The prevalence and prognostic value of systemic inflammation in good performance status patients with advanced, inoperable non-small cell lung cancer receiving palliative radiotherapy: Comparison of composite ratios and cumulative scores.

INTRODUCTION: The present study sought to examine the relationships between systemic inflammatory composite ratios/cumulative scores, magnitude of systemic inflammatory response (SIR) and survival in good performance status patients (ECOG-PS 0/1) with advanced NSCLC receiving palliative radiotherapy. METHODS: Systemic inflammatory composite ratios/cumulative scores included the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), C-reactive protein, (CRP)-albumin ratio (CAR), neutrophil- lymphocyte score (NLS), platelet-lymphocyte score (PLS), lymphocyte-monocyte score (LMS), neutrophil-platelet score (NPS), modified Glasgow prognostic score (mGPS). The magnitude of SIR was determined by serum CRP concentration, with a median CRP concentration of >10 m mg/L considered to be systemically inflamed. Relationships between systemic inflammatory composite ratios/ cumulative scores and clinicopathological characteristics were examined using chi-square analysis. Relationships between overall survival (OS) and systemic inflammatory composite ratios/ cumulative scores were examined using cox regression analysis. RESULTS: 479 patients were included. 48% (n = 231) of patients were male and 70% (n = 338) were ≥65 years of age. 29% (n = 140) patients were ECOG-PS 0 and 71% (n = 339) were ECOG-PS 1. 98% (n = 469) of patients died during follow-up. The median survival was 5 months (2-11). A similar prevalence of systemic inflammation was noted across the various ratios/scores (NLR >3 68%; LMR <2.4 65%; PLR >150 70%; CAR >0.20 83%; NLS ≥1 66%; LMS ≥1 71%; NPS≥1 50%; PLS≥1 60% and mGPS≥1 75%). Despite not considered to be systemically inflamed, an NLR <3, LMR ≥2.4, PLR ≤150, NLS 0, LMS 0, NPS 0 and PLS 0 all had a median CRP concentration of >10 mg/L. When adjusted for ECOG-PS, CAR>0.40 (p < 0.001) and mGPS 2 (p < 0.05) remained significantly associated with OS. CONCLUSION: Liver-based measures of systemic inflammation (CAR and mGPS) appear more reliable for the quantification of the magnitude of SIR and have prognostic value in patients with advanced NSCLC.

Endothelial progenitor cells in patients with chronic obstructive pulmonary disease.

The pathogenesis of chronic obstructive pulmonary disease is not fully understood. The objective of this study was to compare circulating endothelial progenitor cells in patients with chronic obstructive pulmonary disease to age, sex, and cigarette smoking matched healthy controls. Patients with chronic obstructive pulmonary disease (n = 37) and healthy controls (n = 19) were matched by age, sex, and smoking status. Circulating hematopoietic progenitor cells (CD34(+) or CD133(+) mononuclear cells) and endothelial progenitor cells (CD34(+)KDR(+) or CD34(+)CD133(+)KDR(+) mononuclear cells) were quantified by flow cytometry. Endothelial cell-colony forming units from peripheral blood mononuclear cells were quantified in vitro and phenotypic analysis carried out using immunocytochemistry. Patients with chronic obstructive pulmonary disease had more circulating mononuclear cells compared with controls (8.4 ± 0.6 vs. 5.9 ± 0.4 × 10(9) cells/l; P = 0.02). CD34(+) hematopoietic progenitor cells were reduced as a proportion of mononuclear cells in patients compared with controls (0.99 ± 0.12 vs. 1.9 ± 0.12%; P = 0.02); however, there were no differences in the absolute number of CD34(+), CD34(+)KDR(+), or CD34(+)CD133(+)KDR(+) cells (P > 0.05 for all). Endothelial cell-colony forming units were increased in patients with chronic obstructive pulmonary disease compared with controls (13.7 ± 5.2 vs. 2.7 ± 0.9 colonies; P = 0.048). In contrast to previous studies, the number of circulating progenitor cells was not reduced in patients with chronic obstructive pulmonary disease compared with carefully matched controls. It seems unlikely that circulating endothelial progenitor cells or failure of angiogenesis plays a central role in the development of emphysema.

A Comparative Evaluation of Mediastinal Nodal SUVmax and Derived Ratios from 18F-FDG PET/CT Imaging to Predict Nodal Metastases in Non-Small Cell Lung Cancer.

18F-FDG positron emission tomography with computed tomography (PET/CT) is a standard imaging modality for the nodal staging of non-small cell lung cancer (NSCLC). To improve the accuracy of pre-operative staging, we compare the staging accuracy of mediastinal lymph node (LN) standard uptake values (SUV) with four derived SUV ratios based on the SUV values of primary tumours (TR), the mediastinal blood pool (MR), liver (LR), and nodal size (SR). In 2015-2017, 53 patients (29 women and 24 men, mean age 67.4 years, range 53-87) receiving surgical resection have pre-operative evidence of mediastinal nodal involvement (cN2). Among these, 114 mediastinal nodes are resected and available for correlative PET/CT analysis. cN2 status accuracy is low, with only 32.5% of the cN2 cases confirmed pathologically. Using receiver operating characteristic (ROC) curve analyses, a SUVmax of N2 LN performs well in predicting the presence of N2 disease (AUC, 0.822). Based on the respective selected thresholds for each ROC curve, normalisation of LN SUVmax to that for mediastinum, liver and tumour improved sensitivities of LN SUVmax from 68% to 81.1-89.2% while maintaining acceptable specificity (68-70.1%). In conclusion, normalised SUV ratios (particularly LR) improve current pre-operative staging performance in detecting mediastinal nodal involvement.

Systemic elastin degradation in chronic obstructive pulmonary disease.

BACKGROUND: Development of emphysema and vascular stiffness in chronic obstructive pulmonary disease (COPD) may be due to a common mechanism of susceptibility to pulmonary and systemic elastin degradation. OBJECTIVES: To investigate whether patients with COPD have evidence of systemic elastin degradation in the skin. METHODS: The authors measured cutaneous elastin degradation using immunohistochemistry (percentage area of elastin fibres) in sun-exposed (exposed) and non-sun-exposed (non-exposed) skin biopsies in 16 men with COPD and 15 controls matched for age and cigarette smoke exposure. Quantitative PCR of matrix metalloproteinase (MMP)-2, -9, -12 and tissue inhibitor of metalloproteinase-1 mRNA and zymography for protein expression of MMP-2 and -9 were performed on homogenised skin. Arterial stiffness and emphysema severity were measured using carotid-femoral pulse wave velocity and quantitative CT scanning. RESULTS: Skin elastin degradation was greater in exposed and non-exposed skin of patients with COPD compared with controls (exposed, mean (SD); 43.5 (12.1)% vs 26.3 (6.9)%, p<0.001; non-exposed 22.4 (5.2)% vs 18.1 (4.3)%, p=0.02). Cutaneous expression of MMP-9 mRNA and proMMP-9 concentrations was increased in exposed skin of COPD patients (p=0.004 and p=0.02, respectively) and was also associated with increased skin elastin degradation (r=0.62, p<0.001 and r=0.47, p=0.01, respectively). In the entire cohort of ex-smokers, cutaneous elastin degradation was associated with emphysema severity, FEV(1) and pulse wave velocity. CONCLUSIONS: Patients with COPD have increased skin elastin degradation compared with controls, which is related to emphysema severity and arterial stiffness. Systemic elastin degradation due to increased proteolytic activity may represent a novel shared mechanism for the pulmonary, vascular and cutaneous features of COPD.

Diagnosis of myocardial infarction following hospitalisation for exacerbation of COPD.

Cardiovascular disease is common in chronic obstructive pulmonary disease (COPD) and raised troponin is common in exacerbations. However, the prevalence of myocardial infarction following hospitalisation for exacerbation of COPD is unknown. Patients aged ≥ 40 yrs hospitalised with acute exacerbation of COPD (n = 242) with ≥ 10 pack-yrs of cigarette smoking were included in a prospective case series conducted in four hospitals. Patients whose primary presenting complaint was chest pain or who had an alternative diagnosis were excluded. Chest pain histories, serial ECGs and troponin levels were obtained. The mean ± SD age was 69 ± 9 yrs; 108 (45%) patients were male and almost half were current smokers. 124 (51%; 95% CI 48-58%) patients had chest pain, which was exertional in 62 (26%). 24 (10%) had raised troponin, among whom, 20 (8.3%; 95% CI 5.1-12.5%) had chest pain and/or serial ECG changes, fulfilling the 2007 Universal Definition of Myocardial Infarction. Neither chest pain (p = 0.77) nor serial ECG changes (p = 0.39) were associated with raised troponin. Raised troponin, chest pain and serial ECG changes are common in patients admitted to hospital with exacerbation of COPD. Overall, one in 12 patients met the criteria for myocardial infarction. Whether these patients would benefit from further cardiac investigation is unknown.

Increased platelet activation in patients with stable and acute exacerbation of COPD.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and cardiovascular disease. Interaction between inflammatory cells and activated platelets is important in the pathogenesis of atherothrombosis and may contribute to cardiovascular risk in patients with COPD. OBJECTIVES: To assess platelet-monocyte aggregation in patients with COPD and matched controls, and in patients with an acute exacerbation of COPD. METHODS: 18 men with COPD and 16 male controls matched for age and cigarette smoke exposure were recruited. A further 12 patients were investigated during and at least 2 weeks after hospitalisation for an acute exacerbation. Platelet-monocyte aggregation and platelet P-selectin expression were determined using flow cytometry. RESULTS: Patients with COPD had increased circulating platelet-monocyte aggregates compared with controls (mean (SD) 25.3 (8.3)% vs 19.5 (4.0)%, p=0.01). Platelet-monocyte aggregation was further increased during an acute exacerbation compared with convalescence (32.0 (11.0)% vs 25.5 (6.4)%, p=0.03). Platelet P-selectin expression and soluble P-selectin did not differ between groups. CONCLUSIONS: Patients with stable COPD have increased circulating platelet-monocyte aggregates compared with well-matched controls. Platelet activation is further increased in patients with COPD during an acute exacerbation. These findings identify a novel mechanism to explain the increased cardiovascular risk in COPD and suggest platelet inhibition as a plausible therapeutic target.

Vascular dysfunction in chronic obstructive pulmonary disease.

RATIONALE: Cardiovascular disease is a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), which may in part be attributable to abnormalities of systemic vascular function. It is unclear whether such associations relate to the presence of COPD or prior smoking habit. OBJECTIVES: To undertake a comprehensive assessment of vascular function in patients with COPD and healthy control subjects matched for smoking history. METHODS: Eighteen men with COPD were compared with 17 healthy male control subjects matched for age and lifetime cigarette smoke exposure. Participants were free from clinically evident cardiovascular disease. MEASUREMENTS AND MAIN RESULTS: Pulse wave velocity and pulse wave analysis were measured via applanation tonometry at carotid, radial, and femoral arteries. Blood flow was measured in both forearms using venous occlusion plethysmography during intrabrachial infusion of endothelium-dependent vasodilators (bradykinin, 100-1,000 pmol/min; acetylcholine, 5-20 microg/min) and endothelium-independent vasodilators (sodium nitroprusside, 2-8 microg/min; verapamil, 10-100 microg/min). Tissue plasminogen activator (t-PA) was measured in venous plasma before and during bradykinin infusions. Patients with COPD have greater arterial stiffness (pulse wave velocity, 11 +/- 2 vs. 9 +/- 2 m/s; P = 0.003; augmentation index, 27 +/- 10 vs. 21 +/- 6%; P = 0.028), but there were no differences in endothelium-dependent and -independent vasomotor function or bradykinin-induced endothelial t-PA release (P > 0.05 for all). CONCLUSIONS: COPD is associated with increased arterial stiffness independent of cigarette smoke exposure. However, this abnormality is not explained by systemic endothelial dysfunction. Increased arterial stiffness may represent the mechanistic link between COPD and the increased risk for cardiovascular disease associated with this condition.

The relationship between 18F-FDG-PETCT-derived tumour metabolic activity, nutritional risk, body composition, systemic inflammation and survival in patients with lung cancer.

The aim of this study was to examine the relationship between PET-CT derived tumour glucose uptake as measured by maximum standard glucose uptake (SUVmax) and total lesion glycolysis (TLG), nutritional risk as measured by the malnutrition universal screening tool (MUST), CT derived body composition as measured by skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD), the systemic inflammatory response as measured by the modified Glasgow prognostic score (mGPS) and the neutrophil to lymphocyte ratio (NLR) and survival in patients with lung cancer, treated with radiotherapy. In a retrospective cohort study, 119 patients were included in final analyses. The majority of patients were over 65 (86%), female (52%), had a performance status (ECOG-PS) of 0 or 1 (57%), were at nutritional risk (57%), were overweight (53%), had visceral obesity (62%), had a normal SMI (51%), had a low SMD (62%) and were systemically inflammed (mGPS 1/2, 51%). An elevated TLG was associated with sex (p < 0.05), TNM stage (p < 0.001), MUST (p < 0.01) and mGPS (p < 0.01). An elevated mGPS was associated with age (p < 0.05), NLR (p < 0.01), MUST (p < 0.01), and TLG (p < 0.01). On univariate survival analysis, TNM stage (p < 0.01), mGPS (p < 0.05), NLR (p < 0.01), MUST (p ≤ 0.001), Low SMD (p < 0.05), SUVmax (p ≤ 0.001) and TLG (p < 0.001) were associated with overall survival. On multivariate survival analysis MUST (HR: 1.49 95%CI 1.12-01.98 p < 0.01) and TLG (HR: 2.02 95%CI 1.34-3.04 p = 0.001) remained independently associated with survival. In conclusion, elevated tumour metabolic activity was associated with more advanced stage, greater nutritional risk, the systemic inflammatory response and poorer survival but not body composition analysis in patients with lung cancer. These results suggest that detrimental body composition is not directly determined by tumour metabolic activity but rather an ongoing systemic inflammatory response.

Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease.

RATIONALE: More patients with chronic obstructive pulmonary disease (COPD) die of cardiovascular causes than of respiratory causes, and patients with COPD have increased morbidity and mortality from stroke and coronary heart disease. Arterial stiffness independently predicts cardiovascular risk, is associated with atheromatous plaque burden, and is increased in patients with COPD compared with control subjects matched for cardiovascular risk factors. Elastin fragmentation and changes in collagen are found in the connective tissue of both emphysematous lungs and stiff arteries, but it is not known whether the severity of arterial stiffness in patients with COPD is associated with the severity of emphysema. OBJECTIVES: To identify whether the extent of arterial stiffness is associated with emphysema severity. METHODS: We performed a cross-sectional study in 157 patients with COPD. MEASUREMENTS AND MAIN RESULTS: We measured pulse wave velocity (a validated measure of arterial stiffness), blood pressure, smoking pack-years, glucose, cholesterol, and C-reactive protein in 157 patients with COPD. We assessed emphysema using quantitative computed tomography scanning in a subgroup of 73 patients. We found that emphysema severity was associated with arterial stiffness (r = 0.471, P < 0.001). The association was independent of smoking, age, sex, FEV(1)% predicted, highly sensitive C-reactive protein and glucose concentrations, cholesterol-high-density lipoprotein ratio, and pulse oximetry oxygen saturations. CONCLUSIONS: Emphysema severity is associated with arterial stiffness in patients with COPD. Similar pathophysiological processes may be involved in both lung and arterial tissue and further studies are now required to identify the mechanism underlying this newly described association.

Obtaining tissue diagnosis in lung cancer patients with poor performance status and its influence on treatment and survival.

INTRODUCTION: 25% of patients with lung cancer have performance status 3 or 4. A pragmatic approach to investigative procedures is often adopted based on the risks and benefits in these patients and whether tissue diagnosis is necessary for anticipated future treatment. This cohort study investigated factors influencing a clinician's decision to pursue a tissue diagnosis in patients with lung cancer and performance status 3 and 4 and to examine the association of tissue diagnosis with subsequent management and survival. METHODS: All patients with lung cancer diagnosed in North Glasgow from 2009 to 2012 were prospectively recorded in a registry. We investigated the relationships between achieving a tissue diagnosis, treatment and survival. RESULTS: Of 2493 patients diagnosed with lung cancer, 490 patients (20%) were PS 3 and 122 patients (5%) were PS 4. Tissue diagnosis was attempted in 60% and 35% patients with PS 3 and PS 4 respectively. Younger age, better performance status and having stage 4 disease were independently associated with a diagnostic procedure being performed. Only 5% of patients with poor performance status received treatment conventionally requiring a tissue diagnosis. Age, stage and performance status were independent predictors of mortality. Achieving a tissue diagnosis was not associated with mortality. Receiving treatment requiring tissue diagnosis is associated with survival benefit. CONCLUSIONS: The majority of patients with poor fitness undergo a diagnostic procedure which does not influence further treatment or affect survival. However, the cohort of patients who do undergo therapy determined by tissue diagnosis have improved survival.

Cardiovascular disease in COPD: mechanisms.

It is now well established that cardiovascular disease contributes significantly to both morbidity and mortality in COPD. Shared risk factors for cardiovascular disease and COPD, such as smoking, low socioeconomic class, and a sedentary lifestyle contribute to the natural history of each of these conditions. However, it is now apparent that alternative, novel mechanisms are involved in the pathogenesis of cardiovascular disease, and these may play an important role in driving the increased cardiovascular risk associated with COPD. In this article, we discuss the potential mechanisms that link COPD to an increased risk of cardiovascular disease.

Forced expiratory volume in one second predicts length of stay and in-hospital mortality in patients undergoing cardiac surgery: a retrospective cohort study.

OBJECTIVE: An aging population and increasing use of percutaneous therapies have resulted in older patients with more co-morbidity being referred for cardiac surgery. Objective measurements of physiological reserve and severity of co-morbid disease are required to improve risk stratification. We hypothesised that FEV1 would predict mortality and length of stay following cardiac surgery. METHODS: We assessed clinical outcomes in 2,241 consecutive patients undergoing coronary artery bypass grafting and/or valve surgery from 2001 to 2007 in a regional cardiac centre. Generalized linear models of the association between FEV1 and length of hospital stay and mortality were adjusted for age, sex, height, body mass index, socioeconomic status, smoking, cardiovascular risk factors, long-term use of bronchodilators or steroids for lung disease, and type and urgency of surgery. FEV1 was compared to an established risk prediction model, the EuroSCORE. RESULTS: Spirometry was performed in 2,082 patients (93%) whose mean (SD) age was 67 (10) years. Median hospital stay was 3 days longer in patients in the lowest compared to the highest quintile for FEV1, 1.35-fold higher (95% CI 1.20-1.52; p<0.001). The adjusted odds ratio for mortality was increased 2.11-fold (95% CI 1.45-3.08; p<0.001) per standard deviation decrement in FEV1 (800 ml). FEV1 improved discrimination of the EuroSCORE for mortality. Similar associations were found after excluding people with known pulmonary disease and/or airflow limitation on spirometry. CONCLUSIONS: Reduced FEV1 strongly predicted increased length of stay and in-hospital mortality following cardiac surgery. FEV1 is a widely available measure of physiological health that may improve risk stratification of complex patients undergoing cardiac surgery and should be evaluated for inclusion in new prediction tools.

Cardiovascular risk in chronic obstructive pulmonary disease.

Cardiovascular disease (CVD) contributes significantly to morbidity and mortality in COPD. There is a high prevalence of traditional risk factors in this patient group including smoking, sedentary behaviour and low socio-economic class. However, large studies have shown that airflow limitation is an independent risk factor for CVD. Therefore there may be a 'COPD effect' that contributes to CVD in this condition, adding to the body of evidence that COPD has important systemic consequences, as well as being a lung disease. In this article, we review the evidence for CVD in COPD. Next, we examine systemic factors present in COPD, and link these to the pathogenesis of atherosclerosis, including inflammation, oxidative stress and hypoxia. Finally, we review those studies that have investigated therapeutic interventions in COPD that may modify cardiovascular risk.