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International guidelines dictate that magnetic resonance imaging (MRI) should be part of the primary standard work up of patients with rectal cancer because MRI can accurately identify the main risk factors for local recurrence and stratify patients into a differentiated treatment. The role of endoscopic ultrasound (EUS) is restricted to staging of superficial tumors because EUS is able to differentiate between T1 and T2 rectal cancer. Recent guidelines recommend the addition of diffusion-weighted (DWI) MRI to clinical and endoscopic assessment of response to preoperative radiochemotherapy (RCT). MRI is able to identify significant tumor regression which may alter the surgical approach.

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International guidelines dictate that magnetic resonance imaging (MRI) should be part of the primary standard work up of patients with rectal cancer because MRI can accurately identify the main risk factors for local recurrence and stratify patients into a differentiated treatment. The role of endoscopic ultrasound (EUS) is restricted to staging of superficial tumors because EUS is able to differentiate between T1 and T2 rectal cancer. Recent guidelines recommend the addition of diffusion-weighted (DWI) MRI to clinical and endoscopic assessment of response to preoperative radiochemotherapy (RCT). MRI is able to identify significant tumor regression which may alter the surgical approach.

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BACKGROUND: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. OBJECTIVES: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study. METHODS: Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge. RESULTS: Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly with lung function and sputum eosinophil counts. CONCLUSION: Our RNA extraction and profiling protocols allowed reproducible assessments of inflammatory signatures in sputum including quantification of drug effects on this response in allergic asthmatics. This approach offers novel possibilities for the development of pharmacodynamic (PD) biomarkers in asthma.

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BACKGROUND: The safety and tolerability of a mite allergoid subcutaneous allergen immunotherapy (SCIT) product was previously established. The aim of this study (EudraCT number: 2011-000393-61) was to find the optimally safe and effective allergoid dose by evaluating several dosages in patients with house dust mite (HDM)-induced allergic rhinoconjunctivitis (ARC) using a titrated nasal provocation test (TNPT). METHODS: In total, 290 adult ARC patients (148 females; 142 males) with established HDM allergy and with a positive TNPT were randomized to receive placebo or mite allergoid SCIT 6667, 20 000, 50 000 or 100 000 AUeq/ml for 12 months. Patients were updosed weekly, followed by monthly maintenance dosing. The primary study endpoint comprised the clinical response to TNPT after 12 months of treatment. Secondary endpoints included response to TNPT after 6 months, PNIF measurements, symptom and medication scores during the last 8 weeks of treatment, serum immunoglobulins and safety assessments. RESULTS: After 12 months, a dose-response was observed showing statistically significant improvements in the TNPT with SCIT concentrations of ≥20 000 AUeq/ml, while no significantly different outcomes were reached after 6 months. Specific serum IgG and IgG4 levels were dose dependently increased. In the highest dose group, more treatment-emergent adverse events were observed compared with the lower dose groups. CONCLUSION: In this mite allergoid SCIT dose finding study in HDM-induced ARC, concentrations of ≥20 000 AUeq/ml showed both immunological effects and clinical efficacy in the TNPT compared with placebo. The risk-benefit ratio favours 20 000 AUeq/ml and 50 000 AUeq/ml strengths for further clinical development.

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Upon inhalation, house dust mite (HDM) allergens are deposited at the nasal and oral mucosa, where IgA is produced abundantly. IgA subclasses have been linked to protection against respiratory allergy previously. It is currently not known whether and how the human IgA subclasses IgA1 and IgA2 contribute to the clinical status of house dust mite-allergic patients. Saliva and serum samples were collected, and HDM-specific, IgE, IgG4, IgA1 and IgA2 levels were determined. HDM-specific levels of IgA in serum were similar to levels measured in nonallergic controls, but HDM-specific levels of IgA2 in saliva were decreased in allergic subjects. HDM-allergic patients who suffered from rhinitis and eczema showed a significant decrease in IgA2-levels compared to patients who suffered from rhinitis only. Taken together, our findings indicate that HDM-specific IgA2, but not IgA1, levels in serum and saliva are reduced in HDM-allergic patients suffering from eczema.

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BACKGROUND: Sublingual immunotherapy (SLIT) is a potential efficacious and safe treatment option for patients with respiratory, IgE-mediated allergic diseases. A combined tolerability, dose-finding study with a sublingual liquid birch pollen preparation (SB) was conducted. METHODS: Two hundred and sixty-nine adults with birch-pollen-induced AR were randomized to placebo, SB: 3333, 10,000, 20,000 or 40,000 AUN/ml. Differences in symptom scores following a titrated nasal provocation test (TNPT) at baseline and after 5 months of treatment were determined. Safety, tolerability, birch-pollen-specific immunoglobulin levels and peak nasal inspiratory flow (PNIF) were also measured (all measures determined outside the birch pollen season). RESULTS: In all treatment groups, an improvement in symptom scores after treatment compared to baseline was observed, with an additional stepwise improvement in the active groups compared to placebo, which was significant in high-dose groups (P = 0.008 and P < 0.001, respectively). For this primary endpoint, a significant linear dose-response curve was observed: the higher the dose, the better the improvement observed. Likewise, active treatment resulted in an increase in PNIF and serum IgG levels compared to placebo. The highest improvements were found in the 40,000 AUN/ml group. All active dosages resulted in more adverse reactions than placebo, which were mainly mild and well-controlled. CONCLUSIONS: A multicentre trial evaluated the dose-response and tolerability of SB. All active treatment groups showed better responses than placebo for both primary and secondary parameters. The results indicate that, within the studied dose range, SB 40,000 AUN/ml is the most optimal effective and safe dose (ClinicalTrials.gov: NCT01639768).

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BACKGROUND: Allergen-induced late airway response offers important pharmacodynamic targets, including T helper 2 (TH2) biomarkers. However, detection of inflammatory markers has been limited in dithiothreitol-processed sputum. OBJECTIVES: To test whether allergen-induced TH2 inflammatory markers can be reproducibly quantified by sensitive detection techniques in ultracentrifuged sputum and the effect of fluticasone (FP) on these endpoints. METHODS: Thirteen allergic asthmatics with dual allergen-induced airway responses, documented during a single-blind placebo run-in period, participated in a double-blind, two-period crossover study. Each period consisted of three consecutive days, separated by ≥3 weeks. Following randomization, subjects inhaled FP (500 µg bid, five doses total) or placebo. On Day 2 in each study period, allergen challenge was performed and airway response measured by forced expiratory volume in 1 sec (FEV1) until 7 h post-challenge. Sputum was induced 24 h pre-allergen and 7 and 24 h post-allergen. Sputum samples were split into two portions: TH2 biomarkers were quantified by Meso Scale multiplex platform following ultracentrifugation, and cell differentials were counted on Giemsa-May-Grünwald-stained cytospins. Allergen-induced changes in inflammatory endpoints were compared between FP and placebo using a mixed model ANCOVA. RESULTS: Inhaled allergen induced dual airway responses in all subjects during both placebo periods with reproducible late asthmatic response (LAR) and increased sputum inflammatory biomarkers (IL-2, IL-4, IL-13, and eotaxin-1) and eosinophil counts. FP effectively blunted both the LAR and the inflammatory biomarkers. CONCLUSIONS: Combining novel, sensitive quantification methods with ultracentrifugation allows reproducible quantification of sputum biomarkers following allergen challenge, reversed by FP. This approach allows non-invasive identification of pharmacodynamic targets for anti-asthma therapies.

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RATIONALE: Soluble inflammatory markers obtained from non-invasive airway sampling such as induced sputum may be useful biomarkers for targeted pharmaceutical interventions. However, before these soluble markers can be used as potential targets, their variability and reproducibility need to be established in distinct study populations. OBJECTIVE: This study aimed to assess the reproducibility of biomarkers obtained from induced sputum and serum in chronic smokers and non-smokers. METHOD: Sputum and serum samples were obtained from 16 healthy non-smokers and 16 asymptomatic chronic smokers (for both groups: 8M/8F, 30-52 years, FEV1 ≥80% pred.; ≥10 pack years for the smokers) on 2 separate visits 4-10 days apart. Soluble markers in serum and sputum were analysed by ELISA. The differences between smokers vs non-smokers were analysed with a t-test and variability was assessed on log-transformed data by a mixed model ANOVA. RESULTS: Analysable sputum samples could be obtained from all 32 subjects. In both study populations neutrophils and macrophages were the predominant cell types. Serum Pulmonary Surfactant Associated Protein D had favourable reproducibility criteria for reliability ratio (0.99), intra-subject coefficient of variation (11.2%) and the Bland Altman limits of agreement. Furthermore, chronic smokers, compared to non-smokers, had significantly higher sputum concentrations of IL-8 (1094.6 pg/mL vs 460.8 pg/mL, p = 0.006)), and higher serum concentrations of Pulmonary Surfactant Associated Protein D (110.9 pg/mL vs 64.7 pg/mL, p = 0.019), and lower concentrations of Serum Amyloid A (1352.4 pg/mL vs 2297.5 pg/mL, p = 0.022). CONCLUSION: Serum Pulmonary Surfactant Associated Protein D proved to be a biomarker that fulfilled the criteria for reproducibility in both study groups.

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A biological marker (biomarker) is a physical sign or laboratory measurement that can serve as an indicator of biological or pathophysiological processes or as a response to a therapeutic intervention. An applicable biomarker possesses the characteristics of clinical relevance (sensitivity and specificity for the disease) and is responsive to treatment effects, in combination with simplicity, reliability and repeatability of the sampling technique. Presently, there are several biomarkers for asthma and allergic rhinitis that can be obtained by non-invasive or semi-invasive airway sampling methods meeting at least some of these criteria. In clinical practice, such biomarkers can provide complementary information to conventional disease markers, including clinical signs, spirometry and PC(20)methacholine or histamine. Consequently, biomarkers can aid to establish the diagnosis, in staging and monitoring of the disease activity/progression or in predicting or monitoring of a treatment response. Especially in (young) children, reliable, non-invasive biomarkers would be valuable. Apart from diagnostic purposes, biomarkers can also be used as (surrogate) markers to predict a (novel) drug's efficacy in target populations. Therefore, biomarkers are increasingly applied in early drug development. When implementing biomarkers in clinical practice or trials of asthma and allergic rhinitis, it is important to consider the heterogeneous nature of the inflammatory response which should direct the selection of adequate biomarkers. Some biomarker sampling techniques await further development and/or validation, and should therefore be applied as a "back up" of established biomarkers or methods. In addition, some biomarkers or sampling techniques are less suitable for (very young) children. Hence, on a case by case basis, a decision needs to be made what biomarker is adequate for the target population or purpose pursued. Future development of more sophisticated sampling methods and quantification techniques, such as--omics and biomedical imaging, will enable detection of adequate biomarkers for both clinical and research applications.

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BACKGROUND: Secretory leucocyte protease inhibitor (SLPI), which is present in many physiological fluids including saliva, sputum and nasal discharge, is the most effective inhibitor of chymase. Previously, we demonstrated that chymase is able to cleave SLPI and that the cleaved portion, cSLPI, is a biomarker of chymase activity. OBJECTIVE: We investigated the potential of cSLPI as a biomarker of chymase activity in subjects with allergic rhinitis (AR) and asthmatic airway disease. METHODS: Baseline sputum samples were collected from atopic asthmatics and healthy controls (HC). Nasal lavages (NAL) were performed in subjects with AR both at baseline and following a nasal challenge with allergen or placebo. Levels of cSLPI and chymase were determined by Western analysis, and tryptase and alpha-2 macroglobulin were measured by immunoassay. RESULTS: As compared with HC, asthmatics showed a significant increase in baseline cSLPI/total SLPI ratios and an increase in chymase levels. There was a high correlation of cSLPI/SLPI ratios to chymase levels in normal individuals and untreated asthmatics. In the NAL of patients with AR, as compared with placebo, allergen challenge increased inflammatory biomarkers, including cSLPI/SLPI ratios, chymase levels, tryptase levels and alpha2-macroglobulin levels. Correlations were observed between cSLPI/SLPI ratios and chymase levels and cSLPI/SLPI ratios and alpha2-macroglobulin levels; no correlation was seen between cSLPI/SLPI ratios and tryptase levels. CONCLUSION: Our data indicate that cSLPI reflects chymase activity in AR and asthma. Hence, cSLPI may serve as a biomarker for disease activity and for monitoring the efficacy of novel anti-inflammatory treatments in chymase-mediated diseases.

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BACKGROUND: Exhaled nitric oxide (eNO) is an established, noninvasive biomarker of active airway inflammation in (atopic) asthma. Treatment with anti-inflammatory therapy, such as inhaled corticosteroids, effectively decreases eNO levels. The NIOX MINO (MINO) is a hand-held, relatively inexpensive, electrochemical device that has been shown to yield comparable eNO measurements to the NIOX stationary unit. AIM: To compare measurements of MINO with another widely used and validated stationary chemiluminescence analyzer, the Ecomedics (ECO). METHODS: We performed subsequent eNO measurements on ECO and MINO in 50 subjects (19 healthy volunteers, 18 healthy smokers and 13 non-smoking, atopic asthmatics, not on controller therapy) on two visits 4-10 days apart. The mean of three acceptable measurements by ECO and the first acceptable measurement with the MINO were used for analysis. RESULTS: Both devices yielded reproducible eNO values for all subjects on both visits, with an overall CV of 22.7% (ECO) and 18.3% (MINO). A significant correlation was found between both devices (r=0.97, p<0.0001). Bland-Altman plots showed a high degree of agreement for the entire study population (mean difference MINO vs ECO=-10%; 95% limit of agreement were -36% and +28%) and in the three individual subgroups. CONCLUSIONS: Exhaled NO values measured with the MINO are reproducible and in agreement with the ECO. Our results add further evidence to the reliability of the MINO and warrant its applicability in research and clinical practice.

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BACKGROUND: MK-0873 is a novel selective phosphodiesterase-4 inhibitor, which has been in development for the treatment of chronic obstructive pulmonary disease (COPD). In this indication, theophylline is still an important treatment, despite its relatively small therapeutic window. In view of this, it is important to investigate whether MK-0873 could affect the pharmacokinetics, safety and tolerability of theophylline, when both drugs are given concomitantly. AIM: The objective of this study was to investigate the effect of multiple doses of oral MK-0873, a selective phosphodiesterase-4 inhibitor, on the pharmacokinetics, safety and tolerability profile of orally administered theophylline in healthy volunteers. METHODS: Eight healthy, non-smoking male subjects participated in this randomized, open-label, 2-period, cross-over study. In one period subjects received an oral dose of 2.5mg MK-0873 for 6 days co-administered with a single oral dose of 250 mg theophylline on day 5. The other period consisted of a single dose of 250 mg theophylline on day 1. In each period, blood samples were collected at predefined time points to evaluate theophylline pharmacokinetics. RESULTS: All subjects completed the study. The study medications were generally well tolerated and no clinically relevant changes were observed in either treatment periods. No significant difference was found in the AUC 0-infinity (77.7 vs. 83.8h ng/ml; p=0.280) and Cmax (6.70 vs. 7.77 ng/ml; p=0.125) of theophylline between the MK-0873+theophylline and theophylline only treatment, and bioequivalence was demonstrated for AUC0-infinity (geometric mean ratio with 90% confidence interval: 0.930 (0.826, 1.047)). CONCLUSION: In this study, in a limited number of subjects, co-administration of oral MK-0873 did not affect the pharmacokinetics, safety, and tolerability of oral theophylline in non-smoking healthy male subjects.

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BACKGROUND: We aimed to study the reproducibility of several biomarkers of allergic rhinitis to investigate their potential as outcome measures in clinical intervention trials. Furthermore, we investigated the kinetics of the biomarkers studied in nasal lavage and brush material following a placebo-controlled nasal allergen challenge. METHODS: We performed a skin prick test and measured serum specific immunoglobulin (Ig) E levels and inflammatory biomarkers in nasal lavage and brush material in 20 patients with allergic rhinitis on 2 separate days (washout, 14-21 days). The patients were then randomly assigned to undergo an intranasal challenge with a relevant allergen (n=10) or diluent (n=10) in order to assess the kinetics of several biomarkers of allergic airway inflammation in nasal lavage and brush samples. RESULTS: Baseline serum IgE levels and skin wheal sizes were highly reproducible measurements, with a coefficient of variation (CV) of 13.4% and 18.2%, respectively. This was not the case with the majority of inflammatory biomarkers, whose CV varied considerably (range, 6.1%-224.1%). The nasal allergen challenge induced an increase in composite symptom scores in all patients. Compared to placebo, tryptase (P=.004), eosinophilic cationic protein (ECP) (P=.03) and alpha2-macroglobulin (P=.002) were increased in nasal lavage at 20 minutes post allergen. Nasal lavage ECP levels and nasal brush eosinophils were still significantly increased at 7 hours (P=.03 and P=.04), but all statistical significance had been lost at 24 hours post challenge. CONCLUSION: Serum specific IgE assays and skin prick tests exhibited good reproducibility in patients with clinically stable allergic rhinitis. We were also able to investigate the kinetics of allergen-induced upper airway inflammatory markers in nasal lavage and brush material. Hence, nasal allergen challenge, when used in combination with nasal lavage and brush sampling, is a suitable research tool for early drug development.

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This paper reports on the development of a low-cost, rapidly deployable sensor for surveying live sewers for blockages and structural failures. The anticipated cost is an order of magnitude lower than current techniques. The technology is based on acoustic normal model decomposition, The instrument emits short coded acoustic signals which are reflected from any sewer wall defect. The acoustic signals can be short Gaussian pulses or longer sinusoidal sweeps and pseudo-random noise. The processing algorithms used on the reflected signal can predict the extent and geometry of the pipe deformation, and the locations and approximate size of common blockages. The effect of the water level on the frequency of the fundamental mode has also been investigated. It is shown that the technique can be adapted to work reliably in relatively large 600 mm diameter sewer pipes.

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BACKGROUND: Exhaled nitric oxide (eNO) is a validated noninvasive marker of airway inflammation in asthma. In patients with allergic rhinitis (AR), increased levels of nasal nitric oxide (nNO) have also been measured. However, the applicability of nNO as a marker of upper airway inflammation awaits validation. AIM: To test the longitudinal reproducibility of standardized nNO measurements in patients with AR and the effects of nasal allergen challenge. METHODS: Twenty patients with clinically stable, untreated AR participated in a combined study design. First, reproducibility of nNO was tested over 1, 7, and 14-21 days. Subsequently, the effect of nasal allergen challenge on nNO was studied in a placebo-controlled, parallel design. Nasal NO was measured with a chemoluminescence analyzer. Ten subjects randomly underwent a standardized nasal allergen challenge; 10 subjects received placebo. Response to nasal challenge was monitored by composite symptom scores. RESULTS: There was a good reproducibility of nNO up to 7 days [coefficient of variation (CV) over 1 (16.45%) and 7 days (21.5%)], decreasing over time [CV (14-21 days): 38.3%]. As compared with placebo, allergen challenge caused a significant increase in symptom scores (P < 0.001), accompanied by a decrease in nNO at 20 min postchallenge (P = 0.001). Furthermore, there was a gradual increase in nNO at 7 h, reaching significance at 24-h postallergen (P = 0.04). CONCLUSIONS: Similar to eNO in asthma, nNO is a noninvasive marker, potentially suitable to monitor upper airway inflammation following allergen-induced late response. Present data show a good reproducibility of nNO measurements, decreasing over time, probably because of subclinical seasonal influences.

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In this review, we aim to lead the readers through the historical highlights of pathophysiological concepts and treatment of asthma. Understanding the nature and links of asthma has modeled our diagnostic, pathophysiological and therapeutic thinking and acting. The recognition of its heterogeneous nature in combination with several refined and sophisticated technologies will mark a new era of phenotype-specific approach and treatment of asthma.

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Asthma is a heterogeneous disorder characterized by chronic airway inflammation, hyperresponsiveness and remodeling. Being the hallmark of asthma, airway inflammation has become the most important target for therapeutic agents. Consequently, during the past decade various semi-and non-invasive methods have been explored to sample the airway inflammation in asthma. In this review, we provide a practical overview of the current status of various sampling techniques including sputum induction, exhaled breath analysis, and bronchoprovocation tests (BPTs). We focus on their applicability for monitoring in clinical practice and in intervention trials in asthma.

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