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BACKGROUND Persistent dizziness symptoms after cochlear implantation have an impact on quality of life. In this study, the effects of bilateral cochlear implants (CI) on quality of life as well as on subjective dizziness complaints are analyzed using questionnaires, some of which have never been applied before in these patient collectives. OBJECTIVE In this article, questionnaires for the assessment of dizziness symptoms and quality of life are introduced in order to realize quality assurance. MATERIALS AND METHODS A total of 32 patients with bilateral CI were questioned regarding dizziness symptoms and quality of life. The Nijmegen Cochlear Implant Questionnaire (NCIQ) was used. In the case of reported regular dizziness, the Vertigo Handicap Questionnaire (VHQ) and the Vertigo Symptom Scale (VSS) were also assessed. RESULTS Persistent dizziness symptoms were shown in 8 of 32 patients. Quality of life was measured with the NCIQ and was improved significantly (p < 0.001) by 23.7% after the second CI. The dizziness symptoms changed slightly (VHQ -11.2%; VSS +16.4%) after the second implantation. CONCLUSION The results show that the questionnaires are valid instruments for documenting quality of life and dizziness symptoms for quality assurance. These questionnaires may be applied as a complement or an alternative to device-based measurements of peripheral vestibular dysfunction.

In Deutschland ist die hochauflosende Sonographie mit Verwendung von Farbduplexverfahren neben der Computertomographie (CT) ein gangiges und bewahrtes Verfahren im Rahmen der Therapiekontrolle („restaging“) nach der Primartherapie von Kopf-Hals-Karzinomen (HNSCC). Im internationalen Kontext existieren fur HNSCC keine evidenzbasierten Leitlinien fur das Re-Staging oder die Tumornachsorge. Entscheidungen fur und wider eine „neck dissection“ (ND) nach primarer Radiochemotherapie (RCT) werden in den Tumorkonferenzen haufig individuell getroffen und unterliegen damit einer Variabilitat. Anders als in Grosbritannien oder den USA besteht in Deutschland eine hohe Expertise in der Anwendung des Ultraschalls in Kombination mit der CT zum routinemasigen Re-Staging von HNSCC nach RCT. Mittels der hochauflosenden Sonographie (B-Mode und Farbdoppler) sind morphologische Veranderungen von Halslymphknoten hervorragend darstellbar. Ein weiterer wichtiger Aspekt ist die genaue und standardisierte Dokumentation von Befunden und deren Dynamik im Verlauf. Zusammen mit der klinischen Prasentation ermoglicht die Sonographie eine konkrete Entscheidungsfindung und „Therapie aus einer Hand“.

Rezidivsituation und Fernmetastasierung stellen bei Plattenepithelkarzinomen des Kopf-Hals-Bereichs (HNSCC) eine grose therapeutische Herausforderung dar. Es besteht fur die betroffenen Patienten eine hohe Morbiditat sowie meist eine unbefriedigende, mediane Gesamtuberlebensrate selbst unter intensiven Kombinationschemotherapien. Die Einfuhrung des Epidermal Growth Factor Receptor (EGFR)-Antikorpers Cetuximab 2008 stellte in Verbindung mit einer platinhaltigen Chemotherapie eine erste Verbesserung in Bezug auf das Gesamtuberleben seit Jahrzehnten dar. Da aber eine Monotherapie mit Cetuximab bei besserer Vertraglichkeit eine deutlich geringere Effektivitat als eine Kombination mit platinhaltiger Chemotherapie aufweist, besteht groser Bedarf, neue Ziele fur zielgerichtete Therapien zu identifizieren und mogliche Kombinationen zu evaluieren. Neue Zielstrukturen umfassen EGFR und seine nachgeschalteten Rezeptor- Tyrosinkinasen, sowie Inhibitoren des VEGF- und des PI3K/AKT/ mTOR-Signalweges. Ferner liegt aktuell groses Potenzial in einer Immuntherapie mittels Checkpoint-Blockade. Aufgrund der nur eingeschrankten Effektivitat einer zielgerichteten Monotherapie sind gegenwartig mogliche Kombinationstherapien und deren Toxizitaten sowie der Zeitpunkt des Therapiebeginns von grosem klinischem Interesse. Recurrent squamous cell carcinomas of the head and neck (HNSCC) is a challenging disease due to morbidity and limited median overall survival rates even after aggressive chemotherapeutic regimen. The clinical establishment of the epidermal growth factor receptor (EGFR) antibody Cetuximab in 2008 brought the first significant survival benefit in palliative chemotherapy of HNSCC for decades. With regard to rather high toxicity of palliative chemotherapy and low remission rates after Cetuximab monotherapy, there is an urgent need for new targeted therapies. New targeted therapeutics include antagonists of EGFR and its downstream kinases, as well as inhibitors of VEGF- and PI3K/AKTmTOR signaling pathways. Furthermore, novel immunological checkpoint inhibition provides new hopeful perspectives. Due to limited remission rates of monotherapies using antibodies or tyrosine kinase inhibitors the evaluation of less toxic combination therapies is of great current clinical interest.

The "Comprehensive ICF Core Set for Head and Neck Cancer" (ICF-HNC) is an application of the "International Classification of Functioning, Disability and Health" (ICF), representing the characteristic spectrum of issues in patients with head and neck cancer (HNC). Our primary aim was to evaluate which categories of the ICF-HNC are dealt with by speech and language therapists (SLTs) in Germany, Austria, and Switzerland. The secondary aim was to identify outcome measures used by SLTs to measure the categories of the ICF-HNC in clinical practice. SLTs experienced in the treatment of HNC patients evaluated the categories of the ICF-HNC in a three-round Delphi survey. They were asked whether the listed categories represented issues treated by SLTs in HNC patients, and what outcome measures were used to assess them. Altogether, 31 SLTs completed the survey. 47 of 108 previously selected categories of the ICF-HNC achieved the cut-off value. Out of these, 40.4% were derived from the component "Body Functions", 36.2% from "Body Structures", 12.8% from "Environmental Factors", and 10.6% from "Activities and Participation". Altogether, 82 of the mentioned outcome measures were considered as reasonable from the perspective of SLTs. Of these, only 37 achieved more than 50% approval. This study emphasises the importance of "Body Structures" and "Body Functions" for SLTs in Germany and Switzerland in treating patients with HNC. Moreover, the results highlighted the need to agree on evidence-based outcome measures in speech and language therapy.

The article Hearing preservation in children with electric-acoustic stimulation after cochlear implantation—Outcome after electrode insertion with minimal insertion trauma, written by T. Rader, A. Bohnert, C. Matthias, D. Koutsimpelas, M‑A. Kainz, S. Strieth was originally published electronically

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

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

ObjectiveFitting cochlear implants, especially the precise determination of electrical hearing thresholds, is a time-consuming and complex task for patients as well as audiologists. Aim of the study was to develop a method that enables cochlear implant (CI) patients to determine their electrical hearing thresholds precisely and independently. Applicability and impact of this method on speech perception in noise at soft speech levels were evaluated.MethodAn adaptive psychoacoustic procedure for precise hearing threshold determination (precT) was implemented using MatLab (MathWorks) and a graphical user interface was created. Sound signals were calibrated with a CIC4-Implant-Decoder. Study design: A prospective study including 15 experienced adult cochlear implant users was conducted. Electrical hearing thresholds were determined using the automated precT procedure (auto-precT). Speech perception in noise at 50 dB SPL presentation levels was measured for three conditions: (P1) T-levels kept at the previously established T-levels; (P2) T-levels set to the hearing thresholds determined using auto-precT application; (P3) T-levels set 10 cu below the values determined with auto-precT.ResultsAll subjects were able to perform the auto-precT application independently. T-levels were altered on average by an absolute value of 10.5 cu using auto-precT. Median speech reception thresholds were significantly improved from 2.5 dB SNR (P1) to 1.6 dB SNR (P2, p = 0.02). Speech perception was lowest using the globally lowered T-levels, median 2.9 dB SNR (P3, not significant compared to P1 and P2).ConclusionThe applicability of the developed auto-precT application was confirmed in the present clinical study. Patients benefited from adjusting previously established T-levels to the threshold levels determined by the auto-precT application. The integration of the application in the clinical fitting routine as well as a remote fitting software approach is recommended. Furthermore, future possibilities of auto-precT include the implementation of the application on tablets or smart phones.

Free text reports (FTR) of head and neck ultrasound studies are currently deployed in most departments. Because of a lack of composition and language, these reports vary greatly in terms of quality and reliability. This may impair the learning process during residency. The purpose of the study was to analyze the longitudinal effects of using structured reports (SR) of head and neck ultrasound studies during residency. Attending residents (n = 24) of a tripartite course on head and neck ultrasound, accredited by the German Society for Ultrasound in Medicine (DEGUM), were randomly allocated to pictures of common diseases. Both SRs and FTRs were compiled. All reports were analyzed concerning completeness, acquired time and legibility. Overall user contentment was evaluated by a questionnaire. SRs achieved significantly higher ratings regarding completeness (95.6% vs. 26.4%, p

Background Reports of head and neck ultrasound examinations are frequently written by hand as free texts. Naturally, quality and structure of free text reports is variable, depending on the examiner’s individual level of experience. Aim of the present study was to compare the quality of free text reports (FTR) and structured reports (SR) of head and neck ultrasound examinations. Methods Both standard FTRs and SRs of head and neck ultrasound examinations of 43 patients were acquired by nine independent examiners with comparable levels of experience. A template for structured reporting of head and neck ultrasound examinations was created using a web-based approach. FTRs and SRs were evaluated with regard to overall quality, completeness, required time to completion, and readability by four independent raters with different specializations (Paired Wilcoxon test, 95% CI) and inter-rater reliability was assessed (Fleiss’ kappa). A questionnaire was used to compare FTRs vs. SRs with respect to user satisfaction (Mann-Whitney U test, 95% CI). Results By comparison, completeness scores of SRs were significantly higher than FTRs’ completeness scores (94.4% vs. 45.6%, p

Background The number of patients affected by allergies is increasing worldwide. The resulting allergic diseases are leading to significant costs for health care and social systems. Integrated care pathways are needed to enable comprehensive care within the national health systems. The ARIA (Allergic Rhinitis and its Impact on Asthma) initiative develops internationally applicable guidelines for allergic respiratory diseases. Methods ARIA serves to improve the care of patients with allergies and chronic respiratory diseases. In collaboration with other international initiatives, national associations and patient organizations in the field of allergies and respiratory diseases, real-life integrated care pathways have been developed for a digitally assisted, integrative, individualized treatment of allergic rhinitis (AR) with comorbid asthma. In the present work, these integrated care pathways have been adapted to the German situation and health system. Results The present ICP (integrated care pathways) guideline covers key areas of the care of AR patients with and without asthma. It includes the views of patients and other healthcare providers. Discussion A comprehensive ICP guideline can reflect real-life care better than traditional guideline models.

This article contains supporting information on data collection for the research article entitled “Aircraft noise exposure drives the activation of white blood cells and induces microvascular dysfunction in mice” by Eckrich et al. We found that noise-induced stress triggered microvascular dysfunction via involvement of innate immune-derived reactive oxygen species. In this article, we present the instrumentation of mice with dorsal skinfold chambers for in vivo microscopic imaging of blood flow, interaction of leukocytes with the vascular wall (also by fluorescent labelling of blood cells) and vessel diameter. In addition, we explain the preparation of cerebral arterioles for measurement of vascular reactivity in vitro.•visualization of noise-dependent effects in dorsal skinfold chamber.•in vivo microscopy of noise-dependent activation of white blood cells.•analysis of noise-dependent microvascular dysfunction in dorsal skinfold chamber and cannulated cerebral arterioles., Graphical abstract Image, graphical abstract

Gentamicin treatment induces hair cell death or survival in the inner ear. Besides the well-known toxic effects, the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway was found to be involved in cell protection. After gentamicin application, the spatiotemporal expression patterns of Akt and its activated form (p-Akt) were determined in male guinea pigs. A single dose of 0.1 mL gentamicin (4 mg/ear/animal) was intratympanically injected. The auditory brainstem responses (ABRs) were recorded prior to application and 1, 2 and 7 days afterward. At these three time points the cochleae (n=10 in each case) were removed, transferred to fixative and embedded in paraffin. Seven ears were used as untreated controls. Gentamicin, Akt and p-Akt were identified immunohistochemically in various regions of the cochlea and their staining intensities were quantified on sections using digital image analysis. The application of gentamicin resulted in hearing loss with a concomitant up-regulation of Akt-expression in the organ of Corti and spiral ganglion cells and an additional activation in spiral ganglion cells. At the level of individual ears, clear intracellular correlations were found between Akt- and p-Akt-expression in the stria vascularis and interdental cells and, to a minor extent, in the spiral ligament and the organ of Corti. Furthermore, statistical evidence for the connection between gentamicin up-take and hearing loss was detected. The increase in Akt- and p-Akt-expression in the organ of Corti and spiral ganglion cells indicates a selected response of the cochlea against gentamicin toxicity.

Computed tomography (CT) scans represent the gold standard in the planning of functional endoscopic sinus surgeries (FESS). Yet, radiologists and otolaryngologists have different perspectives on these scans. In general, residents often struggle with aspects involved in both reporting and operation planning. The aim of this study was to compare the completeness of structured reports (SR) of preoperative CT images and structured operation planning (SOP) to conventional reports (CR) and conventional operation planning (COP) to potentially improve future treatment decisions on an individual level. In total, 30 preoperative CT scans obtained for surgical planning of patients scheduled for FESS were evaluated using SR and CR by radiology residents. Subsequently, otolaryngology residents performed a COP using free texts and a SOP using a specific template. All radiology reports and operation plannings were evaluated by two experienced FESS surgeons regarding their completeness for surgical planning. User satisfaction of otolaryngology residents was assessed by using visual analogue scales. Overall radiology report completeness was significantly higher using SRs regarding surgically important structures compared to CRs (84.4 vs. 22.0%, p

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

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

The objective of this study is to analyze the outcome of treatment for solitary fibrous tumors (SFTs) in the head and neck area. SFTs present as slow-growing masses, often with local compressive symptoms that are difficult to distinguish from other soft-tissue tumors. SFTs are commonly treated using local excision without adjuvant therapy. To date, only heterogeneous small series have been published, documenting the treatment results and outcome with these tumors. Retrospective study of patients with histopathologically confirmed SFT treated at two tertiary referral hospitals between 2004 and 2014. Eight men and four women with histologically confirmed SFT were identified in the records. Their age range was 37-82 years (mean 57.8 years). The mean follow-up period for eight patients was 6.75 years (range 1-24 years). Four patients were lost to follow-up. Sublocalizations were neck (n = 3), orbit (n = 2), paranasal sinus (n = 2), cheek (n = 2), hard palate (n = 1), parotid gland (n = 1), and tongue (n = 1). The first-line treatment for all of the tumors identified was surgical excision. In four cases, the surgical margins were narrow or unclear due to piecemeal resection in the paranasal sinus and orbit (n = 3) or a tumor location deep in the parapharyngeal space (n = 1). Recurrences developed in two of these cases (in the orbit and parapharyngeal space), and the other two patients were lost to follow-up. Radiotherapy and chemotherapy were not administered as first-line treatments. Overall, the local recurrence rate (n = 2/8) was 25 %. The disease-specific survival rate was 100 %. These results are consistent with the literature data and show that safe surgical excision, without opening of the tumor capsule, reduces the risk of local recurrence and leads to a favorable outcome. Tumors in the head and neck often represent a surgical challenge, and wide surgical margins are rarely possible due to the complex three-dimensional anatomic compartments in the region. Head and neck surgeons should therefore be aware that there is an increased risk of recurrence in these patients; tightly scheduled follow-up visits are mandatory for at least 10 years, if not longer. Radiotherapy only appears to be an option in patients with unresectable tumors or when wide surgical excision would cause severe functional morbidity.

Objectives/Hypothesis Dexamethasone is widely used in the treatment of various inner ear diseases. However, knowledge about its direct impact on glucocorticoid receptor (GR) expression is still limited. Study Design Prospective animal study in male guinea pigs. Methods A therapeutic concentration of dexamethasone (8mg/mL) or a physiological concentration of NaCl (0.9% solution) were intratympanically injected into the ears of guinea pigs (n = 10 in each case) 14 hours prior to 90 dB noise exposure (1 hour). Eighteen ears were exposed to noise only. Seven untreated ears were used as controls. Auditory brainstem responses were recorded prior to noise exposure or treatment and 2 hours thereafter. The cochleae were removed from the bullae, transferred to fixative, and embedded in paraffin. GR expression was identified immunohistochemically in the cochlea. Local staining intensities were quantified for seven regions by a computer. Results Dexamethasone application significantly lowered noise-induced hearing loss. Statistically significant alterations in the average GR expression levels were identified exclusively in the spiral ligament. Comparing GR expression at the level of individual ear, numerous highly significant local associations were identified in the other six cochlear regions. Conclusions The intratympanic application of dexamethasone is suitable for supporting cochlear homeostasis under stress conditions. The lateral wall, mainly responsible for potassium recycling, seems to be the main target in glucocorticoid therapy. Level of Evidence NA Laryngoscope, 2015

Background The purpose of this phase I/II clinical trial was to test safety and effectiveness of 2 doses of vascular targeting cationic liposomes encapsulating paclitaxel (EndoTAG-1 [ET]) in human head and neck squamous cell carcinoma (HNSCC). Methods Patients with nonresectable therapy-refractory HNSCC were recruited for both ET treatment groups (3 or 4 patients per group). In cutaneous metastases, laser Doppler blood flow measurements were conducted during infusions. Results Only adverse events of grade 1 or 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 3.0) – in particular fatigue, chills, and hypertension – occurred. Follow-up tumor volume measurements revealed stable disease in 4 of 5 cases. Reproducible dose-dependent blood flow reductions in skin metastases during ET infusions provide evidence of biological effectiveness. Conclusion Infusions of ET seem to be safe and further phase II and III studies are warranted to prove efficacy in the treatment of HNSCC. © 2013 Wiley Periodicals, Inc. Head Neck 36: 976–984, 2014

Oropharyngeal cancer of the soft palate is a therapeutic challenge. This is due to crucial importance of velopharyngeal competence for articulation and swallowing. Patient counseling must present the whole therapeutic spectrum in order to receive informed consent. Basically, in primary therapy of oropharyngeal cancer multimodal concepts have to be considered including surgical resection and radiochemotherapy. With regard to the occasional difficulties predicting the functional outcome after primary therapy the ladder of reconstructive options has to be discussed a priori. Among numerous pedicled flaps the radial forearm free flap nowadays belongs definitely in the surgical armoury, which offers almost ideal reconstructive possibilities after extensive resections. This implies some additional aspects in pre- and postoperative workup that are reviewed in this article.

Intensity-time gradients (ITGs) of contrast-enhanced ultrasound (CEUS) can be used for non-invasive monitoring of gland-preserving treatment effects in sialolithiasis-related chronic sialadenitis as well as for imaging vascularization in tumors. The aim of this clinical trial was to evaluate feasibility to distinguish different entities of submandibular gland disease including inflammatory alterations of the submandibular gland as well as benign and malignant tumors. In this prospective clinical study, ITGs in 30 patients with sialolithiasis-related chronic sialadenitis or an unilateral submandibular mass and 18 disease-free submandibular gland controls were quantitatively analyzed by CEUS using the contrast agent SonoVue. In addition, clinical complaints according to visual analog scales (VAS) were documented. VAS data documented significantly less complaints only in benign tumors compared with the other pathologies of the submandibular gland. In parallel, CEUS-derived ITGs revealed significantly reduced ITGs only in benign tumors (n = 5) compared to the controls (n = 18). Despite of comparably reduced wash-in velocities in malignant lesions (n = 3) statistical significance was not reached. Chronic sialadenitis (n = 18) and its sclerosing variant (Küttner tumor, n = 4) revealed comparable ITGs as controls. Tumors of the submandibular gland present with reduced functional microcirculatory networks comparing with healthy gland controls and chronically inflamed submandibular glands. Thus, dynamic CEUS-derived ITGs in combination with conventional clinical measures--for example VAS--appear as a safe and promising strategy for non-invasive diagnostic workup of submandibular lesions and warrant further validation in a larger set of patients.

Funktionelle Beeintrachtigungen bei Kopf-Hals-Tumoren werden bisher im klinischen Alltag selten standardisiert erhoben. Klinische Studien mit der Zielgrose Funktionserhalt bei KHT verwenden viele verschiedene Instrumente. Die Ergebnisse sind deshalb oft schlecht vergleichbar und lassen zu wenig klinische Schlussfolgerungen zu. Es war daher notwendig und Ziel dieser Studie, die nach bisheriger Evidenz und interdisziplinarem Expertenkonsens am besten geeigneten Instrumente zur Beurteilung von Funktionsfahigkeit bei KHT zu identifizieren und Empfehlungen fur deren Verwendung in einem Leitfaden zusammenzustellen. In Vorstudien wurde unter Verwendung festgelegter Kriterien eine Vorauswahl an Instrumenten getroffen. Teilnehmer einer interdisziplinaren Konsensuskonferenz bewerteten die Instrumente und stimmten ab, welche Instrumente empfohlen werden fur die Anwendungsbereiche: Screening, Therapiebeurteilung und klinische Studien. Beteiligte Berufsgruppen waren HNO-Arzte, Radioonkologen, Mund-Kiefer-Gesichtschirurgen, internistische Onkologen, Phoniater, Logopaden, Psychologen, Physiotherapeuten und Sozialarbeiter. 98 Instrumente wurden auf der Konsensuskonferenz detailliert bewertet. 21 Teilnehmer empfahlen daraus fur die 3 Anwendungsbereiche jeweils Instrumente zur Beurteilung von 6 Funktionsbereichen: Therapiekon­trolle – Schmerz – Nahrungsaufnahme – Stimme, Sprechen, Atmung – weitere organische Probleme – Psychosoziale Funktion. Es wurden Instrumente ausgewahlt, interdisziplinar bewertet und fur die Anwendung im klinischen Alltag und in klinischen Studien empfohlen. Damit steht ein Tool zur schnellen, umfassenden funktionellen Beurteilung von Patienten mit KHT zur Verfugung, das nun implementiert und auf seine Praxistauglichkeit getestet werden kann.

BACKGROUND: Key factors for successful porous polyethylene (PPE) implantation are rapid vascularization and low inflammatory response. Dermal fibroblasts produce a variety of pro-angiogenic and immunmodulatory factors. OBJECTIVE: The aim of this tissue engineering study was to investigate whether coating PPE implants with dermal fibroblasts in vitro is sustainable in vivo and whether the kinetics of blood vessel ingrowth and immunological responses are hereby affected. METHODS: PPE implants were cultured with syngeneic GFP-transfected dermal fibroblasts. Cells on the biomaterial were quantified before implantation into dorsal skinfold chamber preparations of C57Bl/6 mice. Uncoated implants served as controls. Angiogenic activity and leukocyte-endothelial cell interactions were repeatedly analyzed. After 10 days, mechanical integration was measured and surviving fluorescently labeled fibroblasts were quantified. Expression of inflammatory cytokines was assessed by quantitative real time-reverse transcription PCR. RESULTS: PPE implants were successfully coated with dermal fibroblasts in vitro and 69% of the cells were still detectable at the end of observation. Angiogenic parameters increased during the observation period in both groups. IL-2, IL17A and IL-10 tended to be increased in coated implants, but did not affect leukocyte-endothelial cell interactions. CONCLUSIONS: Dermal fibroblast-coating of porous polyethylene implants is feasible and sustainable in vivo. Alone it does not improve biocompatibility but may be beneficial in combination with specific growth factor supplements.

The aim of this first-time-in-human non-randomized dose-escalating prospective phase I clinical trial was to analyze safety of two doses of fluorescent rhodamine-labeled cationic liposomes (LDF01) in head and neck squamous cell carcinoma (HNSCC). Patients had resectable UICC stadium I-IV A HNSCCs. LDF01 was administered before tumor resection under general anesthesia as an intravenous infusion with effective lipid doses of 0.5 or 2 mg/kg b.w., respectively. In addition to clinical monitoring for safety assessment, tumor biopsies were taken during the surgical procedure for fluorescence histological analysis. Eight patients were assigned to the two dose groups. During safety follow-up no clinically relevant adverse events occurred. Fluorescence histology revealed some evidence of favorable selectivity of LDF01 for tumor microvessels in the high-dose group. LDF01 is safe applied as infusion at both tested dose levels. Furthermore, LDF01 can be detected in the vicinity of tumor cells and could be assigned to the microvessel target in individual HNSSC cases. Detailed analysis of targeting properties of LDF01 has to be performed in upcoming clinical phase II trials.

Impairment of microcirculation is a possible cause of sudden sensorineural hearing loss (SSNHL). Fibrinogen is known as a risk factor for both microvascular dysfunction and SSNHL. Therefore, the aim of this study was to investigate the effect of elevated serum levels of fibrinogen on cochlear blood flow and hearing function in vivo.One group of guinea pigs received two consecutive injections of 100 mg fibrinogen while a control group received equimolar doses of albumin. Measurements of cochlear microcirculation by intravital microscopy and of hearing thresholds by auditory brainstem response (ABR) recordings were carried out before, after first and after second injection.Ten healthy guinea pigs were randomly assigned to a treatment group or a control group of five animals each.Serum fibrinogen levels were elevated after the first and second injections of fibrinogen compared to basal values and control group respectively. Increasing levels of fibrinogen were paralleled by decreasing cochlear blood flow as well as increasing hearing thresholds. Hearing threshold correlated negatively with cochlear blood flow.The effect of microcirculatory impairment on hearing function could be explained by a malfunction of the cochlear amplifier. Further investigation is needed to quantify cochlear potentials under elevated serum fibrinogen levels.

Distortion product otoacoustic emissions (DPOAEs) have been proposed for monitoring the intracranial pressure (ICP) noninvasively. Aim of this study was to establish an animal model in the guinea pig for a detailed characterisation of ICP-related DPOAE alterations. In guinea pigs, the ICP was elevated experimentally and the DPOAE levels were continuously monitored. Two different patterns of DPOAE level changes were observed: (1) a decrease of few decibels affecting mainly the frequency = 2 kHz with instant recovery after normalization of ICP, probably related to alterations of middle ear sound transmission; (2) a more pronounced level decrease affecting all frequencies, combined with a second decrease and prolonged recovery after ICP normalization, which might be related to alterations of the cochlear blood flow. Alterations of the levels of DPOAEs might not only provide information about ICP but also indicate critical ICP-induced reductions of the cochlear and the cerebral perfusion pressure.

The objective was to compare functional outcome in patients with advanced head and neck cancer (HNC) treated with (a) surgical resection and reconstruction with microvascular free flaps (MVFF) followed by radiochemotherapy versus (b) primary radiochemotherapy (RCT) on the basis of the International Classification of Functioning, Disability and Health (ICF) from WHO. This was a cross-sectional, multi-institutional study. The outcome measures included ICF Core Sets for HNC, the EORTC-QLQ, modules c30 + hn35 and the University of Washington-Quality of life Questionnaire (UW-QOL). Analyses included descriptive statistics, ranking exercises, and regression analyses in a cumulative logit model; 27 patients were treated with MVFF and 22 with RCT. Global Quality of life scores suggested a slightly better functional outcome for the surgical approach. The majority of ICF categories (81/93, 87%) did not show a difference in functional outcome between the two treatment approaches. In the remaining 12 ICF categories, n = 3 body structures were more affected in the MVFF group, while n = 3 body functions, and n = 6 activities/participations were more problematic in the RCT group. This included oral swallowing and weight maintenance functions as well as social relationships, acquiring a job, and economic self-sufficiency. In addition, nine contextual environmental factors were more relevant to the RCT group. Both treatment approaches seemed appropriate to advanced HNC from the perspective of functional outcome. The influence of treatment modalities on the social and economic lives of cancer survivors needs to be explored further. In order to guide rehabilitation according to patients' needs, the ICF offers a multidimensional view comprising body structures, body functions, and activities and participation in life.

Background and Purpose— We sought to demonstrate that tumor necrosis factor (TNF)-α, via sphingosine-1-phosphate signaling, has the potential to alter cochlear blood flow and thus, cause ischemic hearing loss. Methods— We performed intravital fluorescence microscopy to measure blood flow and capillary diameter in anesthetized guinea pigs. To measure capillary diameter ex vivo, capillary beds from the gerbil spiral ligament were isolated from the cochlear lateral wall and maintained in an organ bath. Isolated gerbil spiral modiolar arteries, maintained and transfected in organ culture, were used to measure calcium sensitivity (calcium-tone relationship). In a clinical study, a total of 12 adult patients presenting with typical symptoms of sudden hearing loss who were not responsive or only partially responsive to prednisolone treatment were identified and selected for etanercept treatment. Etanercept (25 mg s.c. ) was self-administered twice a week for 12 weeks. Results— TNF-α induced a proconstrictive state throughout the cochlear microvasculature, which reduced capillary diameter and cochlear blood flow in vivo. In vitro isolated preparations of the spiral modiolar artery and spiral ligament capillaries confirmed these observations. Antagonizing sphingosine-1-phosphate receptor 2 subtype signaling (by 1 μmol/L JTE013) attenuated the effects of TNF-α in all models. TNF-α activated sphingosine kinase 1 (Sk1) and induced its translocation to the smooth muscle cell membrane. Expression of a dominant-negative Sk1 mutant (Sk1 G82D ) eliminated both baseline spiral modiolar artery calcium sensitivity and TNF-α effects, whereas a nonphosphorylatable Sk1 mutant (Sk1 S225A ) blocked the effects of TNF-α only. A small group of etanercept-treated, hearing loss patients recovered according to a 1-phase exponential decay (half-life=1.56±0.20 weeks), which matched the kinetics predicted for a vascular origin. Conclusions— TNF-α indeed reduces cochlear blood flow via activation of vascular sphingosine-1-phosphate signaling. This integrates hearing loss into the family of ischemic microvascular pathologies, with implications for risk stratification, diagnosis, and treatment.

Subclinical conductive hearing losses (CHLs) can affect otoacoustic emissions and therefore limit their potential in the assessment of the cochlear function. Theoretical considerations to estimate a minor CHL from DPOAE measurements [Kummer et al. (2006). HNO 54, 457-467] are evaluated experimentally. They are based on the fact, that the level difference of the stimulus tones L(1) and L(2) for optimal excitation of the inner ear is given by L(1)=aL(2)+b. A CHL is presumed to attenuate both L(1) and L(2) to the same extent such that excitation of the inner ear is no longer optimal. From the change of L(1) that is necessary to restore optimal excitation of the inner ear and thus to produce maximal DPOAE levels, the CHL can be estimated. In 10 guinea pig ears an experimental CHL was produced, quantified by determination of compound action potential (CAP) thresholds at 8 kHz (CHL(CAP)) and estimated from DPOAE measurements at 8 kHz (CHL(DPOAE)). CHLs up to 12 dB could be assessed. CHL(DPOAE) correlated well with CHL(CAP) (R=0.741, p=0.0142). Mean difference between CHL(DPOAE) and CHL(CAP) was 4.2±2.6 dB. Estimation of minor CHL from DPOAE measurements might help to increase the diagnostic value of DPOAEs.