The caspase-inhibitor Emricasan efficiently counteracts cisplatin- and neomycin-induced cytotoxicity in cochlear cells.

Cisplatin is a chemotherapeutic agent widely used to treat solid tumors. However, it can also be highly ototoxic, resulting in high-frequency hearing loss. Cisplatin causes degeneration of hair cells (HCs) and spiral ganglion neurons (SGNs) in the inner ear, which are essential components of the hearing process and cannot be regenerated in mammals. As the affected cells primarily die by apoptosis, we tested several anti-apoptotic small molecules to protect these cells from drug-induced toxicity. We found that the general caspase inhibitor Emricasan could significantly counteract the toxic effects of cisplatin in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, phoenix auditory cells, and primary SGNs. Importantly, the anti-cytotoxic effect in neuronal cells was even more pronounced than the effect of sodium thiosulfate (STS), which is currently the only approved prevention option for cisplatin-induced ototoxicity. Finally, we tested the protective effect of Emricasan treatment in the context of another ototoxic drug, i.e., the aminoglycoside antibiotic neomycin, and again found a significant increase in cell viability when the cultures were co-treated with Emricasan. These results suggest a promising strategy to prevent ototoxicity in patients by temporarily blocking the apoptotic pathway when applying cisplatin or aminoglycoside antibiotics. KEY MESSAGES: Anti-apoptotic small molecules can reduce cisplatin-induced toxicity. Emricasan can effectively exert its anti-apoptotic effect on cochlear cells. Strong protection from cisplatin- and neomycin-induced cytotoxicity with Emricasan. Sodium thiosulfate and Emricasan provide similar protective effects to cisplatin-treated cells. Emricasan is more potent than sodium thiosulfate in reducing neomycin-induced cytotoxicity.

Long-term experience with biohybrid cochlear implants in human neurosensory restoration.

OBJECTIVE: The implantation of biohybrid electrodes was introduced a few years ago in our clinic. These electrodes coated with autologous mononuclear cells releasing anti-inflammatory and neuroprotective factors are thought to reduce insertion trauma and maintain the vitality of surviving spiral ganglion neurons. The clinical feasibility of this approach has already been demonstrated. In the present retrospective study, the four-year results of the two sides (classical electrode and biohybrid electrode) in the bilaterally implanted patients were compared in order to investigate possible adverse long-term effects. METHODS: All patients received a complete audiological diagnosis which also included a speech audiogram and impedance measurement. The measurements were carried out 1 month, 3 months, 6 months, 1 year, 2 years, 3 years and 4 years after implantation. The hearing results were assessed by pure tone audiometry. RESULTS: All patients showed satisfactory speech understanding and similar impedances on both sides although they had a long-term deafness before implantation of the side provided with a biohybrid electrode array. The results of speech understanding and impedance measurements were stable for years. Cone beam computed tomography was performed in 4 patients three years after implantation and could rule out cochlear ossification. Other complications were also not registered in any of the patients. CONCLUSION: Due to satisfactory outcomes and lack of complications, the biohybrid electrode is considered to be a safe option in cochlear implantation. The simplicity of application of autologous cells as a source of anti-inflammatory and neuroprotective factors via a biohybrid electrode array is a key step for cell-based, regenerative therapies for deafness.

Hamartomas of the Tuber Cinereum Associated with X-Linked Deafness Show Signs of Pubertas Tarda Instead of Pubertas Praecox and No Gelastic Seizures-Long-Term Follow-Up of 12 Years.

PURPOSE: Hamartomas of tuber cinereum present as ectopic tissue in the hypothalamic region. Clinically, the usual hypothalamic hamartomas manifest themself by gelastic seizures and pubertas praecox. We observed an increased coincidence of the presence of X-linked recessive deafness DFNX2 (DFN3) and a hamartoma of the tuber cinereum. Initially five patients presented with hearing loss in childhood, two additional were already adults, not showing any characteristic symptoms for a hamartoma but signs of delayed puberty. METHODS: Seven patients who underwent computed tomography imaging due to a sensorineural hearing loss and had a hamartoma of the tuber cinereum in addition to X-linked deafness DFNX2 (DFN3) were included in a retrospective study. Patients underwent initial neurologic, endocrinologic, and genetic evaluation. Long-term follow-up was performed after 10 to 12 years. RESULTS: The average age at the initial exam was 12.9 years (range 4-29). All patients genetically proven nonsyndromic, X-linked deafness associated with the POU3F4 gene. Three out of six patients presented signs of delayed puberty. None of all seven showed any evidence of pubertas praecox or gelastic seizures at mean age of 17 years (range 17-29 years) at any time. CONCLUSION: Hamartomas of tuber cinereum are often coincident with DFNX2. Clinically, half of the cases are-in contrary to the usual pubertas praecox-associated with growth hormone deficiency and delayed puberty, in the sense of pubertas tarda, when coincident. Clinicians' and radiologists' knowledge and awareness of this rare combination are crucial to identify children early enough for hormone-sensitive treatment.

A burden shared: The evolutionary case for studying human deafness in Drosophila.

Hearing impairment is the most prevalent sensory disease in humans and can have dramatic effects on the development, and preservation, of our cognitive abilities and social interactions. Currently 20 % of the world's population suffer from a form of hearing impairment; this is predicted to rise to 25 % by 2050. Despite this staggering disease load, and the vast damage it inflicts on the social, medical and economic fabric of humankind, our ability to predict, or prevent, the loss of hearing is very poor indeed. We here make the case for a paradigm shift in our approach to studying deafness. By exploiting more forcefully the molecular-genetic conservation between human hearing and hearing in morphologically distinct models, such as the fruit fly Drosophila melanogaster, we believe, a deeper understanding of hearing and deafness can be achieved. An understanding that moves beyond the surface of the 'deafness genes' to probe the underlying bedrock of hearing, which is shared across taxa, and partly shared across modalities. When it comes to understanding the workings (and failings) of human sensory function, a simple fruit fly has a lot to offer and a fly eye might sometimes be a powerful model for a human ear. Particularly the use of fly avatars, in which specific molecular (genetic or proteomic) states of humans (e.g. specific patients) are experimentally reproduced, in order to study the corresponding molecular mechanisms (e.g. specific diseases) in a controlled yet naturalistic environment, is a tool that promises multiple unprecedented insights. The use of the fly - and fly avatars - would benefit humans and will help enhance the power of other scientific models, such as the mouse.

Exploring Inner Ear and Brain Connectivity through Perilymph Sampling for Early Detection of Neurological Diseases: A Provocative Proposal.

Recent evidence shows that it is possible to identify the elements responsible for sensorineural hearing loss, such as pro-inflammatory cytokines and macrophages, by performing perilymph sampling. However, current studies have only focused on the diagnosis of such as otologic conditions. Hearing loss is a feature of certain neuroinflammatory disorders such as multiple sclerosis, and sensorineural hearing loss (SNHL) is widely detected in Alzheimer's disease. Although the environment of the inner ear is highly regulated, there are several communication pathways between the perilymph of the inner ear and cerebrospinal fluid (CSF). Thus, examination of the perilymph may help understand the mechanism behind the hearing loss observed in certain neuroinflammatory and neurodegenerative diseases. Herein, we review the constituents of CSF and perilymph, the anatomy of the inner ear and its connection with the brain. Then, we discuss the relevance of perilymph sampling in neurology. Currently, perilymph sampling is only performed during surgical procedures, but we hypothesize a simplified and low-invasive technique that could allow sampling in a clinical setting with the same ease as performing an intratympanic injection under direct visual check. The use of this modified technique could allow for perilymph sampling in people with hearing loss and neuroinflammatory/neurodegenerative disorders and clarify the relationship between these conditions; in fact, by measuring the concentration of neuroinflammatory and/or neurodegenerative biomarkers and those typically expressed in the inner ear in aging SNHL, it could be possible to understand if SNHL is caused by aging or neuroinflammation.

Can Multifrequency Tympanometry Be Used in the Diagnosis of Meniere's Disease? A Systematic Review and Meta-Analysis.

(1) Background: Ménière's disease (MD) is a disease of the inner ear, presenting with episodes of vertigo, hearing loss, and tinnitus.The aim of this study is to examine the role of multifrequency tympanometry (MFT) in the diagnosis of MD. (2) Methods: A systematic review of MEDLINE (via PubMed), Scopus, Google Scholar, and the Cochrane Library was performed, aligned with the PRISMA guidelines. Only studies that directly compare ears affected by Ménière's disease with unaffected or control ears were included. Random-effects model meta-analyses were performed. (3) Results: Seven prospective case-control studies reported a total of 899 ears, 282 of which were affected by Ménière's disease (affected ears-AE), 197 unaffected ears in patients with MD (UE), and 420 control ears (CE) in healthy controls. No statistically significant differences between the groups were observed regarding resonant frequency (RF). The pure tone audiometry average of the lower frequencies (PTA basic) was significantly greater in affected ears when compared with unaffected ears. The conductance tympanogram at 2 kHz revealed a statistically significantly greater G width of 2 kHz in the affected ears when compared to both unaffected and control ears, while control ears had a statistically significant lesser G width of 2 kHz compared to both the other two groups. (4) Conclusions: MFT, and specifically G width at 2 kHz, could be an important tool in the diagnosis of MD.

Protection from cisplatin-induced hearing loss with lentiviral vector-mediated ectopic expression of the anti-apoptotic protein BCL-XL.

Cisplatin is a highly effective chemotherapeutic agent, but it can cause sensorineural hearing loss (SNHL) in patients. Cisplatin-induced ototoxicity is closely related to the accumulation of reactive oxygen species (ROS) and subsequent death of hair cells (HCs) and spiral ganglion neurons (SGNs). Despite various strategies to combat ototoxicity, only one therapeutic agent has thus far been clinically approved. Therefore, we have developed a gene therapy concept to protect cochlear cells from cisplatin-induced toxicity. Self-inactivating lentiviral (LV) vectors were used to ectopically express various antioxidant enzymes or anti-apoptotic proteins to enhance the cellular ROS scavenging or prevent apoptosis in affected cell types. In direct comparison, anti-apoptotic proteins mediated a stronger reduction in cytotoxicity than antioxidant enzymes. Importantly, overexpression of the most promising candidate, Bcl-xl, achieved an up to 2.5-fold reduction in cisplatin-induced cytotoxicity in HEI-OC1 cells, phoenix auditory neurons, and primary SGN cultures. BCL-XL protected against cisplatin-mediated tissue destruction in cochlear explants. Strikingly, in vivo application of the LV BCL-XL vector improved hearing and increased HC survival in cisplatin-treated mice. In conclusion, we have established a preclinical gene therapy approach to protect mice from cisplatin-induced ototoxicity that has the potential to be translated to clinical use in cancer patients.

Langerhans cell histiocytosis involving the temporal bone with destruction and subsequent reossification of the bony labyrinth boundaries.

PURPOSE: With an incidence between 1-9/100 000 per year, Langerhans cell histiocytosis (LCH) is a rather rare disease from the hemato-oncologic disease spectrum (Hayes et al. 2009). The tumorlike disease with proliferation of histiocytic cells may manifest as localized to one organ or disseminated with infiltration of a wide variety of organs. Approximately 25-30 % of these cases show involvement of the temporal bone (Ni et al. 2017). CASE DESCRIPTION: With vertigo persisting for three years, chronic mastoiditis, and acute progressive hearing loss bilaterally (r > l) for three weeks, a 41-year-old woman presented at an emergency department. The DVT showed extensive bony destruction of large parts of the temporal bone on both sides, involving the vestibular organ, the cochlea, and the internal auditory canal. To confirm the suspicion of a systemic inflammatory process, a PE was performed from the mastoid with bioptic confirmation of an LCH. Systemic therapy was initiated. Post-therapeutic imaging showed almost complete remission with reossification of the preexisting defect zones and the internal auditory canal and labyrinth structures again showed bony margins. Clinically, there was an improvement of the vegetative symptoms with remaining bilateral sensorineural hearing loss. DISCUSSION: LCH of the temporal bone is a rare and often misdiagnosed disease due to its nonspecific clinical presentation. Awareness of temporal bone LCH and its occurrence in adults is essential for accurate and consistent diagnosis. KEY POINTS: · LCH is a rather rare disease from the hemato-oncological spectrum. · Affection of the temporal bone, especially such an extensive one (as in this case report), is rather atypical in adulthood. · Use of systemic therapy resulted in remission. · There was complete reossification of the osseous structures post-therapy. · A cochlear implant was able to be implanted to compensate for hearing loss.

Correlation of Scalar Cochlear Volume and Hearing Preservation in Cochlear Implant Recipients with Residual Hearing.

OBJECTIVE: Preservation of residual hearing is one of the main goals in cochlear implantation. There are many factors that can influence hearing preservation after cochlear implantation. The purpose of the present study was to develop an algorithm for validated preoperative cochlear volume analysis and to elucidate the role of cochlear volume in preservation of residual hearing preservation after atraumatic cochlear implantation. STUDY DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENTS: A total of 166 cochlear implant recipients were analyzed. All patients were implanted with either a MED-EL (Innsbruck, Austria) FLEXSOFT (n = 3), FLEX28 (n = 72), FLEX26 (n = 1), FLEX24 (n = 41), FLEX20 (n = 38), or FLEX16 (n = 11, custom made device) electrode array through a round window approach. Main outcome measures: Cochlear volume as assessed after manual segmentation of cochlear cross-sections in cone beam computed tomography, and preservation of residual hearing 6 months after implantation were analyzed. The association between residual hearing preservation and cochlear volume was then assessed statistically. RESULTS: Rapid and valid cochlear volume analysis was possible using the individual cross-sections and a newly developed and validated algorithm. Cochlear volume had the tendency to be larger in patients with hearing preservation than in those with hearing loss. Significant correlations with hearing preservation could be observed for the basal width and length of the basal turn. CONCLUSIONS: Preservation of residual hearing after cochlear implantation may depend on cochlear volume but appears to be influenced more strongly by other cochlear dimensions.

Relapsing Polychondritis with Tracheobronchial Involvement: A Detailed Description of Two Pediatric Cases and Review of the Literature.

Relapsing polychondritis (RP) is a rare immune-mediated disease that primarily affects the cartilaginous structures of the ears, nose and airways. The clinical spectrum ranges from mild to severe disease characterized by progressive destruction of cartilage in the tracheobronchial tree leading to airway obstruction and acute respiratory failure. Early diagnosis is crucial to prevent irreversible airway damage and life-threatening complications. Due to its rarity and variability of symptoms, the diagnosis of RP is often delayed particularly in childhood. To address this and increase awareness of this rare disease, we present a detailed case report of two adolescent females affected by RP. We aim to describe the clinical findings, consequences of a delayed diagnosis and provide a review of the current literature.

Third-generation lentiviral gene therapy rescues function in a mouse model of Usher 1B.

Usher syndrome 1B (USH1B) is a devastating genetic disorder with congenital deafness, loss of balance, and blindness caused by mutations in the myosin-VIIa (MYO7A) gene, for which there is currently no cure. We developed a gene therapy approach addressing the vestibulo-cochlear deficits of USH1B using a third-generation, high-capacity lentiviral vector system capable of delivering the large 6,645-bp MYO7A cDNA. Lentivirally delivered MYO7A and co-encoded dTomato were successfully expressed in the cochlear cell line HEI-OC1. In normal-hearing mice, both cochlea and the vestibular organ were efficiently transduced, and ectopic MYO7A overexpression did not show any adverse effects. In Shaker-1 mice, an USH1B disease model based on Myo7a mutation, cochlear and vestibular hair cells, the main inner ear cell types affected in USH1B, were successfully transduced. In homozygous mutant mice, delivery of MYO7A at postnatal day 16 resulted in a trend for partial recovery of auditory function and in strongly reduced balance deficits. Heterozygous mutant mice were found to develop severe hearing loss at 6 months of age without balance deficits, and lentiviral MYO7A gene therapy completely rescued hearing to wild-type hearing thresholds. In summary, this study demonstrates improved hearing and balance function through lentiviral gene therapy in the inner ear.

Neuroinflammatory disorders of the brain and inner ear: a systematic review of auditory function in patients with migraine, multiple sclerosis, and neurodegeneration to support the idea of an innovative 'window of discovery'.

Background: Hearing can be impaired in many neurological conditions and can even represent a forme fruste of specific disorders. Auditory function can be measured by either subjective or objective tests. Objective tests are more useful in identifying which auditory pathway (superior or inferior) is most affected by disease. The inner ear's perilymphatic fluid communicates with the cerebrospinal fluid (CSF) via the cochlear aqueduct representing a window from which pathological changes in the contents of the CSF due to brain inflammation could, therefore, spread to and cause inflammation in the inner ear, damaging inner hair cells and leading to hearing impairment identifiable on tests of auditory function. Methods: A systematic review of the literature was performed, searching for papers with case-control studies that analyzed the hearing and migraine function in patients with neuro-inflammatory, neurodegenerative disorders. With data extracted from these papers, the risk of patients with neurological distortion product otoacoustic emission (DPOAE) was then calculated. Results: Patients with neurological disorders (headache, Parkinson's disease, and multiple sclerosis) had a higher risk of having peripheral auditory deficits when compared to healthy individuals. Conclusion: Existing data lend credence to the hypothesis that inflammatory mediators transmitted via fluid exchange across this communication window, thereby represents a key pathobiological mechanism capable of culminating in hearing disturbances associated with neuroimmunological and neuroinflammatory disorders of the nervous system.

Deep intracochlear injection of triamcinolone-acetonide with an inner ear catheter in patients with residual hearing.

Introduction: In a previous study, an inner ear catheter was used to deliver low- and high-dose steroids into the cochlea prior to cochlear implant electrode insertion. With this approach, more apical regions of the cochlea could be reached and a reduction of electrode impedances in the short term was achieved in cochlear implant recipients. Whether intracochlear application of drugs via the catheter is a safe method also for patients with residual hearing has not been investigated hitherto. The aim of the present study was therefore to investigate the effect of intracochlear triamcinolone application in cochlear implant recipients with residual hearing. Patients and methods: Patients with residual hearing were administered triamcinolone-acetonide (4 mg/ml; n = 10) via an inner ear catheter just prior to insertion of a MED-EL FLEX28 electrode. Impedances were measured at defined time points (intra-operatively, post-operatively and at first fitting) and retrospectively compared with a control group (no steroid application) and low- and high-dose group. Hearing thresholds were measured preoperatively, 3 days after surgery and at first fitting by pure tone audiometry. Pre- to postoperative hearing loss was determined at first fitting and compared to results from a previous study. Results: The median hearing loss after implantation (125-1,500 Hz) was 20.6 dB. Four patients (40%) showed a median hearing loss of less than 15 dB, three patients (30%) between 15 and 30 dB and three patients (30%) more than 30 dB. The median hearing loss was similar to the results obtained from our previous study showing a median hearing loss of 24 dB when using FLEX28 electrode arrays. Conclusion: No difference in residual hearing loss was found when comparing application of triamcinolone-acetonide using an inner ear catheter prior to the insertion of a FLEX28 electrode array to the use of the FLEX28 electrode array without the catheter. Thus, we conclude that application of drugs to the cochlea with an inner ear catheter could be a feasible approach in patients with residual hearing.

A Chemical Chaperone Restores Connexin 26 Mutant Activity.

Mutations in connexin 26 (Cx26) cause hearing disorders of a varying degree. Herein, to identify compounds capable of restoring the function of mutated Cx26, a novel miniaturized microarray-based screening system was developed to perform an optical assay of Cx26 functionality. These molecules were identified through a viability assay using HeLa cells expressing wild-type (WT) Cx26, which exhibited sensitivity toward the HSP90 inhibitor radicicol in the submicromolar concentration range. Open Cx26 hemichannels are assumed to mediate the passage of molecules up to 1000 Da in size. Thus, by releasing radicicol, WT Cx26 active hemichannels in HeLa cells contribute to a higher survival rate and lower cell viability when Cx26 is mutated. HeLa cells expressing Cx26 mutations exhibited reduced viability in the presence of radicicol, such as the mutants F161S or R184P. Next, molecules exhibiting chemical chaperoning activity, suspected of restoring channel function, were assessed regarding whether they induced superior sensitivity toward radicicol and increased HeLa cell viability. Through a viability assay and microarray-based flux assay that uses Lucifer yellow in HeLa cells, compounds 3 and 8 were identified to restore mutant functionality. Furthermore, thermophoresis experiments revealed that only 3 (VRT-534) exhibited dose-responsive binding to recombinant WT Cx26 and mutant Cx26K188N with half maximal effective concentration values of 19 and ∼5 µM, respectively. The findings of this study reveal that repurposing compounds already being used to treat other diseases, such as cystic fibrosis, in combination with functional bioassays and binding tests can help identify novel potential candidates that can be used to treat hearing disorders.

Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss.

OBJECTIVES: The variability in outcomes of cochlear implantation is largely unexplained, and clinical factors are not sufficient for predicting performance. Genetic factors have been suggested to impact outcomes, but the clinical and genetic heterogeneity of hereditary hearing loss makes it difficult to determine and interpret postoperative performance. It is hypothesized that genetic mutations that affect the neuronal components of the cochlea and auditory pathway, targeted by the cochlear implant (CI), may lead to poor performance. A large cohort of CI recipients was studied to verify this hypothesis. DESIGN: This study included a large German cohort of CI recipients (n = 123 implanted ears; n = 76 probands) with a definitive genetic etiology of hearing loss according to the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines and documented postoperative audiological outcomes. All patients underwent preoperative clinical and audiological examinations. Postoperative CI outcome measures were based on at least 1 year of postoperative audiological follow-up for patients with postlingual hearing loss onset (>6 years) and 5 years for children with congenital or pre/perilingual hearing loss onset (≤6 years). Genetic analysis was performed based on three different methods that included single-gene screening, custom-designed hearing loss gene panel sequencing, targeting known syndromic and nonsyndromic hearing loss genes, and whole-genome sequencing. RESULTS: The genetic diagnosis of the 76 probands in the genetic cohort involved 35 genes and 61 different clinically relevant (pathogenic, likely pathogenic) variants. With regard to implanted ears (n = 123), the six most frequently affected genes affecting nearly one-half of implanted ears were GJB2 (21%; n = 26), TMPRSS3 (7%; n = 9), MYO15A (7%; n = 8), SLC26A4 (5%; n = 6), and LOXHD1 and USH2A (each 4%; n = 5). CI recipients with pathogenic variants that influence the sensory nonneural structures performed at or above the median level of speech performance of all ears at 70% [monosyllable word recognition score in quiet at 65 decibels sound pressure level (SPL)]. When gene expression categories were compared to demographic and clinical categories (total number of compared categories: n = 30), mutations in genes expressed in the spiral ganglion emerged as a significant factor more negatively affecting cochlear implantation outcomes than all clinical parameters. An ANOVA of a reduced set of genetic and clinical categories (n = 10) identified five detrimental factors leading to poorer performance with highly significant effects ( p < 0.001), accounting for a total of 11.8% of the observed variance. The single strongest category was neural gene expression accounting for 3.1% of the variance. CONCLUSIONS: The analysis of the relationship between the molecular genetic diagnoses of a hereditary etiology of hearing loss and cochlear implantation outcomes in a large German cohort of CI recipients revealed significant variabilities. Poor performance was observed with genetic mutations that affected the neural components of the cochlea, supporting the "spiral ganglion hypothesis."

CAR-NK Cells Targeting HER1 (EGFR) Show Efficient Anti-Tumor Activity against Head and Neck Squamous Cell Carcinoma (HNSCC).

(1) Background: HNSCC is a highly heterogeneous and relapse-prone form of cancer. We aimed to expand the immunological tool kit against HNSCC by conducting a functional screen to generate chimeric antigen receptor (CAR)-NK-92 cells that target HER1/epidermal growth factor receptor (EGFR). (2) Methods: Selected CAR-NK-92 cell candidates were tested for enhanced reduction of target cells, CD107a expression and IFNγ secretion in different co-culture models. For representative HNSCC models, patient-derived primary HNSCC (pHNSCC) cell lines were generated by employing an EpCAM-sorting approach to eliminate the high percentage of non-malignant cells found. (3) Results: 2D and 3D spheroid co-culture experiments showed that anti-HER1 CAR-NK-92 cells effectively eliminated SCC cell lines and primary HNSCC (pHNSCC) cells. Co-culture of tumor models with anti-HER1 CAR-NK-92 cells led to enhanced degranulation and IFNγ secretion of NK-92 cells and apoptosis of target cells. Furthermore, remaining pHNSCC cells showed upregulated expression of putative cancer stem cell marker CD44v6. (4) Conclusions: These results highlight the promising potential of CAR-NK cell therapy in HNSCC and the likely necessity to target multiple tumor-associated antigens to reduce currently high relapse rates.

Genetic Evaluation of Prelingual Hearing Impairment: Recommendations of an European Network for Genetic Hearing Impairment.

The cause of childhood hearing impairment (excluding infectious pathology of the middle ear) can be extrinsic (embryofoetopathy, meningitis, trauma, drug ototoxicity, noise trauma, etc [...].

[Hypertrophy of lingual tonsil following tonsillectomy and correlation with BMI]. / Zungengrundhyperplasie nach Tonsillektomie und Korrelation mit dem BMI.

OBJECTIVE: The hyperplasia of the lingual tonsil is a rare and at the same time potentially dangerous change in the area of the upper respiratory tract. The pathogenesis of the lingual tonsillar hyperplasia is still largely unknown. In this study, we investigated if there is a compensatory lingual tonsil hyperplasia after tonsillectomy. MATERIAL AND METHODS: 300 patients were examined consecutively in the ENT clinic of the Hannover Medical School. In the context of indirect laryngoscopy, the lingual tonsil, the visibility of the larynx and its subregions were assessed according to a scheme. The data were then evaluated depending on the status of the palatal tonsils. In addition, the body mass index (BMI) was determined and compared with the results of laryngoscopy. RESULTS: Out of 300 patients, 89 (29.6%) were in condition after bilateral tonsillectomy. In the total population, a greatly enlarged lingual tonsil was only detectable in 14 cases (4.6%). Of these 14 patients, 4 had a history of tonsillectomy. In patients with severe lingual tonsil hyperplasia the mean BMI was 27.3 compared to 24.4 in patients with a normal lingual tonsil. CONCLUSION: In our population the incidence of severe lingual tonsil hyperplasia is 4.7%. We couldn't prove s a connection between a condition after tonsillectomy and compensatory lingual hyperplasia statistically. However, there was a significant relationship between BMI and lingual tonsil hyperplasia.

Anti-EGFR-Based Therapy in Recurrent or Metastatic HNSCC - What Difference Does it Make?

Patients with R/M HNSCC treated with palliative first-line therapy at Hannover Medical School between October 2005 and December 2016 have been included to show changes in survival following broad utilization of cetuximab. Treatment periods were defined from 10/2005 to 12/2008 (Period A) and 01/2009 to 12/2016. Overall survival did not improve over time. However, in subgroup analysis cetuximab utilized at any time vs. never showed a significant improve of overall survival (11.3 vs. 6.3 months, HR: 0.55, 95%-CI: 0.4-0.8, p = 0.04). Therefore, this study supports the application of cetuximab in this real-world population.

CRISPR-Cas9 Engineered Extracellular Vesicles for the Treatment of Dominant Progressive Hearing Loss.

Clinical translation of gene therapy has been challenging, due to limitations in current delivery vehicles such as traditional viral vectors. Herein, we report the use of gRNA:Cas9 ribonucleoprotein (RNP) complexes engineered extracellular vesicles (EVs) for in vivo gene therapy. By leveraging a novel high-throughput microfluidic droplet-based electroporation system (µDES), we achieved 10-fold enhancement of loading efficiency and more than 1000-fold increase in processing throughput on loading RNP complexes into EVs (RNP-EVs), compared with conventional bulk electroporation. The flow-through droplets serve as enormous bioreactors for offering millisecond pulsed, low-voltage electroporation in a continuous-flow and scalable manner, which minimizes the Joule heating influence and surface alteration to retain natural EV stability and integrity. In the Shaker-1 mouse model of dominant progressive hearing loss, we demonstrated the effective delivery of RNP-EVs into inner ear hair cells, with a clear reduction of Myo7ash1 mRNA expression compared to RNP-loaded lipid-like nanoparticles (RNP-LNPs), leading to significant hearing recovery measured by auditory brainstem responses (ABR).