The Roles of Type 2 Cytotoxic T Cells in Inflammation, Tissue Remodeling, and Prostaglandin (PG) D2 Production Are Attenuated by PGD2 Receptor 2 Antagonism.

Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. PGD2 and its receptor PGD2 receptor 2 (DP2) play important roles in Tc2 cell activation, including migration, cytokine production, and survival. In this study, we revealed novel, to our knowledge, functions of the PGD2/DP2 axis in Tc2 cells to induce tissue-remodeling effects and IgE-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue-remodeling genes in Tc2 cells that enhanced the fibroblast proliferation and protein production required for tissue repair and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to TCR-dependent PGD2 production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production, and survival of Tc2 cells triggered by PGD2 but also attenuated the tissue-remodeling effects and autocrine/paracrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding of the role of Tc2 cells in the pathogenesis of asthma.

Complications Associated with Alloplastic Materials in Rhinoplasty and Their Operative Management.

Whereas rhinoplasty with a reduction of the dorsum and modification of the tip is a common procedure among Caucasians, augmentation of the dorsum remains a challenge in Asians. Choice of the ideal grafting material for dorsal augmentation is a matter of preference and remains under discussion. Autologous and alloplastic materials have their advantages and disadvantages. We report our experiences of the extrusion of alloplastic materials and their management. We report of 18 patients, who had rhinoplasty in the past for dorsal augmentation with alloplastic material. Augmentation rhinoplasty was performed in Asia (n = 15) and Germany (n = 3). All cases showed recurrent signs of foreign body infection and/or partial extrusion and therefore underwent revision surgery in our centers. Once all patients had been successfully treated with antibiotics, we performed a one-stage revision rhinoplasty with explantation of the alloplastic material and subsequent reconstruction with autologous rib cartilage. The nasal dorsum was augmented with either solid rib cartilage grafts, diced cartilage in fascia, or free diced cartilage in platelet-rich fibrin. All patients received pre-, peri-, and postoperative antibiotics. The outcome was screened via clinical examination, ultrasound examination pre- and postoperatively, two-dimensional/three-dimensional (3D) imaging, and magnetic resonance imaging scans.Alloplastic augmentation of the nasal dorsum runs the risk of foreign body reaction, recurrent infections, uncontrolled scarring, and unsatisfying long-term results. We have obtained a series of aesthetically and functionally satisfying results after single-stage revision surgery with autologous cartilage and demonstrate a variety of novel postoperative screening tools including 3D imaging and high-frequency ultrasound. LEVEL OF EVIDENCE: N/A.

Prostaglandin D2 metabolites activate asthmatic patient-derived type 2 innate lymphoid cells and eosinophils via the DP2 receptor.

BACKGROUND: Prostaglandin D2 (PGD2) signaling via prostaglandin D2 receptor 2 (DP2) contributes to atopic and non-atopic asthma. Inhibiting DP2 has shown therapeutic benefit in certain subsets of asthma patients, improving eosinophilic airway inflammation. PGD2 metabolites prolong the inflammatory response in asthmatic patients via DP2 signaling. The role of PGD2 metabolites on eosinophil and ILC2 activity is not fully understood. METHODS: Eosinophils and ILC2s were isolated from peripheral blood of atopic asthmatic patients. Eosinophil shape change, ILC2 migration and IL-5/IL-13 cytokine secretion were measured after stimulation with seven PGD2 metabolites in presence or absence of the selective DP2 antagonist fevipiprant. RESULTS: Selected metabolites induced eosinophil shape change with similar nanomolar potencies except for 9α,11ß-PGF2. Maximal values in forward scatter of eosinophils were comparable between metabolites. ILC2s migrated dose-dependently in the presence of selected metabolites except for 9α,11ß-PGF2 with EC50 values ranging from 17.4 to 91.7 nM. Compared to PGD2, the absolute cell migration was enhanced in the presence of Δ12-PGD2, 15-deoxy-Δ12,14-PGD2, PGJ2, Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2. ILC2 cytokine production was dose dependent as well but with an average sixfold reduced potency compared to cell migration (IL-5 range 108.1 to 526.9 nM, IL-13 range: 125.2 to 788.3 nM). Compared to PGD2, the absolute cytokine secretion was reduced in the presence of most metabolites. Fevipiprant dose-dependently inhibited eosinophil shape change, ILC2 migration and ILC2 cytokine secretion with (sub)-nanomolar potencies. CONCLUSION: Prostaglandin D2 metabolites initiate ILC2 migration and IL-5 and IL-13 cytokine secretion in a DP2 dependent manner. Our data indicate that metabolites may be important for in vivo eosinophil activation and ILC2 migration and to a lesser extent for ILC2 cytokine secretion.

[Dorsal preservation septorhinoplasty]. / Die nasenrückenerhaltende "Dorsal-Preservation"-Septorhinoplastik.

BACKGROUND: Nasal dorsum deprojection is a very important tool in functional and aesthetic rhinoplasty. In classic techniques, resection of dorsal bone and cartilage renders dorsal reconstruction necessary. The concept of dorsal preservation rhinoplasty has been known for more than a century but has experienced a renaissance in recent years, with many critical technical modifications. MATERIALS AND METHODS: We present the latest technique of piezo-assisted dorsal preservation rhinoplasty with subdorsal triangular resection and subdorsal Cottle modification based on clinical experience of 205 cases. Furthermore, the advantages and disadvantages of this technique are discussed and several other current variations are presented. RESULTS AND DISCUSSION: Piezo-assisted osteotomy enables a very precise fracture line and sparing of periosteum, with bone sculpting possible even after mobilization. Subdorsal septal height reduction always precedes completion of the osteotomy and nasal bone mobilization, to ensure patient safety with regard to skull base injury. Using the presented technical modifications, the risk of step deformities in the radix is minimized. In selected patients, dorsal preservation septorhinoplasty enables the surgeon to perform very conservative and precise deprojection of the nose with excellent outcomes, although the spectrum of possible complications is shifted in comparison to classic techniques. CONCLUSION: The preliminary experience of 205 cases with a revision rate of less than 10% is promising. A final evaluation of the technique will only be possible after further studies and evaluation of long-term results.

A Study of the Effect of Cyclosporine on Fevipiprant Pharmacokinetics and its Absolute Bioavailability Using an Intravenous Microdose Approach.

This drug-drug interaction study determined the effect of cyclosporine, an inhibitor of organic anion transporting polypeptide (OATP) 1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant as well as mechanistic insights into its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios [90% confidence interval (CI)] for oral fevipiprant with or without cyclosporine were 3.02 (2.38, 3.82) for C max, 2.50 (2.17, 2.88) for AUClast, and 2.35 (1.99, 2.77) for AUCinf The geometric mean ratios (90% CI) for fevipiprant intravenous microdose with or without cyclosporine were 1.04 (0.86, 1.25) for C max, 2.04 (1.83, 2.28) for AUClast, and 1.95 (1.76, 2.16) for AUCinf The absolute bioavailability for fevipiprant was approximately 0.3 to 0.4 in the absence and 0.5 in the presence of cyclosporine. The intravenous microdose allowed differentiation between systemic and presystemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) presystemic effect of cyclosporine and a larger (approximately twofold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant, whereas P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT: The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied intravenous microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic drug-drug interaction understanding.

Increased type 2 inflammation post rhinovirus infection in patients with moderate asthma.

Rhinovirus (RV) infections are a major cause of exacerbations in patients with asthma. Experimental RV challenges can provide insight into the pathophysiology of viral exacerbations. Previous reports, investigating mild or moderate asthma patients, have shown an upregulation in type 2 inflammation post RV infection, however, studies specifically involving asthma patients taking inhaled corticosteroids have concentrated on symptoms and lung function, rather than the inflammatory response. Eleven moderate asthma patients were inoculated with RV. Cold symptoms and asthma control were assessed at baseline and post infection. Nasal epithelial lining fluid and bronchial alveolar lavage (BAL) fluid were collected at baseline and 4 days post infection for assessment of inflammatory proteins. Patients suffered increased cold symptoms and decreased asthma control within 7 days of infection. Antiviral mechanisms were induced following inoculation, with increases in interferon -α, ß, γ and λ, as well as CXCL10 and CXCL11. Type 2 inflammatory cytokines were also significantly elevated post RV infection in both nasal and bronchial samples. In BAL, epithelial derived IL-25 and IL-33 levels strongly correlated with Th2 cytokines, IL-4, IL-5 and IL-13. We show how experimental rhinovirus challenge regulates lung and nasal biomarkers in asthma patients taking inhaled corticosteroids. These biomarkers could be used to evaluate the effects of novel drugs for asthma.

Omalizumab normalizes the gene expression signature of lesional skin in patients with chronic spontaneous urticaria: A randomized, double-blind, placebo-controlled study.

BACKGROUND: Omalizumab, a humanized recombinant monoclonal anti-IgE antibody, proved to be effective in patients with chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU. Here, we report omalizumab's effect on gene expression in skin biopsies from CSU patients enrolled in a double-blind, placebo-controlled study. METHODS: Chronic spontaneous urticaria patients (18-75 years) were randomized to either 300 mg omalizumab (n = 20) or placebo (n = 10) administered s.c. every 4 weeks for 12 weeks (NCT01599637). Lesional and nonlesional skin biopsies were collected from the same area of consenting patients and assessed at baseline and on Day 85 compared with skin biopsies from the same area of 10 untreated healthy volunteers (HVs). Gene expression data were generated using Affymetrix HG-U133Plus2.0 microarrays. Statistical analyses were performed using R packages. RESULTS: At baseline, 63 transcripts were differentially expressed between lesional and nonlesional skin. Two-thirds of these lesional signatures were also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, >75% of lesional signatures changed to reflect nonlesional skin expression levels (different vs placebo, P < 0.01). Transcripts upregulated in lesional skin (vs nonlesional and/or HV skin) suggested increased mast cell/leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8, and S100A9), increased oxidative stress, vascularization (CYR61), and skin repair events (KRT6A, KRT16). Lesional signatures were not modulated by treatment in nonresponders (defined based on UAS7 longitudinal changes ≥16). CONCLUSION: Omalizumab, in treatment responders, reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/HV expression levels; this is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU.

Treatment-induced changes of lymphocyte subsets in patients with adenoid cystic carcinoma of the head and neck.

PURPOSE: Adenoid cystic carcinoma (ACC) of the head and neck is a rare and highly malignant tumor, characterized by perineural growth and early distant metastases. The composition of immune cells in the peripheral blood and the tumor microenvironment is critical to tumor growth and control. However, little is known about the frequency and function of the relevant immune cell subsets in this entity. METHODS: In ACC patients (n = 11) and matched healthy donors (n = 11), the frequency of peripheral blood T and B cells was measured by flow cytometry at different treatment stages of disease (24 samples). Cells were further characterized by their expression of CCR7, PD-1, CD39 and CD73. Tumor-infiltrating lymphocytes (TIL) were analyzed by immunohistochemistry for ten patients and for three patients by flow cytometry. RESULTS: CD4+ T cells had significantly lower frequency after radiotherapy (RT). All other cell frequencies, including Treg, were stable through course of the disease. In B cells, CD73 was reduced after RT. CCR7 expression on T and B cells in patients with relapse/metastases (R/M) differed significantly from patients with active disease. PD-1 remained stable. Treg were more present in TIL compared to peripheral blood. CONCLUSION: Composition of lymphocyte subgroups behaves similar to squamous cell carcinoma in the head and neck, except for Treg, which remained stable. Nevertheless, the CD4+/Treg ratio was lower after RT, which could stand for an immunosuppressive effect in these patients. Therefore, it could be beneficial treating ACC with combined RT and immunomodulatory drugs.

The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation.

Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response.Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in asthma.

Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro.

Fevipiprant is a novel oral prostaglandin D2 receptor 2 (DP2; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [14C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.

Treatment of ear keloids: algorithm for a multimodal therapy regimen.

Keloids are benign cutaneous lesions, arising from proliferating fibroblasts. Keloids of the ear may occur after trauma, surgery or helix piercings and are difficult to treat, since they tend to form recurrences. Guidelines suggest multimodal therapy; however, recurrence rates remain high and distinct algorithms for the combination of different modalities are missing. To unravel the most effective combination of therapeutic options for keloids of the ear, 38 patients with the diagnosis of an ear keloid were included in our cohort. In a prospective subgroup (B) of this cohort (n = 17), patients either underwent surgery using the "fillet technique" (a meticulous peeling of the keloid skin) and intra-lesional injections of triamcinolone 10 mg/ml every 4-6 weeks for 6 months, or they were additionally treated with a non-customized pressure device which was recommended for at least 16/24 h per day over 6 months. To further compare our results, the remaining 21 patients of our cohort, who were treated at our clinic before, were retrospectively evaluated concerning their recurrence rates. The mean follow-up was 48 months. The mean count of adjuvant steroid injections was two in all patients, four in subgroup B. The recurrence rate was 30% (13/38) in all patients (subgroup B 0/17). Aesthetic results were good to excellent in all non-recurrent cases. No patient treated with fillet technique showed recurrence (p < 0.001). However, we could not confirm a significant effect but a trend of repeated steroid injections for preventing recurrences (p = 0.099). The application of pressure using our non-customized clip also showed a clear trend towards preventing recurrences in cross-table analysis (p = 0.057). Although several studies on different treatment regimens for keloids of the ear exist, the effectiveness of a multimodal treatment regimen needs to be elucidated. Overall, the best results in preventing recurrences were achieved by combining three different treatments. However, the fillet technique was the only modality preventing recurrences of keloids in uni- and multivariate analysis. The application of pressure with a non-customized clip and repeated steroid injections also showed a positive trend but failed level of significance. Based on our data and the literature we recommend, when feasible, the combination of more than one therapeutic regimen, since relapse risk went down from single to dual and triple therapy from 40% (8/20) to 14.3% (2/14) to 0% (0/4), respectively in our cohort. The use of "fillet technique" was especially beneficial.

[The 8th edition of the AJCC Cancer Staging Manual : Updates in otorhinolaryngology, head and neck surgery]. / Die 8. Ausgabe der TNM­Klassifikation : Neuerungen für das Fachgebiet Hals­Nasen­Ohren­Heilkunde, Kopf- und Halschirurgie.

BACKGROUND: The TNM system is an established tool for classification of solid tumors by means of tumor size and extent, the involvement of local lymph nodes, and the presence of distant metastases. The classification was established in order to visualize prognostic implications and to allow establishment of systematic therapeutic algorithms. Since the beginning of 2017 a revised version of the classification has applied. Particularly the classification of otorhinolaryngologic tumors has been thoroughly revised in the 8th edition, partly on the basis of new prognostically relevant parameters, such as infection with oncogenic human papillomavirus (HPV) subtypes. MATERIALS AND METHODS: The 8th edition of the American Joint Committee on Cancer (AJCC) served as a basis for the review. The highlighted changes were supplemented by a literature review and the most important elements were summarized. RESULTS: Substantial changes were made for oropharyngeal carcinomas caused by HPV, for the classification of lymph node metastases under consideration of extranodal extension, and for classification of tumors of the oral cavity. Due to their frequency and special biology, skin tumors in the head and neck area are now described in a separate chapter. CONCLUSION: The new classification is a challenge for all specialties involved in tumor staging and therapy. The advantage for the patient lies in a more accurately adjustable treatment modality through more precise classification of tumors. Good collaboration and rapid implementation of the new classification is required in all disciplines involved in head neck tumor diagnostics and therapy.

[Nasal turbinate surgery]. / Nasenmuschelchirurgie.

The nose forms the first 8 cm of the upper respiratory tract and is responsible for cleansing, humidification, and temperature control of the supplied air. This is also referred to as conditioning. The nasal valve region, formed by the head of the lower nasal concha, portions of the cartilaginous septum, and the upper lateral cartilage, is responsible for diffusing and accelerating the respiratory airflow. Prerequisite are regular mucociliary clearance and sufficient air passage. Hypertrophy of the lower nasal turbinate is one of the most common causes of symptomatic nasal congestion. In unclear cases, rhinometric procedures are available. In addition to conservative therapy of allergic or vasomotor rhinitis by specific immunotherapy or topical corticoids, numerous interventional procedures are available to reduce conchal tissue. All modern methods have a high degree of protection of the respiratory mucosa in common.

The oral CRTh2 antagonist QAW039 (fevipiprant): A phase II study in uncontrolled allergic asthma.

BACKGROUND: There is an unmet medical need for allergic asthma patients who are uncontrolled on conventional therapies. The aim of this study was to collect efficacy and safety data for QAW039, an oral chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist, for the treatment of asthma. METHODS: This was an exploratory phase II, double-blind, randomized, placebo-controlled multi-center study. Patients with mild-to-moderate uncontrolled allergic asthma (N = 170) were either without or weaned off inhaled corticosteroids (ICS) and long-acting ß-agonists (LABA) and randomized (1:1) to QAW039 (500 mg once daily) or to placebo for 28 days. RESULTS: Overall, 157 patients completed the study. There were no significant differences between QAW039 and placebo for trough forced expiratory volume in 1 s (FEV1) or Asthma control questionnaire (ACQ) in the total population. Subgroup analyses demonstrated that patients with a FEV1 <70% of predicted at baseline treated with QAW039 had significant improvement compared with placebo in trough FEV1 (QAW039- Placebo [Δ] = 207 mL; 90% confidence interval [CI]: 96, 319; P = 0.002) and ACQ7 (Δ = -0.41; 90%CI: -0.69, -0.13; P = 0.009). QAW039 reached a mean maximum concentration (Cmax) of 3440 ng/mL on day 28 at a median Tmax of 1 h (range 0.5-4 h). Most adverse events (AEs) were mild/moderate and balanced between both groups, with no serious AEs. CONCLUSIONS: In the general study population, no improvement in lung function was observed with QAW039. However, a subgroup analysis revealed that patients with greater severity of airflow limitation (FEV1 < 70%) had improved lung function and asthma control when treated with QAW039. QAW039 also demonstrated a favorable safety profile. TRIALS REGISTRATION: ClinicalTrials.govNCT01253603.

The impact of chemotherapy for breast cancer on sexual function and health-related quality of life.

PURPOSE: In this prospective trial, we evaluated the influence of chemotherapy for breast cancer on women's health-related quality of life (HR-QoL), sexual function, and mental status. METHODS: The patients completed validated questionnaires on HR-QoL, sexual function, and depression before, during, and at the end and finally 6 months after chemotherapy. Special attention was paid to possible differences between pre- and postmenopausal patients. RESULTS: Between 2008 and 2012, 79 patients were enrolled in the trial (mean age 47.46 years). Premenopausal participants were 63.3 %. Sexual activity dropped from 71.9 % before chemotherapy to a minimum of 47 % at the end of chemotherapy. A similar effect was seen for pleasure and discomfort. Depression values were the highest at the beginning of chemotherapy, with spontaneous improvement in many patients during the course of time. HR-QoL and global health status both increased 6 months after therapy. For almost all parameters, changes were more obvious in pre- than in postmenopausal patients. CONCLUSIONS: In a close monitoring, we observed significant changes in HR-QoL, depression, and sexual function in breast cancer patients. Special attention needs to be paid to premenopausal patients. The knowledge of effective recovery and spontaneous improvement of HR-QoL in spite of still impaired sexuality are important information in counseling both pre- and postmenopausal patients with diagnosis of breast cancer prior to upcoming therapy.

Exacerbation of atopic dermatitis on grass pollen exposure in an environmental challenge chamber.

BACKGROUND: It has frequently been speculated that pruritus and skin lesions develop after topical exposure to aeroallergens in sensitized patients with atopic dermatitis (AD). OBJECTIVE: We sought to study cutaneous reactions to grass pollen in adult patients with AD with accompanying clear IgE sensitization to grass allergen in an environmental challenge chamber using a monocenter, double-blind, placebo-controlled study design. METHODS: Subjects were challenged on 2 consecutive days with either 4000 pollen grains/m(3) of Dactylis glomerata pollen or clean air. The severity of AD was assessed at each study visit up to 5 days after challenge by (objective) scoring of AD (SCORAD). Additionally, air-exposed and non-air-exposed skin areas were each scored using local SCORAD scoring and investigator global assessments. Levels of a series of serum cytokines and chemokines were determined by using a Luminex-based immunoassay. The primary end point of the study was the change in objective SCORAD scores between prechallenge and postchallenge values. RESULTS: Exposure to grass pollen induced a significant worsening of AD. A pronounced eczema flare-up of air-exposed rather than covered skin areas occurred. In grass pollen-exposed subjects a significantly higher increase in CCL17, CCL22, and IL-4 serum levels was observed. CONCLUSIONS: This study demonstrates that controlled exposure to airborne allergens of patients with a so-called extrinsic IgE-mediated form of AD induced a worsening of cutaneous symptoms.

[Autologous composite grafts from the cavum conchae for reconstruction of multilayer nasal defects]. / Das autologe Haut-Knorpel-Transplantat aus dem Cavum conchae zur Rekonstruktion mehrschichtiger nasaler Defekte.

BACKGROUND: Autologous transplants comprising skin and cartilage, so-called composite grafts (cgs), are an important reconstructive tool for multilayered defects of the nose. A cg from the auricular cavum conchae needs to fulfill both functional and esthetic demands. OBJECTIVE: This article illustrates the indications for and requirements of cgs, and also investigates graft healing and functional-aesthetic results. The current publication is a review article; the original data were published with the award of the 2014 APKO prize under the title "The auricle's cavum conchae composite graft in nasal reconstruction". MATERIALS AND METHODS: At the ENT department of Ulm University Medical School, multilayered defects of different nasal esthetic subunits are reconstructed with cgs. Based on these experiences, the authors report on long-term functional and esthetic results in the areas of the donor and recipient sites. CONCLUSION: Auricular cgs are versatile and reliable autologous transplants. The ease of harvesting, minimal donor site morbidity, and stable convex shape of these grafts render them ideal for reconstruction of multilayered nasal defects. Septal splints and custom-made prosthesis promote healing and prevent stenotic scarring.

Oncologic treatment landscape for head and neck squamous cell carcinoma : Treatment infrastructure in German-speaking countries.

BACKGROUND: The treatment of head and neck squamous cell carcinoma (HNSCC) is highly complex and requires a multimodal approach. However, guidelines for the treatment of most forms of HNSCC do not exist in German-speaking countries with the exception of oral cavity cancer. The aim of this cross-sectional study was to describe the current treatment landscape and infrastructure in German-speaking countries. METHODS: From November 2013 to July 2014, 204 departments of otorhinolaryngology (ORL) in Germany, Austria, and the German-speaking part of Switzerland were contacted and invited to take part in a web-based survey on the treatment of HNSCC. In order to cover the study in its entirety, we published three consecutive papers of which this paper is the first. RESULTS: In all, 62 treatment centers (30.4 %) participated in the survey. These centers included 21 university hospitals, 16 certified cancer centers, and 35 large centers, which diagnose at least 75 HNSCC patients annually. In 91.9 % of all cases, there were outpatient consultation hours (that were monodisciplinary in 61.4 %). A multidisciplinary tumor board was existent in 98.4 % of the cases. Of 62 ORL departments, 50 had a hospital cancer registry, 41 of 62 conducted oncological studies, and 35 of 62 assessed their patients' quality of life. CONCLUSION: The infrastructure of the treatment for HNSCC can be considered mostly well-developed and supports interdisciplinary cooperation. Potential improvements can be made regarding the standardization of tumor boards, the participation in clinical trials, and the availability of cancer registries and the data gathered therein.

Palliative treatment standards for head and neck squamous cell carcinoma : Survey of clinical routine in German-speaking countries.

BACKGROUND: The EXTREME (Erbitux in First-Line Treatment of Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma) protocol is generally considered the gold standard in palliative first-line treatment. However, there is some disagreement about its effectivity, toxicity, and applicability in daily clinical routine. The purpose of this cross-sectional survey was to describe the palliative treatment offered in German-speaking countries. METHODS: From November 2013 to July 2014, 204 departments of otorhinolaryngology (ORL) in Germany, Austria, and the German-speaking parts of Switzerland were contacted and invited to take part in a web-based survey on the treatment of HNSCC. RESULTS: In all, 62 of 204 treatment centers (30.4 %) participated in the survey. Of these, 58 departments offered palliative systemic therapy to their patients; 19 of 58 (32.8 %) treated patients undergoing palliative chemotherapy in their own ORL departments, while 40 of 58 (69 %) upheld a cooperation with medical oncologists in the same hospital and 24 of 58 (41.4 %) with medical oncologic practices. Many of these treatment centers offered multiple locations for treatment. Of the 58 departments, 56 provided an institutional standard for first-line palliative treatment, 13 for second-line, and two for third-line treatment. In 42 of 58 departments the EXTREME protocol was the institutional standard of care for first-line treatment. Moreover, 12 of 58 departments mentioned an individual protocol and two of 58 the inclusion in clinical trials as their local standard. The assessment of patients who could be treated with the first-line standard ranged from 0 to 95 % with a mean of 44.5 %. CONCLUSION: Palliative systemic therapy seems to be well standardized for first-line treatment, whereas there is little standardization in second- and third-line treatments. A large variation was found regarding the estimate of the applicability of the institutional standard. Reasons for this could be the physicians' individual experience as well as the varying assessment regarding the toxicity of palliative systemic therapy.

[Primary Parotid Carcinoma: Influence of a Two-step Procedure on the Oncological Outcome]. / Primäre Parotiskarzinome: Einfluss einer zweizeitigen Operation auf das onkologisches Outcome.

BACKGROUND: Malignancies of the parotid gland represent a rare form of head and neck cancer. Advanced stages are usually recognized as such, whereas early tumor stages are sometimes diagnosed only after parotidectomy due to lack of signs of malignancy. The present study investigates whether this unplanned 2-stage approach has a negative impact on the outcome. MATERIAL AND METHODS: The study includes clinical and histological data of patients with parotid cancer which were treated in the Department of Oto-Rhino-Laryngology and Head and Neck Surgery of the University Medical Center Ulm between 2004 and 2014. RESULTS: 42 patients were included into the study with a median follow-up of 38 months. The RFS and OS at 5 years was 68.6 and 80.1%, respectively, which corresponds to the current literature. 24/42 patients received one-step radical surgery. In 18/42 patients a parotidectomy was performed initially followed by oncologic surgery after receiving histology. The patient group with 2-stage surgery included less advanced tumor stages and more entities with better prognosis. Interestingly, these patients presented with an excellent RFS of 84.4% compared to 56,5% (p=0,16) in the patient group with one-step procedure, correspondent to the tumor stages, entities and the current literature. CONCLUSIONS: According to the available data and compared to the literature, an unplanned 2-stage procedure in clinically silent parotid cancer seems not necessarily to have a negative impact on the outcome. Nevertheless, the preoperative diagnosis should be improved to detect these malignancies more sensitive in early stages.