"Seeing inside out": revealing the effectiveness of otoscopy training in virtual reality enhanced practical exams - a randomized controlled trial.

BACKGROUND: The study aimed to assess the impact of different training modalities on otoscopy performance during a practical exam using a high-fidelity simulator and to determine if objective evaluation of otoscopy is feasible using a simulator that records insertion depth and tympanic membrane coverage. METHODS: Participants were assigned to one of four groups: control and three intervention groups with varying training approaches. Participants received otoscopy training and then were assessed through a practical exam on a high-fidelity simulator that uses virtual reality to visualize the ear canal and middle ear. Performance was evaluated using a modified Objective Structured Assessment of Technical Skills checklist and Integrated Procedural Performance Instrument checklist. Insertion depth, tympanic membrane coverage, and correct diagnosis were recorded. Data were tested for normal distribution using the Shapiro-Wilk test. One-way ANOVA and, for non-normally distributed data, Kruskal-Wallis test combined with Dunn's test for multiple comparisons were used. Interrater reliability was assessed using Cohen's κ and Intraclass correlation coefficient. RESULTS: All groups rated their training sessions positively. Performance on the OSATS checklist was similar among groups. IPPI scores indicated comparable patient handling skills. The feedback group examined larger tympanic membrane areas and had higher rates of correct diagnosis. The correct insertion depth was rarely achieved by all participants. Interrater reliability for OSATS was strong. IPPI reliability showed good correlation. CONCLUSION: Regardless of training modality, participants perceived learning improvement and skill acquisition. Feedback improved examination performance, indicating simulator-guided training enhances skills. High-fidelity simulator usage in exams provides an objective assessment of performance.

[Trauma of the midface : Symptoms, diagnostics and treatment]. / Trauma des Mittelgesichts : Symptomatik, Diagnostik und Therapie.

Midface fractures present a clinical challenge in otorhinolaryngology due to their often complex injury pattern and nonspecific symptoms. Precise diagnostics, including differentiated imaging procedures, are required. Interdisciplinary consultation between otorhinolaryngology, maxillofacial surgery, neurosurgery, and ophthalmology is often necessary. When selecting radiographic modalities, radiation hygiene should be taken into account. Sonography provides a radiation-free imaging alternative for fractures of the nasal framework and anterior wall of the frontal sinus. The goal of treatment is to achieve stable and symmetrical reconstruction. Depending on the injury pattern, different osteosynthesis materials, individual access routes, and various surgical procedures can be used. In clinical practice, the management of midface fractures requires a multidisciplinary, flexible, and pragmatic approach based on the fracture pattern and clinical experience.

[From Learning Objective to Examination: Constructive Alignment in Education and Training]. / Vom Lernziel zur Prüfung: Constructive Alignment in der Aus- und Weiterbildung.

An examination that is as transparent, performance-based, and fair as possible is something that teachers and learners both desire. This article is intended to help sharpen the basic understanding of examination designs and to shed light on the variable interplay of teaching and examination formats. This article is intended to help sharpen the basic understanding of examination designs and to shed light on the variable interplay of teaching and examination formats.

Cross-cultural adaptation and validation of the 22-item sinonasal outcome test (SNOT-22) in German-speaking patients: a prospective, multicenter cohort study.

PURPOSE: Chronic rhinosinusitis (CRS) is a common condition associated with a significant reduction of the health-related quality of life. One of the most widely used assessment tools in CRS is the disease-specific, health-related questionnaire SNOT-22. The aim of this study was to translate and validate the SNOT-22 into the German language. METHODS: The questionnaire was translated using the forward-backward translation technique. After the translation its reliability, validity, and sensitivity were evaluated. For this purpose, the questionnaire was completed by patients diagnosed with CRS before, 3 months and 1 year after endoscopic sinus surgery and by healthy individuals as controls at three university hospitals in Germany. The individual scores of the questionnaire before surgery was correlated with the Lund-Mackay score as well as a global disease-specific question. RESULTS: A total of 139 CRS patients and 31 healthy individuals participated in the study. Internal consistency at all timepoints was very good, with Cronbach's alpha scores of 0.897, 0.941, and 0.945. The questionnaire was able to discriminate between CRS patients and control subjects (p < 0.0001) and scores improved significantly 3 month and 1 year after sinus surgery (p < 0.0001), indicating a good test-retest reliability, validity, and responsiveness. A significant correlation to the single global disease-specific question could be found (p < 0.0001), but no correlation with the Lund-Mackay score. CONCLUSION: The German Version of the SNOT-22 is a reliable, valid, and sensitive instrument for measuring health-related quality of life in patients with CRS. It can be recommended for clinical practice and outcome research for German-speaking patients.

Chronic rhinosinusitis with nasal polyps is associated with impaired TMEM16A-mediated epithelial chloride secretion.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most common chronic disorders with limited therapeutic options. However, the pathogenesis of CRSwNP remains poorly understood. OBJECTIVE: We sought to determine the role of abnormalities in nasal epithelial ion transport in primary epithelial cultures and patients with CRSwNP. METHODS: We studied epithelial ion transport and transcript levels of the Cl- channels cystic fibrosis transmembrane conductance regulator and transmembrane protein 16A (TMEM16A) in human primary nasal epithelial cultures of patients with CRSwNP and healthy controls. Furthermore, we determined expression levels of proinflammatory cytokines that have been implicated in the regulation of epithelial ion channels (IL-1ß, INF-γ, TNF-α, IL-13) and studied effects of the key TH2 signaling molecule IL-13 in CRSwNP and control nasal epithelial cultures. Finally, we measured in vivo nasal potential difference to compare epithelial ion transport in patients with CRSwNP and controls. RESULTS: Bioelectric studies demonstrated that Ca2+-activated Cl- secretion was reduced in CRSwNP versus control nasal epithelial cultures. Transcript levels of IL-13 and the Ca2+-activated Cl- channel TMEM16A were increased in CRSwNP cultures. Stimulation with IL-13 increased TMEM16A expression further and restored Ca2+-activated Cl- secretion in CRSwNP cultures. Nasal potential difference measurements demonstrated reduced Ca2+-activated Cl- transport in patients with CRSwNP versus controls. CONCLUSIONS: This study demonstrates that TMEM16A-mediated Ca2+-activated Cl- secretion is reduced in primary nasal epithelial cultures and nasal epithelia of patients with CRSwNP. Our data suggest that the Ca2+-activated Cl- channel TMEM16A may be implicated in the pathogenesis and serve as a novel therapeutic target in patients with CRSwNP.

[Quality management in a postgraduate refresher course in otolaryngology]. / Qualitätssicherungssystem zur Bewertung eines HNO-Facharztrepetitoriums.

BACKGROUND: Residency training is often characterized by locally influenced training content and focus, which can lead to heterogeneous training outcomes. Refresher courses before the speciality certificate examinations can harmonize the situation. OBJECTIVE: The current publication aims to present a quality management system for evaluation of a postgraduate refresher course for otolaryngology residents. MATERIALS AND METHODS: The teaching sessions of a postgraduate course were evaluated using questionnaires. Descriptive statistics and multivariable binary logistic regression analysis were performed. To evaluate the factors leading to a negative perception of a teaching session, the focus was set on the worst 15% of all total ratings. An exemplary strength/weakness profile of a lecturer was created for individual feedback. RESULTS: Analysis of the evaluation results showed an overall average rating of 12.8 (±2.4) out of a maximum of 15 possible points. Multivariable regression determined the items "friendliness," "systematic structure," "own involvement," "prior knowledge," and "efficient teaching session" to be significant for a negative perception of a teaching session. Using the lecturer profile, the strengths and weaknesses of the individual lecturer can be shown in an objective manner. CONCLUSION: The developed questionnaire represents a good tool for quality management of a postgraduate refresher course for otolaryngology residents. This is achieved by regression analysis and creation of an individual lecturer profile, which provides an objective basis for improving the individual teaching session through detailed feedback to the lecturer.

Location and Volume of MRI Artifacts in Patients With Implanted Sphenopalatine Ganglion Neurostimulators for Treatment of Chronic Cluster Headache.

INTRODUCTION: Sphenopalatine ganglion stimulation (SPG-S) is an invasive form of neuromodulation by which a neurostimulator is implanted into the pterygopalatine fossa to treat refractory chronic cluster headache. The implant is MRI conditional, up to 3 T, however there is no clinical data on the shape, size, and location of the artifact produced by the implant. MATERIALS AND METHODS: Records of patients with SPG-S were analyzed for postoperative cranial MRI scans. MRI and intraoperative CT scans for visualization of the implant were fused and volumetry was performed for both the implant and the MRI artifact in different MRI sequences. RESULTS: In total, n = 3 patients with postoperative MRI scans were identified. The mean CT artifact volume was 0.73 cm3 (±0.15 cm3 ). MRI artifact volume differed between sequences (range: 25.2-220.7 cm3 ). The intracranial space was largely unaffected besides the pole of the ipsilateral temporal lobe and the basal frontal gyrus. MRI artifacts affected the extracranial space (orbit, maxillary and ethmoid sinuses, and parts of the parotid gland). No adverse events occurred during or after MRI scans. CONCLUSIONS: Cranial MRI scans with SPG-S implants were safely performed in three patients following the manufacturer's MRI conditions. MRI artifacts were mostly located in the extracranial space. Brain MRI imaging is largely unaffected. CONFLICT OF INTEREST: The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

Three-dimensional endoscopic visualization in functional endoscopic sinus surgery.

Three-dimensional (3D) stereoscopic vision in sinus surgery has been achieved with the microscope so far. The introduction of two-dimensional (2D) endoscopes set a milestone in the visualization of the surgical field and paved the way to functional endoscopic sinus surgery (FESS), although the 2D endoscopes cannot provide a stereoscopic visualization. The latest technology of 3D endoscopes allows stereoscopic vision. We provide a clinical investigation of all commercially available 3D endoscopes in FESS to compare their clinical value and efficacy to routinely used conventional 2D HD endoscopes. In this prospective, randomized, controlled clinical study, 46 patients with polypoid chronic rhinosinusitis underwent FESS with one of the following three endoscopes: 2D 0° high definition (HD), 3D 0° standard definition (SD) and 3D 0° HD. Four surgeons qualitatively assessed endoscopes on stereoscopic depth perception (SDP) of the surgeon, sharpness and brightness of the image, as well as their comfort in use during surgery. Surgeons assessed the brightness of the control (2D HD) significantly better than 3D SD (p = 0.009) and brightness of 3D HD was rated significantly better than 3D SD (p = 0.038). Stereoscopic depth perception (SDP) of 3D SD was assessed highly significantly better than the control (2D HD) (p = 0.021), whereas 3D HD displayed best SDP (p = 0.0001). The comfort in use was rated significantly higher in the 3D HD group compared to the control group (p = 0.025). No significant differences in sharpness could be seen among all endoscopes. 3D HD endoscopy provides an improvement in SDP and brightness of the surgical field. It enhances the intraoperative visualization and is therefore an important and efficient development in endoscopic sinus surgery.

Effects of insulin on human pancreatic cancer progression modeled in vitro.

BACKGROUND: Pancreatic adenocarcinoma is one of the most lethal cancers, yet it remains understudied and poorly understood. Hyperinsulinemia has been reported to be a risk factor of pancreatic cancer, and the rapid rise of hyperinsulinemia associated with obesity and type 2 diabetes foreshadows a rise in cancer incidence. However, the actions of insulin at the various stages of pancreatic cancer progression remain poorly defined. METHODS: Here, we examined the effects of a range of insulin doses on signalling, proliferation and survival in three human cell models meant to represent three stages in pancreatic cancer progression: primary pancreatic duct cells, the HPDE immortalized pancreatic ductal cell line, and the PANC1 metastatic pancreatic cancer cell line. Cells were treated with a range of insulin doses, and their proliferation/viability were tracked via live cell imaging and XTT assays. Signal transduction was assessed through the AKT and ERK signalling pathways via immunoblotting. Inhibitors of AKT and ERK signalling were used to determine the relative contribution of these pathways to the survival of each cell model. RESULTS: While all three cell types responded to insulin, as indicated by phosphorylation of AKT and ERK, we found that there were stark differences in insulin-dependent proliferation, cell viability and cell survival among the cell types. High concentrations of insulin increased PANC1 and HPDE cell number, but did not alter primary duct cell proliferation in vitro. Cell survival was enhanced by insulin in both primary duct cells and HPDE cells. Moreover, we found that primary cells were more dependent on AKT signalling, while HPDE cells and PANC1 cells were more dependent on RAF/ERK signalling. CONCLUSIONS: Our data suggest that excessive insulin signalling may contribute to proliferation and survival in human immortalized pancreatic ductal cells and metastatic pancreatic cancer cells, but not in normal adult human pancreatic ductal cells. These data suggest that signalling pathways involved in cell survival may be rewired during pancreatic cancer progression.

Real-world evidence for the effectiveness and safety of dupilumab in patients with CRSwNP after 1 year of therapy.

Objectives: For nearly 3 years, the monoclonal antibody dupilumab has been approved in Germany for the treatment of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Although efficacy has been demonstrated in large double-blind, placebo-controlled clinical trials, few reports of real-world data on this therapy have been published to date. Methods: Patients with an indication for treatment with dupilumab for CRSwNP were included in the study and followed up every 3 months for a period of 1 year. At the baseline visit, demographic data, medical history, comorbidities, nasal polyp score, disease-related quality of life (SNOT-22), nasal congestion, and sense of smell (VAS and Sniffin Sticks test) were recorded. In addition, total blood eosinophil counts and serum total IgE were measured. During follow-up, all of the described parameters and possible adverse events were recorded. Results: Eighty-one patients were enrolled in the study, of whom 68 patients were still receiving dupilumab after 1 year of follow-up. Eight patients discontinued therapy, with only 1 patient discontinuing due to severe side effects. The Polyp score decreased substantially during follow-up, and parameters for disease-related quality of life and sense of smell increased significantly. Total IgE levels decreased significantly, and eosinophils leveled off at baseline after an initial increase after three months of therapy. No clinical data could be identified to a priori predict a treatment response. Conclusions: Dupilumab shows effectiveness and safety in the treatment of CRSwNP under real-world conditions. More research on systemic biomarkers and clinical parameters to predict treatment response is necessary.

Predictors of persistent disease in biologic treated type 2 diffuse/eosinophilic chronic rhinosinusitis undergoing surgery.

BACKGROUND: Biologic therapy targeting type 2 chronic rhinosinusitis with nasal polyps (CRSwNP) has greatly improved disease control but nonresponders exist in a proportion of patients in phase 3 trials and clinical practice. This study explores the serum and histologic changes in biologic treated CRSwNP that predict disease control. METHODS: A cross-sectional study was performed of patients with CRSwNP on biologics for their asthma, who underwent endoscopic sinus surgery while on biologic therapy. At the 6-month postoperative assessment, patients with poorly controlled CRSwNP while on biologic therapy were compared to patients who were controlled. Blood and mucosal samples taken at the time of surgery 6 months prior were assessed to predict disease control. RESULTS: A total of 37 patients were included (age 47.8 ± 12.4 years, 43.2% female). Those with poorly controlled disease had reduced tissue eosinophils (% >100 cells/high-powered field: 8.3% vs. 50.0%, p < 0.001) and increased serum neutrophils (5.2 ± 2.7 vs. 3.7 ± 1.1 × 109 cells/L, p = 0.02). Logistic regression analysis demonstrated that reduced tissue eosinophil was predictive for poorly controlled disease (OR = 0.21, 95% CI [0.05, 0.83], p = 0.03). Receiver-operating characteristic analysis showed that need for rescue systemic corticosteroid was predicted at a serum neutrophil cut-off level of 5.75 × 109 cells/L (sensitivity = 80.0%, specificity = 96.9%, AUC = 0.938, p = 0.002). CONCLUSION: Low tissue eosinophils and increased serum neutrophils while on biologics predict for poor response in the biological treatment of with CRSwNP. A serum neutrophil level of ≥5.75 × 109 cells/L predicts for poor response to current biologic therapy.

Face, Content, and Construct Validity of a Virtual Reality Otoscopy Simulator and Applicability to Medical Training.

OBJECTIVE: Otologic diseases are common in all age groups and can significantly impair the function of this important sensory organ. To make a correct diagnosis, the correct handling of the otoscope and a correctly performed examination are essential. A virtual reality simulator could make it easier to teach this difficult-to-teach skill. The aim of this study was to assess the face, content, and construct validity of the novel virtual reality otoscopy simulator and the applicability to otologic training. STUDY DESIGN: Face and content validity was assessed with a questionnaire. Construct validity was assessed in a prospectively designed controlled trial. SETTING: Training for medical students at a tertiary referral center. METHOD: The questionnaire used a 6-point Likert scale. The otoscopy was rated with a modified Objective Structured Assessment of Technical Skills. Time to complete the task and the percentage of the assessed eardrum surface were recorded. RESULTS: The realism of the simulator and the applicability to medical training were assessed across several items. The ratings suggested good face and content validity as well as usefulness and functionality of the simulator. The otolaryngologists significantly outperformed the student group in all categories measured (P < .0001), suggesting construct validity of the simulator. CONCLUSION: In this study, we could demonstrate face, content, and construct validity for a novel high-fidelity virtual reality otoscopy simulator. The results encourage the use of the otoscopy simulator as a complementary tool to traditional teaching methods in a curriculum for medical students.

Decalcification method for nondestructive exposure of human inner ear specimens using ultrasonic EDTA scrubbing.

Owing to the density of the surrounding bone, preparation for histological preparation of the delicate inner ear is difficult and time-consuming; long preparation time increases the risk of deterioration. We present an EDTA decalcification method using an ultrasonic bath and microscopic removal of tissue along defined anatomical landmarks. Our method is rapid and enables preservation of delicate inner ear structures while minimizing the bony capsule. The reduction in volume made possible by our method creates ideal conditions for further processing with digital imaging techniques, in which the resolution is increased with reduced volume.

Treatment of choanal atresia in a cohort of 29 patients: Determinants for success or failure.

BACKGROUND: Choanal Atresia is a congenital condition that presents as a blockage from the nasal cavity to the nasopharynx. According to the German statistical Institute (Statistisches Bundesamt), the incidence in Germany in 2018 reached 2.74 in 10,000 live births. It can present unilaterally or bilaterally. As newborns are obligate nasal breathers, management of bilateral atresia has to be performed early after birth. As for unilateral atresia, the optimal age for treatment was determined to be between 6 and 12 months in a recently published consensus. OBJECTIVE: The main purpose of this study is to characterize the patients treated for choanal atresia in the Department of Otorhinolaryngology and Head and Neck Surgery at a tertiary hospital in the south of Germany and, based in the demographic characteristics as well as intra- and post-operative treatment, to identify factors for success or failure of the surgery. A secondary goal was to describe the complications in the use of stents and analyse its influence in the results. MATERIAL AND METHODS: The cohort-based observational study included 29 patients, with a minimum follow up of one year, who underwent surgical endoscopic correction of both unilateral and bilateral choanal atresia from 2003 to 2020. Analysis of the demographics, intraoperative, and postoperative treatment, and their results, was performed. Multinomial logistic regression was applied for categorical values. Comparisons were performed using Fischer/chi-square test where applicable. A significance level of 0.05 was reached. RESULTS: The population was comprised of 34.5% male and 65.5% female patients. The age varied from 2 days to 20 years old, with a mean of 4.98 years and Standard Deviation (SD) 6.88. The weight of the patients varied between 1.4 kg and 85.0 kg, with a mean of 19.36 and SD 22.58. Unilateral choanal atresia was present in 58.6%, and bilateral in 41.4%. Out of this population, 48.3% presented with associated malformations. The number of procedures per patient performed in general anesthesia varied from 1 to 9, with a mean of 2.52 and SD of 2.23: statistically higher for patients presenting with bilateral atresia with a p value of 0.001*. 20 patients had a tube (Vygon, France) placed at first surgery. In 5 patients, a drug-eluting stent (Propel mini (R); Intersect ENT, USA) was applied intraoperatively, without complications. In unilateral choanal atresia, surgical and functional success was attained in 88.2% of the cases. In bilateral cases, it reached 75%. We observed a strong linear relationship between the weight of the patient and the size of the choana perioperatively: R quadrat 0.596, which may be a determinant factor in the wound healing. Weight, age, and concomitant pathology achieved statistical significance in the logistic regression model (p respectively 0.001*, 0.001* and 0.010*), which shows its influence in the result of the surgery. In particular, weight inferior to 3 kg (p 0.001*, chi-square test) at the time of the first surgery is a determinant demographic factor for need of revision in order to achieve patency. There were no major complications associated with the use of a stent, besides its dislodgement. We could not infer an implication of its use on the success of the surgery in the present cohort. LIMITATIONS: for this study were the small size of the cohort and non-standardized records for some variables. CONCLUSIONS: Younger patients presenting with low weight and concomitant pathology have worse results after surgical endoscopic treatment of choanal atresia, revealing these characteristics to be determinant for success. The size of the neochoana is related to the weight of the patient, which is a limiting factor. In particular, patients under 3 kg had to undergo more procedures in order to achieve patency. The implication of the use of locally applied medication needs to be further studied.

Increased Inflammatory Markers Detected in Nasal Lavage Correlate with Paranasal Sinus Abnormalities at MRI in Adolescent Patients with Cystic Fibrosis.

Chronic rhinosinusitis (CRS) is a characteristic feature of cystic fibrosis (CF) multiorgan disease and develops early in the life of patients with CF. The study aimed to correlate the inflammatory markers and the presence of structural abnormalities detected by MRI in the paranasal sinuses of patients with CF. Methods: Nasal lavage and MRI of the paranasal sinuses was performed in a cohort of 30 CF patients (median age 14 y; range 7-20 y). Morphological abnormalities characteristic of CF were evaluated with a dedicated CRS MRI scoring system and correlated with different inflammation parameters measured in nasal lavage. Inflammation of the paranasal sinuses was positively associated with structural abnormalities in MRI. The concentration of the pro-inflammatory markers neutrophil elastase (NE) and the neutrophil elastase/alpha1-antitrypsin (NE/A1AT) complex correlated significantly with CRS-MRI sum score (p < 0.05, r = 0.416 and p < 0.05, r = 0.366, respectively). S. aureus infection was associated with the increased pro-inflammatory cytokine activity of IL-6 and IL-8, and increased levels of NE/A1AT complex in our patients (p < 0.05, respectively). CRS-MRI sum score and individual sinus MRI scores were positively associated with inflammatory activity as a sign of CRS pathology present in CF.

Clivus chordomas: Heterogeneous tumor extension requires adapted surgical approaches.

OBJECTIVE: Clivus chordomas are semi-malignant, but infiltratively growing tumors. Currently, a widely-accepted treatment concept encompasses maximal, but safe, surgical resection and radiotherapy. Caused by the size and the tumor extension, different surgical approaches, especially in recurrent cases, might be necessary. METHODS: Retrospective review of 50 patients on whom 70 surgeries were performed: 29 in primary and 41 in recurrent cases. Based on MRI images, all cases were asserted according to the size and the extension of the tumor. Used surgical approaches were evaluated. Postoperative complications, neurological function prior to and after the surgery, the extent of tumor resection on postoperative MR images were assessed and progression-free survival was calculated. RESULTS: Tumor size was estimated as small (< 5 cm3) in 8, as medium (5-20 cm3) in 21, as large (20-100 cm3) in 17, and as giant (> 100 cm3) in 4 patients. Most frequently used surgical approaches in primary cases were the transsphenoidal one and midfacial degloving (51.7 % and 17.2 %, respectively). In recurrent cases, dependent on the tumor extension, transsphenoidal (21.9 %), retrosigmoidal (29.3 %), and pterional (19.5 %) approaches, as well as midfacial degloving (17.1 %) were used. Due to the vast tumor extension and infiltration, gross total or near total resection could be achieved in 12 patients (24 %), only. There was no mortality and no major complications in primary cases. In recurrences, however, postoperative hemorrhages and strokes emerged in 4.9 % and 7.1 %. Minor complications occurred in 17.1 % and were dominated by CSF leaks (12.2 %), both in primary in recurrent cases. While most cranial nerve impairments were caused by tumor infiltration of the cavernous sinus, and hence have not improved by treatment, the sixth nerve palsy as a consequence of tumor mass compression, could significantly be improved by surgery. Following surgery, patients were subjected to radiotherapy (68.9 % for primary cases, and 36.6 % for recurrences) mainly with carbon ions. Overall, 5-year progression-free survival was 44.7 %. CONCLUSION: Caused by the heterogenous pattern of growth of clivus chordomas, surgical approaches should be chosen individually. Vast and infiltrative tumor extension constitute major limitations of surgical resection, and hence result in poor progression-frees survival.

Identification of the Tetraspanin CD9 as an Interaction Partner of Organic Cation Transporters 1 and 2.

Organic cation transporters (OCTs) are membrane proteins with relevant physiological (because they accept neurotransmitters as substrate) and pharmacological (because of their interaction with drugs) roles. The human OCTs hOCT1 (SLC22A1/hOCT1) and hOCT2 (SLC22A2/hOCT2) are highly expressed in hepatic (hOCT1) and in renal and neuronal tissue (hOCT2), suggesting a possible role in modulating neurotransmitter activity in the liver, kidney, and brain, and their clearance from the blood. Even though there are several data demonstrating that OCTs are regulated under various patho-physiological conditions, it remains largely unknown which proteins directly interact with OCTs and thereby influence their cellular processing, localization, and function. In this work, using a mating-based split-ubiquitin yeast two-hybrid system, we characterized the potential interactome of hOCT1 and 2. It became evident that these OCTs share some potential interaction partners, such as the tetraspanins CD63 and CD9. Moreover, we confirmed interaction of hOCT2 with CD9 by fluorescence-activated cell sorting coupled with Förster resonance energy transfer analysis. Together with other proteins, tetraspanins build "tetraspanins webs" in the plasma membrane, which are able to regulate cellular trafficking and compartmentalization of interacting partners. While CD63 was demonstrated to mediate the localization of the hOCT2 to the endosomal system, we show here that co-expression of hOCT2 and CD9 led to strong cell surface localization of the transporter. These data suggest that tetraspanins regulate the cellular localization and function of OCTs. Co-localization of CD9 and hOCT was confirmed in tissues endogenously expressing proteins, highlighting the potential biological relevance of this interaction.

Are human ATP-binding cassette transporter C11 and earwax associated with the incidence of cholesteatoma?

Cholesteatoma is an ear disease based on a locally destructive noncancerous conglomerate of epidermis and keratin debris. Abnormal growth of stratified keratinized squamous epithelium in the temporal bone causes destruction of the outer and middle ear, potentially leading to hearing impairment, facial palsy, vertigo, lateral sinus thrombosis, and intracranial complications. Although cholesteatoma is effectively treated by surgical resection (mastoidectomy), the lack of effective and nonsurgical therapies potentially results in fatal consequences, establishing the need for a comprehensive investigation of cholesteatoma pathogenesis. Although its etiology is still being debated, interestingly, we found that the trend associated with the 538G allele frequency of the adenosine triphosphate-binding cassette transporter C11 (ABCC11) gene, the determinant of wet-type earwax, and ethnic groups was similar to that between the incidence of cholesteatoma and ethnic groups (countries). The incidences of cholesteatoma in Europe (Denmark, Finland, and Scotland) are higher than in East Asia (Japan), and the frequencies of the ABCC11 538G allele in African, American, and European (Finland and Scotland) populations are higher than those in East Asian populations (Japan). Additionally, a single-nucleotide polymorphism in the ABCC11 gene (rs17822931, 538G > A; Gly180Arg) is closely related to earwax morphotypes. While earwax is often beneficial to ear health, it is sometimes harmful in cases where it causes hearing impairment. Based on independent findings of associations between ABCC11 and the physiological environment of the auditory canal, we hypothesize a possible link between ABCC11, earwax, and the incidence of cholesteatoma.

Outcomes in Advanced Head and Neck Cancer Treated with Up-front Neck Dissection prior to (Chemo)Radiotherapy.

OBJECTIVE: Our aim was to compare outcomes with and without up-front neck dissection prior to (chemo)radiotherapy in head and neck squamous cell carcinoma. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Outcomes of oropharyngeal, laryngeal, and hypopharyngeal squamous cell carcinoma cases with neck lymph node metastases treated from January 2001 to March 2012 were analyzed. Due to imbalances in baseline characteristics between groups treated with (n = 129) and without (n = 95) up-front neck dissection, propensity score matching was performed. RESULTS: Median follow-up was 48 months (range, 12-148). With up-front neck dissection, the hazard ratio for the primary end point, disease-free survival, was 0.63 (95% confidence interval: 0.37-1.06, P = .08). Up-front neck dissection reduced acute grade ≥3 toxicity significantly when xerostomia was excluded (odds ratio: 0.40, 95% confidence interval: 0.20-0.82, P = .012). CONCLUSION: Our results indicate less acute treatment toxicity without any significant difference in terms of oncologic outcome with up-front neck dissection prior to (chemo)radiotherapy as compared with (chemo)radiotherapy alone. Well-designed randomized trials are required to verify this result and further investigate the impact of this strategy on late toxicity and oncologic outcome.