solid pulmonary nodule assessment using FDG PET-CT.

AIM: To compare the interobserver reliability and diagnostic accuracy of the British Thoracic Society (BTS) scale and other visual assessment criteria in the context of 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)-computed tomography (CT) evaluation of solid pulmonary nodules (SPNs). MATERIALS AND METHODS: Fifty patients who underwent FDG PET-CT for assessment of a SPN were identified. Seven reporters with varied experience at four centres graded FDG uptake visually using the British Thoracic Society (BTS) four-point scale. Five reporters also scored SPNs according to three- and five-point visual assessment scales and using semi-quantitative assessment (maximum standardised uptake value [SUVmax]). Interobserver reliability was assessed with the intra-class correlation coefficient (ICC) and weighted Cohen's kappa (κ). Diagnostic performance was evaluated by receiver operator characteristic (ROC) analysis. RESULTS: Good interobserver reliability was demonstrated with the BTS scale (ICC=0.78, 95% confidence interval [CI]: 0.69-0.85) and five-point scale (ICC=0.78, 95 CI 0.68-0.86), whilst the three-point scale demonstrated moderate reliability (ICC=0.70, 95% CI: 0.59-0.80). Almost perfect agreement was achieved between two consultants (κ=0.85), and substantial agreement between two other consultants (κ=0.78) using the BTS scale. ROC curves for the BTS and five-point scales demonstrated equivalent accuracy (BTS area under the ROC curve [AUC]=0.768; five-point AUC=0.768). SUVmax was no more accurate compared to the BTS scale (SUVmax AUC=0.794; BTS AUC=0.768, p=0.43). CONCLUSIONS: The BTS scale can be applied reliably by reporters with varied levels of PET-CT reporting experience, across different centres and has a diagnostic performance that is not surpassed by alternative scales.

Accuracy and cost-effectiveness of dynamic contrast-enhanced CT in the characterisation of solitary pulmonary nodules-the SPUtNIk study.

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) (18FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for 18FDG-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.

What is the Optimum Screening Strategy for the Early Detection of Lung Cancer.

Early diagnosis of lung cancer is currently the most effective way of reducing lung cancer mortality other than quitting smoking because the treatment of late stage disease has little impact. Improving the awareness of the risk of lung cancer and warning symptoms, recognition and prompt referral, and screening with low dose computed tomography (LDCT) are potential ways to improve early diagnosis. Currently the evidence is strongest for LDCT, where one large trial, the US National Lung Screening Trial (NLST), showed a 20% relative reduction in lung cancer-related mortality and a 6.7% reduction in all-cause mortality in patients who had LDCT compared with chest X-ray. Although many questions remain about optimal methodology and cost-effectiveness, lung cancer screening is now being implemented in the USA using the NLST screening criteria. Many of these questions are being answered by on-going European trials that are reporting their findings. Here we review the research evidence for LDCT screening and explore the important issues that need to be addressed to optimise effectiveness.

Modelling the cost-effectiveness of public awareness campaigns for the early detection of non-small-cell lung cancer.

BACKGROUND: Survival rates in lung cancer in England are significantly lower than in many similar countries. A range of Be Clear on Cancer (BCOC) campaigns have been conducted targeting lung cancer and found to improve the proportion of diagnoses at the early stage of disease. This paper considers the cost-effectiveness of such campaigns, evaluating the effect of both the regional and national BCOC campaigns on the stage distribution of non-small-cell lung cancer (NSCLC) at diagnosis. METHODS: A natural history model of NSCLC was developed using incidence data, data elicited from clinical experts and model calibration techniques. This structure is used to consider the lifetime cost and quality-adjusted survival implications of the early awareness campaigns. Incremental cost-effectiveness ratios (ICERs) in terms of additional costs per quality-adjusted life-years (QALYs) gained are presented. Two scenario analyses were conducted to investigate the role of changes in the 'worried-well' population and the route of diagnosis that might occur as a result of the campaigns. RESULTS: The base-case theoretical model found the regional and national early awareness campaigns to be associated with QALY gains of 289 and 178 QALYs and ICERs of £13 660 and £18 173 per QALY gained, respectively. The scenarios found that increases in the 'worried-well' population may impact the cost-effectiveness conclusions. CONCLUSIONS: Subject to the available evidence, the analysis suggests that early awareness campaigns in lung cancer have the potential to be cost-effective. However, significant additional research is required to address many of the limitations of this study. In addition, the estimated natural history model presents previously unavailable estimates of the prevalence and rate of disease progression in the undiagnosed population.

Social deprivation does not affect lung cancer stage at presentation or disease outcome.

INTRODUCTION: Lung cancer mortality rates are higher in more deprived populations. This may simply reflect higher incidence of the disease, or additionally delayed presentation and worse outcomes amongst more deprived patients. Low socio-economic status (SES) has also been linked to cancer fatalism which might account for such differences. We determined the interaction between SES, patient's characteristics at presentation with lung cancer, and disease outcome at a large UK teaching hospital. METHODS: Stage, PS at presentation, treatment and survival data, index of multiple deprivation score and ACORN group (geo-demographic segmentation tool) were analysed for 1432 patients. RESULTS: There were no significant differences in stage or PS distribution by IMD quintile or ACORN group. When patients with stage I/II disease were considered, there were no differences in IMD or ACORN group for those undergoing or not undergoing surgical resection. Similarly when the whole cohort was considered, there were no differences in these parameters between those receiving and not receiving any anti-cancer therapy. There was a non-significant trend to lower IMD score (i.e. less deprivation) in the stage IIIb/IV patients receiving palliative chemotherapy compared to those not receiving chemotherapy. There was no significant difference in median survival or one-year survival according to IMD quintile or ACORN group. CONCLUSION: In our patient cohort, deprivation does not appear to affect stage or performance status at presentation, nor survival from lung cancer. If cancer fatalism is more prevalent in deprived populations, this does not appear to lead to later diagnosis nor worse disease outcome.

PMX464, a thiol-reactive quinol and putative thioredoxin inhibitor, inhibits NF-kappaB-dependent proinflammatory activation of alveolar epithelial cells.

BACKGROUND AND PURPOSE: Subtle changes in the intracellular reduction-oxidation (redox) state can modulate nuclear factor-kappaB (NF-kappaB) activity. Thioredoxin-1 (Trx) is a small, ubiquitous, redox-active thiol (-SH) protein that, with thioredoxin reductase-1 (TrxR), modifies the redox status of NF-kappaB pathway components. PMX464 is a novel thiol-reactive quinol thought to inhibit the Trx/TrxR system. The aim of this work was to investigate whether PMX464 inhibited NF-kappaB-mediated proinflammatory activation of human type II alveolar epithelial cells (A549). EXPERIMENTAL APPROACH: Intercellular adhesion molecule-1 (ICAM-1), granulocyte-macrophage colony-stimulating factor (GM-CSF) and CXCL8, NF-kappaB DNA binding, nuclear translocation of NF-kappaB p65 subunit, IkappaBalpha degradation, IkappaB phosphorylation and IkappaB kinase (IKK) activity were assessed in A549 cells stimulated with IL-1beta with or without PMX464 pretreatment. Effects of PMX464 on ICAM-1 expression in human lung microvascular endothelial cells (HLMVEC) were also investigated. For comparison, selected measurements (ICAM-1 and IkappaB-alpha phospho-IkappaB-alpha) were made on A549 cells after RNA interference-mediated silencing (siRNA) of Trx. KEY RESULTS: PMX464 reduced ICAM-1, GM-CSF and CXCL8 expression in IL-1beta-stimulated A549 cells and ICAM-1 in HLMVEC. PMX464 inhibited IL-1beta-induced NF-kappaB DNA binding, nuclear translocation of NF-kappaB p65 subunit and factors involved in NF-kappaB activation; specifically, IkappaBalpha degradation, IkappaB phosphorylation and IkappaB kinase (IKK) activity in A549. By contrast, Trx siRNA did not alter ICAM-1 expression or IkappaBalpha degradation/phosphorylation in IL-1beta-stimulated A549 cells. CONCLUSION AND IMPLICATIONS: PMX464 inhibits a proinflammatory response in A549 cells targeting the NFkappaB pathway above IKK. The lack of effect with Trx siRNA suggests that PMX464 acts on thiol proteins, in addition to Trx, to elicit anti-inflammatory responses in lung epithelial cells.

Extracellular thioredoxin levels are increased in patients with acute lung injury.

BACKGROUND: Acute lung injury (ALI) and its extreme manifestation the acute respiratory distress syndrome (ARDS) complicate a wide variety of serious medical and surgical conditions. Thioredoxin is a small ubiquitous thiol protein with redox/inflammation modulatory properties relevant to the pathogenesis of ALI. We therefore investigated whether thioredoxin is raised extracellulary in patients with ALI and whether the extent of any increase is dependent upon the nature of the precipitating insult. METHODS: Bronchoalveolar lavage (BAL) fluid and plasma samples were collected from patients with ALI (n=30) and healthy controls (n=18, plasma; n=14, BAL fluid). Lung tissue was harvested from a separate group of patients and controls (n=10). Thioredoxin was measured by ELISA in fluids and by immunohistochemistry in tissue. Interleukin (IL)-8 levels were determined by ELISA. Disease severity was assessed as APACHE II and SOFA scores. RESULTS: BAL fluid levels of thioredoxin were higher in patients with ALI than in controls (median 61.6 ng/ml (IQR 34.9-132.9) v 16.0 ng/ml (IQR 8.9-25.1), p<0.0001); plasma levels were also significantly higher. When compared with controls, sections of wax embedded lung tissue from patients with ALI showed greater positive staining for thioredoxin in alveolar macrophages and type II epithelial cells. BAL fluid levels of thioredoxin correlated with IL-8 levels in BAL fluid but not with severity of illness scores or mortality. BAL fluid levels of thioredoxin, IL-8, and neutrophils were significantly greater in patients with ALI of pulmonary origin. CONCLUSIONS: Extracellular thioredoxin levels are raised in patients with ALI, particularly of pulmonary origin, and have a significant positive association with IL-8. Extracellular thioredoxin levels could provide a useful indication of inflammation in ALI.

A fatal case of disseminated aspergillosis caused by a non-sporulating strain of Aspergillus fumigatus.

This report describes the case of a 38 year old pregnant woman with fatal disseminated aspergillosis and multiorgan failure, which was preceded by a long history of allergic bronchopulmonary aspergillosis. Postmortem revealed massive infarction and abscess formation in both lungs. Histology revealed a focal granulomatous response. Fungal infiltration with areas of necrosis were also seen in the liver, spleen, and paratracheal, mediastinal, para-aortic, and hilar lymph nodes. Culture of tissue samples produced a non-sporulating, beige coloured fungus that developed green pigmentation only after three weeks of incubation. Nucleotide sequencing of the D1-D2 region of the large ribosomal subunit revealed 100% homology with Aspergillus fumigatus. Minimum inhibitory concentrations for amphotericin B and itraconazole were both 0.25 mg/litre (susceptible). Further work is urgently required to determine the prevalence of such non-sporulating strains and their relevance to clinical infection.

KL-6 levels are elevated in plasma from patients with acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) is an extreme form of lung injury characterised by disruption to the alveolar epithelium. KL-6 is a mucin-like glycoprotein expressed on type II pneumocytes. Circulating levels of KL-6 have diagnostic and prognostic significance in a number of interstitial lung diseases, and when elevated are thought to indicate disruption of the alveolar epithelial lining. In this study, the authors sought to determine whether plasma KL-6 levels were elevated in patients with ARDS and whether these were associated with aetiology, disease severity, outcome or ventilatory strategy. Plasma samples were collected from 28 patients with ARDS, nine ventilated controls of matched illness severity and 10 healthy individuals. KL-6 concentrations were measured by enzyme-linked immunosorbent assay. Patients with ARDS had higher plasma levels of KL-6 (median 537 U x mL(-1), interquartile range (IQR) 383-1,119), as compared to ventilated controls (median 255 U x mL(-1), IQR 83-338) and normal individuals (median 215 U x mL(-1), IQR 149-307). In patients with ARDS, plasma KL-6 levels were higher in nonsurvivors than survivors, and correlated positively with oxygenation index and negatively with arterial oxygen tension:inspiratory oxygen fraction ratio. There were also significant positive correlations with mean and peak airway pressures. Elevated levels of plasma KL-6 may provide a useful marker for acute respiratory distress syndrome in ventilated patients and have possible prognostic significance. Alveolar epithelial cell damage may be influenced by the nature of mechanical ventilatory support.

Pulmonary tuberculosis among political asylum seekers screened at Heathrow Airport, London, 1995-9.

BACKGROUND: Over 50% of cases of tuberculosis (TB) in the UK occur in people born overseas, and new entrants to the country are screened for TB. A study was undertaken to determine the prevalence and disease characteristics of pulmonary TB in new entrants to the UK seeking political asylum. METHODS: A retrospective analysis of the results of screening 53 911 political asylum seekers arriving at Heathrow Airport between 1995 and 1999 was performed by studying Airport Health Control Unit records and hospital medical records. Outcome measures were chest radiograph abnormalities, sputum smear, culture, and drug resistance data for Mycobacterium tuberculosis. RESULTS: The overall prevalence of active TB in political asylum seekers was 241 per 100 000. There were large variations in prevalences of TB between asylum seekers from different regions, with low rates from the Middle East and high rates from the Indian subcontinent and sub-Saharan Africa. The frequency of drug resistance was high; 22.6% of culture positive cases were isoniazid resistant, 7.5% were multidrug resistant (resistant to both isoniazid and rifampicin), and 4% of cases diagnosed with active disease had multidrug resistant TB. CONCLUSIONS: The prevalence rate of TB in political asylum seekers entering the UK through Heathrow Airport is high and more M tuberculosis isolates from asylum seekers are drug resistant than in the UK population. Extrapolating these figures, it is estimated that 101 political asylum seekers with active pulmonary TB enter the UK every year, of whom about 25 would have smear positive disease.

Descending necrotizing mediastinitis caused by group A streptococcus (serotype M1T1).

We present a fatal case of descending necrotizing mediastinitis secondary to group A Streptococcus (serotype M1T1). Group A Streptococcus is a well-described cause of necrotizing fasciitis, but there have only been 4 previous cases documenting its involvement in descending necrotizing mediastinitis. This is the first case report to describe involvement of the M1 serotype in this condition.