Stefan Rüdiger

Omalizumab in patients with severe asthma: the XCLUSIVE study.

Background and Aims:  Although the efficacy and safety of omalizumab (OMA) in uncontrolled severe allergic asthma has been demonstrated in several randomised controlled trials (RCTs), information on the treatment in a practice‐related setting is limited. Thus, the purpose of this prospective multi‐centre study (XCLUSIVE) was to investigate the efficacy, compliance and utilisation of OMA therapy in real‐life clinical practice in Germany.

Circulating biomarkers of tissue remodelling in pulmonary hypertension.

Objective: Besides persisting high pulmonary arterial pressure and increased pulmonary vascular resistance, remodelling of pulmonary tissues and subsequently the right heart are the key pathomechanisms of pulmonary hypertension (PH). Extracellular matrix maintenance in this context plays a central role. Methods: We tested the hypothesis that plasma concentration of matrix metalloproteinase (MMP)-2, tissue inhibitor of matrix metalloproteinases (TIMP)-4 and tenascin C (TNC) might be useful as biomarkers for assessing the severity of PH. Therefore, the concentrations of MMP-2, TIMP-4, TNC and N-terminal b-type natriuretic peptide (NT-proBNP) of 36 PH patients were compared with those of 44 age- and gender-matched healthy volunteers. Additionally, lung function, 6-min walk distance and right heart function were assessed. Results: In PH patients, significantly elevated plasma levels of MMP-2, TIMP-4, TNC and NT-proBNP were detected. In particular, TIMP-4 was significantly increased in patients with higher NYHA classification, and in patients with severe right ventricular hypertrophy. Conclusion: Monitoring of plasma TIMP-4 and to a lesser extent of MMP-2 and TNC levels in PH patients might help to assess the beneficial effects of PH pharmacotherapy on tissue remodelling.

Cytokine regulation by epidermal growth factor receptor inhibitors and epidermal growth factor receptor inhibitor associated skin toxicity in cancer patients.

AIM Epidermal growth factor receptor inhibitor (EGFRI) induced skin toxicity has a prognostic value suggesting skin toxicity can be a useful surrogate marker for successful epidermal growth factor receptor (EGFR) inhibition, improved response and survival. But the pathophysiology of EGFRI induced skin toxicity remains elusive. However the involvement of immunological mechanisms has been speculated. This study investigates the possible underlying mechanism of EGFR inhibition associated cytokine production in keratinocytes as well as in patients after treatment with epidermal growth factor receptor inhibitors (EGFRIs). METHODS Normal human epidermal keratinocytes (NHEK) were incubated for 2 and 24h with different concentrations of EGFRI (erlotinib) for Western blot analysis and cytokine expression analysis, respectively. Inhibition of EGFR, extracellular-signal-regulated kinase 1/2 (Erk 1/2) and c-Jun was examined by Western blot analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the NHEK cell supernatant and also in the serum of 186 cancer patients who are followed up for EGFRI induced skin rash. RESULTS A significant inhibitory effect of EGFRI was seen on EGFR (Y845), Erk 1/2 and c-Jun in a dose dependent manner. Further downstream, increased CC-chemokine ligand 2 (CCL2), CC-chemokine ligand 5 (CCL5) and decreased interleukin-8 (IL-8) or CXCL8 expression was observed in keratinocytes. In EGFRI treated patients, low levels of serum CXCL8 corresponding to stronger EGFR inhibition were associated with a higher grade of skin toxicity (p=0.0016) and a prolonged overall survival (p=0.018). CONCLUSIONS The results obtained in this study indicate that EGFRI can regulate cytokines by modulating EGFR signalling pathway in keratinocytes. Moreover, serum levels of CXCL8 in EGFRI treated patients may be important for individual EGFRI induced skin toxicity and patients survival.

Isolated IgG4-related interstitial lung disease: unusual histological and radiological features of a pathologically proven case

IgG4-related lung disease is commonly associated with autoimmune pancreatitis. Recently, isolated IgG4-related interstitial lung disease (ILD) without other organ involvement has newly been reported in two cases with clinical features of nonspecific interstitial pneumonitis (NSIP).We report the first case of an isolated IgG4-related ILD in a 78-year-old man with dry cough and dyspnea, whose clinical findings proved to be different from NSIP. Serum IgG4 levels were increased. Chest CT scan revealed bilateral consolidations especially in the lower lobes, enlarged mediastinal and hilar lymph nodes and pleural effusions. Video-assisted thoracoscopic (VATS) lung biopsy revealed a pattern similar to usual interstitial pneumonia (UIP) and an abundant IgG4-positive plasma cell infiltration. He was effectively treated by steroid therapy.Increasing recognition of IgG4 related diseases has led to a growing number of new entities. The novel concept of isolated IgG4-related ILD as a pulmonary manifestation of a systemic IgG4-related disorder should be taken into account as a possible differential diagnosis of ILD and mass-forming lesions, even when no other organ manifestation is clinically apparent at the time of diagnosis. Lung specific diagnostic criteria and algorithms are required to enhance diagnostic accuracy in cases of possible IgG4-related ILD.

Effects of Nasal Positive Expiratory Pressure on Dynamic Hyperinflation and 6-Minute Walk Test in Patients With COPD

INTRODUCTION: Dynamic hyperinflation is an important target in the treatment of COPD. There is increasing evidence that positive expiratory pressure (PEP) could reduce dynamic hyperinflation during exercise. PEP application through a nasal mask and a flow resistance device might have the potential to be used during daily physical activities as an auxiliary strategy of ventilatory assistance. The aim of this study was to determine the effects of nasal PEP on lung volumes during physical exercise in patients with COPD. METHODS: Twenty subjects (mean ± SD age 69.4 ± 6.4 years) with stable mild-to-severe COPD were randomized to undergo physical exercise with nasal PEP breathing, followed by physical exercise with habitual breathing, or vice versa. Physical exercise was induced by a standard 6-min walk test (6MWT) protocol. PEP was applied by means of a silicone nasal mask loaded with a fixed-orifice flow resistor. Body plethysmography was performed immediately pre-exercise and post-exercise. RESULTS: Differences in mean pre- to post-exercise changes in total lung capacity (−0.63 ± 0.80 L, P = .002), functional residual capacity (−0.48 ± 0.86 L, P = .021), residual volume (−0.56 ± 0.75 L, P = .004), SpO2 (−1.7 ± 3.4%, P = .041), and 6MWT distance (−30.8 ± 30.0 m, P = .001) were statistically significant between the experimental and the control interventions. CONCLUSIONS: The use of flow-dependent expiratory pressure, applied with a nasal mask and a PEP device, might promote significant reduction of dynamic hyperinflation during walking exercise. Further studies are warranted addressing improvements in endurance performance under regular application of nasal PEP during physical activities.

HLA polymorphisms influence the development of skin rash arising from treatment with EGF receptor inhibitors

AIM Development of a skin rash under treatment with EGF receptor (EGFR) inhibitors (EGFRIs) has been linked to a favorable prognosis in some studies, suggesting a possible immunological role for EGFRIs in addition to direct antagonistic downstream effects. The present study aimed to investigate whether particular HLA polymorphisms found in cancer patients treated with EGFRIs are associated with the development of skin rash and overall survival rates. PATIENTS & METHODS HLA typing was performed on 105 cancer patients and the development of skin rash was rated during the first 4 weeks of therapy with EGFRIs. RESULTS A significantly lower incidence of skin rash was found in patients carrying the HLA-A*02:01 or HLA-A*03:01 alleles (hazard ratio: 0.277; 95% CI: 0.121-0.634; p = 0.002 and hazard ratio: 0.292; 95% CI: 0.113-0.752; p = 0.011, respectively); however, no association with worse survival was seen. CONCLUSION The chances of developing a skin rash in patients treated with EGFRIs may be lower in patients that carry the HLA-A*02:01 or HLA-A*03:01 alleles, while the antitumor efficacy of EGFRIs does not seem to be significantly impaired in these patients.

Dosing to rash?--The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash.

AIM The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors. METHODS From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis. RESULTS Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10(-4)) and OS (p = 5.8 × 10(-5)). CONCLUSION The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients.

Blood pressure monitoring during exercise: Comparison of pulse transit time and volume clamp methods

During physical exercise, pulse transit time (PTT), expressed as the interval between ventricular electrical activity and peripheral pulse wave, may provide a surrogate estimate for blood pressure by the use of specific calibration procedures. The objective of this study was to determine systolic blood pressure (SBP) values derived from the PTT method and from an established method of non-invasive continuous blood pressure measurement based on the volume clamp technique, and to compare their agreement with sphygmomanometry during exercise tests. In 18 subjects, electrocardiogram (ECG) and finger-photoplethysmography were continuously recorded during maximal cycle exercise tests. Intermittent and continuous blood pressure measurements were simultaneously taken using automated sphygmomanometry and a Portapres Model-2 device, respectively. PTT was calculated for each ECG R-wave and the corresponding steepest upstroke slope in the photoplethysmogram, and was transformed to a continuous blood pressure estimate using multipoint nonlinear regression calibration based on the individual subjects sphygmomanometer readings. Bland–Altman limits of agreement between PTT-derived SBP estimates and sphygmomanometer values were –24.7 to 24.1 mmHg, and between Portapres and sphygmomanometer SBP values were –42.0 to 70.1 mmHg. For beat-to-beat SBP estimation during exercise, PTT measurement combined with multipoint nonlinear regression calibration based on intermittent sphygmomanometry may be an alternative to volume clamp devices.

High-throughput screening identified inherited genetic variations in the EGFR pathway contributing to skin toxicity of EGFR inhibitors

AIM To identify genomic variants in the EGFR pathway and in cytokines predisposing to skin toxicity from EGFR inhibitors. PATIENTS & METHODS In 126 patients with cancer and EGFR inhibitor therapy skin toxicity was quantified and EGFR and inflammatory pathway genes were analyzed by deep sequencing. RESULTS We found 1437 SNPs in the 382-kb target region. Three SNPs in EGFR intron 1 were found exclusively in patients without skin rash. Another EGFR intron 23 SNP was associated with skin rash, overall survival and IL8 plasma concentrations. Moreover, carriers of the PIK3R1 326I variant were predisposed to skin rash and better survival. CONCLUSION Comprehensive pathway-based resequencing revealed some new but only moderately strong genomic predictors of skin toxicity.

Pulmonary pulse transit time: a novel echocardiographic indicator of hemodynamic and vascular alterations in pulmonary hypertension and pulmonary fibrosis.

Pulse transit time (PTT) is generally assumed to be a surrogate marker for blood pressure changes and arterial stiffness. The aim was to evaluate whether pulmonary PTT (pPTT) may be noninvasively measured by Doppler echocardiography and whether it might be valuable for detecting pulmonary hemodynamic and vascular alterations.