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Radiogenic side effects are frequently seen in patients undergoing radiotherapy for head and neck tumors. Intensified dental and mucosal care reduce oral hygienic deficits. The aim of this study was the optimization of mouth hygiene using dexpanthenol rinsing solution applied with a dental waterjet system (DWS). 30 consecutive head and neck tumor patients (44–75 years) were analyzed, who received intensity-modulated radiation treatment (IMRT; total dose range: 54–66 Gy) with helical Tomotherapy HiArt II. The group under investigation (n = 10) additionally received a professional DWS using dexpanthenol mouthrinse (Bepanthen). The first control group received dexpanthenol mouthrinse alone. The second control group only performed the standardized mouth hygiene protocol. Grade of xerostomia, taste, dysphagia, thrush, and mucositis was evaluated on a daily basis. 29 of 30 patients completed radiation therapy. Change in taste occurred in all patients in all groups, however, with a delay in the study group. The occurrence of grade III stomatitis and Xerostomia grade II was significantly reduced in the study arm. No patient suffered from grade III xerostomia in the study arm versus four patients in the control groups. Dysphagia grade II was observed significantly less frequent in the study group (p = 0.0004). Thrush occurrence showed a delay in the study group. Our study underlines the importance of an intensified mouth hygiene during radiation therapy. The combination of dexpanthenol rinsing solution + DWS reduces the incidence of high-grade early side effects which often lead to a reduced quality of life and abortion of the treatment.

Purpose: Recurrent tumors (RT) of head and neck squamous cell carcinoma (HNSCC) occur in up to 60%, with poor therapeutic response and detrimental prognosis. We hypothesized that HNSCC RTs successfully evade antitumor immune response and aimed to reveal tumor immune microenvironment (TIME) changes of primary tumors (PT) and corresponding RTs. Experimental Design: Tumor-infiltrating leukocytes (TIL) of 300 PTs and 108 RTs from two large independent and clinically well-characterized HNSCC cohorts [discovery cohort (DC), validation cohort (VD)] were compared by IHC. mRNA expression analysis of 730 immune-related genes was performed for 18 PTs and RTs after adjuvant chemoradiotherapy (CRT). The effect of chemotherapy and radiation resistance was assessed with an in vitro spheroid/immunocyte coculture model. Results: TIME analysis revealed overall decrease of TILs with significant loss of CD8+ T cells (DC P = 0.045/VC P < 0.0001) and B lymphocytes (DC P = 0.036/VC P < 0.0001) in RTs compared with PTs in both cohorts. Decrease predominantly occurred in RTs after CRT. Gene expression analysis confirmed loss of TILs (P = 0.0004) and B lymphocytes (P < 0.0001) and showed relative increase of neutrophils (P = 0.018), macrophages (P < 0.0001), dendritic cells (P = 0.0002), and mast cells (P = 0.0057) as well as lower overall expression of immune-related genes (P = 0.018) in RTs after CRT. Genes involved in B-lymphocyte functions and number of tertiary lymphoid structures showed the strongest decrease. SPP1 and MAPK1 were upregulated in vivo and in vitro, indicating their potential suitability as therapeutic targets in CRT resistance. Conclusions: HNSCC RTs have an immunosuppressive TIME, which is particularly apparent after adjuvant CRT and might substantially contribute to poor therapeutic response and prognosis.

// Alina Franzen 1 , Timo J. Vogt 1 , Tim Muller 2 , Jorn Dietrich 1 , Andreas Schrock 1 , Carsten Golletz 2 , Peter Brossart 3 , Friedrich Bootz 1 , Jennifer Landsberg 4 , Glen Kristiansen 2 and Dimo Dietrich 1 1 Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany 2 Institute of Pathology, University Hospital Bonn, Bonn, Germany 3 Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany 4 Department of Dermatology, Bonn, University Hospital Bonn, Germany Correspondence to: Dimo Dietrich, email: dimo.dietrich@gmail.com Keywords: PD-L1; PD-1; PD-L2; CD274; PDCD1LG2 Received: May 31, 2017 Accepted: November 15, 2017 Published: December 07, 2017 ABSTRACT Background: DNA methylation of the immune checkpoint gene PD-L1 has recently been shown to be associated with PD-L1 mRNA expression in various malignancies. This study aimed to investigate the association of PD-L1 and PD-L2 methylation with mRNA expression, immune cell infitration, protein expression and human papilloma virus (HPV) infection in head and neck squamous cell carcinoma (HNSCC) patients. Results: DNA methylation of PD-L1 and PD-L2 correlates inversely with mRNA expression ( PD-L1 : p ≤ 0.002; PD-L2 : p ≤ 0.014). Methylation of specific CpG-sites of both PD-L1 and PD-L2 were further significantly associated with HPV infection in the TCGA cohort. Immune cell infiltrates correlated significantly with PD-L1 and PD-L2 methylation. In the validation cohort, PD-L1 protein expression was associated with PD-L1 hypomethylation ( p = 0.012). Conclusions: DNA methylation of PD-L1 and PD-L2 is associated with transcriptional silencing and HPV infection in HNSCCs. Additional studies are warranted to test PD-L1 and PD-L2 methylation as predictive biomarkers for response to immunotherapies (e.g. pembrolizumab and nivolumab) that target the PD-L1/ PD-L2/PD-1 immune checkpoint axis. Materials and Methods: PD-L1 and PD-L2 promoter methylation and its mRNA expression were analyzed based on Infinium HumanMethylation450 BeadChip and RNA-Seq (both Illumina, Inc.) data in a representative HNSCC patient cohort ( n = 528) enrolled by The Cancer Genome Atlas (TCGA) Research Network. A validation cohort consisting of 168 HNSCC patients treated at the University Hospital Bonn was analyzed regarding PD-L1 and PD-L2 promoter methylation by means of methylation-specific quantitative real-time PCR. PD-L1 protein expression in the validation cohort was quantified via immunohistochemistry (PD-L1 antibody clone 22C3, Dako/Agilent Technologies, Inc.).

Gefasverschliesende Masnahmen neuroradiologischer Interventionen sind ein wichtiges und hilfreiches Werkzeug in der Behandlung verschiedener Erkrankungen im Kopf-Hals-Bereich. Diese interventionellen Masnahmen erfolgen einerseits in kurativer Intention, zur Reduktion des Operationsrisikos im Rahmen eines multimodalen Therapiekonzepts oder auch zur Verbesserung oder zumindest zum Erhalt einer guten Lebensqualitat. Essenziell fur die erfolgreiche Behandlung ist neben dem Verstandnis der Erkrankung das Wissen um die Gefasanatomie sog. gefahrlicher Anastomosen zwischen extra- und intrakraniellen Gefasen und der Einsatz geeigneter Techniken und Materialien. Indikationen fur einen transarteriellen Gefasverschluss sind einerseits unkontrollierbare Blutungen unterschiedlicher Genese (traumatisch, vaskulare Malformation, Tumor), andererseits die Reduktion des intraoperativen Blutverlusts bei hypervaskularisierten Tumoren durch eine praoperative Embolisationsbehandlungen und drittens die Induktion einer Tumornekrose zur regionalen Tumorkontrolle im Rahmen palliativer Embolisationen. Gravierende Komplikationen wie z. B. Schlaganfall, Erblindung und Hirnnervenlahmungen sind nicht selten auf eine unzureichende prainterventionelle Evaluation zuruckzufuhren. Bei Interventionen im Versorgungsgebiet der A. carotis externa liegt die Komplikationsrate fur schwere neurologische Defizite unter 1 %.

// Verena Sailer 1, 2, * , Emily Eva Holmes 3, * , Heidrun Gevensleben 3 , Diane Goltz 3 , Freya Droge 4 , Luka de Vos 6 , Alina Franzen 6 , Friederike Schrock 5 , Friedrich Bootz 6 , Glen Kristiansen 3 , Andreas Schrock 6, † , Dimo Dietrich 3, 6, † 1 Weill Medical College of Cornell University and New York Presbyterian Hospital, Department of Pathology and Laboratory Medicine, New York, NY, USA 2 Weill Medical College of Cornell University and New York Presbyterian Hospital, Englander Institute for Precision Medicine, New York, NY, USA 3 Institute of Pathology, University Hospital of Bonn, Bonn, Germany 4 Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany 5 Department of Addictive Disorders and Addiction Medicine, LVR Hospital Bonn, Bonn, Germany 6 University Hospital Bonn, Department of Otolaryngology, Head and Neck Surgery, Bonn, Germany * These authors have contributed equally to this work † These authors are joined senior authors on this work Correspondence to: Dimo Dietrich, email: dimo.dietrich@gmail.com Keywords: PITX2, biomarker, head and neck squamous cell carcinoma, DNA methylation, PANCR Received: July 25, 2016 Accepted: September 20, 2016 Published: October 3, 2016 ABSTRACT Background: Squamous cell carcinoma of the head and neck region (HNSCC) is a common malignant disease accompanied by a high risk of local or distant recurrence after curative-intent treatment. Biomarkers that allow for the prediction of disease outcome can guide clinicians with respect to treatment and surveillance strategies. Here, the methylation status of PITX2 and an adjacent lncRNA ( PANCR ) were evaluated for their ability to predict overall survival in HNSCC patients. Results: PITX2 hypermethylation was associated with a better overall survival (hazard ratio, HR = 0.51, 95%CI: 0.35-0.74, p

6551 Background: Immune cell (IC) infiltrates in primary tumors (PT) have been identified as prognostic markers in head and neck squamous cell carcinoma (HNSCC). IC densities may differ among PT, lymph node metastasis (LNM) and recurrent disease (RD) and by primary disease site (oral cavity- OC, oropharynx- OP, hypopharynx- HP, larynx- L). Here, we compare CD3 and CD20 IC densities in PT, LNM and RD in paired samples from different disease sites and determine the prognostic impact of IC infiltrates. Methods: Tissue microarrays with 425 PT, 198 LNM and 46 RD samples--each in triplicate--were stained immunohistochemically for CD3 and CD20 in the same slide. Immune cell densities per mm2 were determined using a digital image analysis software (QuPath). Individual means were calculated from triplicates of each sample. IC infiltrates from different sample types (PT, LNM, RD) and primary tumor sites were compared using Kruskal-Wallis and Mann-Whitney-U tests. Paired samples were compared using Wilcoxon signed rank test. IC densities were classified as CD3 high/low and CD20 high/low for each primary tumor site using the individual median as a cut-off. Overall survival (OS) was calculated using the Kaplan-Meier method. P-values for each hypothesis were corrected using a false discovery rate of 5%. Results: CD3 and CD20 IC densities differed significantly by sample type (both p0.05). CD3 densities were significantly higher than CD20 densities in all sample types. CD3high patients had the best prognosis in all sites except for OC (qlow/CD20high patients had the worst OS compared to CD3low/CD20low and CD3high/CD20high or even CD3high/CD20low patients (p=0.018) who had the best prognosis. Conclusions: IC densities of CD3 and CD20 vary by sample type and primary site. Except for OC, in all sites the prognostic impact is determined by CD3high, whereas in OSCC only the combination of CD3 and CD20 IC densities achieves a good prognostic value. Interestingly, CD3low/CD20high patients have the worst overall survival in OC patients. Further work is needed to understand the interaction of B- and T cell infiltrates in the tumor, especially in OC.

Head and neck squamous cell carcinoma (HNSCC) progression depends on various dysregulated pathways. Regulation of diverse pathways is mediated by the mediator complex. The mediator subunit MED15 is essential for transforming growth factor (TGF)-β signaling and involved in breast and prostate cancers. We investigated the implication of MED15 in HNSCC. IHC for MED15 was performed on 324 tissue samples, and TGF-β assessed the use of Ki-67 and pSMAD3 as markers. MED15 knockdown followed by proliferation and migration assays, as well as TGF-β1 treatment followed by MED15 analysis, was also performed. MED15 was overexpressed in 35% of primary tumors, 30% of lymph node metastases, and 70% of recurrences in contrast to no or low expression in benign tumors. MED15 overexpression in primary tumors from patients who developed recurrences was associated with higher mortality rates and occurred at highest frequency in oral cavity or oropharyngeal tumors. Furthermore, MED15 expression correlated between primary tumors and corresponding lymph node metastases. MED15 correlated with proliferation in tissues, and MED15 knockdown reduced proliferation and migration. We observed an association between MED15 and TGF-β activity in tissues because TGF-β activation led to increased MED15 expression and reduced pSMAD3 on MED15 knockdown. Taken together, our results implicate MED15 in HNSCC and hint that MED15 overexpression is a clonal event during HNSCC progression. MED15 may serve as a prognostic marker for recurrence and as a therapeutic target.

Molecular biomarkers assisting risk-group assignment and subsequent treatment stratification are urgently needed for patients with squamous cell cancer of the head and neck region (HNSCC). Aberrant methylation is a frequent event in cancer and, therefore, a promising source for potential biomarkers. Here, the methylation status of the paired-like homeodomain transcription factor 3 (PITX3) was evaluated in HNSCC. Using a quantitative real-time PCR, PITX3 methylation was assessed in a cohort of 326 HNSCC patients treated for localized or locally advanced disease (training cohort). The results were validated with Infinium HumanMethylation450 BeadChip data from a 528 HNSCC patient cohort (validation cohort) generated by The Cancer Genome Atlas (TCGA) Research Network. PITX3 methylation was significantly higher methylated in tumor compared to normal adjacent tissue (NAT; training cohort: median methylation NAT 32.3%, tumor 71.8%, p

Recently, the fibroblast growth factor receptor 1 (FGFR1) has been identified as the first actionable target in squamous cell lung cancer. Clinical trials testing specific FGFR inhibitors are in progress, and patients are selected based on their FGFR1 gene copy number status. Fluorescent in situ hybridization is the most commonly used method for detecting FGFR1 amplifications, but it has its limitations. In this paper, we describe a new non-fading and easy to assess assay for detecting FGFR1 amplification using a combination of chromogenic and silver in situ hybridization. We assessed 394 patients diagnosed with head and neck squamous cell carcinoma with the new assay and compared the results with those obtained by FGFR1 fluorescent in situ hybridization. We could assess copy number by the fluorescent in situ hybridization in 86.8 % (342/394) of cases, whereas with chromogenic and silver in situ hybridization, this was 79.4 % (313/394). By fluorescent in situ hybridization, a FGFR1 amplification was detected in 12.6 % (43/342) of cases, a low-level amplification (LLA) in 7.6 % (26/342) and a high-level amplification (HLA) in 5.0 % (17/342). By chromogenic and silver in situ hybridization, a FGFR1 amplification was found in 10.2 % (32/313) (5.7 % LLA, 4.5 % HLA). The two techniques showed highly concordant results (Pearson’s correlation coefficient = 0.971, p

BACKGROUND Circulating cell-free DNA methylation testing in blood has recently received regulatory approval for screening of colorectal cancer. Its application in other clinical settings, including staging, prognosis, prediction, and recurrence monitoring is highly promising, and of particular interest in head and neck squamous cell carcinomas (HNSCCs) that represent a heterogeneous group of cancers with unsatisfactory treatment guidelines. METHODS Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) DNA methylation in plasma from 649 prospectively enrolled patients (training study: 284 HNSCC/122 control patients; testing study: 141 HNSCC/102 control patients) was quantified before treatment and longitudinally during surveillance. RESULTS In the training study, 59% of HNSCC patients were methylation-positive at 96% specificity. Methylation levels correlated with tumor and nodal category (P < 0.001). Initially increased methylation levels were associated with a higher risk of death [SEPT9: hazard ratio (HR) = 5.27, P = 0.001; SHOX2: HR = 2.32, P = 0.024]. Disease recurrence/metastases were detected in 47% of patients up to 377 days earlier compared to current clinical practice. The onset of second cancers was detected up to 343 days earlier. In the testing study, sensitivity (52%), specificity (95%), prediction of overall survival (SEPT9: HR = 2.78, P = 0.022; SHOX2: HR = 2.50, P = 0.026), and correlation with tumor and nodal category (P CONCLUSIONS Methylation testing in plasma is a powerful diagnostic tool for molecular disease staging, risk stratification, and disease monitoring. Patients with initially high biomarker levels might benefit from intensified treatment and posttherapeutic surveillance. The early detection of a recurrent/metastatic disease or a second malignancy could lead to an earlier consecutive treatment, thereby improving patients' outcomes.

// Tim Muller 1, * , Martin Braun 1, * , Dimo Dietrich 1 , Seher Aktekin 1 , Simon Hoft 1 , Glen Kristiansen 1 , Friederike Goke 2 , Andreas Schrock 2 , Johannes Bragelmann 3 , Stefanie A.E. Held 3 , Friedrich Bootz 2, * and Peter Brossart 3, * 1 Institute of Pathology, University Hospital Bonn, Bonn, Germany 2 Department of Otorhinolaryngology/Head and Neck Surgery, University Hospital Bonn, Bonn, Germany 3 Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany * These authors have contributed equally to this work Correspondence to: Peter Brossart, email: Peter.Brossart@ukb.uni-bonn.de Keywords: PD-L1, prognostic biomarker, head and neck squamous cell carcinoma, immunohistochemistry Received: December 14, 2016 Accepted: March 17, 2017 Published: May 02, 2017 ABSTRACT Background: The PD-1 receptor and its ligands PD-L1 and PD-L2 are known to be significantly involved in T-cell regulation. Recent studies suggest that PD-L1 expression in malignant tumors contributes to an immunosuppressive microenvironment and disruption of antitumoral immune response. Drugs targeting this pathway are already tested in clinical trials against several tumor entities with promising results. However, until now comprehensive data with regard to PD-L1 and PD-L2 expression in head and neck squamous cell carcinoma (HNSCC) is still lacking. Patients and methods: We assessed PD-L1 and PD-L2 expression via immunohistochemistry in two independent cohorts of 293 HNSCC patients. Results: A significant subset of HNSCC showed high expression levels of PD-L1. Most remarkable, we detected a strong correlation between PD-L1 expression and overall survival time in both HNSCC cohorts. Further, in multivariate cox proportional hazard models, PD-L1 dominates as the strongest prognostic factor of patient’s outcome in HNSCC, leaving even tumor stage and distant metastasis behind. Moreover, strong PD-L1 expression was associated with the presence of distant metastases in a subset of cases. Conclusions: In summary, while the significance of PD-L2 in HNSCC seems to minor, we show that PD-L1 expression is common in HNSCC and, more importantly, a both robust and strong prognostic biomarker. In this respect, our results provide hints on further application of therapies targeting the PD-1/PD-L1 pathway in HNSCC. Investigation of response and outcome of patients receiving anti-PD-1/PD-L1 containing therapies in correlation with PD-L1 expression analysis should be an important task for the future. STATEMENT OF TRANSLATIONAL RELEVANCE In spite of improved treatment options and increasing knowledge of molecular alterations in HNSCC, the survival rate has not been dramatically changed in the past decades. Pies are missing in HNSCC. One promising candidate in cancer immune therapy is PD-L1. Drugs targeting PD-L1 or its receptor PD-1 are subject of several clinical studies in different cancer entities. However, comprehensive data about PD-L1 expression in HNSCC and therefore a rational basis for anti PD-L1/PD-1 therapy in HNSCC is lacking. Here, we provide wide-ranging data about PD-L1 expression in HNSCC of all major localizations. We observed a strong correlation between expression of PD-L1 and reduced overall survival time. Furthermore, high PD-L1 expression was identified as a strong prognostic factor of patient’s outcome when verified together with recognized prognostic factors.

BACKGROUND/AIM: Ectopic myoglobin (MB) expression, mediated by alternative and hypoxia-inducible transcription, has recently been demonstrated in several epithelial tumours. This study aimed to examine the expression of MB in hormone-independent head and neck squamous cell carcinomas (HNSCCs). PATIENTS AND METHODS: Using imunohistochemistry, ectopic MB expression was analyzed on tissue microarrays (TMAs) of 524 patients with localized and locally advanced primary and recurrent HNSCC who had undergone surgical treatment with curative intent. Associations of MB expression with survival and clinicopathological parameters were analyzed. RESULTS: MB expression was found in 45.8% of HNSCC patients being significantly lower in normal adjacent tissue (NAT) compared to primary and recurrent tumours (p

Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge and identification of novel therapeutic targets is necessary. The receptor tyrosine kinase AXL has been implicated in several tumor entities and a selective AXL small molecule inhibitor (BGB324) is currently being tested in clinical trials for patients suffering from non-small cell lung cancer or acute myeloid leukemia. Our study investigates AXL expression during HNSCC progression and its use as a potential therapeutic target in HNSCC. AXL protein expression was determined in a HNSCC cohort (n = 364) using immunohistochemical staining. For functional validation, AXL was either overexpressed or inhibited with BGB324 in HNSCC cell lines to assess proliferation, migration and invasion. We found AXL protein expression increasing during tumor progression with highest expression levels in recurrent tumors. In HNSCC cell lines in vitro, AXL overexpression increased migration as well as invasion. Both properties could be reduced through treatment with BGB324. In contrast, proliferation was neither affected by AXL overexpression nor by inhibition with BGB324. Our patient-derived data and in vitro results show that, in HNSCC, AXL is important for the progression to more advanced tumor stages. Moreover, they suggest that AXL could be a target for precision medicine approaches in this dismal tumor entity.

Contains fulltext : 174819.pdf (Publisher’s version ) (Open Access) Melanoma associated antigens (MAGE) are potential targets for immunotherapy and have been associated with poor overall survival (OS) in head and neck squamous cell carcinoma (HNSCC). However, little is known about MAGE in lymph node metastases (LNM) and recurrent disease (RD) of HNSCC.To assess whether MAGE expression increases with metastasis or recurrence, a tissue microarray (TMA) of 552 primary tumors (PT), 219 LNM and 75 RD was evaluated by immunohistochemistry for MAGE antigens using three monoclonal antibodies to multiple MAGE family members. Mean expression intensity (MEI) was obtained from triplicates of each tumor specimen.The median MEI compared between PT, LNM and RD was significantly higher in LNM and RD. In paired samples, MEI was comparable in PT to respective LNM, but significantly different from RD. Up to 25% of patients were negative for pan-MAGE or MAGE-A3/A4 in PT, but positive in RD. The prognostic impact of MAGE expression was validated in the TMA cohort and also in TCGA data (mRNA). OS was significantly lower for patients expressing pan-MAGE or MAGE-A3/A4 in both independent cohorts.MAGE expression was confirmed as a prognostic marker in HNSCC and may be important for immunotherapeutic strategies as a shared antigen.

Recently, we characterized fibroblast growth factor receptor 1 amplification as a target for a rational therapy in lung squamous cell carcinoma. Patients harboring this genetic event are currently eligible for treatment with antifibroblast growth factor receptor small-molecule inhibitors in phase I clinical trials. This has the potential to significantly improve standard therapy for lung squamous cell carcinoma patients. The aim of this study was to elucidate whether fibroblast growth factor receptor 1 amplification is also a common genetic event in head and neck squamous cell carcinoma. For this purpose, we assembled a cohort of 555 patients, including 264 with metastatic disease and 147 with recurrent disease. Formalin-fixed, paraffin-embedded material of primary tumors, metastases and recurrences were assessed for fibroblast growth factor receptor 1 copy number status using fluorescence in situ hybridization. Human papilloma virus status was detected by p16 immunohistochemistry staining and PCR-ELISA. Molecular parameters were correlated with each other and with clinicopathological data. We found 15% of primary head and neck squamous cell carcinoma to display a fibroblast growth factor receptor 1 amplification. In nearly all cases, metastatic and recurrent tumor samples shared the same amplification status as the corresponding primary tumor. Fibroblast growth factor receptor 1 amplification was associated with nicotine and alcohol consumption, but was mutually exclusive with human papilloma virus infection. Amplification of the gene was associated with parameters of worse outcome. Our data identify fibroblast growth factor receptor 1 amplification as a frequent event in primary and metastatic head and neck squamous cell carcinoma and represents a potential biomarker for more aggressive disease. Fibroblast growth factor receptor 1-amplified tumors could potentially comprise a subset of head and neck squamous cell carcinoma against which targeted small-molecule inhibitors hold therapeutic efficacy.

Das Leitsymptom der intra- und postsakkalen Tranenwegsstenose ist die Epiphora. Aufgrund der Anatomie der Tranenwege, die an der Grenze zwischen den Fachgebieten der Augenheilkunde und der HNO-Heilkunde liegen und aufgrund in den letzten Jahren entwickelter interventionell-radiologischer Techniken stehen unterschiedliche Moglichkeiten der Diagnostik und Therapie von intra- und postsakkalen Tranenwegsstenosen zur Verfugung. Eine interdisziplinare Vorgehensweise hat sich bewahrt. Ergebnisse bei 107 Patienten, die sich im Zeitraum zwischen 2005 und 2011 einer Dakryozystorhinostomie (DCR) nach West unterzogen, werden berichtet. Vor der DCR wurde bei 95 der 107 Patienten eine Dakryozystographie durchgefuhrt. Bei 68 dieser 95 Patienten erfolgte wahrend dieser Masnahme eine langfristig nicht erfolgreiche Ballondilatation der Tranenabflusswege. Bei 64 Patienten wurde das Gewebe histologisch untersucht, was bei 61 Patienten den Nachweis einer Entzundung unterschiedlicher Schweregrade erbrachte. Bei einem Patienten wurde ein Aspergillom und bei zwei Patienten ein Non-Hodgkin-Lymphom diagnostiziert. In einem Nachbeobachtungszeitraum von minimal 6 Monaten bis maximal 7 Jahren wurden bei 15 der 107 Patienten DCR-Revisionen durchgefuhrt, da es nach Entfernung des Silikonschlauchs zu einem Verschluss des Tranensackfensters gekommen war. Bei keinem dieser revidierten Patienten trat erneut Epiphora auf. Die endonasal durchgefuhrte DCR nach West hat im Vergleich zu dem nach Toti beschriebenen extranasalen Verfahren mehrere Vorteile, wie z. B. eine geringere Invasivitat, fehlende sichtbare Narben durch das rein endonasale Vorgehen und der Funktionserhalt der Tranenpumpe. Auserdem besteht die Moglichkeit der Mitbehandlung endonasaler Pathologien in gleicher Operation. In dem hier untersuchten Patientenkollektiv wurden keine gravierenden Komplikationen beobachtet und die Erfolgsrate war mit der ahnlicher Studien vergleichbar.

In der vorliegenden Querschnitts­studie wurden retrospektiv die Patientencharakteristika und die posttherapeutische Lebensqualitat (LQ) nach der Behandlung eines Nasopharynxkarzinoms (NPC) erhoben und ausgewertet. Das Patientenkollektiv umfasst 20 Patienten, die im Zeitraum 2001–2009 aufgrund eines NPC an der Universitatsklinik Bonn mittels Radiotherapie (RT) oder Radiochemotherapie (RCT) behandelt wurden. Die Lebensqualitatsanalyse wurde mit dem Fragebogen FACT-NP (functional assessment of cancer therapy-nasopharyngeal) durchgefuhrt. Das mittlere Alter der Patienten war 57±13 Jahre, das Verhaltnis Manner zu Frauen betrug 2,33/1. 3 (15%) der Patienten wurden mit einer RT und 17 (85%) mit einer kombinierten RCT behandelt. Die allgemeine posttherapeutische LQ der Patienten war gut. Mundtrockenheit, Geschmacksminderung, der Einfluss der Erkrankung auf das Sexualleben und otologische Symptome waren LQ mindernd. Schmerzen, der Verlust der Arbeitsfahigkeit, seelische oder familiare Probleme standen nicht im Vordergrund. Die zu erwartenden Funktions- und Lebensqualitatseinbusen bei der Behandlung des NPC mussen dem Patienten ausfuhrlich erlautert werden. Die Einbindung der Familie in das Therapiekonzept, eine antidepressive Therapie oder psychoonkologische Unterstutzung kann sinnvoll und notwendig sein.

Im Gegensatz zur endemischen Verbreitung in Asien oder Afrika ist das Nasopharynxkarzinom (NPC) in Deutschland eine seltene Tumorentitat. In der vorliegenden Studie wurden retrospektiv die Patientencharakteristika und prognostischen Faktoren in Abhangigkeit von der Behandlung beim NPC untersucht. Das Patientenkollektiv umfasst 63 Patienten mit NPC, die im Zeitraum 1990–2009 am Universitatsklinikum Bonn behandelt wurden. Das mittlere Alter war 56,4 Jahre, das Verhaltnis Manner zu Frauen betrug 3,2:1, ein Tumorstadium I/II nach Union Internationale Contre le Cancer (UICC) lag bei 23,8% und ein Stadium III/IV bei 76,2% der Falle vor. Histologisch lag ein Typ I nach World Health Organization (WHO) in 9,6%, Typ II in 33,3% und Typ III in 57,1% der Falle vor. Die 5-Jahres-Uberlebensrate nach Radiochemotherapie (RCT) betrug 75% und nach Bestrahlungstherapie (RT) 60%. Die Sterberate vervielfachte sich um den Faktor 3,5 im nachst hoheren Tumorstadium (p ≤ 0,047). Die Rezidivquote (RQ) unter RCT lag bei 34% und unter RT bei 68% (p ≤ 0,04) nach 5 Jahren. Eine Tumorablation steigerte die RQ signifikant (p ≤ 0,047). Die RCT ist auserst effektiv und der alleinigen RT bei der Behandlung des NPC uberlegen. Die Tumorablation vor RCT/RT ist obsolet und verschlechtert die Prognose signifikant.

Maligne sinunasale Tumoren sind mit einer jahrlichen Inzidenz von weltweit 1/200.000 selten. Es wurden retrospektiv alle Patienten erfasst (n = 177), welche im Zeitraum 1996–2010 an der HNO-Universitatsklinik Bonn aufgrund sinunasaler Malignome therapiert wurden. Inzidenz, Alter und Geschlecht waren fur alle Entitaten vorhanden. Weitere demographische Daten, Therapie und Follow-up wurden ausschlieslich fur Karzinome analysiert. Die haufigste Entitat war das Karzinom (58%). Unspezifische Beschwerden vor Erstdiagnose dauerten 4,7 ± 5 Monate an. Obwohl 64% der Karzinompatienten ein lokal fortgeschrittenes Tumorleiden (T3–4) aufwiesen, zeigten nur 15% lokoregionare Lymphknotenmetastasen. Die Gesamt-3-Jahres-Uberlebenswahrscheinlichkeit lag bei 61%. Patienten mit ausschlieslich operativer Therapie hatten eine deutlich bessere Prognose als Patienten nach kombinierter oder primarer Radio(chemo)therapie. Das T-Stadium konnte als unabhangiger prognostischer Faktor identifiziert werden. Aufgrund unspezifischer Beschwerdesymtomatik werden sinunasale Malignome meist erst in fortgeschrittenem Tumorstadium diagnostiziert. Trotz multimodaler Therapieansatze ist die Prognose schlecht.

Pfahlungsverletzungen im Kindesalter sind sehr selten und haufig Folge eines akzidentiellen Geschehens. Wir berichten daher von 2 Patientinnen im Kindesalter, die zur Notfallversorgung mit einer kraniofazialen Pfahlungsverletzung des Gesichts im interdisziplinaren Notfallzentrum der Universitatsklinik Bonn durch den Rettungsdienst vorgestellt wurden. Das Ausmas der Verletzungen war in der Ersteinschatzung nicht abschliesend beurteilbar. Mittels Computertomographie und operativer Exploration konnten auser Weichteilverletzungen im Gesichtsbereich schwerwiegende Verletzungen ausgeschlossen werden. Die Indikation zur Computer- oder Magnetresonanztomographie muss bei Kindern streng gestellt werden, doch sind diese bei Pfahlungsverletzungen vor der Entfernung des Fremdkorpers zwingend notwendig.

Hintergrund Interdisziplinare Notfallzentren (INZ) sollen durch eine facherubergreifende Kompetenz die Qualitat der Patientenversorgung erhohen und dabei den steigenden okonomischen Anforderungen gerecht werden.

BACKGROUND Otorhinolaryngologists require new diagnostic methods to give further insight into the physiology of nasal breathing. The functional aspects of radiological data in the field of ENT have rarely been examined. This study compares computed tomography (CT) scan area measurements of the paranasal sinuses with physiological data from rhinomanometry. PATIENTS AND METHODS In a retrospective study, paranasal CT scans from 36 patients were analysed for volume, width and hydraulic diameter of the five key regions of the nasal cavity (CT rhinometry) and compared to the active anterior rhinomanometric (RMM) results representing the gold standard in nasal flow description. RESULTS The highest correlation between the rhinomanometric results and CT rhinometry was found at the internal ostium, followed by the diffuser region. The structures important for regulating nasal flow could thus be identified in the CT area data. CONCLUSION CT rhinometry revealed structures important for nasal breathing, in addition to providing anatomical and topographical data. CT rhinometry measured volumes, width and hydraulic diameters of the nasal cavity correlated with measurements of transnasal flow.

Although head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3). The aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC. FGFR3 protein expression was analysed in a large HNSCC tissue cohort (n = 536) and FGFR3 mRNA expression from The Cancer Genome Atlas (TCGA; n = 520). Moreover, FGFR3 wild-type and mutant versions were overexpressed in vitro, and both proliferation and migration was assessed with and without BGJ398 (a specific FGFR1-3 inhibitor) treatment. Although FGFR3 expression for both cohorts decreased during tumour progression, high FGFR3 expression levels were observed in a small subset of patients. In vitro, FGFR3 overexpression led to increased proliferation, whereas migration was not altered. Moreover, FGFR3-overexpressing cells were more sensitive to BGJ398. Cells overexpressing FGFR3 mutant versions showed increased proliferation compared to wild-type FGFR3 under serum-reduced conditions and were largely as sensitive as the wild-type protein to BGJ398. Taken together, the results of this study demonstrate that although FGFR3 expression decreases during HNSSC progression, it plays an important role in tumour cell proliferation and thus may be a potential target for therapy in selected patients suffering from this dismal tumour entity.

Squamous cell carcinoma of the head and neck (HNSCC) is the tenth most common tumor entity in men worldwide. Nevertheless therapeutic options are mostly limited to surgery and radio-chemotherapy resulting in 5-year survival rates of around 50%. Therefore new therapeutic options are urgently needed. During the last years, targeting of receptor tyrosine kinases has emerged as a promising strategy that can complement standard therapeutical approaches. Here, we aimed at investigating if the receptor tyrosine kinase DDR2 is a targetable structure in HNSCC. DDR2 expression was assessed on a large HNSCC cohort (554 patients) including primary tumors, lymph node metastases and recurrences and normal mucosa as control. Subsequently, DDR2 was stably overexpressed in two different cell lines (FaDu and HSC-3) using lentiviral technology. Different tumorigenic properties such as proliferation, migration, invasion, adhesion and anchorage independent growth were assessed with and without dasatinib treatment using in-vitro cell models and in-vivo zebrafish xenografts. DDR2 was overexpressed in all tumor tissues when compared to normal mucosa. DDR2 overexpression led to increased migration, invasion, adhesion and anchorage independent growth whereas proliferation remained unaltered. Upon dasatinib treatment migration, invasion and adhesion could be inhibited in-vitro and in-vivo whereas proliferation was unchanged. Our data suggest treatment with dasatinib as a promising new therapeutic option for patients suffering from DDR2 overexpressing HNSCC. Since dasatinib is already FDA-approved we propose to test this drug in clinical trials so that patients could directly benefit from this new treatment option.

// Anne von Massenhausen 1, 2, 3, * , Christine Sanders 1, 2, 3, * , Britta Thewes 1, 2, 3 , Mario Deng 4, 5 , Angela Queisser 1, 2, 3 , Wenzel Vogel 4, 5 , Glen Kristiansen 2, 3 , Stefan Duensing 6 , Andreas Schrock 3, 7 , Friedrich Bootz 3, 7 , Peter Brossart 3, 8 , Jutta Kirfel 2, 3 , Lynn Heasley 9 , Johannes Bragelmann 1, 3, 8, * , Sven Perner 4, 5 * 1 Section of Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany 2 Institute of Pathology, University Hospital of Bonn, Bonn, Germany 3 Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany 4 Pathology of the University Hospital of Luebeck, Luebeck, Germany 5 Leibniz Research Center Borstel, Borstel, Germany 6 Department of Urology, University of Heidelberg, Heidelberg, Germany 7 Department of Otorhinolaryngology/Head and Neck Surgery, University Hospital of Bonn, Bonn, Germany 8 Department of Hematology/Oncology, University Hospital of Bonn, Bonn, Germany 9 Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA * These authors have contributed equally to this work Correspondence to: Sven Perner, email: Sven.Perner@uksh.de Keywords: head and neck cancer, MERTK, targeted therapy Abbreviations: HNSCC, head and neck squamous cell carcinoma; MERTK, MER proto-oncogene tyrosine kinase; FAK, focal adhesion kinase; TCGA, The Cancer Genome Atlas Received: January 07, 2016 Accepted: March 28, 2016 Published: April 13, 2016 ABSTRACT Although head and neck cancer (HNSCC) is the sixth most common tumor entity worldwide therapy options remain limited leading to 5-year survival rates of only 50 %. MERTK is a promising therapeutic target in several tumor entities, however, its role in HNSCC has not been described yet. The aim of our study was to investigate the biological significance of MERTK and to evaluate its potential as a novel therapeutic target in this dismal tumor entity. In two large HNSCC cohorts (n=537 and n=520) we found that MERTK is overexpressed in one third of patients. In-vitro, MERTK overexpression led to increased proliferation, migration and invasion whereas MERTK inhibition with the small molecule inhibitor UNC1062 or MERTK knockdown reduced cell motility via the small GTPase RhoA. Taken together, we are the first to show that MERTK is frequently overexpressed in HNSCC and plays an important role in tumor cell motility. It might therefore be a potential target for selected patients suffering from this dismal tumor entity.

Management of life-threatening postsurgical bleeding is complex. If conservative or surgical therapy is demanding, an endovascular treatment can be considered. The goal of this study was to evaluate the outcome of endovascular approaches in the diagnosis and therapy of otherwise intractable postoperative haemorrhages with a study design of outcomes research. Charts of all patients with postsurgical bleedings receiving endovascular treatment were reviewed for clinical outcome, complications, and demographic data. 15 patients were identified. They had rhinosurgery (12/15), tonsillectomy (2/15) or transoral tumour debulking (1/15) prior to the endovascular procedure. In more than 70%, the source of bleeding was directly located angiographically and subsequently superselectively embolized. The remaining patients suffered from post-rhinosurgical epistaxis and underwent a bilateral embolization of the sphenopalatine artery. All bleedings were successfully controlled and no procedure-related complication was noted. In conclusion, endovascular treatment of life-threatening postsurgical haemorrhages should be considered if the source of bleeding is unknown or if surgery is difficult and may result in devastating postoperative complications.

Die Inzidenz von Tuberkuloseneuerkrankungen ist deutschlandweit rucklaufig. Hauptmanifestationsort der Erkrankung ist die Lunge, in selteneren Fallen kann der Kopf-Hals-Bereich betroffen sein. Retrospektiv wurden am HNO Universitatsklinikum Bonn im Zeitraum zwischen 1997 und 2010 alle Patienten mit Erstdiagnose einer Tuberkulose im Kopf-Hals-Bereich ausgewertet. Es wurden 38 Patienten (24 weiblich, 14 mannlich, Altersmedian 43,5±19,7 Jahre) erfasst. In uber 60% der Falle waren die Patienten auslandische Staatsburger. Hauptsachlich betroffen waren die zervikalen Lymphknoten (87% ), seltener kam es zu extranodularen Manifestationen mit organspezifischen Beschwerden (Sinus maxillaris, Cavum tympani, Larynx, Tonsillen). In nur 3 Fallen wurde praoperativ der explizite Verdacht auf eine Tuberkulose gestellt. Nur die Kenntnis der unterschiedlichen Manifestationsorte sowie eine genaue Infektionsanamnese konnen zur praoperativen Verdachsdiagnose einer mykobakteriellen Erkrankung fuhren.

Epistaxis is a common clinical problem, and the majority of bleedings can be managed conservatively. However, due to extensive and sometimes life-threatening bleeding, further treatment, such as superselective embolization, may be required. We report our experience with endovascular treatment of life-threatening epistaxis. All patients presenting with excessive epistaxis, which received endovascular treatment at a German tertiary care facility between January 2001 and December 2009, were retrospectively identified. Demographic data, etiology, origin and clinical relevance of bleeding, interventional approach, therapy-associated complications, and outcome were assessed. A total of 48 patients required 53 embolizations. Depending on the etiology of bleeding, patients were assigned to three groups: 1) idiopathic epistaxis (31/48), 2) traumatic or iatrogenic epistaxis (12/48), and 3) hereditary hemorrhagic telangiectasia (HHT) (5/48). Eleven of 48 patients required blood transfusions, and 9 of these 11 patients (82%) were termed clinically unstable. The sphenopalatine artery was embolized unilaterally in 10 of 53 (18.9%) and bilaterally in 41 of 53 (77.4%) procedures. During the same procedure, additional vessels were embolized in three patients (3/53; 5.7%). In 2 of 53(3.8%) cases, the internal carotid artery (ICA) was occluded. Long-term success rates of embolization were 29 of 31 (93.5%) for group 1 and 11 of 12 (91.7%) for group 2 patients. Embolization of patients with HHT offered at least a temporary relief in three of five (60%) cases. Two major complications (necrosis of nasal tip and transient hemiparesis) occurred after embolization. Endovascular treatment proves to be effective for prolonged and life-threatening epistaxis. It is easily repeatable if the first procedure is not successful and offers a good risk–benefit profile.

A 24-year-old female patient complained of odynophagy, rhinitis, general apathy and fever (38.5 degrees C) which had persisted for 5 days. Treatment had initially been a combination of paracetamol, ibuprofen and acetylsalicylic acid and when no improvement occurred amoxicillin was prescribed. Nutrition and fluid intake was not possible due to excessive odynophagy. In addition to leukocytosis and increased C-reactive protein, there were pronounced erosive, reddened edematous and fibrin-covered alterations of the whole oral, pharyngeal and laryngeal mucous membranes as well as conjunctivitis. The lips were red with hemorrhagic scabs. The diagnosis was Fuchs' syndrome which is a severe medication-induced skin reaction. Abstinence from the agent (medication) responsible and early cortisone therapy are decisive.

Hintergrund Die Notwendigkeit der routinemasigen histologischen Untersuchung von operativ gewonnenem Tonsillengewebe zum Ausschluss eines okkulten Malignoms wird kontrovers diskutiert.

Tonsillectomy is a frequently performed surgical procedure in children and adults. Postoperative bleeding is the most severe complication; however, the factors leading to postoperative haemorrhage are still discussed controversially. 1,522 tonsillectomies were retrospectively reviewed. Histopathological tonsil composition was correlated with the incidence of postoperative haemorrhage. Patient charts were analysed with regard to demographic data, characteristics of postoperative haemorrhage and indication for surgery. Patients with post-tonsillectomy haemorrhage were compared with uneventful cases. Histopathological signs of cryptic tonsillitis and actinomyces infection displayed a statistically significant correlation with the risk of postoperative haemorrhage (P = 0.018 and P = 0.02), but the odds ratio was low (1.9 and 2.0). 7.7% of all patients had postoperative bleeding and 3.5% had to return to theatre for haemostasis. The incidence of haemorrhages within hospitalization (5 postoperative days) was 45% and after discharge 55%, respectively. In 11% of cases bleeding occurred on the fourth or fifth day after surgery. While gender, season of surgery, abscess tonsillectomy “en chaud” in comparison with elective tonsillectomy were not associated with an increased rate of postoperative haemorrhage (P > 0.05), significant more postoperative haemorrhages were detected in the group of adults (P = 0.02). Despite significant correlation of cryptic tonsillitis and actinomyces infection with postoperative haemorrhage, the risk for postoperative bleeding is only slightly elevated and, therefore, the predictive value is low. Because a multifactorial aetiology of post-tonsillectomy haemorrhage has to be assumed, large multicenter studies are necessary to evaluate the significance of different risk factors.

Die Laryngoskopie erfolgt mittels starrer und flexibler Endoskope. Wahrend die starren Optiken (SO) gegenuber den flexiblen Endoskopen (FE) bislang Vorteile in der Bildqualitat bieten, ist der Einsatz der FE physiologischer und ermoglicht zudem einen besseren Uberblick uber den Ansatzraum. Neuartige flexible Chip-on-the-tip- (Tip-chip-)Endoskope (TCE) versprechen die Vorteile beider Verfahren miteinander zu kombinieren. 38 Patienten mit Dysphonie wurden sowohl mit SO, mit konventionellen FE als auch mit TCE untersucht. Die Bildqualitat/Bildubersicht der 3 Untersuchungsmodalitaten wurde verglichen und die Untersuchungen hinsichtlich Patientenzufriedenheit evaluiert. Die Bildqualitat der TCE und der SO ubertraf in allen Fallen die der konventionellen FE. In 55% der Falle waren die Bildqualitat und Bildubersicht der TCE und der SO vergleichbar, in 24% wurde die SO und in 21% die TCE besser bewertet. Im Vergleich mit den SO konnte mit den FE eine hohere Patientenzufriedenheit erzielt werden. Mit dem Einsatz der TCE lassen sich die Vorteile einer physiologischen Untersuchungstechnik mit der Gewinnung hochauflosender Bildbefunde kombinieren.

Sudden sensorineural hearing loss is a symptom of cochlear injury. Potential aetiologies are vascular diseases, viral infections, allergic reactions, autoimmune disorders, and traumatic rupture of the intralabyrinthe membrane. Unlike in unilateral cases bilateral sensorineural hearing loss is often associated with specific disease entities. We report a case of sudden bilateral deafness after intravenous heroin abuse. The putative pathophysiological mechanisms are discussed.

Der Warthin-Tumor ist der zweithaufigste gutartige Tumor der Speicheldrusen und manifestiert sich meist in der Ohrspeicheldruse. Ein extraparotideales Auftreten im Bereich der kleinen Speicheldrusen ist selten, sollte aber bei Raumforderungen im Bereich des Nasopharynx, des Augenlids, der Mundhohle sowie der Taschenfalten differenzialdiagnostisch in Betracht gezogen werden. Die Therapie der Wahl ist die komplette chirurgische Entfernung des Tumors.

Recently, SOX2 has been identified as a potential lineage-specific oncogene in lung squamous cell carcinomas. Since head and neck squamous cell carcinomas (HNSCC) are morphologically and clinically highly related to lung squamous cell carcinomas, we hypothesized that SOX2 also plays an oncogenic role in this tumor entity. We assembled a cohort of 496 patients with HNSCC, including 253 metastases and 135 recurrences. SOX2 amplification (FISH) and SOX2 protein expression (immunohistochemistry) were correlated with molecular and clinicopathological parameters. In order to investigate the functional role of SOX2 in human HNSCC, SOX2 knockdown and overexpression in SCC-25 cells were generated by lentiviral constructs and subjected to cell cycle analysis, proliferation and apoptosis assays. Furthermore, SOX2 expression was correlated with the expression of proliferation and apoptosis-related proteins in primary HNSCC samples. SOX2 amplification was detected in 21% of primary HNSCC and mostly observed in a concordant manner between primary tumors and corresponding metastatic tissues. Overall, SOX2 amplification resulted in protein overexpression and was mutually exclusive with human papillomavirus infection. SOX2 protein overexpression was associated with clinicopathological parameters of worse outcome. Functionally, SOX2 induced the expression of the antiapoptotic protein BCL-2 and enhanced resistance to apoptosis-inducing agents including cisplatin, indicating SOX2 as a mediator of therapy resistance in human HNSCC. Targeting SOX2 and related molecular downstream pathways such as BCL-2 may enhance therapy efficacy in SOX2-expressing HNSCC.

Einleitung: Die atypische Mykobakteriose ist eine seltene Ursache einer zervikalen Lymphadenitis und betrifft in der Regel immunkompetente Kinder zwischen dem 1.–5. Lebensjahr. Die unspezifische Klinik und Diagnostik führt häufig zu einer späten Diagnose. Hierdurch wird das therapeutische Management erschwert. Material und Methoden: Wir berichten exemplarisch über den typische Krankheitsverlauf und das therapeutische Vorgehen bei einer 14 Monate alten Patientin mit einer zervikalen atypischen Mykobakteriose. Ergebnisse: Die Patientin wurde aufgrund einer seit 3 Wochen progredienten unilateralen, indolenten und derben Halsschwellung vorgestellt. Im weiteren Verlauf kam es zu einer Hautrötung und perkutaner Fistelbildung. Nach der chirurgischen Sanierung kam es zur kompletten Ausheilung der Erkrankung. Atypische Mykobakterien weisen ein sehr langsames Wachstumsmuster auf, so dass erste mikrobiologischen Ergebnisse frühestens nach 2–3 Wochen vorliegen. Der Nachweis von spezifischen atypischen Mykobakterien gelingt nur in 40–60% der Fälle. Molekularbiologische Methoden verbessern die Diagnostik, weisen jedoch bei der Spezifität Schwächen auf. Neben der totalen Exstirpation wird immer wieder die antimykobakterielle Therapie mit Clarythromycin, Rifampicin und Ethambutol als alternative Behandlungsoption diskutiert. Unklarheit herrscht jedoch über Dosis, Dauer und genaue Indikationen. Nach zwei größeren retrospektiven Studien scheint die alleinige Observation mit Spontanremission ebenfalls eine Behandlungsoption darzustellen. Schlussfolgerung: Die komplette chirurgische Exzision aller Entzündungsherde der atypischen Mykobakteriose ist die effektivste Behandlungsform, in der Regel begleitet von einer antimykobakteriellen Therapie. Der Erstautor gibt keinen Interessenkonflikt an., GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; 10:Doc021; ISSN 1865-1038

Background Despite multimodal treatment, sinonasal malignancies have an unfavorable prognosis. The purpose of this study was to elucidate if these tumors harbor amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, which has recently been identified as a potential therapeutic target in squamous cell lung cancer. Methods One hundred twelve primary tumors (including squamous cell carcinoma [SCC], carcinoma associated with an inverted papilloma, sinonasal undifferentiated carcinoma [SNUC], adenocarcinoma, adenoid cystic carcinoma [ACC], esthesioneuroblastoma, and 9 corresponding lymph node metastases) were assessed by fluorescence in situ hybridization (FISH) for FGFR1 copy number status. Human papillomavirus (HPV) status was assessed by p16 immunohistochemical as a surrogate marker. Results FGFR1 amplification was found in subsets of sinonasal SCCs (20%), carcinomas associated with an inverted papilloma (33%), and SNUCs (5%). In all cases, metastatic tumor samples shared the same FGFR1 amplification status as the corresponding primary tumor tissue. None of the FGFR1-amplified tumors expressed p16. Conclusion FGFR1 amplification represents a potential molecular target in a subset of patients with sinonasal cancer. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1253–1257, 2014

We report a case of solitary metastasis of lung carcinoma into the internal auditory canal. On admission, the 60-year-old patient was complaining about a rapidly developing hearing loss with ipsilateral facial nerve paralysis. Magnetic resonance imaging revealed an intracanalicular tumor, which was interpreted as vestibular schwannoma. After tumor resection, the histopathologic examination revealed a metastasis of a squamous cell carcinoma. Computed tomographic scan and bronchoscopy identified an asymptomatic primary pulmonary neoplasm.

ObjectivesThe transcription factor SOX2 (3q26.3-q27) is an embryonic stem cell factor contributing to the induction of pluripotency in terminally differentiated somatic cells. Recently, amplification of the SOX2 gene locus has been described in squamous cell carcinoma (SCC) of different organ sites. Aim of this study was to investigate amplification and expression status of SOX2 in sinonasal carcinomas and to correlate the results with clinico-pathological data.Materials and methodsA total of 119 primary tumor samples from the sinonasal region were assessed by fluorescence in-situ hybridization and immunohistochemistry for SOX2 gene amplification and protein expression, respectively. Of these, 59 were SSCs, 18 sinonasal undifferentiated carcinomas (SNUC), 10 carcinomas associated with an inverted papilloma (INVC), 19 adenocarcinomas (AD) and 13 adenoid cystic carcinomas (ACC).ResultsSOX2 amplifications were found in subsets of SCCs (37.5%), SNUCs (35.3%), INVCs (37.5%) and ADs (8.3%) but not in ACCs. SOX2 amplification resulted in increased protein expression. Patients with SOX2-amplified sinonasal carcinomas showed a significantly higher rate of tumor recurrences than SOX2 non-amplified tumors.ConclusionThis is the first study assessing SOX2 amplification and expression in a large cohort of sinonasal carcinomas. As opposed to AD and ACC, SOX2 amplifications were detected in more than 1/3 of all SCCs, SNUCs and INVCs. We therefore suggest that SNUCs are molecularly closely related to SCCs and INVCs and that these entities represent a subgroup of sinonasal carcinomas relying on SOX2 acquisition during oncogenesis. SOX2 amplification appears to identify sinonasal carcinomas that are more likely to relapse after primary therapy, suggesting that these patients might benefit from a more aggressive therapy regime.

Despite multimodal treatment, sinonasal malignancies have an unfavorable prognosis. The purpose of this study was to elucidate if these tumors harbor amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, which has recently been identified as a potential therapeutic target in squamous cell lung cancer.One hundred twelve primary tumors (including squamous cell carcinoma [SCC], carcinoma associated with an inverted papilloma, sinonasal undifferentiated carcinoma [SNUC], adenocarcinoma, adenoid cystic carcinoma [ACC], esthesioneuroblastoma, and 9 corresponding lymph node metastases) were assessed by fluorescence in situ hybridization (FISH) for FGFR1 copy number status. Human papillomavirus (HPV) status was assessed by p16 immunohistochemical as a surrogate marker.FGFR1 amplification was found in subsets of sinonasal SCCs (20%), carcinomas associated with an inverted papilloma (33%), and SNUCs (5%). In all cases, metastatic tumor samples shared the same FGFR1 amplification status as the corresponding primary tumor tissue. None of the FGFR1-amplified tumors expressed p16.FGFR1 amplification represents a potential molecular target in a subset of patients with sinonasal cancer. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1253-1257, 2014.

SOX2 (SRY (sex determining region Y)-box 2) is a transcriptional master regulator that confers “stemness” in early embryogenesis and acts as an oncogene in various cancers. Recently, SOX2 expression has been shown in several solid tumor types. However, the SOX2 expression pattern and the correlation with histopathologic status and clinical outcome are highly variable among tumors, suggesting distinct roles of SOX2 in individual tumors. In head and neck squamous cell carcinoma (HNSCC), we reported that expression of SOX2 is detectable and associates with high-risk disease in non-HPV human HNSCC. Functionally, SOX2 overexpression enhanced apoptosis resistance in response to treatments with cisplatin and other apoptosis-inducing agents, indicating SOX2 as a mediator of therapy resistance in human HNSCC. On the molecular level, induction of the anti-apoptotic protein BCL2 was observed following SOX2-induction. Here we explore if the anti-apoptotic effects of SOX2 are functionally mediated through up-regulation of BCL2 expression and explore BCL2 as a potential direct downstream target of SOX2. We tested SOX2 and BCL2 expression in different human HNSCC cell-lines by qPCR and respectively immunoblot. To analyse the functional effect of SOX2, SOX2 overexpressing and control SCC25 cells generated via transduction with lentiviral particles were analysed in in vitro apoptosis assays after treatments with staurosporine, TRAIL or cisplatin. Furthermore, to analyse the influence of BCL2 in SOX2-overexpressing cells, treatment with the BCL2 inhibitor ABT-199 was used. We could confirm the strong inductive effect of SOX2 overexpression on BCL2 gene and protein levels in the human SCC25 cell line. In line, cells treated with SOX2 overexpressing lentiviruses showed enhanced apoptotic resistance as compared to control-transduced cells. Notably, HNSCC cells were less sensitive to ABT-199 as previously reported for lymphatic leukemic cells (5-10 μM versus 0.1-1 μM for EC50). However, ABT-199 treatment in low dosage (1 μM) was indeed able to sensitize SOX2-overexpressing human HNSCC cells to apoptosis, indicating up-regulation of BCL2 as an important mechanism by which SOX2 confers treatment resistance in these cells. Moreover, analysis of the BCL2 promoter revealed a potential SOX2-binding site, and a direct association of SOX2 protein with this site could be confirmed by chromatin immunoprecipitation assays (CHIP). We are currently further exploring the effect of ABT-199 on the therapy resistance of SOX2-overexpressing cells using in vivo models. Taken together, our findings indicate that, in human HNSCC cells, SOX2 plays an important role in drug resistance by elevating BCL2 expression. In patients with SOX2-expressing HNSCC, combinatorial treatment with ABT-199 may enhance response to conventional chemotherapies by re-sensitizing cells to apoptosis induction. Citation Format: Hui Wang, Angela Quiesser, Andreas Schröck, Sven Perner, Claudia Lengerke. Overcoming therapy resistance in SOX2-expressing head and neck squamous cell carcinoma cells by targeting the downstream BCL2-pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2910.

Adult rhabdomyosarcoma of the larynx is a rare disease. Two cases of laryngeal rhabdomyosarcoma of the pleomorphic subtype are presented. One case was treated with surgery followed by chemotherapy and radiotherapy, the other by surgery alone. At present 20 months after treatment the patients are without local reccurrence or metastases. The pathology of the tumor, diagnosis, and treatment are discussed.

Numerous neurological diseases lead to paralysis of intact skeletal muscles. Electrical stimulation of these to restore contraction is problematic due to side effects, the lack of cellspecificity and simultaneous activation of antagonist muscles.Optogenetic stimulation of skeletal muscles expressing the light-sensitive cation channel Channelrhodopsin2 (ChR2) could overcome these limitations. Therefore we have generated a transgenic mouse line with expression of ChR2 fused to EYFP in skeletal muscles under the control of the chicken-β-actin promotor. Soleus muscles showed membrane bound EYFP fluorescence and light induced force was analyzed by isometric force measurements upon illumination (470nm) with different durations, intensities and repetition rates. Using single light pulses, the highest force generation (52.7±3.4mN, sd, n=4) was reached by 100ms long pulses with a light intensity of 0.51mW/mm2. For tetanus stimulation we found that 5ms pulses at 30Hz and 1.4mW/mm2 were most efficient and led to the force of 69.1±7.7mN (sd,n=4). This was ∼70% of the force generated by electrical tetanus stimulation.Bilateral laryngeal paralysis is a severe disease resulting in immobility of the vocal cords and life-threatening dyspnea. In this disease electrical stimulation is problematic due to electrode corrosion, recognition of the stimuli and non-selective stimulation of agonist and antagonist muscles (Zealer DL et al., Laryngoscope 2003,113:1149-1156). We therefore tested the feasibility of selective optogenetic stimulation of the posterior cricoarytenoid muscle, which is the only intralaryngeal muscle opening the vocal cords. Larynges were isolated from ChR2-transgenic mice and locally stimulated with a light guide (O400μm,NA=0,48) in the postarytenoid region. Application of light pulses (470nm,50ms,35.7mW/mm2) led to a repetitive opening of the vocal cords. The distance between vocal cords during illumination was 230±38% of baseline (sd,n=3).Thus optogenetic muscle stimulation is a promising method for therapy of nerve lesions and might be useful to treat bilaryngeal paralysis.