M. A. van de Pol

Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial

The European Organisation for Research and Treatment of Cancer (EORTC; protocol 08031) phase II trial investigated the feasibility of trimodality therapy consisting of induction chemotherapy followed by extrapleural pneumonectomy and post-operative radiotherapy in patients with malignant pleural mesothelioma (with a severity of cT3N1M0 or less). Induction chemotherapy consisted of three courses of cisplatin 75 mg·m−2 and pemetrexed 500 mg·m−2. Nonprogressing patients underwent extrapleural pneumonectomy followed by post-operative radiotherapy (54 Gy, 30 fractions). Our primary end-point was “success of treatment” and our secondary end-points were toxicity, and overall and progression-free survival. 59 patients were registered, one of whom was ineligible. Subjects’ median age was 57 yrs. The subjects’ TNM scores were as follows: cT1, T2 and T3, 36, 16 and six patients, respectively; cN0 and N1, 57 and one patient, respectively. 55 (93%) patients received three cycles of chemotherapy with only mild toxicity. 46 (79%) patients received surgery and 42 (74%) had extrapleural pneumonectomy with a 90-day mortality of 6.5%. Post-operative radiotherapy was completed in 37 (65%) patients. Grade 3–4 toxicity persisted after 90 days in three (5.3%) patients. Median overall survival time was 18.4 months (95% CI 15.6–32.9) and median progression-free survival was 13.9 months (95% CI 10.9–17.2). Only 24 (42%) patients met the definition of success (one-sided 90% CI 0.36–1.00). Although feasible, trimodality therapy in patients with mesothelioma was not completed within the strictly defined timelines of this protocol and adjustments are necessary.

Synbiotics reduce allergen-induced T-helper 2 response and improve peak expiratory flow in allergic asthmatics

To cite this article: van de Pol MA, Lutter R, Smids BS, Weersink EJM, van der Zee JS. Synbiotics reduce allergen‐induced T‐helper 2 response and improve peak expiratory flow in allergic asthmatics. Allergy 2011; 66: 39–47.

Early activation of coagulation after allergen challenge in patients with allergic asthma

Asthma is characterized by allergic airway inflammation which is associated with bronchial hyperreponsiveness and airway obstruction [1]. Recent evidence indicates that activation of coagulation within the airways in asthma may aggravete inflammation [2]. Asthma patients were found to have elevated concentrations of thrombin, thrombin-antithrombin complexes (TATc) and soluble tissue factor and reduced activated protein C (APC)/thrombin ratios in induced sputum [3,4]. However, knowledge on coagulation activation in the lower airways in asthma in humans is limited, especially with regard to the acute impact of an allergen challenge. We therefore determined activation of coagulation in the bronchoalveolar space and the acute effect of a segmental allergen challenge hereon in asthma patients as compared to healthy controls. Our study population has been described previously [5]. In short, thirteen allergic asthmatic subjects and nine healthy volunteers were included. Patients had a positive skin prick test for house dust mite allergens, grass pollen or both. Patients had not experienced an exacerbation of asthma during at least 2 months and had not used bronchodilators for at least 8 h before the investigations. None of the subjects had experienced recent airway infection or used anti-inflammatory or anticoagulant drugs. The study was approved by the Internal Review Board of the Academic Medical Center Amsterdam and written informed consent was obtained from all participants. Intracutaneous dose-response series with house dust mite or grass pollen (ALK Abello, Nieuwegein, The Netherlands) were performed to determine the concentration that produced a 10 mm wheal response 15 min after injection. Asthmatic subjects underwent an intrabronchial challenge with 1 mL of this allergen concentration – brought to a final volume of 5 mL with saline – whereas controls were challenged with the highest concentration applied in the patient group. Levels of lipopolysaccharide in the allergen solution were < 1.3 pg mL )1 in all

Changes in microbiota during experimental human Rhinovirus infection

BackgroundHuman Rhinovirus (HRV) is responsible for the majority of common colds and is frequently accompanied by secondary bacterial infections through poorly understood mechanisms. We investigated the effects of experimental human HRV serotype 16 infection on the upper respiratory tract microbiota.MethodsSix healthy volunteers were infected with HRV16. We performed 16S ribosomal RNA-targeted pyrosequencing on throat swabs taken prior, during and after infection. We compared overall community diversity, phylogenetic structure of the ecosystem and relative abundances of the different bacteria between time points.ResultsDuring acute infection strong trends towards increases in the relative abundances of Haemophilus parainfluenzae and Neisseria subflava were observed, as well as a weaker trend towards increases of Staphylococcus aureus. No major differences were observed between day-1 and day 60, whereas differences between subjects were very high.ConclusionsHRV16 infection is associated with the increase of three genera known to be associated with secondary infections following HRV infections. The observed changes of upper respiratory tract microbiota could help explain why HRV infection predisposes to bacterial otitis media, sinusitis and pneumonia.

Increase in allergen-specific IgE and ex vivo Th2 responses after a single bronchial challenge with house dust mite in allergic asthmatics

To cite this article: van de Pol MA, Lutter R, van Ree R, van der Zee JS. Increase in allergen‐specific IgE and ex vivo Th2 responses after a single bronchial challenge with house dust mite in allergic asthmatics.Allergy 2012; 67: 67–73.

Long-term effects of budesonide on inflammatory status in COPD.

A beneficial effect of long-term corticosteroid treatment in patients with COPD may be linked to suppressing inflammation, in particular neutrophilic inflammation. Effects on neutrophilic and eosinophilic inflammation and on lung function of long-term inhaled budesonide treatment (800 μ g daily, 6 months, double-blind, randomised, cross-over versus placebo) were studied and compared to the effects of 3 weeks oral prednisolone (30 mg daily) in 19 patients with COPD (mean age 63 y, FEV1 65% of predicted). Neither treatment influenced neutrophilic inflammation. Inhaled budesonide compared to placebo significantly reduced sputum % eosinophils at 3 months (−42%, p = 0.036), but not significantly at 6 months (−31%, p = 0.78). Eosinophil count per g sputum was decreased with 30% at 3 months (p = 0.09) and with 9% at 6 months (p = 0.78). FEV1 was slightly higher after 6 months budesonide (+2.5% predicted, p = 0.09). Prednisolone significantly reduced sputum % eosinophils (−87%, p = 0.007), but did not affect eosinophil count per g sputum and did not improve FEV1 (−0.6% predicted, p = 0.40). A higher baseline FEV1 (%) correlated with effects of budesonide on FEV1 (p < 0.001), effects on sputum interleukin-8 and eosinophil cationic protein (both p < 0.05) and tended to correlate with effects on sputum % eosinophils (p = 0.056). Baseline inflammatory data and effects of prednisolone did not correlate with effects of budesonide. Effects of inhaled budesonide in COPD are not restricted to patients with severe disease and may be linked to a suppression of eosinophilic inflammation. Investigating effects of prednisolone has no predictive value for long-term treatment.

Exhaled breath profiles in the monitoring of loss of control and clinical recovery in asthma

Asthma is a chronic inflammatory airway disease, associated with episodes of exacerbations. Therapy with inhaled corticosteroids (ICS) targets airway inflammation, which aims to maintain and restore asthma control. Clinical features are only modestly associated with airways inflammation. Therefore, we hypothesized that exhaled volatile metabolites identify longitudinal changes between clinically stable episodes and loss of asthma control.

Dynamics in cytokine responses during the development of occupational sensitization to rats

To cite this article: Krop EJM, van de Pol MA, Lutter R, Heederik DJJ, Aalberse RC, van der Zee JS. Dynamics in cytokine responses during the development of occupational sensitization to rats. Allergy 2010; 65: 1227–1233.

Loss of asthma control and activation of coagulation and fibrinolysis

Epidemiologic studies have shown that patients with severe asthma have increased risk of pulmonary embolism, in particular patients with frequent asthma exacerbations. Therefore, we hypothesized that asthma exacerbations are associated with increased haemostatic activity.