Bronchodilator Reversibility in the GAN Severe Asthma Cohort.

BACKGROUND AND OBJECTIVE: Positive bronchodilator reversibility (BDR) is a diagnostic criterion for asthma. However, patients with asthma may exhibit a negative BDR response. Aim: To describe the frequency of positive and Negative BDR response in patients with severe asthma and study associations with phenotypic characteristics. METHODS: A positive BDR response was defined as an increase in FEV1 >200 mL and >12% upon testing with a short-acting ß-agonist. RESULTS: BDR data were available for 793 of the 2013 patients included in the German Asthma Net (GAN) severe asthma registry. Of these, 250 (31.5%) had a positive BDR response and 543 (68.5%) a egative BDR response. Comorbidities significantly associated with a negative response were gastroesophageal reflux disease (GERD) (28.0% vs 40.0%, P<.01) and eosinophilic granulomatosis with polyangiitis (0.4% vs 3.0%; P<.05), while smoking history (active: 2.8% vs 2.2%; ex: 40.0% vs 41.7%) and comorbid chronic obstructive pulmonary disease (COPD) (5.2% vs 7.2%) were similar in both groups. Patients with a positive BDR response had worse asthma control (median Asthma Control Questionnaire 5 score, 3.4 vs 3.0, P<.05), more frequently reported dyspnea at rest (26.8% vs 16.4%, P<.001) and chest tightness (36.4% vs 26.2%, P<.001), and had more severe airway obstruction at baseline (FEV1% predicted, 56 vs 64, P<.001) and higher fractional exhaled nitric oxide (FeNO) levels (41 vs 33 ppb, P<0.05). There were no differences in diffusion capacity of the lung for carbon monoxide, single breath (% pred, 70% vs 71%). Multivariate linear regression analysis identified an association between positive BDR response and lower baseline FEV1% (P<.001) and chest tightness (P<.05) and a negative association between BDR and GERD (P<.05). CONCLUSION: In this real-life setting, most patients with severe asthma had a negative BDR response. Interestingly, this was not associated with smoking history or COPD, but with lower FeNO and presence of GERD.

Rhesus CE expression on patient red blood cells is an independent prognostic factor for adenocarcinoma of the lung.

OBJECTIVES: The influence of blood group antigens on cancerogenesis is shown for distinct tumor types, yet the impact of Rhesus blood group antigens in lung cancer is not clarified. MATERIALS AND METHODS: To investigate the impact of Rhesus blood groups a non-small cell lung cancer (NSCLC) collective (n = 1047) was analyzed retrospectively. Using a second cohort of n = 340 primarily operated stage I-III NSCLC patients, we evaluated immunohistochemistry of CD47-antibody stained tissue samples in correlation to histopathologic subtype and Rhesus blood group. RESULTS AND CONCLUSION: In 516 of 1047 patients blood group data were available. Seven different RhCE phenotypes were grouped as "··ee," "ccE·," and "C·E·." Adenocarcinoma patients with Rh "··ee" revealed improved overall survival (29 (21.2-36.8) m; HR 1.00 [index]) compared with Rh "ccE·" (19 (1.9-36.1) m; HR 1.76 [1.15-2.70]) and Rh "C·E·" (10 (7.4-12.6) m; HR 2.65 [1.70-4.12]) univariately (P < .001) and multivariately (P < .001). Rh "··ee" showed reduced incidence of CNS-metastasis (P = .014) and metastasis count (P = .032) in stage IV adenocarcinoma. Immunohistochemistry associated CD47-positivity with adenocarcinomas (n = 340, P = .048). In n = 51 cases blood group data were available. The prognostic effect of Rh "··ee" compared with Rh "ccE·" and Rh "C·E·" was stated (P = .001), foremost in CD47-positive adenocarcinomas (Rh "··ee" vs. Rh "ccE·" and Rh "C·E·," P = .008). Inversely Rh "ccE·" or Rh "C·E·" was found beneficial in CD47-negative non-adenocarcinomas (P = .046). Phenotypic RhCE expression may be an independent prognostic factor for overall survival in adeno-NSCLC. We hypothesize an erythrocytic-immunologic interaction with tumor tissue, possibly altered by RhCE and CD47, resulting in a metastatic prone condition.

Integrated care pathways for airway diseases (AIRWAYS-ICPs).

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

[German guideline for diagnosis and management of idiopathic pulmonary fibrosis]. / S2K-Leitlinie zur Diagnostik und Therapie der idiopathischen Lungenfibrose.

Idiopathic pulmonary fibrosis is a fatal lung disease with a variable and unpredictable natural history and limited treatment options. Since publication of the ATS-ERS statement on IPF in the year 2000 diagnostic standards have improved and a considerable number of randomized controlled treatment trials have been published necessitating a revision. In the years 2006 - 2010 an international panel of IPF experts produced an evidence-based guideline on diagnosis and treatment of IPF, which was published in 2011. In order to implement this evidence-based guideline into the German Health System a group of German IPF experts translated and commented the international guideline, also including new publications in the field. A consensus conference was held in Bochum on December 3rd 2011 under the protectorate of the "Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP)" and supervised by the "Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften" (AWMF). Most recommendations of the international guideline were found to be appropriate for the german situation. Based on recent clinical studies "weak negative" treatment recommendations for pirfenidone and anticoagulation were changed into "weak positive" for pirfenidone and "strong negative" for anticoagulation. Based on negative results from the PANTHER-trial the recommendation for the combination therapy of prednisone plus azathiorpine plus N-acetlycsteine was also changed into strong negative für patients with definite IPF. This document summarizes essential parts of the international IPF guideline and the comments and recommendations of the German IPF consensus conference.

Kalanchoe pinnata inhibits mast cell activation and prevents allergic airway disease.

Aqueous extract of Kalanchoe pinnata (Kp) have been found effective in models to reduce acute anaphylactic reactions. In the present study, we investigate the effect of Kp and the flavonoid quercetin (QE) and quercitrin (QI) on mast cell activation in vitro and in a model of allergic airway disease in vivo. Treatment with Kp and QE in vitro inhibited degranulation and cytokine production of bone marrow-derived mast cells following IgE/FcɛRI crosslinking, whereas treatment with QI had no effect. Similarly, in vivo treatment with Kp and QE decreased development of airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and production of IL-5, IL-13 and TNF. In contrast, treatment with QI had no effect on these parameters. These findings demonstrate that treatment with Kp or QE is effective in treatment of allergic airway disease, providing new insights to the immunomodulatory functions of this plant.

Safety and tolerability of omalizumab.

BACKGROUND: Omalizumab (Xolair) is a recombinant humanized monoclonal anti-IgE antibody with proven efficacy in patients with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma. OBJECTIVE: To review clinical study data to assess the safety profile of omalizumab. METHODS: We analysed the safety of omalizumab using data from completed clinical studies (up to 1 year) involving more than 7500 patients with asthma, rhinitis or related conditions and up to 4 years in one study of patients with severe allergic asthma, as well as post-marketing safety data. Analysis focuses on the risk of immune-system effects, hypersensitivity reactions, malignant neoplasia, parasitic infections and thrombocytopenia. RESULTS: Omalizumab exhibited a good safety and tolerability profile that was maintained up to 4 years in one study. The incidence of anaphylaxis was 0.14% in omalizumab-treated patients and 0.07% in control patients. No omalizumab-treated patient developed measurable anti-omalizumab antibodies. Post-marketing, based on estimated exposure of 57,300 patients (June 2003-December 2006), the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2% of patients. Current clinical trial data do not support an increased risk of malignant neoplasia or thrombocytopenia with omalizumab. CONCLUSION: Data indicate that the proven efficacy of add-on omalizumab in patients with moderate-to-severe or severe allergic asthma is accompanied by a favourable safety and tolerability profile.

[Hemorrhagic pericardial effusion and multiple pulmonary nodules in a 37 year old male who has "never smoked"]. / Hämorrhagischer Perikarderguss mit multiplen pulmonalen Rundherden bei einem 37-jährigen "Nie-Raucher"

Even people which have never smoked can develop lung cancer. In this population a mutation in the exons 19-21 of the Epidermal Growth Factor Receptor (EGFR) can be detected. For this patient group targeted therapies with EGFR tyrosinkinase inhibitors are available. In this case report we describe a 37 year old non-smoker who developed a non-small cell lung cancer. Following therapy with Erlotinib a partial response could be achieved.

Vertebral artery decompression in a patient with rotational occlusion.

We report a patient who suffered drop attacks during head reclination. Computer tomography of the cervical spine demonstrated a stenotic right vertebral artery at C4/5. However, Doppler ultrasonography of the vertebral artery showed no abnormality. Angiography confirmed complete occlusion of the left vertebral and a stenosis of the right vertebral artery. Dynamic angiography indicated occlusion of the stenotic region on the right side during reclination of the head. Surgery using a posterior approach with decompression of the vertebral artery, lead to an excellent outcome and the patient left the hospital without any symptoms. Therefore, in patients with drop attacks and normal ultrasonography, a stenosis of the vertebral artery caused by a spondylophytic compression could still be the cause. At worst, the stenosis could lead to brain infarction if left untreated. Dynamic angiography is crucial for the diagnosis and surgical decompression has excellent results.

Mast cell-derived tumour necrosis factor is essential for allergic airway disease.

Mast cells are thought to contribute to allergic airway disease. However, the role of mast cell-produced mediators, such as tumour necrosis factor (TNF), for the development of allergic airway disease is unclear. In order to define the role of mast cells in acute allergic airway disease two strains of mast cell-deficient mice (Kit(W/Wv) and Kit(W-sh/W-sh)) were studied. Compared with their wild-type littermates, Kit(W/Wv) and Kit(W-sh/W-sh) mice developed significantly lower airway responsiveness to methacholine and less airway inflammation and goblet cell metaplasia, following sensitisation in the absence of adjuvant and airway challenge. Transfer of bone marrow-derived mast cells (BMMCs) from wild-type mice to Kit(W-sh/W-sh) mice reconstituted both airway responsiveness and inflammation to levels similar to those in sensitised and challenged wild-type mice. In contrast, sensitised Kit(W-sh/W-sh) mice reconstituted with BMMCs from TNF-deficient mice were still severely impaired in their ability to develop airway hyperresponsiveness, inflammation or goblet cell metaplasia following allergen challenge. The present results demonstrate the significance of mast cells in the development of airway disease and highlight the importance of mast cell-derived tumour necrosis factor in these responses.

Multidisciplinary interobserver agreement in the diagnosis of idiopathic pulmonary fibrosis.

The purpose of the present study was to evaluate the accuracy of the diagnosis of idiopathic pulmonary fibrosis (IPF) by respiratory physicians in six European countries, and to calculate the interobserver agreement between high-resolution computed tomography reviewers and histology reviewers in IPF diagnosis. The diagnosis of usual interstitial pneumonia (UIP) was assessed by a local investigator, following the American Thoracic Society/European Respiratory Society consensus statement, and confirmed when a minimum of two out of three expert reviewers from each expert panel agreed with the diagnosis. The level of agreement between readers within each expert panel was calculated by weighted kappa. The diagnosis of UIP was confirmed by the expert panels in 87.2% of cases. A total of 179 thoracic high-resolution computed tomography scans were independently reviewed, and an interobserver agreement of 0.40 was found. Open or thoracoscopic lung biopsy was performed in 97 patients, 82 of whom could be reviewed by the expert committee. The weighted kappa between histology readers was 0.30. It is concluded that, although the level of agreement between the readers within each panel was only fair to moderate, the overall accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis in expert centres is good (87.2%).

Reversibility of venous sinus obstruction in idiopathic intracranial hypertension.

Elevated intracranial intravenous pressure seems to be of importance in pseudotumor cerebri syndromes, either as a cause (secondary intracranial hypertension) or as a consequence (idiopathic intracranial hypertension) of increased intracranial pressure. We present 3 case reports in which diagnostic imaging before and after CSF diversion provided evidence that narrowing of the transverse sinuses is a secondary phenomenon. Stent angioplasty of the venous sinuses should not be considered a therapeutic approach in these cases.

MR spectroscopy in patients with intracranial meningiomas.

With magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS), we tried to get more pre-operative information in patients with suspicious meningioma concerning the histologic diagnosis especially regarding WHO Grades I and II meningiomas. Apart from the known spectra and metabolites such as choline, creatine and N-acetyl-aspartate (NAA), recent publications have shown that lactate is often found in necrotic tumor tissue. Within a 2 year period, 39 patients with an intracranial meningioma were studied with MRS. In 62.5% of histologic atypical meningiomas (WHO Grade II), a lactate peak could be demonstrated in the pre-operative MRS. Interestingly, also patients with multiple meningiomas show different spectra of their tumors.

Unusual locations for cavernous hemangiomas: report of two cases and review of the literature.

Cavernous hemangiomas are most commonly found within the subcortical neural parenchyma near the fissura Rolandi, in the basal ganglia, or in the brain stem. Because of advancing neuro-imaging technology and thus resulting in a higher incidence of cavernous hemangiomas they have rising impact in neurosurgery. We present two unusual cases of extra-axial cavernous hemangiomas: one located at the frontal falx, the other within the bone of the right frontal bone. We discuss these and other cases in the literature with respect to the more common differential diagnoses and the appropriate therapy regimen for cavernous hemangiomas in these locations.

Metastatic meningioma WHO grade II of the cervical spine: case report and review of the literature.

The authors report a rare case of metastatic atypical meningioma WHO grade II involving the dorso-lateral region of the cervical spine and causing spinal cord compression in a 76-year-old man. The patient was treated surgically in June 1998 for an atypical parasagittal meningioma in the right frontal lobe. Local recurrence with extension to the left hemisphere required surgical treatment in January 2000, and in December 2000 recurrence caused paraplegia of the lower extremities and paresis of the left arm. A 3 (rd) operation was carried out in January 2001, followed by radiotherapy with a total dose of 45 Gy. The patient presented again in March 2003 because of pain in the neck and a progredient new paresis and paresthesia of the right arm. Computed tomogram of the cervical spine showed a large tumor with compression of the spinal cord. MRI was not possible due to a pacemaker which had been implanted in the meantime. Surgical subtotal removal of the tumor via hemilaminectomy of the 3 (rd) and 4 (th) cervical vertebrae was performed. After decompression of the cervical spine the paresis of the right arm improved, the paraplegia of the legs and the left arm, existing since December 2000, remained unchanged. Histological findings of the cranial lesions and the metastatic lesion had a similar appearance and were compatible with atypical meningioma (WHO grade II).

Glutathione and glutathione peroxidase in sputum samples of adult patients with cystic fibrosis.

BACKGROUND: Reduced glutathione (GSH) is a major antioxidant in the lung. In cystic fibrosis (CF) patients, extracellular GSH levels of lower airways, obtained by bronchoalveolar lavage (BAL), were reported to be lower than non-CF individuals. METHODS: Upper airway secretions of stable adult CF patients (29 spontaneous and 13 induced sputum) and non-CF individuals (14 healthy and 12 asthmatics; all induced sputum) were analyzed for total glutathione (i.e. the sum of reduced, GSH, and oxidized, GSSG, forms), GSH and GSSG levels by enzymatic kinetic assay. RESULTS: In CF, both spontaneous and induced sputum samples were comparable in total glutathione levels which were surprisingly high (median concentration of 9.2 (range 1.4-65.2) and 11.6 (1.1-69.8) microM, respectively). In non-CF individuals, total glutathione levels were significantly lower (healthy 2.8 (1.0-12.3), asthmatics (5.3 (1.3-19.2) microM; p<0.001, both vs. CF). In CF, more than 90% of total glutathione was represented by GSH, whereas in non-CF controls, GSH made up less than 50% of total glutathione (p<0.001). CONCLUSIONS: In contrast to BAL, CF sputum contains high levels of GSH. Sputum induction is a potentially useful procedure to monitor antioxidant levels in upper airways of CF patients.

[Paraneoplastic limbic encephalitis in small cell lung carcinoma]. / Paraneoplastische limbische Enzephalitis bei kleinzelligem Bronchialkarzinom.

We report about a 63-year-old male patient who complained of a recent onset of confusion. A mediastinal mass had been detected in his chest X-ray three days before admission to our clinic. Surprisingly, a CT scan of the brain revealed no signs of cerebral masses or oedema. MRI demonstrated bright hyperintens signals in the medial aspect of both temporal lobes. Biopsy by mediastinoscopy showed small cell lung carcinoma (SCLC). No distant metastases were found by staging procedures. Cerebrospinal fluid and serum contained antineuronal antibodies (anti-Hu). The combination of symptoms, MRI findings and paraneoplastic antibodies established the diagnosis of paraneoplastic limbic encephalitis in a patient with SCLC. Chemotherapy combined with immunosuppression by corticosteroids was started immediately. The primary tumour responded to therapy but improvement of cerebral symptoms was unsatisfactory. Severe memory loss and personality changes remained unchanged while there was a slight improvement in confusion and hallucinations.

[Benign fibro-osseous tumors of the frontal skull base with intracranial extension. Report of 2 cases]. / Gutartige fibroossäre Tumoren der frontalen Schädelbasis mit intrakranieller Ausbreitung. Bericht über 2 Fälle.

We report on two patients with ossifying fibroma of the anterior skull base with intracranial extension. A psammomatoid ossifying fibroma was removed from a 29 year old female patient, and in a 37 year old female patient a cemento ossifying fibroma was removed. The main clinical symptom in both cases was headache. Surgery took place after diagnosis and therapy in an interdisciplinary operation with ENT colleagues. The ossifying fibroma is a benign neoplasm mainly affecting the maxilla and mandible. Complete removal is better than a curettage of the tumor.