Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961 .).

In this prospective study of 45 patients, we tested the hypothesis that markedly elevated levels of plasma von Willebrand antigen (vWf-Ag) a marker of endothelial cell injury, might predict the development of acute lung injury in patients with nonpulmonary sepsis syndrome. Acute lung injury was quantified on a four-point scoring system. At the time of entry into the study, none of the 45 patients had evidence of lung injury. Subsequently, 15 patients developed lung injury and 30 patients did not develop lung injury. The mean plasma vWf-Ag level was markedly elevated in the 15 patients who developed lung injury compared with the 30 patients who did not develop lung injury (588±204 vs. 338±196, percentage of control, P < 0.01). Furthermore, a plasma vWf-Ag level 2 450 was 87% sensitive and 77% specific for predicting the development of acute lung injury in the setting of nonpulmonary sepsis. In addition, the combination of a plasma vWf-Ag > 450 and nonpulmonary organ failure at the time of entry into the study had a positive predictive value of 80% for acute lung injury. Also, a plasma vWf-Ag level > 450 had a positive predictive value of 80% for identifying nonsurvivors. Thus, in patients with nonpulmonary sepsis, an elevated level of plasma vWf-Ag is a useful, early biochemical marker of endothelial injury and it has both predictive and prognostic value. (J. Clin. Invest. 1990. 86:474-480.) Key words: endothelial cells * acute lung injury* von Willebrand antigen level * sepsis * adult respiratory distress syndrome -shock

ObjectiveThe authors' objective was to quantitatively assess angiogenesis or neovascularity within nodenegative colon cancers and to determine if increased angiogenesis correlated with higher recurrence and lower survival rates. Summary Background DataNeovascularization promotes rapid tumor growth by facilitating nutrient and metabolite exchange. Recent work with breast and nonsmall cell lung cancers has shown that low angiogenic activity imparts a lower risk of recurrence and metastasis. Although adjuvant therapy is beneficial for patients with node-positive colon cancers, no such benefit has been demonstrated for patients with node-negative lesions. Nevertheless, up to 30% of this latter group will experience recurrence. We sought to identify a subset of patients with node-negative colon cancers at high risk for recurrence who might benefit from such therapy. MethodsOne hundred five node-negative colon cancers were immunostained for endothelial cell factor ViII-related antigen. Blood vessels within three microscopic fields at 1OOX magnification were counted, the mean calculated, and an angiogenesis score assigned. A subjective angiogenesis grade (1-4) was assigned after each slide was surveyed in its entirety. Score and grade were then assessed with respect to cancer recurrence and patient survival. ResultsMean patient age was 71 years (range, 41-90 years) and mean tumor size, 5.6 cm (range, 2-12 cm). Mean follow-up was 6.5 years; mean angiogenesis score, 27.9 (range, 4-50); and mean grade, 2.0 (range, 1-4). Patients living 5 years had significantly lower angiogenesis scores than did nonsurvivors (22.8 vs. 43.2, p = 0.0004). Each 1 0-vessel increase in score imparted a 2.0-fold greater hazard of death and a 2.7-fold greater hazard of recurrence. The probability of surviving 5 years is estimated by: e2,6290-.0976.A.S. P(survival)= 1 + e26-76AS and the probability of recurrence is estimated by: e-3.5527+.08556. A.S. P(recurrence) 1 e-3.5527+.08556 A.S. ConclusionsAngiogenesis within colon cancer is an important predictor of tumor behavior and may identify patients at higher risk for recurrence and early death. 695

Our results suggest that the growth of rectal cancer is dependent on the ingrowth of new blood vessels, and that increased vascularity promotes dissemination and adversely affects survival.

ObjectiveTo identify subsets of chronic obstructive pulmonary disease (COPD) patients who are more protected from exacerbations with the use of an inhaled corticosteroid/long-acting β2 agonist (ICS/LABA) combination, compared with the use of LABA monotherapy.DesignPost hoc cluster analysis of patients from two randomised clinical trials of salmeterol/fluticasone propionate (SFC) and salmeterol (SAL) that had primary endpoints of moderate/severe exacerbation rates.SettingCentres in North America.Participants1543 COPD patients were studied.InterventionsSFC 50/250 µg or SAL 50 µg, twice daily.Primary and secondary outcome measuresThe analysis identified clusters of COPD patients more responsive to SFC versus SAL with respect to the annual rate of moderate/severe exacerbations and compared their baseline clinical characteristics.ResultsOverall, SFC significantly reduced the annual rate of moderate/severe exacerbations as compared with SAL alone (rate ratio (RR)=0.701, p<0.001). Three-patient clusters were identified: COPD patients receiving diuretics (RR=0.56, p<0.001); patients not receiving diuretics but with forced expiratory volume in 1 s (FEV1) reversibility ≥12% (RR=0.67, p<0.001) exhibited a substantial reduction in the annual rate of moderate/severe exacerbations relative to SAL. A third cluster, consisting of patients not receiving diuretics and without FEV1 reversibility, demonstrated no difference for SFC versus SAL. Patients receiving diuretics had a significantly higher prevalence of comorbid cardiovascular disease.ConclusionsCOPD patients receiving diuretics and those not receiving diuretics but with FEV1 reversibility >12% at baseline were significantly more likely to experience a reduction in COPD-associated exacerbations with SFC versus SAL alone.Trial registrationNCT00115492, NCT00144911

AIMTo investigate the effects of the cytochrome P450 3A4 (CYP3A4) inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics of fluticasone furoate (FF) and vilanterol trifenatate (VI). METHODSTwo double-blind, randomized, placebo-controlled, two-way crossover studies in healthy subjects. In study 1, subjects received single doses of ketoconazole (400 mg) or placebo on days 1-6, with a single dose of inhaled VI (25 mg) on day 5. Pharmacodynamic and PK data were obtained up to 48 h following the VI dose. In study 2, subjects received once daily ketoconazole (400 mg) or placebo for 11 days, with FF/VI (200/25 mg) for the final 7 days. Pharmacodynamic and PK data were obtained up to 48 h following the day 11 dose. RESULTSIn study 1, there was no effect of co-administration of ketoconazole and VI on pharmacodynamic or PK parameters. In study 2, co-administration of ketoconazole and FF/VI had no effect on 0-4 h maximal heart rate or minimal blood potassium {treatment difference [90% confidence interval (CI)] -0.6 beats min -1 (-5.8, 4.5) and 0.04 mmol l -1 (-0.03, 0.11), respectively}, whilst there was a 27% decrease in 24 h weighted mean serum cortisol [treatment ratio (90% CI) 0.73 (0.62, 0.86)]. Co-administration of ketoconazole increased [percentage change (90% CI)] FF area under the curve (0-24) and maximal plasma concentration by 36% (16, 59) and 33% (12, 58), respectively, and VI area under the curve (0-t′) and maximal plasma concentration by 65% (38, 97) and 22% (8, 38), respectively. CONCLUSIONCo-administration of FF/VI or VI with ketoconazole resulted in a less than twofold increase in systemic exposure to FF and VI. There was no increase in b-agonist systemic pharmacodynamic effects, while serum cortisol was decreased by 27%. Co-administration of FF/VI with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Fluticasone furoate, an inhaled corticosteroid, and vilanterol trifenatate, an inhaled b2-agonist, both with 24 h duration, are in development for the treatment of asthma and chronic obstructive pulmonary disease.• Preclinical data suggest that both are predominantly metabolized by cytochrome P450 3A4 (CYP3A4). WHAT THIS STUDY ADDS• In the presence of the potent CYP3A4 inhibitor, ketoconazole, the systemic exposure to fluticasone furoate and vilanterol increased by less than twofold, indicating that they are substrates of CYP3A and are susceptible to interactions with potent CYP3A inhibitors. Co-administration of fluticasone furoate/vilanterol with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol which could lead to an increase in the potential for adverse reactions.

FSC does not reduce aPWV in all patients with moderate to severe COPD, but may have effects in those with elevated arterial stiffness. Additional studies are required to determine if aPWV could serve as a surrogate for cardiovascular events in COPD.

These results indicate that in presence of an established metastasis, there is a weak angiogenic relationship between a primary tumor and its metastasis. Heterogeneity in metastatic lesions cannot be explained solely by studying angiogenesis in primary tumors. Microvessel density in a primary tumor may not be useful as an independent prognostic indicator in late stages of disease. In such cases, assessment of microvessel density in a metastatic tumor whenever possible may be an indicator of prognosis.