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The sensitivity and the complexity of the human inner ear in conjunction with the lack of regenerative capacity are the main reasons for hearing loss and tinnitus. Progress in the development of protective and regenerative therapies for the inner ear often failed in the past not least due to the fact that no suitable model systems for cell biological and pharmacological in vitro studies were available. A novel technology for creating "mini-organs", so-called organoids, could solve this problem and has now also reached inner ear research. It makes it possible to produce inner ear organoids from cochlear stem/progenitor cells, embryonic and induced pluripotent stem cells that mimic the structural characteristics and functional properties of the natural inner ear. This review focuses on the biological basis of these inner ear organoids, the current state of research and the promising prospects that are now opening up for basic and translational inner ear research., Competing Interests: Declarations. Conflict of interest: M. Diensthuber and T. Stöver declare that they have no competing interests. For this article no studies on humans or animals were conducted by the authors. The ethical guidelines stated there apply for the listed studies. The supplement containing this article is not sponsored by industry., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

BACKGROUND: Systemic glucocorticoids are commonly used for primary therapy of idiopathic sudden sensorineural hearing loss (ISSNHL). However, the comparative effectiveness and risk profiles of high-dose over lower-dose regimens remain unknown. METHODS: We randomly assigned patients with sudden hearing loss of greater than or equal to 50 dB within 7 days from onset to receive either 5 days of high-dose intravenous prednisolone at 250 mg/d (HD-Pred), 5 days of high-dose oral dexamethasone at 40 mg/d (HD-Dex), or, as a control, 5 days of oral prednisolone (Pred-Control) at 60 mg/d followed by 5 days of tapering doses. The primary outcome was the change in hearing threshold (pure tone average) in the three most affected contiguous frequencies from baseline to day 30. Secondary outcomes included speech understanding, tinnitus, communication competence, quality of life, hypertension, and insulin resistance. RESULTS: A total of 325 patients were randomly assigned. Mean change in 3PTAmost affected hearing threshold from baseline to 30 days was 34.2 dB (95% CI, 28.4 to 40.0) in the HD-Pred group, 41.4 dB (95% CI, 35.6 to 47.2) in the HD-Dex group, and 41.0 dB (95% CI, 35.2 to 46.8) in the Pred-Control group (P=0.09 for analysis of variance). There were more adverse events related to trial medication in the HD-Pred (n=73) and HD-Dex (n=76) groups than in the Pred-Control group (n=46). CONCLUSIONS: Systemic high-dose glucocorticoid therapy was not superior to a lower-dose regimen in patients with ISSNHL, and it was associated with a higher risk of side effects. (Funded by the Federal Ministry of Education and Research [BMBF]; EudraCT number, 2015‐002602‐36.)

The sensitivity and the complexity of the human inner ear in conjunction with the lack of regenerative capacity are the main reasons for hearing loss and tinnitus. Progress in the development of protective and regenerative therapies for the inner ear often failed in the past not least due to the fact that no suitable model systems for cell biological and pharmacological in vitro studies were available. A novel technology for creating "mini-organs", so-called organoids, could solve this problem and has now also reached inner ear research. It makes it possible to produce inner ear organoids from cochlear stem/progenitor cells, embryonic and induced pluripotent stem cells that mimic the structural characteristics and functional properties of the natural inner ear. This review focuses on the biological basis of these inner ear organoids, the current state of research and the promising prospects that are now opening up for basic and translational inner ear research., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: The Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV‑2) pandemic has significantly changed the education of medical students. Due to the contact restrictions and the associated requirement for distance learning, digital teaching formats had to be implemented within a short period of time. The aim of our work was to analyze student evaluation data for virtual teaching in otorhinolaryngology (ORL) during the SARS-CoV‑2 pandemic and to compare the data with previously obtained evaluation data under face-to-face conditions., Materials and Methods: Evaluation data for the block practical courses in winter semester 2020/21 and summer semester 2021, which were carried out in a virtual format with a short face-to-face phase as well as those for the block practical courses from summer semester 2018 to winter semester 2019/20, which had been performed completely in a conventional face-to-face format, were analyzed. The anonymous survey of the students focused on various aspects of the courses such as organization, didactics and learning atmosphere., Results: Of 16 surveyed categories, 14 (87.5%) showed significantly better evaluation results for the virtual courses compared to the courses carried out previously under face-to-face conditions. This very positive assessment of the digital teaching offer showed no significant change during the course of the pandemic over the period of two semesters., Conclusions: Our data show a high acceptance of digital teaching in ORL for students. Even though essential components of the medical education such as teaching on the patient and clinical-practical skills can still only be realized in a face-to-face format, our data suggest that digital elements could also play a role in medical education after the SARS-CoV‑2 pandemic., (© 2022. The Author(s).)

Background: Due to the coronavirus disease 2019 (COVID-19) pandemic, interventions in the upper airways are considered high-risk procedures for otolaryngologists and their colleagues. The purpose of this study was to evaluate limitations in hearing and communication when using a powered air-purifying respirator (PAPR) system to protect against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission and to assess the benefit of a headset., Methods: Acoustic properties of the PAPR system were measured using a head and torso simulator. Audiological tests (tone audiometry, Freiburg speech test, Oldenburg sentence test (OLSA)) were performed in normal-hearing subjects (n = 10) to assess hearing with PAPR. The audiological test setup also included simulation of conditions in which the target speaker used either a PAPR, a filtering face piece (FFP) 3 respirator, or a surgical face mask., Results: Audiological measurements revealed that sound insulation by the PAPR headtop and noise, generated by the blower-assisted respiratory protection system, resulted in significantly deteriorated hearing thresholds (4.0 ± 7.2 dB hearing level (HL) vs. 49.2 ± 11.0 dB HL, p < 0.001) and speech recognition scores in quiet (100.0 ± 0.0% vs. 2.5 ± 4.2%, p < 0.001; OLSA: 20.8 ± 1.8 dB vs. 61.0 ± 3.3 dB SPL, p < 0.001) when compared to hearing without PAPR. Hearing with PAPR was significantly improved when the subjects were equipped with an in-ear headset (p < 0.001). Sound attenuation by FFP3 respirators and surgical face masks had no clinically relevant impact on speech perception., Conclusions: The PAPR system evaluated here can be considered for high-risk procedures in SARS-CoV-2-positive patients, provided that hearing and communication of the surgical team are optimized by the additional use of a headset., (© 2021. The Author(s).)

The hemorheologic drug pentoxifylline is applied for the treatment of sudden sensorineural hearing loss and tinnitus to improve cochlear microcirculation. Recent studies also suggest protective and trophic effects on neuronal cells. Because the preservation of sensorineural structures of the inner ear is fundamental for normal hearing and hearing restoration with auditory prostheses, pentoxifylline and neurotrophic factors such as brain-derived neurotrophic factor (BDNF) are promising candidates to treat degenerative disorders of the inner ear. We used an in-vitro model to determine the neurotrophic effects of these factors on spiral ganglion cells from postnatal rats. Pentoxifylline, alone and in combination with BDNF, was added at various concentrations to the cultured cells. Cells were immunolabeled and analyzed to determine neuronal survival, neurite length, neuronal branching and morphology. Pentoxifylline did not significantly increase or decrease neuronal survival, neurite length and neuronal branching compared to control cultures. Analysis of cellular morphology showed that diverse neuronal subtypes developed in the presence of pentoxifylline. Our data revealed that pentoxifylline did not interfere with the robust neurotrophic effects of BDNF on spiral ganglion neurons when cultured cells were treated with pentoxifylline and BDNF simultaneously. The results of our study do not suggest major neurotrophic effects of pentoxifylline on cultured spiral ganglion neurons. Because pentoxifylline has no detrimental effects on spiral ganglion neurons and does not reduce the effects of BDNF, both agents could be combined to treat diseases of the inner ear provided that future in vivo experiments and clinical studies support these findings., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) replicates predominantly in the upper respiratory tract and is primarily transmitted by droplets and aerosols. Taking the medical history for typical COVID-19 symptoms and PCR-based SARS-CoV-2 testing have become established as screening procedures. The aim of this work was to describe the clinical appearance of SARS-CoV-2-PCR positive patients and to determine the SARS-CoV-2 contact risk for health care workers (HCW)., Methods: The retrospective study included n = 2283 SARS-CoV-2 PCR tests from n = 1725 patients with otorhinolaryngological (ORL) diseases performed from March to November 2020 prior to inpatient treatment. In addition, demographic data and medical history were assessed., Results: n = 13 PCR tests (0.6%) were positive for SARS-CoV-2 RNA. The positive rate showed a significant increase during the observation period (p < 0.01). None of the patients had clinical symptoms that led to a suspected diagnosis of COVID-19 before PCR testing. The patients were either asymptomatic (n = 4) or had symptoms that were interpreted as symptoms typical of the ORL disease or secondary diagnoses (n = 9)., Conclusion: The identification of SARS-CoV-2-positive patients is a considerable challenge in clinical practice. Our findings illustrate that taking a medical history alone is of limited value and cannot replace molecular SARS-CoV-2 testing, especially for patients with ORL diseases. Our data also demonstrate that there is a high probability of contact with SARS-CoV-2-positive patients in everyday clinical practice, so that the use of personal protective equipment, even in apparently "routine cases", is highly recommended., (© 2021. The Author(s).)

Introduction: The SARS-CoV-2 pandemic has led to profound limitations in patient care and student teaching at the University Hospitals of Otorhinolaryngology (ORL). In contrast, the impact on research has been variable. To classify the pandemic-related effect on research, the development of the number of scientific publications of the German ORL university hospitals before and during the pandemic was analyzed., Material and Methods: The publication performance between 2015 and 2020 of the 39 current chairmen was surveyed using a literature search (Pubmed). All entries relating to the chairmen of the university hospital as first, last or co-author were included. The absolute and relative development of each author's publication performance was determined and evaluated using nonparametric statistical methods., Results: A total of 2420 publications could be documented. From 2015 to 2019, an average of 368 publications were published per year. In 2020, this number increased by 57.9 % to 581 publications. While the number of monthly publications remained constant between 2015 and 2019, a significant increase was seen from May 2020 up to a maximum of 74 publications in September 2020. In 2020, 34 articles (5.9 %) had a thematic relation to the SARS-CoV-2 pandemic, with 7 of these papers (20.6 %) resulting from cross-site publications., Conclusion: In 2020, the number of scientific publications was raised to more than 1.5 times the usual annual publications. This increase was clearly related in time to the reduction of elective patient care during the SARS-CoV-2 pandemic starting in mid-March 2020. Probably, free time capacities enabled this increased publication output. Our results confirm the great scientific potential of the ORL university hospitals, which has been successfully implemented despite the pandemic., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Introduction: Based on current knowledge, the SARS-CoV-2 is transmitted via droplet, aerosols and smear infection. Due to a confirmed high virus load in the upper respiratory tract of COVID-19 patients, there is a potential risk of infection for health care professionals when performing surgical procedures in this area. The aim of this study was the semi-quantitative comparison of ENT-typical interventions in the head and neck area with regard to particle and aerosol generation. These data can potentially contribute to a better risk assessment of aerogenic SARS-CoV-2-transmission caused by medical procedures., Materials and Methods: As a model, a test chamber was created to examine various typical surgical interventions on porcine soft and hard tissues. Simultaneously, particle and aerosol release were recorded and semi-quantitatively evaluated time-dependently. Five typical surgical intervention techniques (mechanical stress with a passive instrument with and without suction, CO 2 laser treatment, drilling and bipolar electrocoagulation) were examined and compared regarding resulting particle release., Results: Neither aerosols nor particles could be detected during mechanical manipulation with and without suction. The use of laser technique showed considerable formation of aerosol. During drilling, mainly solid tissue particles were scattered into the environment (18.2 ± 15.7 particles/cm 2 /min). The strongest particle release was determined during electrocoagulation (77.2 ± 30.4 particles/cm 2 /min). The difference in particle release between electrocoagulation and drilling was significant (p < 0.05), while particle diameter was comparable. In addition, relevant amounts of aerosol were released during electrocoagulation (79.6% of the maximum flue gas emission during laser treatment)., Discussion: Our results demonstrated clear differences comparing surgical model interventions. In contrast to sole mechanical stress with passive instruments, all active instruments (laser, drilling and electrocoagulation) released particles and aerosols. Assuming that particle and aerosol exposure is clinically correlated to the risk of SARS-CoV-2-transmission from the patient to the physician, a potential risk for health care professionals for infection cannot be excluded. Especially electrocautery is frequently used for emergency treatment, e.g., nose bleeding. The use of this technique may, therefore, be considered particularly critical in potentially infectious patients. Alternative methods may be given preference and personal protective equipment should be used consequently.

Background: The corona crisis not only affects professional activities but also teaching and learning at universities. Buzzwords, such as e‑learning and digitalization suggest the possibility of innovative teaching approaches that are readily available to solve the problems of teaching in the current COVID-19 pandemic. The current conversion to digital teaching is not primarily driven by didactic rationale or institutional strategy but by external circumstances., Objective: The aim of the study was to determine the teaching situation at national university ENT clinics and academic teaching hospitals at the start of the virtual corona summer semester in 2020., Material and Methods: A specifically self-designed questionnaire regarding the local situation and conditions as well as nationwide scenarios was sent to all 39 national university ENT clinics and 20 ENT departments at academic teaching hospitals., Results: A total of 31 university hospitals and 10 academic teaching hospitals took part in the survey. There were obvious discrepancies between available resources and effectively available digital teaching and learning contents. Further criticism was expressed regarding the communication with the medical faculty, the digital infrastructure and particularly the frequent lack of collaboration with central support facilities, such as media, didactics and datacenters., Conclusion: There are positive examples of successful transformation of classroom teaching to an exclusively virtual summer semester 2020 within the university ENT clinics; however, critical ratings of assistant professors and medical directors regarding the current teaching situation predominated. A time-critical strategic advancement is urgently needed.

The treatment of patients with severe hearing loss or deafness with a cochlear implant (CI) represents a standard in Germany today. However, there is hardly any data on the current number of clinical CI centers (CI clinics) and their geographical distribution. The patient self-help organization, German Cochlear Implant Society (DCIG), and the German Society for Otorhinolaryngology, Head and Neck Surgery (DGHNO-KHC) have therefore initiated a survey to determine the regional distribution, the range of services, the consideration of existing quality standards and cooperation with patient self-help organizations of the individual clinical CI centers.For this purpose, a total number of 170 ENT departments or their directors (37 professors and 133 chief physicians), respectively, were contacted by e-mail and provided with a questionnaire. The survey took place from October 2019 to February 2020.Of the 170 departments contacted, 71 (41.8 %) took part in the survey. Of these, 70 departments (98.6 %) confirmed to perform CI surgeries. Thus, 41.8 % of all clinics contacted reported to perform CI surgeries (70 of 170 clinics), while this information was not available from 99 clinics. All 70 clinical CI centers (100 %) reported to conduct CI surgeries on adults, 60 centers (85.7 %) also on children (< 18 years). 36 departments (51.4 %) reported that the total number of CI surgeries at their facility in 2018 was more than 50. In 64 departments (91.4 %), the recommendations of the DGHNO-KHC on CI care (according to the White Paper CI care 2018) were followed. A collaboration between the department and patient self-help organization was confirmed by 67 institutions (95.7 %). The geographical distribution of the clinical CI centers showed a heterogeneous distribution pattern between the individual federal states and also within the respective federal state.The work presented here is a first assessment of the situation with regard to the regional distribution of clinical CI centers in Germany. A clustering of CI centers was noticeable in metropolitan areas, sometimes with several facilities in one city. The predominant attention to quality-related aspects, such as the consideration of the DGHNO-KHC white paper and the cooperation with patient self-help, is gratifying. The limitations of the study result from limited participation in the survey (41.8 % of the contacted clinics)., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The SARS-CoV-2 pandemic poses major challenges for the entire medical care system. Especially in university institutions as maximum care providers, a higher exposure to potentially infectious patients or actual COVID-19 patients is to be expected. In a short period of time, an operational concept had to be developed regarding the current hygiene recommendations of the Robert Koch Institute (RKI), the leading medical societies and the internal hospital hygiene plan. Here, patient safety and employee protection are equally important.In cooperation with the Institute for Medical Microbiology and Hospital Hygiene and the occupational medical service, interventions were defined to develop solutions to minimize the COVID-19 transmission risk for examiners and patients despite limited diagnostic and equipment resources. For this purpose, an operational concept was developed, consisting of various individual actions, e. g. the reduction of outpatient treatment to emergencies, life-threatening diseases and urgent aftercare, a double triage of patients and the introduction of treatment teams.The newly developed operational concept was successfully implemented within a few days. After the initial rollout and several "hygiene inspections" only minor improvements to the concept were necessary. All measures were documented in the internal quality handbook and are accessible to all employees. Since the SARS-CoV-2 pandemic is a dynamic process with regular changes in the development and information status, the operational concept is regularly reviewed for validity and adjusted as necessary., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and often has a poor prognosis. The present study investigated the role of the low affinity nerve growth factor receptor CD271 as a putative therapy target in HNSCC. Neurotrophins that bind to CD271 also have a high affinity for the tropomyosin receptor kinase family (Trk), consisting of TrkA, TrkB, and TrkC, which must also be considered in addition to CD271. A retrospective study and functional in vitro cell line tests (migration assay and cell sorting) were conducted in order to evaluate the relevance of CD271 expression alone and with regard to Trk expression. CD271 and Trks were heterogeneously expressed in human HNSCC. The vast majority of tumors exhibited CD271 and TrkA, whereas only half of the tumors expressed TrkB and TrkC. High expression of CD271-positive cells predicted a bad clinical outcome of patients with HNSCC and was associated with distant metastases. However, the human carcinomas that also expressed TrkC had a reduced correlation with distant metastases and better survival rates. In vitro, CD271 expression marked a subpopulation with higher proliferation rates, but proliferation was lower in tumor cells that co-expressed CD271 and TrkC. The CD271 inhibitor LM11A 31 suppressed cell motility in vitro. However, neither TrkA nor TrkB expression were linked to prognosis or cell proliferation. We conclude that CD271 is a promising candidate that provides prognostic information for HNSCC and could be a putative target for HNSCC treatment.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht.

Intact spiral ganglion neurons are a specific requirement for hearing rehabilitation in deaf patients by cochlear implantation. Neurotrophic growth factors have been proposed as effective tools to protect and regenerate spiral ganglion neurons that are degenerated in the majority of patients suffering from hearing loss. Here, we show that growth hormone (GH), a pleiotropic growth factor whose neurotrophic role in the inner ear is still unclear, significantly increases neurite extension, as well as neuronal branching, in spiral ganglion cell cultures derived from early postnatal rats. Our data suggest that GH can act as a potent neurotrophic factor for inner ear neurons, which specifically promotes neurite growth. These effects might be elicited in a direct way or, alternatively, by induction of other growth factors that account for the observed neurotrophic effects. Thus, we conlude that GH might represent a novel candidate for the treatment of neurodegeneration in the hearing-impaired inner ear that has the potential to ultimately improve the performance and outcome of modern auditory implants.

Despite impressive technical progress in the field of conventional hearing aids and implantable hearing systems, the hopes for the treatment of inner ear diseases such as hearing loss and tinnitus have become increasingly directed toward regenerative therapeutic approaches. This review discusses the currently most promising strategies for hair cell regeneration in the inner ear to treat hearing loss, including stem cell-based, gene transfer-based, and pharmacological interventions. Furthermore, previous milestones and ground-breaking work in this scientific field are identified. After many years of basic research, the first clinical trials with a regenerative therapeutic approach for hearing-impaired patients were recently initiated. Although there is still a long and bumpy road ahead until a true breakthrough is achieved, it seems more realistic than ever that regenerative therapies for the inner ear will find their way into clinical practice.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

In head and neck squamous cell carcinoma (HNSCC), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and hyaluronan receptor cluster of differentiation 44 (CD44) are often used as cancer stem cell (CSC) markers. The aim of the present study was to examine the relevance of these proteins for HNSCC in general and for the identification of CSCs. Tumors from 48 patients with primary HNSCC were analyzed for the expression of ALDH1A1 and CD44. Additionally, the association of the proteins with the proliferation rate and epidermal growth factor receptor (EGFR) expression was analyzed. ALDH1A1 was expressed in 54.2% of the carcinoma samples while CD44 was expressed in 89.6% of the carcinoma samples. Most notably, these proteins were often not expressed exclusively in a subpopulation, but also in the majority of tumor cells (ALDH1A1: 30.8% of ALDH1A1 + tumors; CD44: 65.1% of CD44 + tumors). Furthermore, patients with ALDH1A1 + tumors exhibited worse survival rates. CD44 and EGFR expression patterns were overlapping within the tumors and the expression rates were significantly connected. Ki-67 + tumor cells often expressed CD44. ALDH1A1 and CD44 expression patterns only partly overlapped. Consequently, ALDH1A1 and CD44 play significant roles in carcinogenesis and tumor progression. Within the present study, CD44 appeared to interact with EGFR and was more often expressed in primary HNSCC than the marker ALDH1A1. However, ALDH1A1 was a better marker to define a subpopulation of tumor cells. Finally, neither ALDH1A1 nor CD44, alone or combined, were sufficient to determine the CSC population in HNSCC.

Neural stem cells from the central nervous system have the distinct capacity to give rise to clonal neurospheres. These clonal spheres are derived from a single clone-forming cell and represent homogenous, pure cell colonies. Recently, stem/progenitor cells have been isolated from the spiral ganglion of the inner ear using sphere-forming assays. However, the clonality of spiral ganglion-derived spheres has not yet been addressed in detail. Here, we report the isolation of clonal colonies from the spiral ganglion of early postnatal mice. We analyze sphere clonality using coculture experiments with transgenic cells, a semisolid assay, and culture of single cells in isolation. Our data show that sphere clonality differs in primary and secondary cultures and indicate that clonal sphere formation is dependent on specific culture parameters. We also show that the initiation of clonal colony formation does not require cell-to-cell interactions or paracrine signaling from surrounding cells. Generation of clonal colonies from spiral ganglion stem/progenitor cells might be crucial for future clinical applications because pure cell populations are considered to be more efficient and safe for therapeutic use than chimeric, heterogeneous spheres.

The spiral ganglion is an essential functional component of the peripheral auditory system. Most types of hearing loss are associated with spiral ganglion cell degeneration which is irreversible due to the inner ear's lack of regenerative capacity. Recent studies revealed the existence of stem cells in the postnatal spiral ganglion, which gives rise to the hope that these cells might be useful for regenerative inner ear therapies. Here, we provide an in-depth analysis of sphere-forming stem cells isolated from the spiral ganglion of postnatal mice. We show that spiral ganglion spheres have characteristics similar to neurospheres isolated from the brain. Importantly, spiral ganglion sphere cells maintain their major stem cell characteristics after repeated propagation, which enables the culture of spheres for an extended period of time. In this work, we also demonstrate that differentiated sphere-derived cell populations not only adopt the immunophenotype of mature spiral ganglion cells but also develop distinct ultrastructural features of neurons and glial cells. Thus, our work provides further evidence that self-renewing spiral ganglion stem cells might serve as a promising source for the regeneration of lost auditory neurons.

Background/aim: A change in epidemiology of head and neck squamous cell carcinoma (HNSCC) has been noticed: while overall incidence has decreased, the incidence of oropharyngeal SCC (OSCC) has been increasing over the past decades. A growing body of evidence suggests a causative role of the human papillomavirus (HPV) as an independent risk factor in development of OSCC. The aim of this study was to determine the HPV status in all OSCC specimens collected in our biological database since 1988, correlating the results with overall survival, and to compare them with the current literature data., Patients and Methods: A total of 104 tumor samples were obtained and included in this study. Patient records were reviewed. HPV status was determined by a two-step polymerase chain reaction (PCR) combined with p16 immunohistochemistry. Statistical analysis was performed with BiAS™., Results: Overall 12 (12%) of the 104 tumor samples were HPV-positive. Most of the patients had advanced disease [(UICC) stage III or IV)]: 91.7 % in the HPV-positive group versus 78.2% in the HPV-negative group. Multivariate analysis showed that HPV status (p=0.04), UICC stage (p=0.01) and age at initial diagnosis (p=0.0006) were all independent determinants of overall survival. A positive HPV status (hazard ratio=0.52; 95%) was associated with a 48% increase of overall survival compared to patients with HPV-negative tumors., Conclusion: Our findings confirm a prevalence of HPV-positive tumors within OSCC. Due to its epidemiologic and prognostic relevance, HPV status should be considered an important part of tumor staging. For this purpose, HPV detection via two-step PCR combined with p16 immunohistochemistry seems reliable.

Unlabelled: Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common type of cancer worldwide; 600,000 new cases are diagnosed every year. Infected with high-risk human papilloma virus (HPV) types are particularly linked to oropharyngeal cancer. Among over 100 different HPV types, HPV-16 and HPV-18 are detected in the majority of HPV-positive SCCHNs. The p16 gene is often mutated in SCCHN, its overexpression is caused by the viral E7 protein. Consequently, p16 is assumed to be an indirect marker of HPV-induced SCCHN. The aim of the present study was to determine the role of p16 expression as a predictive marker of HPV infection in SCCHN tumors in a retrospective single-center study., Materials and Methods: Oropharyngeal tumor samples from 45 patients (34 males, 11 females) were analyzed. Tumor samples were examined for HPV infection using a two-step PCR. p16 staining by immunohistochemistry was then performed., Results: Samples with strong p16 signal were typed HPV-16-positive. Out of 14 tumor samples with HPV-positive PCR results, 13 samples contained the high risk variant HPV-16. In one sample, HPV-6 DNA was detected. All HPV-16-positive tumors overexpressed p16 (p16(+++)), whereas the HPV-6 sample was p16-negative., Conclusion: p16 is not a surrogate marker for replacing PCR testing, but both methods in combination, PCR and immunohistochemistry, could lead to a higher diagnostic validation.

Inhibition of the polo-like-kinase-1 (PLK-1) has been shown to be effective in several haematological and solid tumor models. In this systemic in vitro study, the antitumor effect of BI2536, a small molecule inhibitor of PLK-1, in combination with cisplatin and docetaxel was examined in nine squamous cell carcinoma cell lines, most of which had a head and neck origin (SCCHN). Dose escalation studies were conducted with nine SCCHN cell lines using BI2536, cisplatin and docetaxel in cell line-specific concentrations. Growth inhibitory and proapoptotic effects were measured quantitatively using cytohistology and a Human Apoptose Array kit. BI2536 in combination with cisplatin and docetaxel showed a markedly higher antiproliferative and apoptotic activity in the SCCHN cell lines investigated (P≤0.008), compared with single agent cisplatin or docetaxel alone. The findings of this study showed that the addition of PLK-1-inhibitor BI2536 to conventional chemotherapeutic drugs led to a statistically higher antiproliferative and apoptotic effect in SCCHN cell lines compared with cisplatin or docetaxel alone. Inaugurating BI2536 in the clinical setting might enhance the antitumoral activity of conventional drugs, possibly leading to less toxic side effects of cancer therapy.

Inhibition of the proteasome with Bortezomib as well as inhibition of Polo-like-kinase-1 (PLK-1) has been shown to be effective in many solid tumour models and also in squamous cell carcinoma of the head and neck (SCCHN) cell lines. For the first time, we systematically examined the antitumour effect of Bortezomib in combination with BI2536 in SCCHN in an in vitro study. Dose escalation studies were performed with nine SCCHN cell lines using Bortezomib and BI2536 as single agent and combination treatments. Growth-inhibitory and pro-apoptotic effects were measured quantitatively using cytohistology and Human Apoptose Array kit. The combination of Bortezomib and BI2536 showed significant anti-proliferative and apoptotic activity in all SCCHN cell lines investigated (P=0.008) compared to both the untreated control group and Bortezomib alone. A combination treatment regime consisting of the proteasome inhibitor, Bortezomib, and the inhibitor of PLK-1, BI2536, leads to an enhanced anti-proliferative and apoptotic effect in SCCHN cell lines, compared to single agent treatment with Bortezomib alone.

Recent studies have shown BI2536 and bortezomib to be effective in squamous cell carcinoma of the head and neck (SCCHN) cell lines. In this systemic in vitro study, we examined the antitumor effect of the small molecules BI2536 and bortezomib in combination with cisplatin or docetaxel in nine squamous cell carcinoma cell lines, most of head and neck origin. Dose escalation studies were performed with these cell lines using bortezomib, BI2536, cisplatin and docetaxel in cell line-specific concentrations. Growth inhibitory and proapoptotic effects were measured quantitatively using cytohistology and the Human Apoptosis Array kit. The combination of bortezomib and BI2536 with cisplatin or docetaxel showed a significantly higher antiproliferative and apoptotic activity in all SCCHN cell lines investigated compared with single agent cisplatin or docetaxel alone (P≤0.021). Combination of conventional chemotherapeutic drugs, such as cisplatin and docetaxel, with small molecules in the clinical setting may enhance the antitumor activity of these agents and may lead to less toxic side-effects and a more effective cancer therapy.

One challenge of squamous cell carcinoma of the head and neck (SCCHN) chemotherapy is a small percentage of tumor cells that arrest in the G0 phase of the cell cycle and are thus not affected by chemotherapy. This could be one reason for tumor recurrence at a later date. The recruitment of these G0-arresting cells into the active cell cycle and thus, proliferation, may increase the efficacy of chemotherapeutic agents. The aim of this study was to investigate whether stimulation with recombinant epidermal growth factor (EGF) or serotonin leads to an increased tumor cell proliferation in xenografts. Detroit 562 cells were injected into NMRI-Foxn1nu mice. Treatment was performed with 15 µg murine or human EGF, or 200 µg serotonin. The control mice were treated with Lactated Ringer's solution (5 mice/group). Tumor size was measured on days 4, 8 and 12 after tumor cell injection. The EGF stimulated mice showed a significantly higher tumor growth compared to the serotonin-stimulated mice and the untreated controls. In the present study, we show that it is possible to stimulate tumor cells in xenografts by EGF and thus, enhance cell proliferation, resulting in a higher tumor growth compared to the untreated control group. In our future investigations, we plan to include a higher number of mice, an adjustment of the EGF dosage and cell subanalysis, considering the heterogeneity of SCCHN tumors.

Background/aim: Besides late diagnosis, tumor metastasis and cancer relapse are the main reasons for the poor prognosis of patients with head and neck cancer. Several investigations have shown that tumor is of heterogeneous molecularity consisting of several subpopulations, with a broad range of biological behaviors. The ability and potential of tumor to infiltrate into vessels and into neighbouring organs, as well as the resistance to chemotherapeutical cancer therapy may be caused by cancer stem cells (CSCs). The aim of the present study was to illuminate the role and behaviour of (CD44) and (ALDH1A1) as tumor stem cell markers in a xenograft mouse model of squamous cell carcinoma., Materials and Methods: Five female NMRI-Foxn1nu mice were injected with five million Detroit 562 cells (100 μl). After sacrifice of the mice, tumors were excised. Then ALDH1A1, CD44, (EGFR), CD31 and Ki 67 were detected as molecular markers for tumor stem cells by immunohistopathology and immunofluorescence., Results: The amount of putative CSC marker proteins CD44 and ALDH1A1 vary. ALDH1A1high tumor cells express low levels of CD44 and EGFR. The CD44+high expressers also exhibit expression of high levels of the EGFR. CSCs must be sub-classified depending on their expression of marker proteins., Conclusion: We assume that CSCs can also be sub-classified into migratory and stationary CSCs. ALDH1A1high/CD44low/EGFRlow tumor cells may be stationary and quiescent, whereas ALDH1A1-/CD44high/EGFRhigh expressers have a migratory, invasive nature. It is likely that a regulatory mechanism, as yet unknown, controls this conversion, from quiescent to active cancer stem cells.

Inhibition of the Polo-like-kinase-1 (PLK1) has been shown to be effective in a number of solid tumor models. In this in vitro study, we examined the antitumor effect of BI2536, a small molecule inhibitor of PLK1, in squamous cell carcinoma of the head and neck (SCCHN) cell lines. Dose escalation studies were performed with nine SCCHN cell lines using BI2536. Growth inhibitory and proapoptotic effects were measured quantitatively using cytohistology and a Human Apoptosis Array Kit. BI2536 demonstrated a significant antiproliferative and apoptotic activity in all nine SCCHN cell lines investigated (p<0.009). Our results indicate that inhibition of PLK1 by BI2536 leads to an antiproliferative and apoptotic effect in SCCHN cell lines. In vivo and in the clinical setting, the application of BI2536 may support the antitumoral activity of conventional drugs that are in current use and could decrease the systemic toxicity of these drugs.

The inner ear is our most sensitive sensory organ and can be subdivided into 3 functional units: organ of Corti, stria vascularis and spiral ganglion. The appropriate stimulus for the organ of hearing is sound which travels through the external auditory canal to the middle ear where it is transmitted to the inner ear. The inner ear habors the hair cells, the sensory cells of hearing. The inner hair cells are capable of mechanotransduction, the transformation of mechanical force into an electrical signal, which is the basic principle of hearing. The stria vascularis generates the endocochlear potential and maintains the ionic homeostasis of the endolymph. The dendrites of the spiral ganglion form synaptic contacts with the hair cells. The spiral ganglion is composed of neurons that transmit the electrical signals from the cochlea to the central nervous system. In the past years there was significant progress in research on the molecular basis of hearing. More and more genes and proteins which are related to hearing can be identified and characterized. The increasing knowledge on these genes contributes not only to a better understanding of the mechanism of hearing but also to a deeper understanding of the molecular basis of hereditary hearing loss. This basic research is a prerequisite for the development of molecular diagnostics and novel therapies for hearing loss., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: In contrast to regenerating hair cell-bearing organs of nonmammalian vertebrates the adult mammalian organ of Corti appears to have lost its ability to maintain stem cells. The result is a lack of regenerative ability and irreversible hearing loss following auditory hair cell death. Unexpectedly, the neonatal auditory sensory epithelium has recently been shown to harbor cells with stem cell features. The origin of these cells within the cochlea's sensory epithelium is unknown., Material and Methods: We applied a modified neurosphere assay to identify stem cells within distinct subregions of the neonatal mouse auditory sensory epithelium. Sphere cells were characterized by multiple markers and morphologic techniques., Results: Our data reveal that both the greater and the lesser epithelial ridge contribute to the sphere-forming stem cell population derived from the auditory sensory epithelium. These self-renewing sphere cells express a variety of markers for neural and otic progenitor cells and mature inner ear cell types., Conclusion: Stem cells can be isolated from specific regions of the auditory sensory epithelium. The distinct features of these cells imply a potential application in the development of a cell replacement therapy to regenerate the damaged sensory epithelium.

Purpose: To report the experience with AdOnco, a computerized database for head and neck cancer patients., Patients and Methods: AdOnco is a Filemaker Pro 6.0 based database integrated into the local network of the host ENT department. It is used by the physicians as a clinical and scientific documentation system to store and retrieve information about all patients with head and neck cancer referred to the host oncology center. This study reviews the achievements to date of AdOnco and, as an example of its enormous data evaluation potential, presents survival curves of patients with laryngeal cancer undergoing laser resection., Results: Over a period of six years, the data of 881 patients with head and neck cancer were entered into the AdOnco database., Conclusion: AdOnco has proven to be a useful patient database and documentation system which has become an integral and essential part of daily clinical routine and also a valuable research tool.

Mechanosensitive sensory hair cells are the linchpin of our senses of hearing and balance. The inability of the mammalian inner ear to regenerate lost hair cells is the major reason for the permanence of hearing loss and certain balance disorders. Here, we present a stepwise guidance protocol starting with mouse embryonic stem and induced pluripotent stem cells, which were directed toward becoming ectoderm capable of responding to otic-inducing growth factors. The resulting otic progenitor cells were subjected to varying differentiation conditions, one of which promoted the organization of the cells into epithelial clusters displaying hair cell-like cells with stereociliary bundles. Bundle-bearing cells in these clusters responded to mechanical stimulation with currents that were reminiscent of immature hair cell transduction currents., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

The expression of neurotrophic factors, such as artemin, glial cell line-derived neurotrophic factor (GDNF), neurturin, transforming growth factors (TGF)-beta1/beta2 and brain-derived neurotrophic factor (BDNF), is enhanced in vestibular schwannomas compared to peripheral nerves. Furthermore, this upregulation may correlate with mitotic activity. Vestibular schwannoma arising from Schwann cells of the vestibular nerve are mostly benign and slow-growing. Most of the pathogenic mechanisms regulating the vestibular schwannoma growth process are unknown. An impaired growth regulation and imbalance between mitosis and apoptosis can be assumed. However, molecular mechanisms interfering with regulation of the vestibular schwannoma growth also modulated by mitogenic factors have to be identified. Neurotrophic factors are involved in regulation of developmental processes in neuronal tissues and regeneration after peripheral nerve trauma and also reveal mitogenic effects on glial cell populations. Gene expression profiles of artemin, BDNF, GDNF, TGF-beta1/beta2 and Ret were determined in the vestibular schwannoma in comparison to the peripheral nerve tissues by using semiquantitative RT-PCR. The expression data were correlated to the proliferation-associated Ki-67 labelling index. A significant higher BDNF expression was observed in the vestibular schwannoma, whereas gene expression of artemin and GDNF was upregulated in peripheral nerves. The correlation between LI and BDNF, TGF-beta1 and Ret was found to be significant in the vestibular schwannoma. Our results demonstrate a coherence between BDNF expression and proliferative activity in the vestibular schwannoma. Based on these results, we propose a pivotal role for BDNF in modulating the vestibular schwannoma growth.

Nonmammalian vertebrates regenerate lost sensory hair cells by means of asymmetric division of supporting cells. Inner ear or lateral line supporting cells in birds, amphibians, and fish consequently serve as bona fide stem cells resulting in high regenerative capacity of hair cell-bearing organs. Hair cell regeneration does not happen in the mammalian cochlea, but cells with proliferative capacity can be isolated from the neonatal cochlea. These cells have the ability to form clonal floating colonies, so-called spheres, when cultured in nonadherent conditions. We noticed that the sphere population derived from mouse cochlear sensory epithelium cells was heterogeneous, consisting of morphologically distinct sphere types, hereby classified as solid, transitional, and hollow. Cochlear sensory epithelium-derived stem/progenitor cells initially give rise to small solid spheres, which subsequently transition into hollow spheres, a change that is accompanied by epithelial differentiation of the majority of sphere cells. Only solid spheres, and to a lesser extent, transitional spheres, appeared to harbor self-renewing stem cells, whereas hollow spheres could not be consistently propagated. Solid spheres contained significantly more rapidly cycling Pax-2-expressing presumptive otic progenitor cells than hollow spheres. Islet-1, which becomes upregulated in nascent sensory patches, was also more abundant in solid than in hollow spheres. Likewise, hair cell-like cells, characterized by the expression of multiple hair cell markers, differentiated in significantly higher numbers in cell populations derived from solid spheres. We conclude that cochlear sensory epithelium cell populations initially give rise to small solid spheres that have self-renewing capacity before they subsequently convert into hollow spheres, a process that is accompanied by loss of stemness and reduced ability to spontaneously give rise to hair cell-like cells. Solid spheres might, therefore, represent the most suitable sphere type for cell-based assays or animal model transplantation studies aimed at development of cell replacement therapies.

Erythropoietin (Epo) expression is regulated via hypoxia-inducible factor (HIF)-1alpha-directed gene transcription. Activation of the erythropoietin receptor (EpoR) by Epo leads to elevated expression of the anti-apoptotic protein, bcl-2, which has recently been shown to promote angiogenesis in malignant tumors. Expression of HIF-1alpha, Epo, EpoR, and bcl-2 was studied by immunohistochemistry in a series of 20 olfactory neuroblastoma (ONB) samples. Data were correlated with microvessel density, proliferative activity, and apoptosis in the specimens and survival analysis was performed to investigate the prognostic value of the examined factors. Immunohistochemical analysis revealed robust expression of HIF-1alpha, Epo, EpoR, and bcl-2 in ONB. Ninety percent of the samples showed HIF-1alpha immunoreactivity and in 60% of the cases, bcl-2 immunoreactivity was observed. A significant positive correlation between the expression levels of HIF-1alpha and bcl-2 and the microvessel density was found. Survival analysis did not reveal any prognostic significance for the tested factors. Expression of HIF-1alpha, Epo, Epo-R, and bcl-2 may play a functional role in ONB pathogenesis. Our data suggest that bcl-2 may act as a stimulator of angiogenesis in ONB, and thus represents a novel target for anti-angiogenic treatment strategies in the therapy of ONB.

Hemangiopericytomas are malignant tumors arising from pericytic cells and account for less than 1% of all vascular neoplasms. We report a rare case of an extra- and intracranial dumbbell-shaped hemangiopericytoma originating from the soft tissue of the neck and penetrating the skull base with invasion into the posterior cranial fossa. The 59-year-old female patient presented with a large pulsating neck mass and reported weakness, abnormal fatigue and headache. MRI revealed an inhomogeneously enhancing tumor and cerebral angiography showed intensive vascularization. Preoperative embolization was performed in order to decrease the operative blood loss. The tumor was operated via a far lateral approach through an osteoclastic suboccipital craniotomy. Total resection of both the intra- and extracranial part of the neoplasm (grade I by Simpson) could be achieved. The histopathological analysis revealed a mesenchymal, hypervascular tumor with the classic staghorn vascular pattern. In this article, we discuss the clinical presentation and multidisciplinary management of hemangiopericytoma and describe the radiological and pathological features of this tumor entity.

Objectives: Current multislice computed tomography (CT) technology can be used for diagnosis and surgical planning applying computer-assisted three-dimensional (3D) visualization and surgical simulation. The usefulness of a technique for surgical simulation of frontoorbital advancement is demonstrated here in a child with metopic synostosis., Materials and Methods: Postprocessing of multi-slice CT data was performed using the software 3D slicer. 3D models were created for the purpose of surgical simulation. These allow planning the course of the osteotomies and individually placing the different bony fragments by an assigned matrix to simulate the surgical result. Photo documentation was obtained before and after surgery. Surgical simulation of the procedure allowed determination of the osteotomy course and assessment of the positioning of the individual bony fragments., Conclusions: Computer-assisted postprocessing and simulation is a useful tool for surgical planning in craniosynostosis surgery. The time-effort for segmentation currently limits the routine clinical use of this technique.

Hypothesis: Hypoxia-inducible factor (HIF)-1alpha, erythropoietin (Epo), Epo receptor (EpoR), and bcl-2 are expressed in both sporadic unilateral vestibular schwannomas (VSs) and those associated with neurofibromatosis Type 2, and the expression data correlate with clinicopathological tumor features including microvessel density and Ki-67-labeling index., Background: Erythropoietin expression is regulated by the transcription factor, HIF-1alpha. Erythropoietin signaling via EpoR results in stimulation of cell proliferation and elevated expression of the antiapoptotic protein, bcl-2, and then inhibition of apoptosis. Erythropoietin has been shown to be associated with Schwann cell proliferation, and a recent report suggested a role in VS growth., Methods: Immunohistochemical analysis of HIF-1alpha, Epo, EpoR, and bcl-2 was performed on formalin-fixed paraffin-embedded archival surgical specimens. Microvessel density and Ki-67-labeling index of VS were analyzed and correlated with the immunoreactivity pattern of the examined factors., Results: Immunoreactivity data demonstrate robust protein expression for HIF-1alpha, Epo, EpoR, and bcl-2 in VS. Sixty-six percent of the cases showed Epo expression, and EpoR was found in 85% of tumor samples. A significantly positive correlation of the immunoreactivity scores of Epo/EpoR and bcl-2 expression could be noted. In case of tumor specimens with high levels of HIF-1alpha expression, a significantly higher Ki-67-labeling index was observed. There was no correlation between the expression of HIF-1alpha, Epo, EpoR, and bcl-2 and microvessel density, tumor size, sex, and age., Conclusion: Expression of Epo and EpoR might suggest a functional role in VS biology. The observed correlation of Epo/EpoR and bcl-2 expression levels may suggest a proliferative and antiapoptotic role of the Epo/EpoR system in VS.

Background: The efficacy of cochlear implant performance depends, among many other factors, on the number of excitable spiral ganglion cells (SGCs) and the nerve-electrode interface. In earlier animal studies it has been demonstrated that neurotrophic factors are effective to improve SGC survival after experimentally induced deafness. With regard to their anti-inflammatoric and anti-proliferative effects, glucocorticoids (e. g. dexamethasone) are potentially interesting therapeutic agents to reduce connective tissue formation around the inserted electrode. The biological effects of a combined intervention of neurotrophic factors with steroids on SGCs are unknown. Therefore the objective of the study was to investigate possible trophic or even toxic effects of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and dexamethasone on neurite outgrowth of cultivated SGCs., Methods: By using dissociated postnatal spiral ganglion cells (p3-5) for cultivation in the present study, the influence of the mentioned factors in various concentrations and combinations on neurite outgrowth of SGCs was analysed., Results: Our results indicate significant trophic effects for BDNF (50 ng/ml) and a combination of BDNF with dexamethasone (100 ng/ml) on SGC neurite outgrowth. In contrast, single application of GDNF or dexamethasone in different concentrations caused no significant changes on neurite outgrowth when compared to the control condition., Conclusions: Neurite outgrowth induced by neurotrophic factors could not be observed to be reduced when dexamethasone is given at the same time. Therefore the demonstrated results provide a basis for further animal studies in this field of research.

The vestibular schwannoma is a benign, slow-growing neoplasm that originates from the neurolemmal sheath of the vestibular branch of the VIIIth cranial nerve. This tumor entity accounts for 6 % of all intracranial tumors and the annual incidence of newly diagnosed vestibular schwannoma is reported as 13 per million. The molecular pathogenesis of both sporadic vestibular schwannoma and those occurring in neurofibromatosis type II appears to be associated with an aberration of a tumor suppressor gene on chromosome 22q12. The biological background for the various growth patterns of vestibular schwannoma is, however, largely unknown. This differing clinical and biological behaviour of vestibular schwannoma may be explained by the presence of neurotrophic factors. The results of recent immunohistochemical studies demonstrate the co-expression of transforming growth factor (TGF)-beta 1 and glial cell line-derived neurotrophic factor (GDNF) in vestibular schwannoma and suggest a trophic synergism of both neurotrophic factors in this tumor. Moreover, expression of numerous different neurotrophic factors has been shown in studies of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), neuregulin (NRG) and erythropoietin (EPO) indicating a biological role in development, maintainance or growth of vestibular schwannoma. In this article, we summarize the findings on neurotrophic factor expression and discuss their characteristics and biological role in vestibular schwannoma.