Publications by authors named "Jan Hagemann"

25 Publications

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Differentiation of COVID-19 signs and symptoms from allergic rhinitis and common cold- An ARIA-EAACI-GA LENconsensus.

Authors:
Jan Hagemann Gabrielle L Onorato Marek Jutel Cezmi A Akdis Ioana Agache Torsten Zuberbier Wienczyslawa Czarlewski Joaquim Mullol Anna Bedbrook Claus Bachert Kazi S Bennoor Karl-Christian Bergmann Fulvio Braido Paulo Camargos Luis Caraballo Victoria Cardona Thomas Casale Lorenzo Cecchi Tomas Chivato Derek K Chu Cemal Cingi Jaime Correia-de-Sousa Stefano Del Giacco Dejan Dokic Mark Dykewicz Motohiro Ebisawa Yehia El-Gamal Regina Emuzyte Jean-Luc Fauquert Alessandro Fiocchi Wytske J Fokkens Joao A Fonseca Bilun Gemicioglu Maximiliano Gomez Gotua Maia Tari Haahtela Eckard Hamelmann Tomohisa Iinuma Juan Carlos Ivancevich Ewa Jassem Omer Kalayci Przemyslaw Kardas Musa Khaitov Piotr Kuna Violeta Kvedariene Desiree E Larenas-Linnemann Brian Lipworth Michael Makris Jorge F Maspero Neven Miculinic Florin Mihaltan Yousser Mohammad Stephen Montefort Mario Morais-Almeida Ralph Mösges Robert Naclerio Hugo Neffen Marek Niedoszytko Robyn E O'Hehir Ken Ohta Yoshitaka Okamoto Kimi Okubo Petr Panzner Nikolaos G Papadopoulos Giovanni Passalacqua Vincenzo Patella Ana Pereira Oliver Pfaar Davor Plavec Todor A Popov Emmanuel P Prokopakis Francesca Puggioni Filip Raciborski Jere Reijula Frederico S Regateiro Sietze Reitsma Antonino Romano Nelson Rosario Menachem Rottem Dermot Ryan Boleslaw Samolinski Joaquin Sastre Dirceu Solé Milan Sova Cristiana Stellato Charlotte Suppli-Ulrik Ioanna Tsiligianni Antonio Valero Arunas Valiulis Erkka Valovirta Tuula Vasankari Maria Teresa Ventura Dana Wallace De Yun Wang Iân Williams Arzu Yorgancioglu Osman M Yusuf Mario Zernotti Jean Bousquet Ludger Klimek

Allergy 2021 Mar 17. Epub 2021 Mar 17.

Department of Otolaryngology, Head and Neck Surgery, Universitätsmedizin Mainz, Mainz, Germany.

Background: Although there are many asymptomatic patients, one of the problems of COVID-19 is early recognition of the disease. COVID-19 symptoms are polymorphic and may include upper respiratory symptoms. However, COVID-19 symptoms may be mistaken withthe common cold or allergic rhinitis. An ARIA-EAACI study group attempted to differentiate upper respiratory symptoms betweenthe three diseases.

Methods: A modified Delphi process was used and ARIA members who were seeing COVID-19 patients were asked to fill in a questionnaire on the upper airway symptoms of COVID-19, common cold andallergic rhinitis.

Results: Among the 192 ARIA members who were invited to respond to the questionnaire, 89 responded. 87 questionnaires were analysed. The consensus was then reported.A two-way ANOVA analysis revealed significant differences inthe symptom intensity between the three diseases (p<0.001).

Conclusions: This modified Delphi approach enabled thedifferentiationof upper respiratory symptoms betweenCOVID-19, common cold and allergic rhinitis. An electronic algorithm will be devised using the questionnaire.
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http://dx.doi.org/10.1111/all.14815DOI Listing
March 2021

The role of structured reporting and structured operation planning in functional endoscopic sinus surgery.

PLoS One 2020 30;15(11):e0242804. Epub 2020 Nov 30.

Department of Radiology and Nuclear Medicine, University Medical Center Mannheim, Mannheim, Baden-Wuerttemberg, Germany.

Computed tomography (CT) scans represent the gold standard in the planning of functional endoscopic sinus surgeries (FESS). Yet, radiologists and otolaryngologists have different perspectives on these scans. In general, residents often struggle with aspects involved in both reporting and operation planning. The aim of this study was to compare the completeness of structured reports (SR) of preoperative CT images and structured operation planning (SOP) to conventional reports (CR) and conventional operation planning (COP) to potentially improve future treatment decisions on an individual level. In total, 30 preoperative CT scans obtained for surgical planning of patients scheduled for FESS were evaluated using SR and CR by radiology residents. Subsequently, otolaryngology residents performed a COP using free texts and a SOP using a specific template. All radiology reports and operation plannings were evaluated by two experienced FESS surgeons regarding their completeness for surgical planning. User satisfaction of otolaryngology residents was assessed by using visual analogue scales. Overall radiology report completeness was significantly higher using SRs regarding surgically important structures compared to CRs (84.4 vs. 22.0%, p<0.001). SOPs produced significantly higher completeness ratings (97% vs. 39.4%, p<0.001) regarding pathologies and anatomical variances. Moreover, time efficiency was not significantly impaired by implementation of SR (148 s vs. 160 s, p = 0.61) and user satisfaction was significantly higher for SOP (VAS 8.1 vs. 4.1, p<0.001). Implementation of SR and SOP results in a significantly increased completeness of radiology reports and operation planning for FESS. Consequently, the combination of both facilitates surgical planning and may decrease potential risks during FESS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242804PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703956PMC
January 2021

Management of patients with chronic rhinosinusitis during the COVID-19 pandemic-An EAACI position paper.

Allergy 2021 03;76(3):677-688

Department of Otorhinolaryngology, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands.

Background: Chronic rhinosinusitis is regarded as a chronic airway disease. According to WHO recommendations, it may be a risk factor for COVID-19 patients. In most CRSwNP cases, the inflammatory changes affecting the nasal and paranasal mucous membranes are type-2 (T2) inflammation endotypes.

Methods: The current knowledge on COVID-19 and on treatment options for CRS was analyzed by a literature search in Medline, Pubmed, international guidelines, the Cochrane Library and the Internet.

Results: Based on international literature, on current recommendations by WHO and other international organizations as well as on previous experience, a panel of experts from EAACI and ARIA provided recommendations for the treatment of CRS during the COVID-19 pandemic.

Conclusion: Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS-CoV-2 infection. Surgical treatments should be reduced to a minimum and surgery preserved for patients with local complications and for those with no other treatment options. Systemic corticosteroids should be avoided. Treatment with biologics can be continued with careful monitoring in noninfected patients and should be temporarily interrupted during the course of the COVID-19 infection.
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http://dx.doi.org/10.1111/all.14629DOI Listing
March 2021

A new form of irritant rhinitis to filtering facepiece particle (FFP) masks (FFP2/N95/KN95 respirators) during COVID-19 pandemic.

World Allergy Organ J 2020 Oct 6;13(10):100474. Epub 2020 Oct 6.

Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center, Mainz, Germany.

Filtering facepiece particle (FFP) masks are important items of personal protective equipment in fighting COVID-19 pandemic. They shall protect the wearer of the mask from particles, droplets, and aerosols, but they also can prevent the spread of aerosol-transmitted viruses if the wearer becomes infected. Most often, FFP respirators consist of multiple layers of non-woven fabric made from polypropylene. Worldwide, FFP respirators are subject to various regulatory standards that specify physical properties and performance characteristics. During the SARS-CoV-2 pandemic, health authorities have temporarily repealed standards for respirators. We report on 46 patients that presented with rhinitis-like symptoms strongly associated to the use of FFP masks. Some of them were obliged to use FFP masks in their work environment. Nasal endoscopy showed edemata of the nasal mucosa that significantly decreased after a period of non-use of FFP masks. Subjectively reported symptom levels decreased after cessation of FFP use for 3 or more days. The presence of polypropylene fibres isolated from nasal rinsing solution was significantly associated with the use of FFP masks in our patients. Material safety and performance deregulation of FFP masks can pose a health risk. Thus, especially health care professionals and other individuals with occupational need for FFP masks should be aware of possible hazards that come with COVID-19 pandemic protection measures.
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http://dx.doi.org/10.1016/j.waojou.2020.100474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538121PMC
October 2020

Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: Position paper of Ärzteverband Deutscher Allergologen (AeDA), Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI), Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA), Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI), Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI), Österreichische Gesellschaft für Pneumologie (ÖGP) in co-operation with the German, Austrian, and Swiss ARIA groups, and the European Academy of Allergy and Clinical Immunology (EAACI).

Authors:
Ludger Klimek Oliver Pfaar Margitta Worm Thomas Eiwegger Jan Hagemann Markus Ollert Eva Untersmayr Karin Hoffmann-Sommergruber Alessandra Vultaggio Ioana Agache Sevim Bavbek Apostolos Bossios Ingrid Casper Susan Chan Alexia Chatzipetrou Christian Vogelberg Davide Firinu Paula Kauppi Antonios Kolios Akash Kothari Andrea Matucci Oscar Palomares Zsolt Szépfalusi Wolfgang Pohl Wolfram Hötzenecker Alexander R Rosenkranz Karl-Christian Bergmann Thomas Bieber Roland Buhl Jeroen Buters Ulf Darsow Thomas Keil Jörg Kleine-Tebbe Susanne Lau Marcus Maurer Hans Merk Ralph Mösges Joachim Saloga Petra Staubach Uta Jappe Klaus F Rabe Uta Rabe Claus Vogelmeier Tilo Biedermann Kirsten Jung Wolfgang Schlenter Johannes Ring Adam Chaker Wolfgang Wehrmann Sven Becker Laura Freudelsperger Norbert Mülleneisen Katja Nemat Wolfgang Czech Holger Wrede Randolf Brehler Thomas Fuchs Peter-Valentin Tomazic Werner Aberer Antje-Henriette Fink-Wagner Fritz Horak Stefan Wöhrl Verena Niederberger-Leppin Isabella Pali-Schöll Wolfgang Pohl Regina Roller-Wirnsberger Otto Spranger Rudolf Valenta Mübecell Akdis Paolo M Matricardi François Spertini Nicolai Khaltaev Jean-Pierre Michel Larent Nicod Peter Schmid-Grendelmeier Marco Idzko Eckard Hamelmann Thilo Jakob Thomas Werfel Martin Wagenmann Christian Taube Erika Jensen-Jarolim Stephanie Korn Francois Hentges Jürgen Schwarze Liam O Mahony Edward F Knol Stefano Del Giacco Tomás Chivato Pérez Jean Bousquet Anna Bedbrook Torsten Zuberbier Cezmi Akdis Marek Jutel

Allergol Select 2020 7;4:53-68. Epub 2020 Sep 7.

European Academy of Allergy and Clinical Immunology (EAACI).

Background: Since the beginning of the COVID-19 pandemic, the treatment of patients with allergic and atopy-associated diseases has faced major challenges. Recommendations for "social distancing" and the fear of patients becoming infected during a visit to a medical facility have led to a drastic decrease in personal doctor-patient contacts. This affects both acute care and treatment of the chronically ill. The immune response after SARS-CoV-2 infection is so far only insufficiently understood and could be altered in a favorable or unfavorable way by therapy with monoclonal antibodies. There is currently no evidence for an increased risk of a severe COVID-19 course in allergic patients. Many patients are under ongoing therapy with biologicals that inhibit type 2 immune responses via various mechanisms. There is uncertainty about possible immunological interactions and potential risks of these biologicals in the case of an infection with SARS-CoV-2.

Materials And Methods: A selective literature search was carried out in PubMed, Livivo, and the internet to cover the past 10 years (May 2010 - April 2020). Additionally, the current German-language publications were analyzed. Based on these data, the present position paper provides recommendations for the biological treatment of patients with allergic and atopy-associated diseases during the COVID-19 pandemic.

Results: In order to maintain in-office consultation services, a safe treatment environment must be created that is adapted to the pandemic situation. To date, there is a lack of reliable study data on the care for patients with complex respiratory, atopic, and allergic diseases in times of an imminent infection risk from SARS-CoV-2. Type-2-dominant immune reactions, as they are frequently seen in allergic patients, could influence various phases of COVID-19, e.g., by slowing down the immune reactions. Theoretically, this could have an unfavorable effect in the early phase of a SARS-Cov-2 infection, but also a positive effect during a cytokine storm in the later phase of severe courses. However, since there is currently no evidence for this, all data from patients treated with a biological directed against type 2 immune reactions who develop COVID-19 should be collected in registries, and their disease courses documented in order to be able to provide experience-based instructions in the future.

Conclusion: The use of biologicals for the treatment of bronchial asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and spontaneous urticaria should be continued as usual in patients without suspected infection or proven SARS-CoV-2 infection. If available, it is recommended to prefer a formulation for self-application and to offer telemedical monitoring. Treatment should aim at the best possible control of difficult-to-control allergic and atopic diseases using adequate rescue and add-on therapy and should avoid the need for systemic glucocorticosteroids. If SARS-CoV-2 infection is proven or reasonably suspected, the therapy should be determined by weighing the benefits and risks individually for the patient in question, and the patient should be involved in the decision-making. It should be kept in mind that the potential effects of biologicals on the immune response in COVID-19 are currently not known. Telemedical offers are particularly desirable for the acute consultation needs of suitable patients.
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http://dx.doi.org/10.5414/ALX02166EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480069PMC
September 2020

[Cost minimization analysis of flexible ENT-endoscopes].

Laryngorhinootologie 2020 Jul 22. Epub 2020 Jul 22.

Hals-, Nasen-, Ohrenklinik und Poliklinik, Johannes-Gutenberg-Universität Mainz, Germany.

Background:  Reprocessing of complex instruments like flexible ENT-endoscopes with and without working channel are challanging for clinics and private practices. Aim of the study was to analyse the costs of an examination with a reusable endoscope-system and to compare it with two single-use endoscope-systems.

Material And Methods:  A cost minimization analysis was performed at the Department of Otorhinolaryngology, Head and Neck Surgery of the University Medical Center in Mainz, Germany. The local reusable endoscopy-system was compared with two single-use endoscopy-systems of Ambu and Karl Storz.

Results:  Overall costs per examination with a reusable-scope were 23.03 € (11.60 € investment costs + 5.09 € repair costs + 6.34 € reprocessing costs). The single-use Endoscopy-system of Ambu resulted in 120.43 € per examination (120.00 € acquisition costs + 0.43 € storage costs). Overall costs for the single-use endoscopy-system of Karl Storz were 223.44 € per examination (investment costs for monitors 3.01 € + 220.00 € acquisition costs + 0.43 € storage costs).

Discussion:  Flexible single-use ENT-endoscopy-systems generate higher costs in comparison to conventional reusable ones. But there are also advantages from the medical and economical side.

Conclusion:  A smart mix of reusable and single-use endoscopy systems seems therefore usefull.
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http://dx.doi.org/10.1055/a-1200-1859DOI Listing
July 2020

[Elevated Eosinophil Count Associated with Dupilumab Therapy in Patients with Type-2 Inflammation].

Laryngorhinootologie 2020 11 24;99(11):811-812. Epub 2020 Jun 24.

Hals-Nasen-Ohrenklinik und Poliklinik, Universitätsmedizin Mainz, Germany.

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http://dx.doi.org/10.1055/a-1200-1830DOI Listing
November 2020

Telemedicine allows quantitative measuring of olfactory dysfunction in COVID-19.

Allergy 2021 03 20;76(3):868-870. Epub 2020 Jul 20.

Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center, Mainz, Germany.

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http://dx.doi.org/10.1111/all.14467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361410PMC
March 2021

Anwendung von Biologika bei allergischen und Typ-2-entzündlichen Erkrankungen in der aktuellen Covid-19-Pandemie: Positionspapier des Ärzteverbands Deutscher Allergologen (AeDA)A, der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI)B, der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI)D, der Luxemburgischen Gesellschaft für Allergologie und Immunologie (LGAI)E, der Österreichischen Gesellschaft für Pneumologie (ÖGP)F in Kooperation mit der deutschen, österreichischen, und schweizerischen ARIA-GruppeG und der Europäischen Akademie für Allergologie und Klinische Immunologie (EAACI)H.

Allergo J 2020 24;29(4):14-27. Epub 2020 Jun 24.

Zentrum für Rhinologie & Allergologie, An den Quellen 10, 65183 Wiesbaden, Germany.

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http://dx.doi.org/10.1007/s15007-020-2553-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289636PMC
June 2020

Nano Meets Micro-Translational Nanotechnology in Medicine: Nano-Based Applications for Early Tumor Detection and Therapy.

Nanomaterials (Basel) 2020 Feb 22;10(2). Epub 2020 Feb 22.

Nanobiomedicine Department, University Medical Center Mainz/ENT, Langenbeckstrasse 1, 55131 Mainz, Germany.

Nanomaterials have great potential for the prevention and treatment of cancer. Circulating tumor cells (CTCs) are cancer cells of solid tumor origin entering the peripheral blood after detachment from a primary tumor. The occurrence and circulation of CTCs are accepted as a prerequisite for the formation of metastases, which is the major cause of cancer-associated deaths. Due to their clinical significance CTCs are intensively discussed to be used as liquid biopsy for early diagnosis and prognosis of cancer. However, there are substantial challenges for the clinical use of CTCs based on their extreme rarity and heterogeneous biology. Therefore, methods for effective isolation and detection of CTCs are urgently needed. With the rapid development of nanotechnology and its wide applications in the biomedical field, researchers have designed various nano-sized systems with the capability of CTCs detection, isolation, and CTCs-targeted cancer therapy. In the present review, we summarize the underlying mechanisms of CTC-associated tumor metastasis, and give detailed information about the unique properties of CTCs that can be harnessed for their effective analytical detection and enrichment. Furthermore, we want to give an overview of representative nano-systems for CTC isolation, and highlight recent achievements in microfluidics and lab-on-a-chip technologies. We also emphasize the recent advances in nano-based CTCs-targeted cancer therapy. We conclude by critically discussing recent CTC-based nano-systems with high therapeutic and diagnostic potential as well as their biocompatibility as a practical example of applied nanotechnology.
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http://dx.doi.org/10.3390/nano10020383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075286PMC
February 2020

Corrigendum to "Staging of oropharyngeal squamous cell carcinoma of the head and neck: Prognostic features and power of the 8th edition of the UICC staging manual" [Eur. J. Surg. Oncol. 45 (6) (2019) 1046-1053].

Eur J Surg Oncol 2019 Sep 12;45(9):1755-1756. Epub 2019 Jul 12.

Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Mainz, Germany; Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Regensburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.ejso.2019.07.006DOI Listing
September 2019

Structured reporting of head and neck ultrasound examinations.

BMC Med Imaging 2019 03 27;19(1):25. Epub 2019 Mar 27.

Department of Otorhinolaryngology, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.

Background: Reports of head and neck ultrasound examinations are frequently written by hand as free texts. Naturally, quality and structure of free text reports is variable, depending on the examiner's individual level of experience. Aim of the present study was to compare the quality of free text reports (FTR) and structured reports (SR) of head and neck ultrasound examinations.

Methods: Both standard FTRs and SRs of head and neck ultrasound examinations of 43 patients were acquired by nine independent examiners with comparable levels of experience. A template for structured reporting of head and neck ultrasound examinations was created using a web-based approach. FTRs and SRs were evaluated with regard to overall quality, completeness, required time to completion, and readability by four independent raters with different specializations (Paired Wilcoxon test, 95% CI) and inter-rater reliability was assessed (Fleiss' kappa). A questionnaire was used to compare FTRs vs. SRs with respect to user satisfaction (Mann-Whitney U test, 95% CI).

Results: By comparison, completeness scores of SRs were significantly higher than FTRs' completeness scores (94.4% vs. 45.6%, p < 0.001), and pathologies were described in more detail (91.1% vs. 54.5%, p < 0.001). Readability was significantly higher in all SRs when compared to FTRs (100% vs. 47.1%, p < 0.001). The mean time to complete a report, however, was significantly higher in SRs (176.5 vs. 107.3 s, p < 0.001). SRs achieved significantly higher user satisfaction ratings (VAS 8.87 vs. 1.41, p < 0.001) and a very high inter-rater reliability (Fleiss' kappa 0.92).

Conclusions: As compared to FTRs, SRs of head and neck ultrasound examinations are more comprehensive and easier to understand. On the balance, the additional time needed for completing a SR is negligible. Also, SRs yield high inter-rater reliability and may be used for high-quality scientific data analyses.
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http://dx.doi.org/10.1186/s12880-019-0325-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437950PMC
March 2019

Staging of oropharyngeal squamous cell carcinoma of the head and neck: Prognostic features and power of the 8th edition of the UICC staging manual.

Eur J Surg Oncol 2019 Jun 2;45(6):1046-1053. Epub 2019 Mar 2.

Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Mainz, Germany. Electronic address:

Introduction: Recognizing the prognostic power differentiating HPV-associated oropharyngeal squamous cell cancer (OPSCC) from OPSCC with other causes, the UICC Cancer Staging Manual 8th edition realizes significant changes from the 7th edition. Purpose of this study was to evaluate the differences of prognostic impact between the 7th and the latest edition of TNM Classification as well as to examine risk factors like extranodal extension (ENE) and lymph node ratio (LNR) for HPV-mediated OPSCC.

Material And Methods: The study includes 255 patients with OPSCC and initial diagnosis between 2008 and 2015. HPV status was determined according to p16 immunohistochemistry (IHC) and all patients were classified as defined by 7th and 8th edition of UICC. Prognostic influence of ENE and LNR was analyzed for patients with HPV-mediated OPSCC.

Results: 41.2% of the OPSCC were p16-positive. Implementation of the 8th edition of the UICC lead to a better differentiation between the respective stages. Regarding HPV-positive OPSCC, Kaplan-Meier survival curves showed a significantly better overall survival (OS) for patients with a LNR ≤10% as well as for patients with negative ENE status (p = 0.004, p = 0.008).

Conclusion: 8th edition of UICC achieves to differentiate properly between the UICC stages. However, the staging rule of ignoring ENE in HPV-mediated OPSCC should be further analyzed. Moreover LNR might be a possible additional prognostic factor - especially regarding HPV-positive tumors.
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http://dx.doi.org/10.1016/j.ejso.2019.02.032DOI Listing
June 2019

Long-term Outcome for Open and Endoscopically Resected Sinonasal Tumors.

Otolaryngol Head Neck Surg 2019 05 4;160(5):862-869. Epub 2018 Dec 4.

6 Department of Otorhinolaryngology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Objective: Endoscopic resection of sinonasal cancer has become an alternative to open craniofacial surgery and leads to safe and satisfying results in emerging numbers. Randomized study data comparing outcomes between approaches are missing. Hence, it remains unclear which subgroups of patients might profit most from each technique. We aimed to identify such patient and tumor characteristics and gather information for future prospective study design.

Study Design: Case series with chart review.

Setting: Tertiary academic center.

Subjects And Methods: This study is based on a retrospective chart review of 225 patients undergoing open craniofacial or endoscopic resection for sinonasal malignancy between 1993 and 2015 at Munich University Hospital. Statistical analyses include t test, chi-square, Kaplan-Meier charts, and univariate and multivariate analyses.

Results: The sample size was similar between the endoscopic and open surgery groups. Tumors were significantly larger in patients who underwent open craniofacial resection. The risk of notable bleeding ( P = .041) was lower and hospital stay shorter ( P = .001) for endoscopic interventions of all tumor stages. Rates of overall ( P = .024) and disease-specific ( P = .036) survival were significantly improved for endoscopic cases; improved recurrence-free survival rates did not achieve statistical significance ( P = .357). For cases matched for tumor size, this improvement was confirmed for T3 tumors ( P = .038). Regional and distant metastatic tumor spread generally worsened survival in both surgical subgroups. Multivariate Cox regression analysis revealed independent prognosticators for overall survival.

Conclusion: Endoscopic tumor resection remains a suitable option for distinct indications and showed improved outcome in intermediate-stage tumors in our collective. Further randomized studies acknowledging the here-identified factors are needed to improve future therapy guidelines and patient care.
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http://dx.doi.org/10.1177/0194599818815881DOI Listing
May 2019

Modulation of Exposure to Static Magnetic Field Affects Targeted Therapy of Solid Tumors .

Anticancer Res 2018 Aug;38(8):4549-4555

Department of Otorhinolaryngology, Head and Neck Surgery, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany.

Background: Static magnetic fields (SMF) exhibit antitumoral activity and enhance the efficacy of chemotherapy by opening the tumor-blood barrier. This study aimed to analyze different SMF-exposure protocols on epidermal growth factor receptor (EGFR)-overexpressing tumors, as well as their combination with cetuximab.

Materials And Methods: Experiments were performed in skinfold chamber preparations of C57Bl/6-and CD-1nu/nu mice bearing LLC-1 tumors. Animals were exposed to 587 mT magnetic field following different exposure protocols. A subgroup received additional cetuximab injections. Using in vivo-fluorescence microscopy and planimetry, tumor angiogenesis, growth and microcirculation were repeatedly analyzed for 13 days.

Results: In contrast to daily short SMF exposure, three-fold SMF exposure for 2 h led to a significant 46% reduction of tumor growth. Adding cetuximab to SMF exposure did not yield any benefit, although cetuximab monotherapy was highly effective (53% reduction of tumor growth), indicating a potential interference of SMF and EGFR signaling. No effects on microcirculation, angiogenesis or leukocyte-endothelium interactions were documented.

Conclusion: The use of SMF is promising in the treatment of solid tumors; however, it appears to interfere with EGFR-targeted therapy.
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http://dx.doi.org/10.21873/anticanres.12759DOI Listing
August 2018

[Essential principles for evaluation and management of upper airway stenoses in children and adults].

MMW Fortschr Med 2018 Jul;160(13):51-54

Klinikum der Universität München, München, Deutschland.

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http://dx.doi.org/10.1007/s15006-018-0773-9DOI Listing
July 2018

Therapy Testing in a Spheroid-based 3D Cell Culture Model for Head and Neck Squamous Cell Carcinoma.

J Vis Exp 2018 04 20(134). Epub 2018 Apr 20.

Department of Otorhinolaryngology, Johannes-Gutenberg University Medical Center; Department of Otorhinolaryngology, Ludwig-Maximilian-University Medical Center.

Current treatment options for advanced and recurrent head and neck squamous cell carcinoma (HNSCC) enclose radiation and chemo-radiation approaches with or without surgery. While platinum-based chemotherapy regimens currently represent the gold standard in terms of efficacy and are given in the vast majority of cases, new chemotherapy regimens, namely immunotherapy are emerging. However, the response rates and therapy resistance mechanisms for either chemo regimen are hard to predict and remain insufficiently understood. Broad variations of chemo and radiation resistance mechanisms are known to date. This study describes the development of a standardized, high-throughput in vitro assay to assess HNSCC cell line's response to various therapy regimens, and hopefully on primary cells from individual patients as a future tool for personalized tumor therapy. The assay is designed to being integrated into the quality-controlled standard algorithm for HNSCC patients at our tertiary care center; however, this will be subject of future studies. Technical feasibility looks promising for primary cells from tumor biopsies from actual patients. Specimens are then transferred into the laboratory. Biopsies are mechanically separated followed by enzymatic digestion. Cells are then cultured in ultra-low adhesion cell culture vials that promote the reproducible, standardized and spontaneous formation of three-dimensional, spheroid-shaped cell conglomerates. Spheroids are then ready to be exposed to chemo-radiation protocols and immunotherapy protocols as needed. The final cell viability and spheroid size are indicators of therapy susceptibility and therefore could be drawn into consideration in future to assess the patients' likely therapy response. This model could be a valuable, cost-efficient tool towards personalized therapy for head and neck cancer.
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http://dx.doi.org/10.3791/57012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100693PMC
April 2018

Prognostic value of the lymph node ratio in oropharyngeal carcinoma stratified for HPV-status.

Eur Arch Otorhinolaryngol 2018 Feb 4;275(2):515-524. Epub 2017 Dec 4.

Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-Universität, Marchioninistr. 15, 81377, Munich, Germany.

Objective: Lymph node ratio (LNR) was shown to be a prognostic factor in laryngeal and oral cavity primaries. The purpose of this study was to investigate the impact of the lymph node ratio in oropharyngeal squamous cell carcinoma (OPSCC) with a high incidence of HPV-related disease. Therefore, the role of LNR was evaluated as an additional predictive parameter to the 8th edition of AJCC TNM staging system.

Methods: From December 2009 to August 2015, patients diagnosed with primary oropharyngeal squamous cell carcinoma were prospectively enrolled. After tumor resection with uni- or bilateral neck dissection, patients with ≥ 1 nodal metastasis (pN+) were eligible for a retrospective LNR analysis.

Results: 137 patients underwent tumor resection with uni- or bilateral neck dissection. The proportion of HPV-associated disease was 42%. Most patients (n = 96; 70%) presented with involved neck nodes. In p16-positive OPSCC, the rate of pN + cases was significantly increased compared to p16-negative OPSCC (86% vs. 58%, p = 0.007). Patients with LNR ≤ 10% had a significant better overall survival (OS) and disease-specific survival (DSS). However, when stratified for p16-status, LNR ≤ 10% had a significant impact on OS only for HPV-associated tumors (p = 0.027), whereas LNR of ≤ 10% was not a significant predictor for better OS in p16-negative OPSCC (p = 0.143).

Conclusion: The LNR with a cut-off value of 10% serves as an additional prognostic parameter in HPV-related OPSCC and may help to improve risk stratification in combination with the revised AJCC 8th edition TNM classification.
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http://dx.doi.org/10.1007/s00405-017-4833-zDOI Listing
February 2018

Disease-relevant signalling-pathways in head and neck cancer: Taspase1's proteolytic activity fine-tunes TFIIA function.

Sci Rep 2017 11 2;7(1):14937. Epub 2017 Nov 2.

Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany.

Head and neck cancer (HNC) is the seventh most common malignancy in the world and its prevailing form, the head and neck squamous cell carcinoma (HNSCC), is characterized as aggressive and invasive cancer type. The transcription factor II A (TFIIA), initially described as general regulator of RNA polymerase II-dependent transcription, is part of complex transcriptional networks also controlling mammalian head morphogenesis. Posttranslational cleavage of the TFIIA precursor by the oncologically relevant protease Taspase1 is crucial in this process. In contrast, the relevance of Taspase1-mediated TFIIA cleavage during oncogenesis of HNSCC is not characterized yet. Here, we performed genome-wide expression profiling of HNSCC which revealed significant downregulation of the TFIIA downstream target CDKN2A. To identify potential regulatory mechanisms of TFIIA on cellular level, we characterized nuclear-cytoplasmic transport and Taspase1-mediated cleavage of TFIIA variants. Unexpectedly, we identified an evolutionary conserved nuclear export signal (NES) counteracting nuclear localization and thus, transcriptional activity of TFIIA. Notably, proteolytic processing of TFIIA by Taspase1 was found to mask the NES, thereby promoting nuclear localization and transcriptional activation of TFIIA target genes, such as CDKN2A. Collectively, we here describe a hitherto unknown mechanism how cellular localization and Taspase1 cleavage fine-tunes transcriptional activity of TFIIA in HNSCC.
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http://dx.doi.org/10.1038/s41598-017-14814-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668323PMC
November 2017

Spheroid-based 3D Cell Cultures Enable Personalized Therapy Testing and Drug Discovery in Head and Neck Cancer.

Anticancer Res 2017 05;37(5):2201-2210

Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of Johannes-Gutenberg University, Mainz, Germany

Background/aim: Chemo-radiation currently serves as first-line therapy of advanced and recurrent head and neck cancer, while new chemotherapy regimens are emerging. However, response rates to any treatment are difficult to predict and underlie broad variation. This study shows the development of a standardized, high-throughput in vitro assay to assess patients' individual response to therapy regimens as a future tool for personalized tumor therapy.

Materials And Methods: Viability and proliferation analyses after chemo +/- radiation treatment of single spheroids (low adhesion plates/Hanging Drop (HD)) were generated from head and neck squamous cell carcinoma (HNSCC) cell lines and primary human cells from fresh tumor specimens.

Results: All cell lines showed reliable growth in all cell culture methods. The spheroids showed significant delay of growth and/or necrosis compared to control groups when exposed to current standard chemotherapeutic regimens. Single 3D spheroids ready for therapy susceptibility testing could be generated from actual tumor specimens after enzymatic and mechanical separation.

Conclusion: In its current form, this single spheroid-based in vitro assay was able to test individual therapy susceptibility to current standard therapy regimens or, potentially, for testing new targeted drugs in HNSCC treatment. With recent discoveries regarding tumor heterogeneity and individual mutation status, a reliable assay is a prerequisite for personalized therapy in head and neck cancer.
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http://dx.doi.org/10.21873/anticanres.11555DOI Listing
May 2017

Toll-like receptor 4-induced IL-22 accelerates kidney regeneration.

J Am Soc Nephrol 2014 May 23;25(5):978-89. Epub 2014 Jan 23.

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Munich, Germany; and

AKI involves early Toll-like receptor (TLR)-driven immunopathology, and resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, activation of TLRs also has been implicated in epithelial repair. We hypothesized that TLR signaling drives tubule regeneration after acute injury through the induction of certain ILs. Systematic screening in vitro identified IL-22 as a candidate proregeneratory factor in primary tubular cell recovery, and IL-22 deficiency or IL-22 blockade impaired post-ischemic tubular recovery after AKI in mice. Interstitial mononuclear cells, such as dendritic cells and macrophages, were the predominant source of IL-22 secretion, whereas IL-22 receptor was expressed by tubular epithelial cells exclusively. Depleting IL-22-producing cells during the healing phase impaired epithelial recovery, which could be rescued entirely by reconstituting mice with IL-22. In vitro, necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4. Although TLR4 blockade during the early injury phase prevented tubular necrosis and AKI, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration. Taken together, these results suggest that necrotic cell-derived TLR4 agonists activate intrarenal mononuclear cells to secrete IL-22, which accelerates tubular regeneration and recovery in AKI.
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http://dx.doi.org/10.1681/ASN.2013050528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005301PMC
May 2014

Danger control programs cause tissue injury and remodeling.

Int J Mol Sci 2013 May 28;14(6):11319-46. Epub 2013 May 28.

Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV der Ludwig-Maximilians Universität, München 80336, Germany.

Are there common pathways underlying the broad spectrum of tissue pathologies that develop upon injuries and from subsequent tissue remodeling? Here, we explain the pathophysiological impact of a set of evolutionary conserved danger control programs for tissue pathology. These programs date back to the survival benefits of the first multicellular organisms upon traumatic injuries by launching a series of danger control responses, i.e., 1. Haemostasis, or clotting to control bleeding; 2. Host defense, to control pathogen entry and spreading; 3. Re-epithelialisation, to recover barrier functions; and 4. Mesenchymal, to repair to regain tissue stability. Taking kidney pathology as an example, we discuss how clotting, inflammation, epithelial healing, and fibrosis/sclerosis determine the spectrum of kidney pathology, especially when they are insufficiently activated or present in an overshooting and deregulated manner. Understanding the evolutionary benefits of these response programs may refine the search for novel therapeutic targets to limit organ dysfunction in acute injuries and in progressive chronic tissue remodeling.
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http://dx.doi.org/10.3390/ijms140611319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709734PMC
May 2013

Nrf2 signalling promotes ex vivo tubular epithelial cell survival and regeneration via murine double minute (MDM)-2.

Nephrol Dial Transplant 2013 Aug 8;28(8):2028-37. Epub 2013 Mar 8.

Renal Division, Medizinische Klinik und Poliklinik IV, Ludwig Maximilian University of Munich, Munich, Germany.

Background: Tubular repair upon injury involves regeneration from either surviving tubular epithelial cells or from their surviving local progenitor cells; hence, compound screening with cell lines may be inadequate. Here, we demonstrate that the renal cell isolation procedure and subsequent outgrowth of tubular cells can mimic the renal injury phase and tubular cell regeneration from whichever surviving renal cells.

Methods: We set up assays to systematically screen and identify mediators of tubular survival and repair.

Results: Forty-eight hours after plating total kidney isolates from C57BL/6 mice, 69% of cells survived when prepared from 2-week-old pups, but only 4% of cells from 8-week-old mice, respectively. This poor survival was not modulated by co-incubation with any of 24 cytokines and growth factors, except for the Nrf2 agonist sulforaphane. In addition, only sulforaphane enhanced the regenerative outgrowth of tubular epithelial cells from the mixed population. Furthermore, sulforaphane enhanced wound closure upon scratching tubular epithelial cell monolayers in a dose-dependent manner. This process was associated with the induction of the tested Nrf2 target genes HO-1, NQO1 and murine-double minute 2 (MDM2). MDM2 blockade with nutlin-3a completely blocked the protective effects of sulforaphane on renal cell survival, outgrowth and wound closure.

Conclusions: Together, renal cell isolation is a model of acute kidney injury (AKI). Primary tubular epithelial cell outgrowth represents a model of tubular regeneration. Nrf2 activation can enhance renal cell survival and tubular repair by inducing the cell cycle regulator MDM2.
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http://dx.doi.org/10.1093/ndt/gft037DOI Listing
August 2013

Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4.

J Am Soc Nephrol 2012 Aug 7;23(8):1375-88. Epub 2012 Jun 7.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Pettenkoferstr. 8a, D-80336 Munich, Germany.

In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF-κB, and mitogen activated protein kinase signaling. Extracellular histones also had directly toxic effects on renal endothelial cells and tubular epithelial cells in vitro. In addition, direct injection of histones into the renal arteries of mice demonstrated that histones induce leukocyte recruitment, microvascular vascular leakage, renal inflammation, and structural features of AKI in a TLR2/TLR4-dependent manner. Antihistone IgG, which neutralizes the immunostimulatory effects of histones, suppressed intrarenal inflammation, neutrophil infiltration, and tubular cell necrosis and improved excretory renal function. In summary, the release of histones from dying cells aggravates AKI via both its direct toxicity to renal cells and its proinflammatory effects. Because the induction of proinflammatory cytokines in dendritic cells requires TLR2 and TLR4, these results support the concept that renal damage triggers an innate immune response, which contributes to the pathogenesis of AKI.
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http://dx.doi.org/10.1681/ASN.2011111077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402284PMC
August 2012