Publications by authors named "Holger Sudhoff"

130 Publications

Sensorineural Hearing Loss After Balloon Eustachian Tube Dilatation.

Front Surg 2021 5;8:615360. Epub 2021 Mar 5.

Medical School OWL, Bielefeld University, Klinikum Bielefeld Mitte, Bielefeld, Germany.

Eustachian tube function is of central importance for the ventilation of the middle ear. A dysfunction can be associated with chronic otitis media, and cholesteatoma. Balloon Eustachian tube dilatation (BET) is a treatment option used to solve eustachian tube dysfunction. Although BET is widely performed, little is known about the occurrence rate of the complications associated with BET. The aim of the present study was to observe the rate of sensorineural hearing loss (SNHL) after BET. We retrospectively evaluated in a chart review 1,547 patients and 2,614 procedures of BET performed in a single center between 2015 and 2019 using the Spiggle and Theis, Overath, Germany eustachian tube dilatation system. We observed seven cases of SNHL after BET. In two cases, the SNHL persisted, and in five cases, the SNHL was transient. In two cases of SNHL, a simultaneous tympanoplasty was performed. The overall rate of SNHL per procedure is 0.3%. The rate of permanent SNHL is 0.08%. BET has a low rate of SNHL. Rapid middle ear pressure changes are assumed to cause BET-related hearing loss.
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http://dx.doi.org/10.3389/fsurg.2021.615360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973464PMC
March 2021

Disulfiram Acts as a Potent Radio-Chemo Sensitizer in Head and Neck Squamous Cell Carcinoma Cell Lines and Transplanted Xenografts.

Cells 2021 Feb 28;10(3). Epub 2021 Feb 28.

Department of Otolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany.

The poor prognosis of locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) is primarily mediated by the functional properties of cancer stem cells (CSCs) and resistance to chemoradiotherapy. We investigated whether the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF) can enhance the sensitivity of therapy. Cell viability was assessed by the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and apoptosis assays, and the cell cycle and reactive oxygen species (ROS) levels were evaluated by fluorescence-activated cell sorting (FACS). The radio-sensitizing effect was measured by a colony formation assay. The synergistic effects were calculated by combination index (CI) analyses. The DSF and DSF/Cu inhibited the cell proliferation (inhibitory concentration 50 (IC) of DSF and DSF/Cu were 13.96 μM and 0.24 μM). DSF and cisplatin displayed a synergistic effect (CI values were < 1). DSF or DSF/Cu abolished the cisplatin-induced G2/M arrest (from 52.9% to 40.7% and 41.1%), and combining irradiation (IR) with DSF or DSF/Cu reduced the colony formation and attenuated the G2/M arrest (from 53.6% to 40.2% and 41.9%). The combination of cisplatin, DSF or DSF/Cu, and IR enhanced the radio-chemo sensitivity by inducing apoptosis (42.04% and 32.21%) and ROS activity (46.3% and 37.4%). DSF and DSF/Cu enhanced the sensitivity of HNSCC to cisplatin and IR. Confirming the initial data from patient-derived tumor xenograft (PDX) supported a strong rationale to repurpose DSF as a radio-chemosensitizer and to assess its therapeutic potential in a clinical setting.
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http://dx.doi.org/10.3390/cells10030517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999545PMC
February 2021

Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism.

Cell Commun Signal 2021 Feb 24;19(1):25. Epub 2021 Feb 24.

Department of Otolaryngology, Head and Neck Surgery, Medical School OWL Campus Klinikum Bielefeld, Bielefeld University, Teutoburger Str. 50, 33604, Bielefeld, Germany.

Background: Cholesteatoma disease is an expanding lesion in the middle ear. Hearing loss and facial paralysis alongside with other intracranial complications are found. No pharmaceutical treatment is available today and recurrence after surgical extraction occurs. We investigated possible TLR4-based mechanisms promoting recurrence and explore possible treatments strategies.

Methods: We isolated fibroblasts and epidermal stem cells from cholesteatoma tissue and healthy auditory canal skin. Subsequently, their expression under standard culture conditions and after stimulation with LPS was investigated by RT-qPCR. Cell metabolism and proliferation were analysed upon LPS treatment, with and without TLR4 antagonist. An indirect co-culture of fibroblasts and epidermal stem cells isolated from cholesteatoma tissue was utilized to monitor epidermal differentiation upon LPS treatment by RT-qPCR and immunocytochemistry.

Results: Under standard culture conditions, we detected a tissue-independent higher expression of IL-1β and IL-8 in stem cells, an upregulation of KGF and IGF-2 in both cell types derived from cholesteatoma and higher expression of TLR4 in stem cells derived from cholesteatoma tissue. Upon LPS challenge, we could detect a significantly higher expression of IL-1α, IL-1β, IL-6 and IL-8 in stem cells and of TNF-a, GM-CSF and CXCL-5 in stem cells and fibroblasts derived from cholesteatoma. The expression of the growth factors KGF, EGF, EREG, IGF-2 and HGF was significantly higher in fibroblasts, particularly when derived from cholesteatoma. Upon treatment with LPS the metabolism was elevated in stem cells and fibroblasts, proliferation was only enhanced in fibroblasts derived from cholesteatoma. This could be reversed by the treatment with a TLR4 antagonist. The cholesteatoma fibroblasts could be triggered by LPS to promote the epidermal differentiation of the stem cells, while no LPS treatment or LPS treatment without the presence of fibroblasts did not result in such a differentiation.

Conclusion: We propose that cholesteatoma recurrence is based on TLR4 signalling imprinted in the cholesteatoma cells. It induces excessive inflammation of stem cells and fibroblasts, proliferation of perimatrix fibroblasts and the generation of epidermal cells from stem cells thru paracrine signalling by fibroblasts. Treatment of the operation site with a TLR4 antagonist might reduce the chance of cholesteatoma recurrence. Video Abstract.
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http://dx.doi.org/10.1186/s12964-020-00690-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903614PMC
February 2021

Imaging of SARS-CoV-2 infected Vero E6 cells by helium ion microscopy.

Beilstein J Nanotechnol 2021 2;12:172-179. Epub 2021 Feb 2.

Physics of Supramolecular Systems and Surfaces, Faculty of Physics, Bielefeld University, Bielefeld, Germany.

Helium ion microscopy (HIM) offers the opportunity to obtain direct views of biological samples such as cellular structures, virus particles, and microbial interactions. Imaging with the HIM combines sub-nanometer resolution, large depth of field, and high surface sensitivity. Due to its charge compensation capability, the HIM can image insulating biological samples without additional conductive coatings. Here, we present an exploratory HIM study of SARS-CoV-2 infected Vero E6 cells, in which several areas of interaction between cells and virus particles, as well as among virus particles, were imaged. The HIM pictures show the three-dimensional appearance of SARS-CoV-2 and the surface of Vero E6 cells at a multiplicity of infection of approximately 1 with great morphological detail. The absence of a conductive coating allows for a distinction between virus particles bound to the cell membrane and virus particles lying on top of the membrane. After prolonged imaging, it was found that ion-induced deposition of hydrocarbons from the vacuum renders the sample sufficiently conductive to allow for imaging even without charge compensation. The presented images demonstrate the potential of the HIM in bioimaging, especially for the imaging of interactions between viruses and their host organisms.
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http://dx.doi.org/10.3762/bjnano.12.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871036PMC
February 2021

Effect of Underwater Insertion on Intracochlear Pressure.

Front Surg 2020 30;7:546779. Epub 2020 Nov 30.

Department of Otolaryngology, Head and Neck Surgery, Bielefeld University, Campus Mitte, Klinikum Bielefeld, Bielefeld, Germany.

The importance of intracochlear pressure during cochlear electrode insertion for the preservation of residual hearing has been widely discussed. Various aspects of pre-insertional, intra-insertional, and post-insertional relevant conditions affect intracochlear pressure. The fluid situation at the round window during electrode insertion has been shown to be an influential factor. The aim of the study was to compare various insertion techniques in terms of the fluid situation at the round window. We performed insertion of cochlear implant electrodes in a curled artificial cochlear model. We placed and fixed the pressure sensor at the tip of the cochlea. In parallel to the insertions, we evaluated the maximum amplitude of intracochlear pressure under four different fluid conditions at the round window: (1) hyaluronic acid; (2) moisturized electrode, dry middle ear; (3) middle ear filled with fluid (underwater); and (4) moisturized electrode, wet middle ear, indirectly inserted. We observed that the insertional intracochlear pressure is dependent on the fluid situation in front of the round window. The lowest amplitude changes were observed for the moisturized electrode indirectly inserted in a wet middle ear (0.13 mmHg ± 0.07), and the highest values were observed for insertion through hyaluronic acid in front of the round window (0.64 mmHg ± 0.31). The fluid state in front of the round window influences the intracochlear pressure value during cochlear implant electrode insertion in our model. Indirect insertion of a moisturized electrode through a wet middle ear experimentally generated the lowest pressure values. Hyaluronic acid in front of the round window leads to high intracochlear pressure in our non-validated artificial model.
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http://dx.doi.org/10.3389/fsurg.2020.546779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793869PMC
November 2020

Laterality of Audiovestibular Symptoms Predicts Laterality of Endolymphatic Hydrops in Hydropic Ear Disease (Menière).

Otol Neurotol 2020 10;41(9):e1140-e1144

Institute for Diagnostic Radiology, University Hospital Bielefeld, Bielefeld, Germany.

Background: For clinical confirmation of the diagnosis of hydropic ear disease (HED) (Menière) by MR imaging, two routes of contrast enhancement of the perilymphatic space are currently being used: intratympanic and intravenous. While unilateral intratympanic contrast application generally enables a higher perilymph signal intensity and image quality, the intravenous route allows for imaging of both inner ears simultaneously. It is conceivable that intratympanic contrast application to one ear would result in a failure to detect endolymphatic hydrops in a given patient if the hydrops is present only in the other ear. Therefore, in this study we examined the question whether the ear with the greater degree of endolymphatic hydrops may be predicted based on clinical features.

Methods: Retrospective study of 50 patients with HED confirmed on MR imaging. Three tesla MR imaging with 3D fluid attenuated inversion recovery 4 hours after intravenous gadolinium contrast application was used to detect endolymphatic hydrops. The index ear was defined by auditory symptoms during attacks, low frequency hearing loss, and caloric canal paresis.

Results: In all patients the ear with more severe symptoms corresponded with the ear showing the more severe hydrops on MR imaging.

Conclusion: In summary, in this study population the degree of low-frequency hearing loss (250 Hz-1 kHz) in combination with auditory symptoms during attacks identified the ear with the greater extent of endolymphatic hydrops in all patients. In conclusion, intratympanic contrast application to the index ear seems to be sufficient to confirm the diagnosis of HED (Menière) on MR imaging.
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http://dx.doi.org/10.1097/MAO.0000000000002775DOI Listing
October 2020

MRI Observation After Intralabyrinthine and Vestibular Schwannoma Resection and Cochlear Implantation.

Front Neurol 2020 12;11:759. Epub 2020 Aug 12.

Department of Otolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Bielefeld University, Bielefeld, Germany.

MRI observation is part of the regular follow-up after vestibular schwannoma (VS) or intralabyrinthine schwannoma (ILS) resection. Because cochlear implantation (CI) after resection is part of the audiological rehabilitation process, the magnet resonance imaging (MRI) behavior of CI systems needs to be considered. In light of recent developments in MRI artifact positioning and pain prevention, this study evaluates reproducible MRI observations after tumor resection and CI surgery as part of follow-up. In a retrospective study, we evaluated 9 patients with a T1 KM, T2 sequence MRI observation, and cone beam computed tomography (CBCT) after ILS/VS resection and CI. In all but one case, a CI with a diametrically bipolar magnet and a receiver positioned 8-9 cm behind the external auditory canal was performed. In all but one case, MRI observation allowed for a pain-free visual assessment of the intralabyrinthine and internal auditory canal (IAC) regions. In one case, a painful dislodgement of the receiver magnet occurred. MRI follow-up after ILS and VS resection and CI is reproducibly possible. Implant choice and positioning should be considered before implantation to allow for a pain-free visual assessment afterward. This finding allows for the first time a widening of the indication into this patient group.
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http://dx.doi.org/10.3389/fneur.2020.00759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434924PMC
August 2020

A novel technique for patulous Eustachian tube augmentation.

Eur Arch Otorhinolaryngol 2020 Aug 14. Epub 2020 Aug 14.

Department of Otorhinolaryngology, Head and Neck Surgery, Medical Faculty OWL, Bielefeld University, Campus Klinikum Bielefeld, Teutoburger Str. 50, 33604, Bielefeld, Germany.

Objective: To determine the effectiveness of a soft-tissue bulking agent comparing novel approaches of Eustachian tube (ET) augmentation procedures: transpalatinatal Eustachian tube augmentation in local and general anesthesia versus an augmentation with velotraction under general anesthesia. The clinical endpoint was the resolution of symptoms related to unilateral patulous Eustachian tube dysfunction (PETD) requiring no additional revision augmentations.

Study Design: Combined retrospective clinical chart review.

Setting: Tertiary referral center.

Methods: Patients suffering from PETD underwent one of the following procedures: Group (A) transpalatinatal soft-tissue bulking agent with infiltration/augmentation under local anesthesia in a sitting position, group (B) transpalatinatal soft-tissue bulking agent infiltration/augmentation under general anesthesia in the flat position or group (C) infiltration/transoral augmentation of the ET with velotraction under general anesthesia in a flat position. The requirement to repeat the procedure due to recurrence of any PETD-related symptoms was recorded and retrospectively analyzed.

Results: A total of 50 procedures were executed in 50 patients with unilateral PETD. The necessity to perform a second procedure has analyzed a mean of 6 months postoperatively (range: 6-17 months). Compared to the transpalatinatal augmentation in local anesthesia (group A) (100% success rate), the 6-month failure rate was significantly higher for transpalatinatal augmentation under general anesthesia (group B) (80% success rate) and velotraction augmentation under general anesthesia (group C) (67% success rate). Patient cohort with transpalatinatal augmentation under general anesthesia required 20% and augmentation with velotraction under general anesthesia in 33% revision augmentation procedures reviewed at 6 months follow-up (mean follow-up 11.2 months).

Conclusions: Although all different approaches resulted in a reduction of PETD related symptoms, the transpalatinatal ET augmentation in local anesthesia achieved a statistically significant superior clinical improvement. A complete resolution of PETD related symptoms was obtained and required additional procedures. This improvement may be related to the intraoperative "feedback" by the patients in local anesthesia in the sitting position eliminating the necessity for repeated procedures.
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http://dx.doi.org/10.1007/s00405-020-06277-0DOI Listing
August 2020

Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck.

Int J Biol Sci 2020 19;16(14):2506-2517. Epub 2020 Jul 19.

Department of Clinical Laboratory, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital); Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences. Hangzhou, P.R. China.

Immunotherapies such as immune checkpoint blockade benefit only a portion of patients with head and neck squamous cell carcinoma. The multidisciplinary field of nanomedicine is emerging as a promising strategy to achieve maximal anti-tumor effect in cancer immunotherapy and to turn non-responders into responders. Various methods have been developed to deliver therapeutic agents that can overcome bio-barriers, improve therapeutic delivery into the tumor and lymphoid tissues and reduce adverse effects in normal tissues. Additional modification strategies also have been employed to improve targeting and boost cytotoxic T cell-based immune responses. Here, we review the state-of-the-art use of nanotechnologies in the laboratory, in advanced preclinical phases as well as those running through clinical trials assessing their advantages and challenges.
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http://dx.doi.org/10.7150/ijbs.47068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415431PMC
July 2020

[Pharyngeal penetration of a screw after ventral cervical spine].

Laryngorhinootologie 2020 10 22;99(10):720-721. Epub 2020 Jul 22.

HNO, Klinikum Bielefeld-Mitte, Bielefeld, Germany.

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http://dx.doi.org/10.1055/a-1213-6185DOI Listing
October 2020

Balloon Eustachian Tuboplasty (BET) in Children: A Retrospective Multicenter Analysis.

Otol Neurotol 2020 08;41(7):e921-e933

Department of Otorhinolaryngology, Head- and Neck Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Objective: Generation of pilot data for planning of prospective BET-studies for treatment of dilatory Eustachian tube (ET) dysfunction in children.

Study Design: Retrospective multicenter analysis.

Setting: Nine ENT departments at tertiary care teaching hospitals.

Patients: 4-12-year-old children with chronic otitis media with effusion (COME) for more than 3 months or more than 3 episodes of acute otitis media during the last year, having failed standard surgical therapy at least once.

Intervention: BET with or without paracentesis, ventilation tube insertion, or tympanoplasty.

Main Outcome Measures: Tympanic membrane appearance, tympanometry, and hearing threshold.

Results: Two hundred ninety-nine ETs of 167 children were treated. Mean age was 9.1 years (95% confidence interval [95% CI]: 8.7-9.4 yr). In 249 ears (83.3%), COME and/or retraction of the tympanic membrane were the indication for BET. Median hearing threshold was 20 dB HL (95% CI: 0-46 dB). One hundred fifty-five ears (51.8%, 95% CI: 46.1-57.4%) showed a tympanogram type B. Treatment consisted of BET without other interventions ("BET-only") in 70 children, 128 ears. Median length of follow-up for 158 (94.6%) children was 2.6 months (95% CI: 0.3-16.1 mo). After treatment, the tympanic membrane appeared normal in 196 ears (65.6%, 95% CI: 60.0-70.8%, p < 0.001). Median hearing threshold improved to 10 dB HL (95% CI: 0-45 dB, p < 0.001). Tympanograms shifted toward type A and C (type A: 39.1%, 95% CI: 33.7-44.7, p < 0.001). These improvements were also observed in subgroup analyses of "BET-only" treatment and the indication of "COME" respectively.

Conclusion: BET is improving a variety of dilatory ET dysfunction-related ear diseases in children. This study provides detailed data for design and planning of prospective studies on BET in children.
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http://dx.doi.org/10.1097/MAO.0000000000002789DOI Listing
August 2020

The Potential of Tumor Debulking to Support Molecular Targeted Therapies.

Front Oncol 2020 18;10:801. Epub 2020 Jun 18.

Department of Otolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Bielefeld, Germany.

Tumors may consist of billions of cells, which in malignant cases disseminate and form distant metastases. The large number of tumor cells formed by the high number of cell divisions during tumor progression creates a heterogeneous set of genetically diverse tumor cell clones. For cancer therapy this poses unique challenges, as distinct clones have to be targeted in different tissue locations. Recent research has led to the development of specific inhibitors of defined targets in cellular signaling cascades which promise more effective and more tumor-specific therapy approaches. Many of these molecular targeted therapy (MTT) compounds have already been translated into clinics or are currently being tested in clinical studies. However, the outgrowth of tumor cell clones resistant to such inhibitors is a drawback that affects specific inhibitors in a similar way as classical cytotoxic chemotherapeutics, because additionally acquired genetic alterations can enable tumor cells to circumvent the particular regulators of cellular signaling being targeted. Thus, it might be desirable to reduce genetic heterogeneity prior to molecular targeting, which could reduce the statistical chance of tumor relapse initiated by resistant clones. One way to achieve this is employing unspecific methods to remove as much tumor material as possible before MTT, e.g., by tumor debulking (TD). Currently, this is successfully applied in the clinical treatment of ovarian cancer. We believe that TD followed by treatment with a combination of molecular targeted drugs, optimally guided by biomarkers, might advance survival of patients suffering from various cancer types.
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http://dx.doi.org/10.3389/fonc.2020.00801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314947PMC
June 2020

Management of Complex Facial Injuries: Cutting Traumas by Angle Grinders.

Int J Otolaryngol 2020 17;2020:1891250. Epub 2020 May 17.

Department of Otolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Bielefeld, Germany.

The use of angle grinders can lead to complex facial injuries. The most frequent sites affected are within the head and face region. Anatomical boundaries or structures are not respected by the high-speed disc of angle grinders, and thus, injuries can be mutilating, permanently disabling, or even lethal. Functional and aesthetical satisfying results can be reached through debridement, excision of wound edges, and meticulous layered functional closure after appropriate reconstruction of additional facial bony defects. The management and short-term outcome of a complex facial cutting trauma by an angle grinder are presented and discussed.
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http://dx.doi.org/10.1155/2020/1891250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251467PMC
May 2020

Noise Exposure on the London Underground, an Observational Study over a Decade.

Laryngoscope 2020 12 7;130(12):2891-2895. Epub 2020 Feb 7.

Department of Otolaryngology / Head & Neck Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.

Objectives: There are no hearing protection regulations in place for passengers using public transport, such as the London Underground. In light of this, we sought to examine sound pressure levels experienced by regular users of the London Underground.

Methods: Sound pressure levels (A-weighted decibels: dBA) were taken on moving London Underground carriages between Euston and South Wimbledon on the Northern Line, and between Euston and Vauxhall on the Victoria Line, during 2006 and 2018. In addition, carriage sound pressure levels travelling within Zone 1 of the London Underground were tested in 2019. Three experimental and three technical repeats were undertaken using a hand-held calibrated multi-function sound level meter.

Results: Passengers are routinely and consistently subjected to sound pressure levels exceeding 80 dBA, with levels sometimes reaching over 100 dBA.

Conclusion: This study is unique within the literature, with no published studies outlining exposure levels for London Underground passengers. It provides evidence of elevated noise exposure to passengers, consistently along large stretches of the London Underground, over a prolonged study period (2006-2019).

Key Words: Sensorineural hearing losssound pressureexposureLondonundergroundtube.

Level Of Evidence: N/A Laryngoscope, 2020.
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http://dx.doi.org/10.1002/lary.28547DOI Listing
December 2020

Stem Cell-Induced Inflammation in Cholesteatoma is Inhibited by the TLR4 Antagonist LPS-RS.

Cells 2020 01 14;9(1). Epub 2020 Jan 14.

Department of Cell Biology, University of Bielefeld, 33619 Bielefeld, Germany.

Cholesteatoma is a severe non-cancerous lesion of the middle ear characterized by massive inflammation, tissue destruction, and an abnormal growth of keratinized squamous epithelium. We recently demonstrated the presence of pathogenic stem cells within cholesteatoma tissue, unfortunately their potential roles in regulating disease-specific chronic inflammation remain poorly understood. In the presented study, we utilized our established human in vitro cholesteatoma stem cell model for treatments with lipopolysaccharides (LPS), tumor necrosis factor α (TNFα), and the TLR4-antagonist LPS from LPS-RS) followed by qPCR, western blot, and immunocytochemistry. Middle ear cholesteatoma stem cells (ME-CSCs) showed a significantly increased expression of TLR4 accompanied by a significantly enhanced LPS-dependent pro-inflammatory gene expression pattern of TNFα, IL-1α, IL-1ß, IL-6, and IL-8 compared to non-pathogenic control cells. LPS-dependent pro-inflammatory gene expression in ME-CSCs was driven by an enhanced activity of NF-B p65 leading to a TNFα-mediated feed-forward-loop of pro-inflammatory NF-B target gene expression. Functional inactivation of TLR4 via the TLR4-antagonist LPS-RS blocked chronic inflammation in ME-CSCs, resulting in a nearly complete loss of IL-1ß, IL-6, and TNFα expression. In summary, we determined that ME-CSCs mediate the inflammatory environment of cholesteatoma via TLR4-mediated NF-B-signaling, suggesting a distinct role of ME-CSCs as drivers of cholesteatoma progression and TLR4 on ME-CSCs as a therapeutic target.
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http://dx.doi.org/10.3390/cells9010199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017370PMC
January 2020

Sekretorische Otitis media – Kombination von Tuboplastie und Paukendrainage.

Authors:
Holger Sudhoff

Laryngorhinootologie 2020 01 14;99(1):7-8. Epub 2020 Jan 14.

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http://dx.doi.org/10.1055/a-0996-6455DOI Listing
January 2020

The Therapeutic Effect of 1,8-Cineol on Pathogenic Bacteria Species Present in Chronic Rhinosinusitis.

Front Microbiol 2019 22;10:2325. Epub 2019 Oct 22.

Department of Otolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Bielefeld, Germany.

Chronic rhinosinusitis (CRS) is marked by an inflamed mucosa of sinuses and is accompanied by a significantly reduced quality of live. Since no guidelines for the treatment of CRS are available, long lasting clinical histories with health care costs adding up to dozens of billion $ annually are caused by CRS. The progression of CRS is often induced by bacterial infections and/or a shift in microbiome as well as biofilm formation. The exact microbiome alterations are still unclear and the impenetrable biofilm renders the treatment with common antibiotics ineffective. This study focuses on characterizing the microbiome changes in CRS and investigating the inhibition of biofilm growth by 1,8-Cineol, a small, non-polar and hence biofilm penetrating molecule with known antimicrobial potential. We performed MALDI-TOF MS based characterization of the microbiomes of healthy individuals and CRS patients ( = 50). The microbiome in our test group was shifted to pathogens (, , and ). In contrast to published studies, solely based on cell culture techniques, we could not verify the abundance of in CRS. The inhibition of bacterial proliferation and biofilm growth by 1,8-Cineol was measured for these three pathogens. Interestingly, , the most prominent germ in CRS, showed a biofilm inhibition not simply correlated to its inhibition of proliferation. RT-qPCR confirmed that this was due to the downregulations of major key players in biofilm generation (agrA, SarA and σ) by 1,8-Cineol. Furthermore we verified this high biofilm inhibition potential in a model host system consisting out of biofilm grown on mature respiratory epithelium. A second host model, comprising organotypic slices, was utilized to investigate the reaction of the innate immune system present in the nasal mucosa upon biofilm formation and treatment with 1,8-Cineol. Interestingly , the cause of very common catheter infections, possesses a biofilm generation pathway very similar to and might be treatable in a similar fashion. The two presented model systems might be transferred to combinations of every biofilm forming bacterial with most kind of epithelium and mucosa.
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http://dx.doi.org/10.3389/fmicb.2019.02325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821979PMC
October 2019

Comparative Analyses of Tumour Volume Doubling Times for Periocular and Non-periocular Head and Neck Basal Cell Carcinomas.

Acta Derm Venereol 2019 Dec;99(13):1266-1269

Basal cell carcinomas are the commonest solid malignancy in humans and thought to grow faster in the periocular region. We measured growth rates between periocular and non-periocular nodular basal cell carcinomas in the head and neck region from high-resolution digital photos and operative notes. The non-periocular basal cell carcinomas (head and neck) showed a mean tumour volume doubling time of 129.8 ± 21.74 (n = 79) days, and the periocular basal cell carcinoma a mean of 177.5 ± 37.21 (n = 47) days. The unpaired t-test with Welch correction showed that this difference was not significant (p = 0.2719). The mean tumour volume doubling time was 147.59 ± 37.75 days for head and neck basal cell carcinomas overall. For the first time, tumour volume doubling times for nodular basal cell carcinomas in the periocular versus non-periocular regions for the head and neck area were analysed, with no significant differences demonstrated. Further, comparison of basal cell carcinoma growth rates with other common solid tumours confirmed that basal cell carcinomas are slow growing malignancies.
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http://dx.doi.org/10.2340/00015555-3325DOI Listing
December 2019

[End-to-side venous anastomosis with a coupler device in microvascular free flaps].

Handchir Mikrochir Plast Chir 2020 Aug 18;52(4):325-329. Epub 2019 Sep 18.

Klinikum Bielefeld Mitte, Klinik für Plastische, Wiederherstellungs- und Ästhetische Chirurgie, Handchirurgie.

The aim of this study was to describe our results and experience with end-to-side venous anastomosis using a coupler device in microvascular free flaps.
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http://dx.doi.org/10.1055/a-0942-9780DOI Listing
August 2020

Stapes piston insertion depth and clinical correlations.

Acta Otolaryngol 2019 Oct 12;139(10):829-832. Epub 2019 Jul 12.

Department of Otolaryngology, Head and Neck Surgery, Ruhr Universität Bochum, Klinikum Bielefeld , Bielefeld , Germany.

The insertion of the stapes piston within the vestibule provides the physical basis for a successful stapedotomy. An insertion depth of 0.5 mm is recommended to avoid the dislocation of the stapes prosthesis (e.g. sneezing). The objective of this study is to analyze the depth of stapes prosthesis insertion and its correlation with clinical outcome. We observed in a retrospective case series 39 otosclerosis patients after a stapedotomy and a postoperative performed flat panel tomography/cone beam CT. The evaluation included the radiologically found depth of prosthesis insertion within the vestibule, the vestibule depth, and the correlation with the bone conduction (BC) threshold, vertigo, and tinnitus. Insertion depth varied between 0.2 and 1.6 mm (mean 0.74 mm). The ratio of insertion depth versus the vestibule depth was between 8% and 59% (mean 26.6%). We observed no correlation between the insertion depth, the length of the prosthesis, the ratio of insertion depth/vestibule depth, postoperative BC, appearance of vertigo, or tinnitus. In our group, we observed no significant relation between insertion depth of the stapes piston, postoperative vertigo, tinnitus, or decrease of the BC.
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http://dx.doi.org/10.1080/00016489.2019.1637019DOI Listing
October 2019

An Effective Primary Head and Neck Squamous Cell Carcinoma In Vitro Model.

Cells 2019 06 7;8(6). Epub 2019 Jun 7.

Department of Otolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Teutoburger Str. 50, 33604 Bielefeld, Germany.

Head and neck squamous cell carcinoma is a highly malignant disease and research is needed to find new therapeutic approaches. Faithful experimental models are required for this purpose. Here, we describe the specific cell culture conditions enabling the efficient establishment of primary cell culture models. Whereas a classical 10% serum-containing medium resulted in the growth of fibroblast-like cells that outcompeted epithelial cells, we found that the use of specific culture conditions enabled the growth of epithelial tumor cells from HPV+ and HPV- head and neck cancer tissue applicable for research. EpCAM and high Thy-1 positivity on the cell surface were mutually exclusive and distinguished epithelial and fibroblast-like subpopulations in all primary cultures examined and thus can be used to monitor stromal contamination and epithelial cell content. Interestingly, cells of an individual patient developed tumor spheroids in suspension without the use of ultra-low attachment plates, whereas all other samples exclusively formed adherent cell layers. Spheroid cells were highly positive for ALDH1A1 and hence displayed a phenotype reminiscent of tumor stem cells. Altogether, we present a system to establish valuable primary cell culture models from head and neck cancer tissue at high efficiency that might be applicable in other tumor entities as well.
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http://dx.doi.org/10.3390/cells8060555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628367PMC
June 2019

Heterogeneity of Head and Neck Squamous Cell Carcinoma Stem Cells.

Adv Exp Med Biol 2019 ;1139:23-40

Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institutes of Health, Berlin, Germany.

Current systemic cancer treatment in head and neck squamous cell carcinoma (HNSCC) is moving toward more personalized approaches such as de-escalation protocols human-papilloma-virus dependent HNSCC or application of checkpoint inhibitors. However, these treatments have been challenged by cancer stem cells (CSC), a small population within the bulk tumor, which are leading to treatment failure, tumor recurrence, or metastases. This review will give an overview of the characteristics of HNSCC-CSC. Specifically, the mechanisms by which HNSCC-CSC induce tumor initiation, progression, recurrence, or metastasis will be discussed. Although evidence-based treatment options targeting HNSCC-CSC specifically are still being sought for, they warrant a promise for additional and sustainable treatment options where for HNSCC patients where others have failed.
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http://dx.doi.org/10.1007/978-3-030-14366-4_2DOI Listing
August 2019

Stapes Prosthesis Length: One Size Fits All?

Audiol Neurootol 2019 19;24(1):1-7. Epub 2019 Feb 19.

Department of Otolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Academic Hospital: Ruhr Universität Bochum, Bielefeld, Germany,

Background: The insertion of the stapes piston into the vestibule provides the physical basis for a successful stapedotomy. In routine clinical practice, two different ways to handle prosthesis length are performed: (1) an individualized measurement of the stapes prosthesis length or (2) a standard prosthesis length for all cases.

Objective: The objective of this study was to compare both ways of handling prosthesis length and the effect of these methods on insertional prosthesis depth.

Material And Method: We retrospectively evaluated 39 patients after performing a stapedotomy for radiologically estimated vestibular stapes prosthesis insertion depth. The individual measured length data were hypothetically changed to a standard length of 4.75, 5, 5.25, and 5.5 mm, and the insertion depths were compared.

Results: The individually measured prosthesis lengths led to an insertion depth between 0.2 and 1.6 mm (mean 0.74 mm). The ratio of insertion depth/vestibular depth was between 8 and 59.1% (mean 26.6%). The different assumed standard lengths led to different rates of the vestibulum positions and possible bony contacts at the vestibulum floor.

Conclusion: The individual measurement led to a zero rate of the vestibulum positions of stapes prosthesis pistons with a low insertion depth/vestibular depth ratio.
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http://dx.doi.org/10.1159/000494915DOI Listing
February 2020

In Vivo Measurement of Middle Ear Pressure Changes during Balloon Eustachian Tuboplasty.

Biomed Res Int 2018 6;2018:9519204. Epub 2018 Sep 6.

Department of Otorhinolaryngology, Head and Neck Surgery, Ruhr Universität Bochum, Klinikum Bielefeld, Germany.

Background: Balloon Eustachian tuboplasty (BET) is known as a treatment for chronic obstructive Eustachian tube dysfunction (OETD). The precise mechanism of action is not fully understood. Observations in sheep cadavers and human cadavers have shown specific middle ear pressure changes related to BET.

Methods: In this prospective study using a microfibre optical pressure sensor, pressure changes during BET were for the first time monitored transtympanically in five normal human middle ears in vivo.

Results: Middle ear pressure changes during 21 BETs consisted of five stages (insertion, inflation, deflation, withdrawal, and recovery). The highest pressure change occurred in most of the cases during the withdrawal of the balloon catheter. Withdrawal pressure yielded a mean middle ear pressure of 4.76 mmHg (61.89 daPa) with a maximum of 13.88 mmHg (179.55 daPa). Pressure amplitudes capable of causing barotrauma to ear structures were not detected. Internal carotid artery dehiscences were detected as causative of sinusidual pressure changes.

Conclusion: The middle ear pressure changes detected in vivo during BET can be attributed to the balloon inflation. Further human studies with patients affected by OETD are necessary to gain more insight into the mechanism of action of BET to clarify a possible pressure related second mechanism of action of BET.
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http://dx.doi.org/10.1155/2018/9519204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146622PMC
January 2019

Specific Targeting of Oncogenes Using CRISPR Technology.

Cancer Res 2018 10 7;78(19):5506-5512. Epub 2018 Sep 7.

Department of Otolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Bielefeld, Germany.

In recent decades, tools of molecular biology have enabled researchers to genetically modify model organisms, including human cells. RNAi, zinc-finger nucleases, transcription activator-like effector nucleases, CRISPR-Cas9 (clustered regularly-interspaced short palindromic repeats and CRISPR-associated protein 9), retro- or lentiviral gene transfer, and many other methods can be utilized to remove genes, add genes, or change their expression. Within the same timeframe, survival rates for many highly malignant tumor diseases have not improved substantially. If modern medicine could apply even a subset of research methods in clinical management, which are already well established and controllable in basic research laboratories, this could strongly impact patients' prognosis. CRISPR-Cas9 is a method to precisely target and manipulate genomic loci and recent studies have attempted to use this method as a genetic treatment for Duchenne muscular dystrophy, blood disorders, autosomal-dominant hearing loss, and cancer. Some of these approaches target mutant genomic sequences specifically and try to avoid affecting the respective normal loci. Considering obvious genetic risks opposing the objected benefits, data are needed to show whether CRISPR technology is suitable as a future cancer therapy approach or not. Here, we develop strategies for the specific targeting of viral cancer drivers and oncogenes activated by mutation, using the latest CRISPR technology. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0571DOI Listing
October 2018

Reactive oxygen species in cancer stem cells of head and neck squamous cancer.

Semin Cancer Biol 2018 12 20;53:248-257. Epub 2018 Jun 20.

Department of Otorhinolaryngology, Head and Neck Surgery, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany. Electronic address:

One of the greatest challenges in systemic treatment of head and neck squamous cell carcinoma (HNSCC) is a small tumor cell population, namely, cancer stem-like cells (CSC). CSC can regenerate and maintain a heterogenic tumor by their self-renewal capacity. Their potential ability to be more resistant to and survival after chemo- and radiation therapy was also identified. Further studies have shown that reactive oxygen species (ROS) contribute to this CSC-associated resistance. In this review, we focus on the current knowledge of HNSCC-CSC, with regard to ROS as a possible and novel therapeutic approach in targeting CSC.
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http://dx.doi.org/10.1016/j.semcancer.2018.06.001DOI Listing
December 2018

The Role of the Eustachian Tube in Middle Ear Disease.

Adv Otorhinolaryngol 2018 6;81:146-152. Epub 2018 Apr 6.

The Eustachian tube is a complex structure connecting the middle ear to the nasopharynx that contributes to the normal function of the middle ear. Eustachian tube dysfunction (ETD) is thought to contribute to the majority of middle ear pathology, although the mechanisms and the degree to which it contributes to middle ear disease is poorly understood. We describe the anatomy and physiology of the Eustachian tube, define ETD, discuss the methods for measuring ETD and describe recent advances in treatment.
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http://dx.doi.org/10.1159/000485581DOI Listing
October 2018

Stem cells in middle ear cholesteatoma contribute to its pathogenesis.

Sci Rep 2018 04 18;8(1):6204. Epub 2018 Apr 18.

Department of Otolaryngology, Head and Neck Surgery, Klinikum Bielefeld, 33604, Bielefeld, Germany.

Cholesteatoma is a potentially life-threatening middle ear lesion due to the formation of an inflamed ectopic mass of keratinizing squamous epithelium. Surgical removal remains the only treatment option, emphasizing the need to gain a better understanding of this severe disease. We show for the first time that stem cells residing in cholesteatoma tissue contribute to disease progression. Cells expressing the "stemness" markers Nestin and S100B were detected in middle ear cholesteatoma and auditory canal skin. Isolated Nestin + /S100B + -cells showed the capability for self-renewal, neurosphere formation and differentiation into mesodermal and ectodermal cell types. Compared to auditory canal skin stem cells middle ear cholesteatoma-derived stem cells displayed an enhanced susceptibility to inflammatory stimuli, and this suggested a possible contribution to the inflammatory environment in cholesteatoma tissue. Cholesteatoma derived stem cells were able to differentiate into keratinocyte-like cells using factors mimicking the microenvironment of cholesteatoma. Our findings demonstrate a new perspective on the pathogenesis of cholesteatoma and may lead to new treatment strategies for this severe middle ear lesion.
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http://dx.doi.org/10.1038/s41598-018-24616-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906547PMC
April 2018

Technical feasibility study for production of tailored multielectrode arrays and patterning of arranged neuronal networks.

PLoS One 2018 23;13(2):e0192647. Epub 2018 Feb 23.

Center for Spinelectronic Materials and Devices, Physics Department, Bielefeld University, Bielefeld, Germany.

In this manuscript, we first reveal a simple ultra violet laser lithographic method to design and produce plain tailored multielectrode arrays. Secondly, we use the same lithographic setup for surface patterning to enable controlled attachment of primary neuronal cells and help neurite guidance. For multielectrode array production, we used flat borosilicate glass directly structured with the laser lithography system. The multi layered electrode system consists of a layer of titanium coated with a layer of di-titanium nitride. Finally, these electrodes are covered with silicon nitride for insulation. The quality of the custom made multielectrode arrays was investigated by light microscopy, electron microscopy and X-ray diffraction. The performance was verified by the detection of action potentials of primary neurons. The electrical noise of the custom-made MEA was equal to commercially available multielectrode arrays. Additionally, we demonstrated that structured coating with poly lysine, obtained with the aid of the same lithographic system, could be used to attach and guide neurons to designed structures. The process of neuron attachment and neurite guidance was investigated by light microscopy and charged particle microscopy. Importantly, the utilization of the same lithographic system for MEA fabrication and poly lysine structuring will make it easy to align the architecture of the neuronal network to the arrangement of the MEA electrode.. In future studies, this will lead to multielectrode arrays, which are able to specifically attach neuronal cell bodies to their chemically defined electrodes and guide their neurites, gaining a controlled connectivity in the neuronal network. This type of multielectrode array would be able to precisely assign a signal to a certain neuron resulting in an efficient way for analyzing the maturation of the neuronal connectivity in small neuronal networks.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192647PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825013PMC
April 2018