Publications by authors named "Sebastian Strieth"

74 Publications

TNF-α-Inhibition Improves the Biocompatibility of Porous Polyethylene Implants In Vivo.

Tissue Eng Regen Med 2021 04 30;18(2):297-303. Epub 2021 Jan 30.

Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University Munich, Marchioninistr. 27, 81377, Munich, Germany.

Background: To improve the biocompatibility of porous polyethylene (PPE) implants and expand their application range for reconstructive surgery in poorly vascularized environments, implants were coated with tumor necrosis factor α (TNFα) inhibitor Etanercept. While approved for systemic application, local application of the drug is a novel experimental approach. Microvascular and mechanical integration as well as parameters of inflammation were analyzed in vivo.

Methods: PPE implants were coated with Etanercept and extracellular matrix (ECM) components prior to implantation into dorsal skinfold chambers of C57BL/6 mice. Fluorescence microscopy analyses of angiogenesis and local inflammatory response were thrice performed in vivo over a period of 14 days to assess tissue integration and biocompatibility. Uncoated implants and ECM-coated implants served as controls.

Results: TNFα inhibition with Etanercept led to a reduced local inflammatory response: leukocyte-endothelial cell adherence was significantly lowered compared to both control groups (n = 6/group) on days 3 and 14, where the lowest values were reached: 3573.88 leukocytes/mm-2 ± 880.16 (uncoated implants) vs. 3939.09 mm-2 ± 623.34 (Matrigel only) vs. 637.98 mm-2 + 176.85 (Matrigel and Etanercept). Implant-coating with Matrigel alone and Matrigel and Etanercept led to significantly higher vessel densities 7 and 14 days vs. 3 days after implantation and compared to uncoated implants. Mechanical implant integration as measured by dynamic breaking strength did not differ after 14 days.

Conclusion: Our data show a reduced local inflammatory response to PPE implants after immunomodulatory coating with Etanercept in vivo, suggesting improved biocompatibility. Application of this tissue engineering approach is therefore warranted in models of a compromised host environment.
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http://dx.doi.org/10.1007/s13770-020-00325-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012447PMC
April 2021

The DNA methylation landscape of () and adjacent lncRNA in head and neck squamous cell carcinoma.

Epigenomics 2021 Jan 22;13(2):113-127. Epub 2020 Dec 22.

Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Bonn, 53127 Bonn, Germany.

expression is associated with DNA methylation in head and neck squamous cell carcinomas (HNSCCs). We performed methylation analysis at single CpG site resolution in order to understand epigenetic regulation. CpG methylation analysis of and long non-coding RNA (lncRNA) was performed in n = 528 HNSCCs and n = 50 normal adjacent tissues provided by The Cancer Genome Atlas and in isolated leukocytes. mRNA and lncRNA expression correlated inversely with promoter and positively with gene body CpG methylation. and are co-expressed. Methylation was sequence-contextually associated with human papillomavirus prognosis, mutational load, and immune infiltrates. The significance of and methylation is highly sequence-contextual. might play a role in HNSCC.
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http://dx.doi.org/10.2217/epi-2020-0208DOI Listing
January 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

CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab).

Cancer Immunol Immunother 2020 Nov 16. Epub 2020 Nov 16.

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Venusberg-Campus, 53127, Bonn, Germany.

Anti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy.
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http://dx.doi.org/10.1007/s00262-020-02777-4DOI Listing
November 2020

The German hearing in noise test.

Int J Audiol 2020 Oct 29:1-7. Epub 2020 Oct 29.

Division of Audiology, Department of Otorhinolaryngology, University Hospital LMU Munich, Munich, Germany.

Objectives: The aims of this study were to develop a German Hearing In Noise Test (HINT) using the same methodology as with previous HINT tests; to develop sentence lists for measuring speech reception thresholds (SRTs); and to determine test-retest reliability and norms for measures obtained under headphones.

Design: The following steps were followed: develop and record sentences, synthesise masking noise, determine the performance-intensity (PI) function, equalise sentence difficulty in the masking noise. Form sentence lists of equal difficulty. Measure SRTs for normal hearing individuals to determine practice/learning effects, test-retest reliability, and norms.

Study Sample: Three groups of adults (median age = 25 years) with average better ear pure-tone averages (PTAs) ≤ 5 dB HL participated.

Results: The 12 20-sentence lists were well-matched phonemically and did not differ significantly in difficulty. Test-retest reliability 95% confidence intervals ranged from 1.3 to 2.5 dB. Norms in quiet and in noise exhibited the same pattern as those for other HINT languages. German norms were approximately 2 dB lower than other languages in the noise conditions.

Conclusions: The German HINT materials are comparable to those for other languages and are partially consistent with recommendations for construction of multilingual speech tests. They can be used for comparing and pooling research results from the international research community.
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http://dx.doi.org/10.1080/14992027.2020.1837969DOI Listing
October 2020

Evaluation of optimal education level to implement structured reporting into ultrasound training.

Med Ultrason 2020 Nov 12;22(4):445-450. Epub 2020 Jul 12.

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

Aims: Reporting of head and neck ultrasound (HNU) has been outlined to be a major obstacle during ultrasound training due to a lack of standardized structure, content and terminology. Consequently, overall report quality differs significantly between various examiners posing a severe risk factor for information loss and miscommunication. Therefore, the present study's purpose is to compare the overall quality of free text reports (FTR) and structured reports (SR) of HNU at various stages of training in order to determine the optimal educational level to implement SR.

Material And Methods: Typical pathologies in HNU were reported upon using SR and FTR by medical students, junior residents and senior residents. The reports were assessed for overall quality, time efficiency and readability. Additionally, user satisfaction was determined using a questionnaire.

Results: SRs exhibited a significantly superior report quality (93.1% vs. 45.6%, p<0.001) at all training levels. Overall time efficiency was significantly better for SRs, especially at the stages of medical school and early residency (89.4 s vs. 160.2 s., p<0.001). Using structured reporting also increased user satisfaction significantly (VAS 8.6 vs. 3.9, p<0.001).

Conclusions: Implementing structured reporting of HNU results in a superior report quality at all training stages. Greatest benefits for time efficiency are achieved by implementation during medical school. Therefore, structured reporting of HNU should be implemented early on in the training of HNU.
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http://dx.doi.org/10.11152/mu-2530DOI Listing
November 2020

Molecular, clinicopathological, and immune correlates of LAG3 promoter DNA methylation in melanoma.

EBioMedicine 2020 Sep 30;59:102962. Epub 2020 Aug 30.

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Electronic address:

Background: The co-receptor lymphocyte-activation gene-3 (LAG3, LAG-3, CD223) is a potential target for immune checkpoint inhibition immunotherapies. However, little is known about the biological and clinical significance of LAG3 DNA methylation in melanoma and its microenvironment.

Methods: We evaluated LAG3 promoter and gene body methylation in a cohort of N = 470 melanoma patients obtained from The Cancer Genome Atlas (TCGA cohort), an independent cohort of N = 120 patients from the University Hospital Bonn, and in subsets of peripheral blood leukocytes, melanocytes, and melanoma cell lines. We validated the association of LAG3 methylation with mRNA expression in vitro in the melanoma cell line A375 treated with the hypomethylating agent 5-azacytidine and stimulated with interferon-γ. Finally, we investigated correlations between LAG3 methylation and progression-free survival in patients treated with immune checkpoint blockade (ICB cohort, N = 118).

Findings: Depending on the analysed locus (promoter, gene body) we found region-dependent significant LAG3 methylation differences between monocytes, B cells, CD8 and CD4 T cells, regulatory T cells, melanocytes, and melanoma cell lines. In tumor tissues, methylation correlated significantly with LAG3 mRNA expression, immune cell infiltrates (histopathologic lymphocyte score and RNA-Seq signatures of distinct immune infiltrates), and an interferon-γ signature. Finally, LAG3 methylation was associated with overall survival in the TCGA cohort and progression-free survival in the ICB cohort. We detected basal LAG3 mRNA expression in the melanoma cell A375 and an interferon-γ inducible expression after demethylation with 5-azacytidine.

Interpretation: Our study points towards an epigenetic regulation of LAG3 via promoter methylation and suggests a prognostic and predictive significance of LAG3 methylation in melanoma. Our results give insight in the tumor cell-intrinsic transcriptional regulation of LAG3 in melanoma. In perspective, our results might pave the way for investigating LAG3 methylation as a predictive biomarker for response to anti-LAG3 immune checkpoint blockage.

Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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http://dx.doi.org/10.1016/j.ebiom.2020.102962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475111PMC
September 2020

, , and DNA methylation in papillary thyroid carcinoma.

Immunotherapy 2020 08 20;12(12):903-920. Epub 2020 Jul 20.

Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Bonn, 53127 Bonn, Germany.

We investigated DNA methylation patterns of immune checkpoint genes , , , and an adjacent long noncoding RNA in papillary thyroid carcinoma (PTC). DNA methylation and mRNA expression were examined in PTCs. DNA methylation was correlated with mRNA expression, and mutational status, and immune cell infiltration. Inverse correlations between DNA methylation and mRNA expression were observed. Immune checkpoint expression correlated positively, and DNA methylation negatively, with immune cell infiltration. Higher DNA methylation levels accompanied by lower immune checkpoint expression were observed in -mutated tumors. We suggest epigenetic regulation of immune checkpoints in PTC. Methylation was associated with and mutation status. DNA methylation might be a promising biomarker candidate in the context of immunotherapies in PTC.
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http://dx.doi.org/10.2217/imt-2020-0037DOI Listing
August 2020

Prognostic and predictive value of PD-L2 DNA methylation and mRNA expression in melanoma.

Clin Epigenetics 2020 06 26;12(1):94. Epub 2020 Jun 26.

Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.

Background: PD-L1 (programmed cell death 1 ligand 1) expression in melanoma has been associated with a better response to anti-PD-1 (programmed cell death 1) therapy. However, patients with PD-L1-negative melanomas can respond to anti-PD-1 blockade, suggesting that the other PD-1 ligand, PD-L2 (programmed cell death 1 ligand 2), might also be relevant for efficacy of PD-1 inhibition. We investigated PD-L2 expression and methylation as a prognostic and predictive biomarker in melanoma.

Methods: DNA methylation at five CpG loci and gene expression of PD-L2 were evaluated with regard to survival in 470 melanomas from The Cancer Genome Atlas. PD-L2 promoter methylation in correlation with PD-L2 mRNA and protein expression was analyzed in human melanoma cell lines. Prognostic and predictive value of PD-L2 methylation was validated using quantitative methylation-specific PCR in a multicenter cohort of 129 melanoma patients receiving anti-PD-1 therapy. mRNA sequencing data of 121 melanoma patients receiving anti-PD-1 therapy provided by Liu et al. were analyzed for PD-L2 mRNA expression.

Results: We found significant correlations between PD-L2 methylation and mRNA expression levels in melanoma tissues and cell lines. Interferon-γ inducible PD-L2 protein expression correlated with PD-L2 promoter methylation in melanoma cells. PD-L2 DNA promoter hypomethylation and high mRNA expression were found to be strong predictors of prolonged overall survival. In pre-treatment melanoma samples from patients receiving anti-PD-1 therapy, low PD-L2 DNA methylation and high PD-L2 mRNA expression predicted longer progression-free survival.

Conclusion: PD-L2 expression seems to be regulated via DNA promoter methylation. PD-L2 DNA methylation and mRNA expression may predict progression-free survival in melanoma patients receiving anti-PD-1 immunotherapy. Assessment of PD-L2 should be included in further clinical trials with anti-PD-1 antibodies.
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http://dx.doi.org/10.1186/s13148-020-00883-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318478PMC
June 2020

ARIA guideline 2019: treatment of allergic rhinitis in the German health system.

Allergol Select 2019 30;3(1):22-50. Epub 2019 Dec 30.

Department of Dermatology, University Medical Center Mainz,Mainz, Germany.

Background: The number of patients affected by allergies is increasing worldwide. The resulting allergic diseases are leading to significant costs for health care and social systems. Integrated care pathways are needed to enable comprehensive care within the national health systems. The ARIA (Allergic Rhinitis and its Impact on Asthma) initiative develops internationally applicable guidelines for allergic respiratory diseases.

Methods: ARIA serves to improve the care of patients with allergies and chronic respiratory diseases. In collaboration with other international initiatives, national associations and patient organizations in the field of allergies and respiratory diseases, real-life integrated care pathways have been developed for a digitally assisted, integrative, individualized treatment of allergic rhinitis (AR) with comorbid asthma. In the present work, these integrated care pathways have been adapted to the German situation and health system.

Results: The present ICP (integrated care pathway) guideline covers key areas of the care of AR patients with and without asthma. It includes the views of patients and other healthcare providers.

Discussion: A comprehensive ICP guideline can reflect real-life care better than traditional guideline models.
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http://dx.doi.org/10.5414/ALX02120EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066682PMC
December 2019

[Therapy of Allergies and Allergy Immunotherapy in Children].

Laryngorhinootologie 2020 01 14;99(1):56-66. Epub 2020 Jan 14.

Adequate diagnostical workup for respiratory allergies and consequent therapy in children determine the individual course of disease. Therapy consists first of symptomatic treatment and includes in the next step the important option of allergy immunotherapy (AIT) as a causative treatment of disease. Children are an important target group for AIT, since AIT offers a proven longterm effect including secondary preventive properties with not only transiently reduced symptoms but moreover longstanding and beneficial disease modification.New strategies with AIT as primary and secondary preventive interventions are being evaluated with the aim to reduce clinical appearance and the amount and extent of sensitizations to allergens in high-risk children. Until implementation of such potentially preventive strategies the currently more attractive early intervention is the early adoption of AIT within the first 12 to 24 months of onset of symptoms as a first-line treatment of allergic rhinitis.Simplified treatment protocols can improve the willingness to perform an AIT and the adherence and compliance of children and their parents. The overall goal is to make AIT as the most important treatment modality available to more affected children.
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http://dx.doi.org/10.1055/a-0899-1202DOI Listing
January 2020

The use of structured reporting of head and neck ultrasound ensures time-efficiency and report quality during residency.

Eur Arch Otorhinolaryngol 2020 Jan 14;277(1):269-276. Epub 2019 Oct 14.

Department of Otorhinolaryngology, Head and Neck Surgery, University of Tübingen Medical Center, 72076, Tübingen, Germany.

Purpose: Free text reports (FTR) of head and neck ultrasound studies are currently deployed in most departments. Because of a lack of composition and language, these reports vary greatly in terms of quality and reliability. This may impair the learning process during residency. The purpose of the study was to analyze the longitudinal effects of using structured reports (SR) of head and neck ultrasound studies during residency.

Methods: Attending residents (n = 24) of a tripartite course on head and neck ultrasound, accredited by the German Society for Ultrasound in Medicine (DEGUM), were randomly allocated to pictures of common diseases. Both SRs and FTRs were compiled. All reports were analyzed concerning completeness, acquired time and legibility. Overall user contentment was evaluated by a questionnaire.

Results: SRs achieved significantly higher ratings regarding completeness (95.6% vs. 26.4%, p < 0.001), description of pathologies (72.2% vs. 58.9%, p < 0.001) and legibility (100% vs. 52.4%, p < 0.001) with a very high inter-rater reliability (Fleiss' kappa 0.9). Reports were finalized significantly faster (99.1 s vs. 115.0 s, p < 0.001) and user contentment was significantly better when using SRs (8.3 vs. 6.3, p < 0.001). In particular, only SRs showed a longitudinally increasing time efficiency (- 20.1 s, p = 0.036) while maintaining consistent completeness ratings.

Conclusions: The use of SRs of head and neck ultrasound studies results in an increased longitudinal time-efficiency while upholding the report quality at the same time. This may indicate an additive learning effect of structured reporting. Superior outcomes in terms of comprehensiveness, legibility and time-efficiency can be observed immediately after implementation.
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http://dx.doi.org/10.1007/s00405-019-05679-zDOI Listing
January 2020

A psychoacoustic application for the adjustment of electrical hearing thresholds in cochlear implant patients.

PLoS One 2019 11;14(10):e0223625. Epub 2019 Oct 11.

Division of Audiological Acoustics, Department of Otolaryngology, University Medical Center, Mainz, Germany.

Objective: Fitting cochlear implants, especially the precise determination of electrical hearing thresholds, is a time-consuming and complex task for patients as well as audiologists. Aim of the study was to develop a method that enables cochlear implant (CI) patients to determine their electrical hearing thresholds precisely and independently. Applicability and impact of this method on speech perception in noise at soft speech levels were evaluated.

Method: An adaptive psychoacoustic procedure for precise hearing threshold determination (precT) was implemented using MatLab (MathWorks) and a graphical user interface was created. Sound signals were calibrated with a CIC4-Implant-Decoder. Study design: A prospective study including 15 experienced adult cochlear implant users was conducted. Electrical hearing thresholds were determined using the automated precT procedure (auto-precT). Speech perception in noise at 50 dB SPL presentation levels was measured for three conditions: (P1) T-levels kept at the previously established T-levels; (P2) T-levels set to the hearing thresholds determined using auto-precT application; (P3) T-levels set 10 cu below the values determined with auto-precT.

Results: All subjects were able to perform the auto-precT application independently. T-levels were altered on average by an absolute value of 10.5 cu using auto-precT. Median speech reception thresholds were significantly improved from 2.5 dB SNR (P1) to 1.6 dB SNR (P2, p = 0.02). Speech perception was lowest using the globally lowered T-levels, median 2.9 dB SNR (P3, not significant compared to P1 and P2).

Conclusion: The applicability of the developed auto-precT application was confirmed in the present clinical study. Patients benefited from adjusting previously established T-levels to the threshold levels determined by the auto-precT application. The integration of the application in the clinical fitting routine as well as a remote fitting software approach is recommended. Furthermore, future possibilities of auto-precT include the implementation of the application on tablets or smart phones.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223625PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788687PMC
March 2020

Early Alterations of Endothelial Nitric Oxide Synthase Expression Patterns in the Guinea Pig Cochlea After Noise Exposure.

J Histochem Cytochem 2019 11 11;67(11):845-855. Epub 2019 Sep 11.

Department of Otorhinolaryngology, University Medical Center Mainz, Mainz, Germany.

Constitutively expressed endothelial nitric oxide synthase (eNOS) is supposed to play a role in noise-induced nitric oxide (NO)-production. It is commonly known that intense noise exposure results in inducible NOS (iNOS) expression and increased NO-production, but knowledge about a contribution of the eNOS isoform is still lacking. Effects of noise exposure on eNOS immunolabeling were determined in male guinea pigs (=24). For light microscopic analysis, 11 animals were exposed to 90 dB for 1 hr and 6 animals were used as controls. After exposure, eNOS immunostaining was performed on paraffin sections, and the staining intensities were quantified for 4 cochlear regions. For electron microscopic analysis, 2 animals were exposed for 2 hr to 90 dB and 5 animals were used as controls. The intensity of eNOS immunolabeling was found to be already comprehensively increased 1 hr after noise exposure to 90 dB. At the ultrastructural level, a clear increase in eNOS immunolabeling was found in microtubules-rich areas of cochlear cuticular structures. Hence, our findings indicate that the forming the endolymph-perilymph barrier at the apical side of the organ of Corti is involved in a fast intrinsic otoprotective mechanism of the cochlea.
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http://dx.doi.org/10.1369/0022155419876644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824004PMC
November 2019

Impact of structured reporting on developing head and neck ultrasound skills.

BMC Med Educ 2019 Apr 11;19(1):102. Epub 2019 Apr 11.

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. This is a serious obstacle to the learning process of the modality due to a missing report structure and terminology. Therefore, there is a great inter-observer variability in overall report quality. Aim of the present study was to evaluate the impact of structured reporting on the learning process as indicated by the overall report quality of head and neck ultrasound examinations within medical school education.

Methods: Following an immersion course on head and neck ultrasound, previously documented images of three common pathologies were handed out to 58 medical students who asked to create both standard free text reports (FTR) and structured reports (SR). 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 two independent raters (Paired Wilcoxon test, 95% CI). Ratings were assessed for inter-rater reliability (Fleiss' kappa). Additionally, a questionnaire was utilized to evaluate user satisfaction.

Results: SRs received significantly better ratings in terms of report completeness (97.7% vs. 53.5%, p < 0.001) regarding all items. In addition, pathologies were described in more detail using SRs (70% vs. 51.1%, p < 0.001). Readability was significantly higher in all SRs when compared to FTRs (100% vs. 54.4%, p < 0.001). Mean time to complete was significantly lower (79.6 vs. 205.4 s, p < 0.001) and user satisfaction was significantly higher when using SRs (8.5 vs. 4.1, p < 0.001). Also, inter-rater reliability was very high (Fleiss' kappa 0.93).

Conclusions: SRs of head and neck ultrasound examinations provide more detailed information with a better readability in a time-saving manner within medical education. Also, medical students may benefit from SRs in their learning process due to the structured approach and standardized terminology.
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http://dx.doi.org/10.1186/s12909-019-1538-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458758PMC
April 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

Randomized controlled single-blinded clinical trial of functional voice outcome after vascular targeting KTP laser microsurgery of early laryngeal cancer.

Head Neck 2019 04 31;41(4):899-907. Epub 2019 Jan 31.

Department of Otorhinolaryngology-Section of Phoniatrics, Ludwig-Maximilians-University Medical Center, Munich, Germany.

Background: Local control rate (LCR) of early glottic cancer is high after radiation therapy or transoral laser microsurgery (TLM). The aim of this study was to investigate functional voice outcome after TLM using a microvessel-ablative potassium-titanyl-phosphate (KTP) laser in comparison with a gold standard cutting CO laser.

Methods: The primary end point of this prospective, randomized, single-blinded, clinical phase II study with control group was voice outcome during a follow-up of 6 months assayed by Voice Handicap Index (VHI-30)-questionnaires in patients with unilateral high-grade dysplasia, carcinoma in situ or early glottic cancer undergoing TLM-KTP (n = 8) or TLM-CO (n = 12). The secondary end point was LCR.

Results: Starting from the 9-week-follow-up visit, TLM-KTP yielded significantly reduced VHI scores compared to TLM-CO . No relapse occurred after TLM-KTP in contrast to one recurrence after TLM-CO within 6 months.

Conclusion: Multicenter phase II or III studies on voice outcome or local control rate after TLM-KTP in early glottic cancer are warranted enrolling larger patient cohorts.
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http://dx.doi.org/10.1002/hed.25474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972647PMC
April 2019

Biomolecule-corona formation confers resistance of bacteria to nanoparticle-induced killing: Implications for the design of improved nanoantibiotics.

Biomaterials 2019 02 21;192:551-559. Epub 2018 Nov 21.

Department of Nanobiomedicine/ENT, University Medical Center of Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany. Electronic address:

Multidrug-resistant bacterial infections are a global health threat. Nanoparticles are thus investigated as novel antibacterial agents for clinical practice, including wound dressings and implants. We report that nanoparticles' bactericidal activity strongly depends on their physical binding to pathogens, including multidrug-resistant primary clinical isolates, such as Staphylococcus aureus, Klebsiella pneumoniae or Enterococcus faecalis. Using controllable nanoparticle models, we found that nanoparticle-pathogen complex formation was enhanced by small nanoparticle size rather than material or charge, and was prevented by 'stealth' modifications. Nanoparticles seem to preferentially bind to Gram-positive pathogens, such as Listeria monocytogenes, S. aureus or Streptococcus pyrogenes, correlating with enhanced antibacterial activity. Bacterial resistance to metal-based nanoparticles was mediated by biomolecule coronas acquired in pathophysiological environments, such as wounds, the lung, or the blood system. Biomolecule corona formation reduced nanoparticles' binding to pathogens, but did not impact nanoparticle dissolution. Our results provide a mechanistic explanation why nano-sized antibiotics may show reduced activity in clinically relevant environments, and may inspire future nanoantibiotic designs with improved and potentially pathogen-specific activity.
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http://dx.doi.org/10.1016/j.biomaterials.2018.11.028DOI Listing
February 2019

Vitronectin promotes the vascularization of porous polyethylene biomaterials.

Acta Biomater 2018 12 6;82:24-33. Epub 2018 Oct 6.

Department of Otorhinolaryngology, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany; Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address:

Rapid implant vascularization is a prerequisite for successful biomaterial engraftment. Vitronectin (VN) is a matricellular glycoprotein well known for its capability to interact with growth factors, proteases, and protease inhibitors/receptors. Since such proteins are highly relevant for angiogenic processes, we hypothesized that VN contributes to the tissue integration of biomaterials. Employing different in vivo and ex vivo microscopy techniques, engraftment of porous polyethylene (PPE) implants was analyzed in the dorsal skinfold chamber model in wild-type (WT) and VN mice. Upon PPE implantation, vascularization of this biomaterial was severely compromised in animals lacking this matricellular protein. Proteome profiling revealed that VN deficiency does not cause major changes in angiogenic protein composition in the implants suggesting that VN promotes PPE vascularization via mechanisms modulating the activity of angiogenic factors rather than by directly enriching them in the implant. Consequently, surface coating with recombinant VN (embedded in Matrigel®) accelerated implant vascularization in WT mice by enhancing the maturation of a vascular network. Thus, VN contributes to the engraftment of PPE implants by promoting the vascularization of this biomaterial. Surface coating with VN might provide a promising strategy to improve the vascularization of PPE implants without affecting the host's integrity. STATEMENT OF SIGNIFICANCE: Porous polyethylene (PPE) is a biomaterial frequently used in reconstructive surgery. The proper vascularization of PPE implants is a fundamental prerequisite for its successful engraftment in host tissue. Although the overall biocompatibility of PPE is good, there are less favorable application sites for its use in tissue reconstruction mostly characterized by low blood supply. Employing advanced in vivo microscopy methods and proteomic analyses in genetically engineered mice, we here describe a previously unrecognized function of vitronectin (VN) that enables this abundantly present glycoprotein to particularly promote the vascularization of PPE biomaterial. These properties of VN specifically facilitate the formation of a dense vessel network within the implant which relies on modulating the activity of angiogenic mediators rather than on the enrichment of these factors in the implant. Consequently, surface coating with this matricellular protein effectively accelerated and intensified implant vascularization which might be beneficial for its implementation at unfavorable sites for implantation without affecting the host's integrity.
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http://dx.doi.org/10.1016/j.actbio.2018.10.004DOI Listing
December 2018

Ultrasound in the Re-Staging of Cervical Metastases after Chemoradiotherapy for Head and Neck Cancer.

Ultraschall Med 2018 Dec 20;39(6):659-666. Epub 2018 Sep 20.

Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Saarlanddical School, Homburg, Germany.

High-resolution ultrasonography, including color duplex modes, is a well-established and proven imaging method that is used in addition to computed tomography for re-staging after primary nonsurgical therapy for head and neck cancer in many European countries. No evidence-based international re-staging guidelines are available. Decisions as to whether to carry out neck dissection after primary radiotherapy or chemoradiotherapy are often made in the relevant tumor boards and are therefore subject to variance. High-resolution ultrasonography clearly detects morphological changes such as intranodal necrotic areas and alterations in the hilar vascularization pattern. Another important aspect of ultrasonography is that it allows accurate check-ups on dynamic changes during the follow-up period. This article reviews the role of ultrasonography in the follow-up and re-staging of patients with neck disease after primary chemoradiotherapy.
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http://dx.doi.org/10.1055/a-0573-0908DOI Listing
December 2018

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

Small Meets Smaller: Effects of Nanomaterials on Microbial Biology, Pathology, and Ecology.

ACS Nano 2018 07 16;12(7):6351-6359. Epub 2018 Jul 16.

Department of Molecular Biology II, Centre for Nanointegration (CENIDE) , University Duisburg-Essen , Universitätsstraße 5 , 45117 Essen , Germany.

As functionalities and levels of complexity in nanomaterials have increased, unprecedented control over microbes has been enabled, as well. In addition to being pathogens and relevant to the human microbiome, microbes are key players for sustainable biotechnology. To overcome current constraints, mechanistic understanding of nanomaterials' physicochemical characteristics and parameters at the nano-bio interface affecting nanomaterial-microbe crosstalk is required. In this Perspective, we describe key nanomaterial parameters and biological outputs that enable controllable microbe-nanomaterial interactions while minimizing design complexity. We discuss the role of biomolecule coronas, including the problem of nanoantibiotic resistance, and speculate on the effects of nanomaterial-microbe complex formation on the outcomes and fates of microbial pathogens. We close by summarizing our current knowledge and noting areas that require further exploration to overcome current limitations for next-generation practical applications of nanotechnology in medicine and agriculture.
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http://dx.doi.org/10.1021/acsnano.8b03241DOI Listing
July 2018

Expressional analysis of disease-relevant signalling-pathways in primary tumours and metastasis of head and neck cancers.

Sci Rep 2018 05 9;8(1):7326. Epub 2018 May 9.

Molecular and Cellular Oncology, ENT/University Hospital of Mainz, Mainz, 55131, Germany.

Head and neck squamous cell carcinoma (HNSCC) often metastasize to lymph nodes resulting in poor prognosis for patients. Unfortunately, the underlying molecular mechanisms contributing to tumour aggressiveness, recurrences, and metastasis are still not fully understood. However, such knowledge is key to identify biomarkers and drug targets to improve prognosis and treatments. Consequently, we performed genome-wide expression profiling of 15 primary HNSSCs compared to corresponding lymph node metastases and non-malignant tissue of the same patient. Differentially expressed genes were bioinformatically exploited applying stringent filter criteria, allowing the discrimination between normal mucosa, primary tumours, and metastases. Signalling networks involved in invasion contain remodelling of the extracellular matrix, hypoxia-induced transcriptional modulation, and the recruitment of cancer associated fibroblasts, ultimately converging into a broad activation of PI3K/AKT-signalling pathway in lymph node metastasis. Notably, when we compared the diagnostic and prognostic value of sequencing data with our expression analysis significant differences were uncovered concerning the expression of the receptor tyrosine kinases EGFR and ERBB2, as well as other oncogenic regulators. Particularly, upregulated receptor tyrosine kinase combinations for individual patients varied, implying potential compensatory and resistance mechanisms against specific targeted therapies. Collectively, we here provide unique transcriptional profiles for disease predictions and comprehensively analyse involved signalling pathways in advanced HNSCC.
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http://dx.doi.org/10.1038/s41598-018-25512-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943339PMC
May 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

A method for determining precise electrical hearing thresholds in cochlear implant users.

Int J Audiol 2018 07 1;57(7):502-509. Epub 2018 Feb 1.

a Division of Audiological Acoustics, ENT Department , University Hospital Frankfurt , Frankfurt , Germany.

Objective: A psychoacoustic procedure designed for the precise assessment of perceptional threshold (T-level) in cochlear implant (CI) users is presented. The impact of this procedure on speech perception was investigated.

Design: Individual T-level measurements were obtained with the proposed procedure and three different speech processor fitting conditions were applied: (1) fitting familiar to the subject, T-levels unchanged, (2) T-level set to thresholds determined with the new procedure, (3) T-level set to thresholds determined with the new procedure, but T-level is decreased by 10 clinical units (CU). The impact of the different fitting conditions was measured by means of categorical loudness scaling (CLS) and speech perception tests in quiet and noise.

Study Sample: A prospective study at a tertiary referral university hospital. 18 experienced postlingually deafened cochlear implanted adult subjects.

Results: Average sound-field thresholds obtained by CLS were lowest in condition using the new procedure yielding a larger dynamic range with significantly higher speech scores in quiet compared to those with a subject's commonly used programme, and significantly improved in noise even after reducing T-levels by 10 CU.

Conclusion: The precise determination of T-levels by means of the proposed procedure improved performance in several speech recognition tasks. Compared to the default behavioural setting, T-level increased on median by 9 CU. Average speech reception threshold in noise for soft speech levels (50 dB sound pressure level) decreased by 1 dB.
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http://dx.doi.org/10.1080/14992027.2017.1412519DOI Listing
July 2018

Association of eIF4E and SPARC Expression with Lymphangiogenesis and Lymph Node Metastasis in Hypopharyngeal Cancer.

Anticancer Res 2018 02;38(2):699-706

Department of Otorhinolaryngology, University Hospital Frankfurt, Frankfurt, Germany.

Background/aim: Head and neck squamous cell carcinomas (HNSCC) are characterized by aggressiveness, early recurrence and lymph node metastasis. Therefore, there is an urgent need to identify new biomarkers and drug targets.

Materials And Methods: Neck dissection specimens from 11 patients diagnosed with hypopharyngeal cancer were analyzed for their lymphatic vessel density (LVD) by lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) immunostaining, expression of eukaryotic initiation factor 4E (eIF4E) and levels of secreted protein acidic and rich in cysteine (SPARC) using immunoblot analysis.

Results: Compared to lymph node biopsies of healthy controIs, LVD was significantly increased in metastatic lymph nodes as well as in advanced primary tumors. Overexpression of eIF4E and SPARC was demonstrated in all hypopharyngeal cancer specimens. Notably, we observed that increased LVD significantly correlated with the expression of eIF4E as well as SPARC levels.

Conclusion: eIF4E- and SPARC-associated signaling pathways may be associated with lymphangiogenesis and could be exploited to counteract the spread of hypopharyngeal cancer cells.
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http://dx.doi.org/10.21873/anticanres.12275DOI 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

[Recent Developments Towards Molecularly Targeted Therapy of Head and Neck Cancer].

Laryngorhinootologie 2017 03 18;96(3):185-198. Epub 2017 Apr 18.

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http://dx.doi.org/10.1055/s-0043-101412DOI Listing
March 2017