[German Guideline for Idiopathic Pulmonary Fibrosis]. / S2K-Leitlinie zur Diagnostik der idiopathischen Lungenfibrose.

Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease. Diagnosis of IPF requires considerable expertise and experience. Since publication of the international IPF guideline in the year 2011 and Update 2018 several studies and technical advances occurred, which made a new assessment of the diagnostic process mandatory. In view of the antifibrotic drugs which have been approved for the treatment of IPF patients, the goal of this guideline is to foster early, confident and effective diagnosis of IPF. The guideline focusses on the typical clinical setting of an IPF patient and provides tools to exclude known causes of interstitial lung disease including standardised questionnaires, serologic testing and cellular analysis of bronchoalveolar lavage. High resolution computed tomography remains crucial in the diagnostic work-up. If it is necessary to obtain specimen for histology transbronchial lung cryobiopsy is the primary approach, while surgical lung biopsy is reserved for patients who are fit for it and in whom bronchoscopic diagnosis did not provide the information needed. Despite considerable progress, IPF remains a diagnosis of exclusion and multidisciplinary discussion remains the golden standard of diagnosis.

Differential regulation of PD-1 and its ligands in allergic asthma.

BACKGROUND: Targeting PD-1/PD-1 ligand signalling is an established treatment option for cancer. The role of these molecules in allergic asthma has been investigated in several mouse studies yielding conflicting results. However, human studies investigating the expression and regulation of PD-1 and its ligands in allergic inflammation are lacking. OBJECTIVE: To analyse the expression and regulation of PD-1 and its ligands in human allergic asthma. METHODS: The well-established human asthma model of segmental allergen challenge (SAC) was used to analyse the regulation of PD-1 and its ligands PD-L1 and PD-L2 on T lymphocytes and dendritic cells by flow cytometry. The impact of immunoglobulin E (IgE)-mediated signalling on PD-L1 expression was analysed on isolated plasmacytoid dendritic cells (pDCs). RESULTS: PD-1 expression by blood CD4+ T cells was negatively associated with total and specific (against the allergen used for provocation) IgE serum concentrations. Twenty-four hours after SAC, a small decrease in endobronchial PD-1+ CD4+ T cells was accompanied by an increase in PD-L1 expression on endobronchial myeloid dendritic cells (mDCs) and pDCs. The PD-L1 up-regulation on pDCs was not induced by IgE-mediated mechanisms. In contrast, PD-L2 was only detected on endobronchial mDCs and was significantly down-regulated 24 hours after SAC. CONCLUSION AND CLINICAL RELEVANCE: This study shows, for the first time, an association of a low PD-1 expression by circulating CD4+ T cells with high total and specific (against the allergen used for provocation) IgE concentrations in allergic asthma. In addition, we demonstrate a differential regulation of PD-1 ligands on endobronchial DCs after allergen challenge which may favour Th2 inflammation. Therefore, modulating PD-1 ligand-mediated pathways might be a promising target in allergic asthma.

[IgE and Anti-IgE in Asthma: A Chequered History]. / IgE und Anti-IgE bei Asthma: eine wechselvolle Geschichte.

A long and winding road led to the discovery of immunoglobulin E (IgE) in 1966 and 1967. We are currently on a long and winding road to understand the immunologic basis of the clinical effects of the anti-IgE antibody omalizumab in asthma. It is possible that patients with asthma (as patients with chronic spontaneous urticaria) benefit in different immunologic ways from omalizumab treatment. This article reviews the history of IgE discovery and current concepts of anti-IgE therapy in asthma.

[Not Available]. / Chirurgie im Rachen - Adenotomie, Tonsillektomie, Tonsillotomie und Eingriffe bei obstruktivem Schlafapnoe-Syndrom.

Surgery in the pharynx belongs to the most frequent otorhinolaryngological procedures. Adenoidectomy and tonsillectomy are amongst the most frequent surgeries at all and belong to the first procedures which are performed by otorhinolaryngology residents during their specialist training. Therefore, it is essential to study early during the specialist training the most frequent pharyngeal procedures, surgical techniques, complications and outcome. A series of excellent clinical trials and meta-analyses have been published in the recent year demonstrating that adenoidectomy is an important therapy element in pediatric otorhinolaryngology. In particular due to the developments in the field of laser surgery, tonsillotomy could experience a revival in the recent years. The indication spectrum is still widening. There are many fields where clinical trials are needed to proof if tonsillotomy is as effective as tonsillectomy but with the advantage of lower morbidity. There are manifold pharyngeal surgical procedures to treat patients with obstructive sleep apnea. These surgical techniques have proved valuable especially as alternative to conservative therapy and in case of treatment failure under airway pressure therapy. As the obstruction during this type of sleep-related respiratory disorder is often not located at one anatomical site, an individual combination of several pharyngeal and other surgeries are needed for an effective treatment of the patient. The present article gives an overview of the most important pharyngeal surgeries for future otorhinolaryngologists under specialist training.

[Optimal Postoperative Pain Management After Tonsillectomy: An Unsolved Problem]. / Optimale Schmerztherapie nach Tonsillektomie: ein ungelöstes Problem.

Tonsillectomy is one of the most painful surgical procedures. Unfortunately, it is not unusual that the patient hear statement like: "There is no way around" or "You receive already enough pain killers". Asking the anesthetist or the otorhinolaryngologist, one may get to hear: "Pain after tonsillectomy is not a real problem. We have a reliable pain management protocol". In contradiction, many clinical studies are showing that many patients have persistent and even severe pain after tonsillectomy despite postoperative pain therapy. Considering the results of many controlled clinical trials analyzing manifold varieties of pain management regimes it becomes obvious that there is no standard pain therapy after tonsillectomy with reliable proof of sufficient pain suppression. This review wants to give an overview on the current status of clinical research on pain measurement methods and pain management after tonsillectomy.

[Allergic rhinitis in the context of chronic rhinosinusitis]. / Allergische Rhinitis im Kontext der chronischen Rhinosinusitis.

Chronic Rhinosinusitis is one of the most frequent chronic diseases. A major cause is allergic rhinitis. Both illnesses and the combination of both, which is the topic of this educational article, as well as the clarification and therapy of differential diagnoses are belonging in the hands of the otorhinolaryngologist. Finally, it is not completely understood which mechanisms of the allergic inflammation in the nose lead or predispose in the individual patient to the development of a chronic sinus disease. A series of excellent national and international guidelines have been published supporting the otorhinolaryngologist in diagnostics and treatment of patients with allergic rhinosinusitis. This article presents the most important and actual diagnostic and therapeutic procedures for the treatment of this important chronic disease in children and adults.

Neuralgic amyotrophy associated with temporary vocal fold paralysis: successful treatment by vocal fold augmentation with hyaluronic acid.

BACKGROUND: Neuralgic amyotrophy is a polyneuropathy that classically involves the brachial plexus. This paper reports an unusual clinical manifestation associated with vocal fold paralysis. CASE REPORT: A 36-year-old male presented with hoarseness and progressive weakness of the right shoulder and upper arm muscles. Laryngoscopy revealed a limited adduction of the right vocal fold. RESULTS: Subsequent speech therapy did not improve the symptoms. Therefore, vocal fold augmentation by application of hyaluronic acid in the right vocal fold was performed. CONCLUSION: Vocal fold augmentation with resorbable material seems to be a more effective transient treatment than speech therapy alone for patients with neuralgic amyotrophy and laryngeal involvement.

Population-based analysis of tonsil surgery and postoperative hemorrhage.

Although tonsil surgery is one of the most frequent otorhinolaryngological procedures, not many population-based regional or country-wide studies are published on the incidence of postoperative bleeding and its risk factors. 2,216 patients underwent tonsil surgery in 2012 in Thuringia, a federal state in Germany. Most frequent indications were recurrent tonsillitis (44 % of all cases), tonsillar abscess (27 %), and tonsillar hyperplasia (20 %). 29 % of the patients were <10 years of age. Most frequent methods of surgery were tonsillectomy (73 %) and tonsillotomy (19 %). 215 patients (10 %) had 221 events of a postoperative hemorrhage. Re-surgery for hemostasis was necessary in 137 patients (6 %). The interval to re-surgery was 4.4 ± 4.6 days. The re-surgery rate was 8, 0.2, and 15 % after tonsillectomy, tonsillotomy, and radical tonsillectomy, respectively. In cases of recurrent tonsillitis, male gender (p < 0.001), age >24.78 years (median; (p = 0.018), and waiving of perioperative antibiotics (p = 0.029) were independent factors associated with hemorrhage. In cases of tonsillar hyperplasia tonsillectomy instead of tonsillotomy, the only significant risk factor was postoperative hemorrhage (p = 0.005). The overall incidence of tonsillar surgery was 87.6/100,000. The highest incidence was seen for patients 3-4 years of age with 862.7/100,000. In children <10 years, the incidence was always higher for boys than for girls. Throughout all age groups, a reverse gender relation was only seen, if surgery was indicated for recurrent tonsillitis. We recommend establishing national guidelines for indication of tonsil surgery, especially of tonsillectomy, including recommendations for perioperative care to decrease variations in tonsil surgery rates and minimize postoperative complications.

Lupus anticoagulant and thrombosis in splenic marginal zone lymphoma.

INTRODUCTION: Splenic marginal zone lymphoma (SMZL) is a rare low-malignant Non-Hodgkin lymphoma (NHL), in which immune mediated paraneoplastic phenomena such as autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common. MATERIALS AND METHODS: We performed a multicenter retrospective study in 70 patients on the prevalence and clinical features of antiphospholipid antibodies (aPLA) in SMZL. RESULTS AND CONCLUSIONS: Nine patients (13%) had the diagnosis of a lupus anticoagulant (LA). The occurrence of venous thromboembolic events was significantly higher in LA positive patients compared to LA negative patients (4/9 [44%] vs 5/61 [8%], p = 0.002), especially within 12 months after splenectomy (3/6 [50%] vs 2/28 [7%], p = 0.007). None of the patients with LA had a persistent complete remission of LA after splenectomy, but complete remission of LA was achieved in 2/2 patients after rituximab-bendamustine immuno-chemotherapy. In conclusion, our data show a relatively high prevalence of aPLA in SMZL and an increased risk of postsplenectomy thrombosis in these patients. The fact that rituximab-bendamustine was effective for eradicating LA may be considered as an argument for using immuno-chemotherapy as first line therapy in SMZL patients with LA.

Olfactory training for patients with olfactory loss after upper respiratory tract infections.

Olfactory training consisting of daily suprathreshold odor exposure over 12 weeks seems to improve olfactory function. It is unknown if a longer period of training might be more effective. A prospective non-randomized clinical study was performed including 39 patients with olfactory loss after an upper respiratory tract infection (URTI) of less than 24 months duration. Patients exposed themselves with suprathreshold concentrations of four odors (rose, eucalyptus, lemon, cloves) applied in ''Sniffin' Sticks'' felt-tip pens over 32 weeks. Olfactory function was performed before (T1), after 16 weeks (T2), and 32 weeks of training (T3) using the 'the Sniffin' Sticks test kit calculating the TDI score (Threshold, Discrimination, Identification). The mean TDI score showed a non-significant trend of improvement at T2, and was significantly increased at T3 (p = 0.021). Overall, 31 patients (79%) showed an increased TDI score at T3. The increase of TDI from T1 to T3 was 4.6 ± 5.1. Age, gender, duration and initial severity of olfactory loss had no influence on the improvement (all p > 0.05). Only patients with a D score lower than the median value of 8 showed a significantly higher increase of the D score at T3 (p = 0.004). The present study confirmed that olfactory training improves olfactory function in patients with olfactory loss after URTI. A longer duration of training over 32 weeks seems to increase the effectiveness in comparison to a 12-week period. This was tested in a completed German multicenter trial to be published soon containing a control group to include the effect of a spontaneous recovery after URTI.

In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

INTRODUCTION: Chemotherapy for advanced well-differentiated carcinoids is characterised by low response rates and short duration of responses. The present study aimed to assess the in vitro activity of novel platinum-based chemotherapeutic drugs in combination with dichloroacetate (DCA), a sensitiser to apoptosis, against lung carcinoid cell lines. METHODS: Three permanent cell lines (UMC-11, H727 and H835) were exposed to 14 different established cytotoxic drugs and the novel platinum-based compounds as satraplatin, JM118 and picoplatin in combination with DCA, and viability of the cells was measured using a tetrazoliumbased dye assay. RESULTS: With exception of the highly chemoresistant UMC- 11 line, the carcinoid cell lines (H727, H835) were sensitive to the majority of chemotherapeutics in vitro. Among the platinum-based drugs, carboplatin and oxaliplatin showed highest efficacy. H835 cells growing as multicellular spheroids were 2.7-8.7-fold more resistant to picoplatin, satraplatin and its metabolite compared to single cell suspensions. DCA (10 mM) inhibited the growth of UMC- 11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4-2.4-fold. CONCLUSION: The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs (AU)

Organic Anion Transporting Polypeptide 5A1 (OATP5A1) in Small Cell Lung Cancer (SCLC) Cells: Possible Involvement in Chemoresistance to Satraplatin.

BACKGROUND: The role of organic anion transporting polypeptide 5A1 (OATP5A1) a member of a family of drug transporters that mediate cellular uptake of drugs has not been characterized so far. METHODS: Gene expression levels of OATP5A1 in small cell lung cancer (SCLC) cell lines were determined by real-time qPCR and chemosensitivity of HEK-293-SLCO5A1-transfected cells to satraplatin in MTT assays. RESULTS: Significant expression of this transporter was found at the mRNA level, primarily in drug-resistant SCLC cells, and SLCO5A1-transfected HEK-293 cells showed higher resistance to satraplatin. OATP5A1 is found preferentially in cytoplasmic membranes of tumor cells, including SCLC. CONCLUSIONS: OATP5A1 seems to effect intracellular transport of drugs and may participate in chemoresistance of SCLC by sequestration, rather than mediating cellular uptake. Since satraplatin failed to improve survival in SCLC patients, the relation of OATP5A1 expression to clinical drug resistance and its use as marker of chemoresistance should be further investigated.

Clinical and prognostic significance of histamine monitoring in patients with CML during treatment with imatinib (STI571).

BACKGROUND: Although imatinib is highly effective in chronic myeloid leukemia (CML), drug-resistance may occur. Therefore, monitoring of minimal residual disease (MRD) during treatment with imatinib is important. However, most MRD-parameters are expensive and require special technology. We determined the value of histamine as MRD-marker in CML. PATIENTS AND METHODS: Histamine levels were measured serially in whole blood samples before and during imatinib therapy in 80 CML patients by radioimmunoassay. RESULTS: Histamine levels were highly upregulated in CML at diagnosis compared to healthy controls, and correlated with the presence of basophils. During treatment with imatinib, histamine levels decreased and returned to normal levels in those achieving a complete cytogenetic response (CCR). Loss of CCR during therapy was invariably accompanied by an increase in histamine. Moreover, a histamine level of >100 ng/ml three or six months after start of imatinib was associated with a significantly reduced probability of survival (p<0.05). Whereas basophils were found to correlate well with histamine during imatinib, no correlations were found between histamine and Ph+ metaphases or histamine and BCR/ABL. CONCLUSION: Histamine-monitoring during treatment with imatinib is of prognostic significance.

Human leukaemic stem cells: a novel target of therapy.

Acute myeloid leukaemia (AML) is a life-threatening haematopoietic disease that is characterized by clonal growth and the accumulation of myelopoietic progenitor cells. Although AML cells only have a limited potential to undergo differentiation and maturation, each AML clone is organized in a hierarchical manner similar to normal haematopoiesis. Recent data have shown that each AML clone consists of leukaemic stem cells and their progeny, and that AML stem cells differ from more mature cells in several aspects, including survival and target antigen profiles. Most importantly, AML stem cells, but not their progeny, have the capacity to repopulate haematopoietic tissues with leukaemias in NOD/SCID mice. Furthermore, AML stem cells are thought to be responsible for the infinite growth of leukaemias in patients with AML. The phenotypic properties of AML stem cells have also been described. In most cases, these cells are detectable within the CD34+, CD38-, Lin-, CD123+ subpopulation of AML cells. Because of their AML-initiating and -renewing capacity and their unique phenotype, which includes several molecular targets of drug therapy, AML stem cells have recently been proposed as novel important target cell populations in the context of curative therapies. The present article gives an overview of our knowledge about AML stem cells, their phenotype, and their role as a 'therapy-target' in new concepts to treat and to cure patients with AML.