Liquid Crystalline Nanoparticles Conjugated with Dexamethasone Prevent Cisplatin Ototoxicity In Vitro.

The conjugation of drugs with nanoparticles represents an innovative approach for controlled and targeted administration of therapeutic agents. Nanoparticle-based systems have been tested for the inner ear therapy, increasing the drug diffusion and being detected in all parts of the cochlea when locally applied near the round window. In this study, glycerol monooleate liquid crystalline NanoParticles were conjugated with Dexamethasone (NPD), a hydrophobic drug already used for inner ear treatments but defective in solubility and bioavailability. NPD has been tested in vitro in the cell line OC-k3, a model of sensory cells of the inner ear, and the therapeutic efficacy has been evaluated against cisplatin, a chemotherapeutic compound known to induce ototoxicity. After comparing the physical chemical characteristics of NPD to the equivalent naïve nanoparticles, an initial investigation was carried out into the nanoparticle's uptake in OC-k3 cells, which takes place within a few hours of treatment without causing toxic damage up to a concentration of 50 µg/mL. The NPD delivered the dexamethasone inside the cells at a significantly increased rate compared to the equivalent free drug administration, increasing the half-life of the therapeutic compound within the cell. Concerning the co-treatment with cisplatin, the NPD significantly lowered the cisplatin cytotoxicity after 48 h of administration, preventing cell apoptosis. To confirm this result, also cell morphology, cell cycle and glucocorticoids receptor expression were investigated. In conclusion, the NPD system has thus preliminarily shown the potential to improve the therapeutic efficacy of treatments delivered in the inner ear and prevent drug-induced ototoxicity.

Multicentre study on resection margins in carcinoma of the oral cavity, oro-hypopharynx and larynx.

Objective: The prognostic significance of the resection margins is still subject of conflicting opinions. The purpose of this paper is to report the results of a study on the margins in carcinoma of the oral cavity, oro-hypopharynx and larynx. Methods: A multicentre prospective study was carried out between 2015 and 2018 with the participation of 10 Italian reference hospitals. The primary objective was to evaluate local control in patients with well-defined clinical characteristics and comprehensive histopathological information. Results: During the study period, 455 patients were enrolled; the minimum follow-up was 2 years. Previous treatment, grading and fresh specimen examination were identified as risk factors for local control in multivariate analysis. On the basis of these results, it seems possible to delineate "risk profiles" for different oncological outcomes. Discussion: The prognostic significance of the margins is reduced, and other risk factors emerge, which require diversified treatment and follow-up. Conclusions: Multidisciplinary treatment with adjuvant therapy, if indicated, reduces the prognostic importance of margins. Collaboration with a pathologist is an additional favourable prognostic factor and quality indicator.An appendix with literature review is present in the online version.

Neuron Compatibility and Antioxidant Activity of Barium Titanate and Lithium Niobate Nanoparticles.

The biocompatibility and the antioxidant activity of barium titanate (BaTiO3) and lithium niobate (LiNbO3) were investigated on a neuronal cell line, the PC12, to explore the possibility of using piezoelectric nanoparticles in the treatment of inner ear diseases, avoiding damage to neurons, the most delicate and sensitive human cells. The cytocompatibility of the compounds was verified by analysing cell viability, cell morphology, apoptotic markers, oxidative stress and neurite outgrowth. The results showed that BaTiO3 and LiNbO3 nanoparticles do not affect the viability, morphological features, cytochrome c distribution and production of reactive oxygen species (ROS) by PC12 cells, and stimulate neurite branching. These data suggest the biocompatibility of BaTiO3 and LiNbO3 nanoparticles, and that they could be suitable candidates to improve the efficiency of new implantable hearing devices without damaging the neuronal cells.

Cochlear implant in vestibular schwannomas: long-term outcomes and critical analysis of indications.

PURPOSE: To describe our institutional experience in cochlear implantation after vestibular schwannoma (VS) resection, and compare the audiological outcomes between sporadic and neurofibromatosis type 2 (NF2) VS sub-cohorts of patients, and in relation to preoperative contralateral hearing. METHODS: Seventeen patients (8 sporadic and 9 NF2-associated VSs) who had undergone VS resection and cochlear implant (CI) were analyzed retrospectively. Audiological outcomes at 24 months were correlated with preoperative clinical variables. The results according to VS type (sporadic vs. NF2-associated) and contralateral hearing (impaired vs. normal) were compared. RESULTS: Fourteen CIs were actively used by the patients (77.8%). Twenty-four months after CI activation, the median postoperative PTA (pure tone average) was 45.6 dB nHL and a measurable WRS (Word Recognition Score) was achieved by 44.4% of patients (median WRS = 40%). The median postoperative PTA in the implanted ear resulted better in the group with an impaired contralateral hearing (36.3 dB nHL vs. 78.8 dB nHL, p = 0.019). Good preoperative contralateral hearing status (A-B classes of AAO-HNS) was a negative prognostic factor for CI performance on open-set discrimination (OR = 28.0, 95% CI 2.07-379.25, p = 0.012). CONCLUSIONS: CI is a viable rehabilitative option for patients with sporadic or NF2-associated VS. A good contralateral hearing adversely affects CI outcome and should be taken into consideration for patients' selection and rehabilitation programs.

Position of Retrosigmoid Craniotomy in Hearing Preservation Surgery for Vestibular Schwannoma.

BACKGROUND: Surgical access to the internal auditory canal (IAC) fundus is a crucial aspect of the retrosigmoid approach for hearing preservation surgery in vestibular schwannoma. An appropriate positioning of the retrosigmoid craniotomy is necessary to obtain an adequate surgical corridor for full fundus exposure and labyrinth preservation. OBJECTIVE: To describe how the position of the posterior edge of the access related to the probability of exposing the fundus and to propose novel criteria for positioning the retrosigmoid craniotomy. METHODS: Data on fundus exposure were retrospectively collected in 33 consecutive cases of sporadic vestibular schwannoma, submitted to the retrosigmoid craniotomy in a park-bench position. Patients' computed tomography images were analyzed to calculate the position of the posterior edge of the craniotomy with reference to the fundus-labyrinth line (FLL), which starts at the fundus and, running just posterior to the labyrinth, reaches the occipital squama. A logistic regression model was used to correlate the craniotomy position with the probability of exposing the fundus. RESULTS: The fundus exposure rate was significantly higher (P = .005) for craniotomies located posteromedially to the FLL. In a logistic regression model, the probability of exposing the fundus reached 95% for craniotomies located 11.3 mm posteromedially to the FLL. CONCLUSION: This study showed a strong association between craniotomy position and fundus exposure rate. Our findings suggest that the posteromedial edge of the retrosigmoid craniotomy should lie approximately 11 mm posteromedially to FLL to maximize the chances of exposing the fundus.

Pediatric Hearing Loss Management in the COVID-19 Era: Possible Consequences and Resources for the Next Future.

Pediatric hearing loss early diagnosis and treatment have been limited by the current restrictions due to the coronavirus disease 2019 pandemic. The difficulty in accessing the multiple facilities required for the rehabilitative process is influencing the timing of each step of the process. Auditory hearing screening programs, etiological characterization, surgical timing, and speech therapies have all been limited in the past year. The current conditions have forced us to adopt different strategies to overcome the necessary social distancing prescriptions. Although their efficacy should be proved over time, some of these resources will be probably useful even in a nonpandemic future.

Deep Neck Abscesses in Children: An Italian Retrospective Study.

BACKGROUND: Retropharyngeal and parapharyngeal abscesses (RPAs, PPAs) usually affect young children. Surgical drainage and/or antibiotic therapy are treatment of choice, but no specific guidelines exist. In order to reduce the risk of severe complications, appropriate diagnosis and therapy are necessary. The aims of the study were to review diagnosis and management of children with RPAs/PPAs and to compare surgical versus medical approach. METHODS: This is a multicenter retrospective study including all patients younger than 15 years admitted at 4 Italian pediatric hospitals of Florence, Padua, Rome, and Treviso, with International Classification of Diseases, Ninth Revision discharge diagnosis code of RPAs and PPAs, from January 1, 2008, to December 31, 2016. RESULTS: One hundred fifty-three children were included. The median age was 4.4 years, with overall male predominance. Heterogeneous signs and symptoms (fever, neck cervical, lymphadenopathy, pain, and stiff neck most frequently) and a large mixture of bacteria from pus cultures were detected. Computer tomography (66.7%) and magnetic resonance imaging (27.5%) were performed to confirm the presence of abscess. Fifty-one percent of abscesses were greater than 3 cm. Eighty-seven patients (56.9%) underwent surgery, and 66 (43.1%) were treated with antibiotics alone (mostly ceftriaxone, metronidazole, amikacin, and clindamycin) with median days of therapy of 26.5 days and length of therapy of 16.0 days of median. Median length of stay was 11 days. None had severe complications. Multivariate analysis indicated as independent predictive factors of surgery abscess of 3 cm or greater, high white blood cell count, and-most of all-the hospital of admission. CONCLUSIONS: Deep neck abscesses mostly affect patients in early childhood, with a combination of nonspecific signs and symptoms, and it still emerges as a heterogeneous approach in diagnosis and management of these infections. Thus, common shared protocols represent an essential tool in order to standardize care and improve patients' outcomes.

Transmeatal microsurgery for intralabyrinthine and intrameatal schwannomas: a reappraisal.

OBJECTIVE: The interest in surgical routes to the internal auditory canal (IAC) through the external auditory canal for vestibular schwannoma removal has been recently raised by the endoscopic approaches to the lateral skull base. The aim of the study was to reappraise the transmeatal microsurgical approach (TMMa) to the labyrinth and IAC, first described 50 years ago. METHODS: A retrospective series of 8 consecutive patients treated for intralabyrinthine and intrameatal schwannomas through TMMa is presented. Main outcome measures consisted of surgical indications, postoperative complications, facial nerve status, bed mobilisation time, hospitalisation time and tumour recurrence rate. RESULTS: Surgical indications for TMMa were tumour growth (62.5%) and disabling vertigo (37.5%) in the present series. Complete tumour removal with no complications and postoperative normal facial nerve function was obtained in all cases. Bed mobilisation occurred after a median of 3 postoperative days (IQR 2.2-3.0) and discharge after a median of 5.6 days (IQR 4.7-7.0). After a median follow-up of 13 months (IQR 7.5-27.5), no tumour recurrence was observed. CONCLUSIONS: TMMa indications are limited to schwannomas of the labyrinth and IAC, which dropped out from observation protocols due to unmanageable symptoms or growth. Despite the narrow mini-invasive surgical corridor, the TMMa was a safe an effective microsurgical technique in terms of tumour removal and postoperative course.

Immune Response After Cochlear Implantation.

A cochlear implant (CI) is an electronic device that enables hearing recovery in patients with severe to profound hearing loss. Although CIs are a successful treatment for profound hearing impairment, their effectivity may be improved by reducing damages associated with insertion of electrodes in the cochlea, thus preserving residual hearing ability. Inner ear trauma leads to inflammatory reactions altering cochlear homeostasis and reducing post-operative audiological performances and electroacoustic stimulation. Strategies to preserve residual hearing ability led to the development of medicated devices to minimize CI-induced cochlear injury. Dexamethasone-eluting electrodes recently showed positive outcomes. In previous studies by our research group, intratympanic release of dexamethasone for 14 days was able to preserve residual hearing from CI insertion trauma in a Guinea pig model. Long-term effects of dexamethasone-eluting electrodes were therefore evaluated in the same animal model. Seven Guinea pigs were bilaterally implanted with medicated rods and four were implanted with non-eluting ones. Hearing threshold audiograms were acquired prior to implantation and up to 60 days by recording compound action potentials. For each sample, we examined the amount of bone and fibrous connective tissue grown within the scala tympani in the basal turn of the cochlea, the cochleostomy healing, the neuronal density, and the correlation between electrophysiological parameters and histological results. Detection of tumor necrosis factor alpha, interleukin-6, and foreign body giant cells showed that long-term electrode implantation was not associated with an ongoing inflammation. Growth of bone and fibrous connective tissue around rods induced by CI was reduced in the scala tympani by dexamethasone release. For cochleostomy sealing, dexamethasone-treated animals showed less bone tissue growth than negative. Dexamethasone did not affect cell density in the spiral ganglion. Overall, these results support the use of dexamethasone as anti-inflammatory additive for eluting electrodes able to protect the cochlea from CI insertion trauma.

High prevalence of human papillomavirus infection in sinonasal inverted papilloma: a single-institution cohort of patients.

BACKGROUND: Both the prevalence of sinonasal inverted papilloma (IP) and the causal association with alpha-human papillomaviruses (alpha-HPVs) are controversial. In this study we aimed to determine HPV status in histologically selected, microdissected, formalin-fixed, and paraffin-embedded tissue samples of IP. METHODS: HPV status was assessed retrospectively by polymerase chain reaction (PCR)-bead-based multiplex genotyping on tissue samples of patients diagnosed with IP and consecutively treated with endoscopic resection. Forty-one HPV genotypes were considered, distinguishing between high risk and low risk. HPV status was correlated with demographics and clinical variables. Sixty sinonasal IP tissue samples were initially considered. After exclusion of 5 cases due to insufficient quality/quantity of the samples, 55 patients were included for analysis. RESULTS: HPV-DNA sequences were identified in 34 of 55 (61.8%) IPs, with a higher prevalence of high-risk than low-risk HPV genotypes (19 [55.9%] and 15 cases [44.1%], respectively). HPV16 strongly prevailed among the high-risk HPV cases (84.2%), and HPV54 prevailed among the low-risk HPV cases (53.3%). IPs with origin within the maxillary sinus were significantly associated with high-risk HPV (p = 0.019). No significant associations emerged between HPV status and demographics or clinical variables. CONCLUSION: In a series of 55 IP tissue samples, HPV-DNA sequences were identified in 61.8% of cases, which differs from the data of previous investigations. Further case-control studies are advocated to confirm this prevalence in the Italian population addressed, and also to clarify any pathogenic involvement of HPV in the natural history of IPs.

Tumor budding is an adverse prognostic marker in intestinal-type sinonasal adenocarcinoma and seems to be unrelated to epithelial-mesenchymal transition.

Intestinal-type adenocarcinoma (ITAC) of sinonasal tract is a rare malignant tumor with strong morphological, immunophenotypical, and molecular similarities to colorectal adenocarcinoma (CRC). Tumor budding (TB) is a well-established adverse prognostic marker in CRC and some head and neck tumors, with features of epithelial-mesenchymal transition (EMT). The aim of this study was to assess TB in ITAC and to evaluate its possible association with EMT markers in this setting. We selected 32 surgically resected specimens of non-mucinous/non-signet ring ITAC and evaluated them for TB according to the international recommendations developed for CRC. The expression of the EMT markers E-cadherin, ZEB1, ZEB2, SLUG, and SNAIL was evaluated by immunohistochemistry (IHC). Results were stratified using clinical and follow-up data (2/32 patients had metastatic disease and 4/32 died of disease). We observed TB in 13/32 (40.6%) ITAC cases including the 7 patients with relapse (p = 0.0005) and the 4 patients dead of disease (p = 0.02). Lymphovascular invasion was associated with TB (p = 0.008). Absence of TB was associated with low ZEB2 expression (p = 0.003). No other association with EMT markers emerged. Occupational exposure to wood and leather dust was not related to the presence of TB. TB interobserver concordance was substantial (proportion of agreement = 87%; Cohen's kappa = 0.73). This work suggests that TB is associated with a worse prognosis in ITAC, but our findings do not seem to support the involvement of EMT in this specific setting. Further larger studies are needed to address this point.

Cochlear implantation in adults with auditory deprivation: What do we know about it?

INTRODUCTION: In the ENT community, auditory deprivation is frequently considered as a negative prognostic factor for a good hearing outcome of cochlear implantation (CI), even if a growing literature suggests that this is not completely true. The purpose of this study is to evaluate the results of CI in patients with hearing deprivation, to compare them to results from non-deprived patients and then estimate how time of deprivation impacts on CI outcome and how a bilateral deprivation can affect the outcome compared to a unilateral deprivation. METHODS: Seventy-eight adults with severe to profound post-verbal hearing loss, with and without auditory deprivation history, received CI; audiological results obtained at 3-6-12-24 months follow up post CI were analyzed. RESULTS: No differences were founded between patients with unilateral deprivation and patients with no deprivation. Patients with bilateral deprivation seem to have a worse hearing outcome compared to that of those patients with unilateral deprivation or no deprivation at all. Long time deprivation (>15 years) seems to have a negative influence on the hearing outcome but results with CI remain excellent. CONCLUSIONS: Auditory deprivation should not be considered a contraindication to CI. The duration of auditory deprivation in the implanted ear seems to be a negative prognostic factor only for ears deprived from more of 15 years.

Endoglin-based assessment of neoangiogenesis in sporadic VIII cranial nerve schwannoma.

Although the diagnosis and treatment of sporadic vestibular schwannoma has improved in recent years, no factors capable of predicting its growth have been identified as yet. Endoglin (CD105) is a proliferation-associated protein expressed in angiogenic endothelial cells, and a potential prognostic indicator for several solid tumors. The aim of the present study was primarily to investigate the expression and role of CD105 in a series of sporadic vestibular nerve schwannomas. In 71 consecutive cases of vestibular schwannoma, vessel cross-sectional area and density were calculated from immunohistochemically assessed CD105 expression using image analysis to correlate them with: (i) tumor dimensions; and (ii) tumor growth rate measured on high-resolution contrast-enhanced MRI (ceMRI). Based on assessments of CD105 expression, a significant positive correlation was identified between vessel cross-sectional area and tumor size at the time of surgery (p = 0.0024), and between vessel density and tumor size (p = 0.013). Vessel cross-sectional area (p = 0.0006) and vessel density (p = 0.003) were significantly greater in tumors measuring ≥10 mm in size than in those <10 mm. Conversely, when tumor growth rate could be calculated from two or more ceMRI (38 cases), there was no significant correlation between tumor growth rate and cross-sectional vessel area or vessel density as assessed with CD105. Further investigations are needed to ascertain the feasibility of: (i) using circulating endoglin assay to monitor tumor growth; and (ii) targeting neoangiogenesis with anti-endoglin antibodies in sporadic vestibular schwannoma.

Cochlear implant outcomes in the elderly: a uni- and multivariate analyses of prognostic factors.

PURPOSE: To assess preoperative features that could predict the audiological outcome after cochlear implantation in the elderly, in terms of pure tone audiometry, speech audiometry, and speech perception performance. METHODS: All available records of patients with cochlear implants aged 65 or more at the time of their implantation at our Institution were reviewed (50 patients, mean age 70.76 ± 4.03 years), recording preoperative clinical features. Pure tone audiometry, speech audiometry, and speech perception performance 1 year after cochlear implant activation and fitting were used as outcome measures. RESULTS: No statistically significant association emerged between clinical features and pure tone audiometry. On univariate analysis, progressive sensorineural hearing loss of unknown origin was associated with a better outcome in terms of speech audiometry and speech perception performance (p = 0.035 and p = 0.033, respectively). On multivariate analysis, progressive sensorineural hearing loss retained its independent prognostic significance in terms of speech perception performance (p = 0.042). The discriminatory power of a two-variable panel (age and etiology of hearing loss) featured an AUC (ROC) of 0.738 (an acceptable discriminatory power according to the Hosmer-Lemeshow scale). CONCLUSIONS: A progressive sensorineural hearing loss of unknown origin was associated with a better outcome in terms of speech perception in the elderly in our case study. Further features that can predict audiological outcome achievable with cochlear implants in the elderly are desirable to perform adequate counselling and rehabilitation programs.

Endoglin (CD105) expression in neurofibromatosis type 2 vestibular schwannoma.

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant, multiple neoplasia syndrome characterized by bilateral vestibular schwannomas (VSs). Endoglin is a proliferation-associated protein expressed in angiogenic endothelial cells. The aim of this study was to investigate endoglin expression in a series of NF2-associated VSs, as compared with a group of sporadic VSs. METHODS: Using image analysis, vessel cross-sectional area (AA) and density (VD) were calculated from CD105 expression in 7 NF2-associated VSs and 14 size-matched sporadic VSs. RESULTS: There were no significant differences between NF2-associated VSs and sporadic cases in terms of AA (P = .28), or VD (P = .39). A positive correlation emerged between tumor growth rate (measured on contrast-enhanced MRI) and VD in the cohort of NF2-associated VSs (rho = 0.95, P = .05). CONCLUSIONS: Further investigations are needed to ascertain the feasibility of (a) measuring circulating endoglin levels to monitor tumor growth rate and (b) targeting tumor neoangiogenesis with anti-endoglin approaches in NF2-associated VS.

HER2 status in sinonasal intestinal-type adenocarcinoma.

Given that the prognosis of patients with sinonasal intestinal-type adenocarcinoma (ITAC) has not significantly changed recently, there is a desire for new therapeutic approaches to improve clinical management. HER2-targeted therapy has remarkably improved the overall survival of patients with HER2 amplified tumors. To date, HER2 assessment has produced contradictory results in ITAC. The aim of this study was to assess HER2 status at both protein and DNA levels in a large series of ITAC. HER2 status was assessed by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) in forty-three patients that underwent surgical resection for ITAC at the Otorhinolaryngology Section, Padua University Hospital, between 2007 and 2016. IHC was evaluated using the four-tier score developed for gastroesophageal cancer. As for IHC, 83.7% (36/43) of ITAC were scored 0, 14% (6/43) 1+, and 2.3% (1/43) 2+. No HER2 amplification was detected by CISH. The present is the largest study of sinonasal ITAC tested with both IHC and CISH confirmation for HER2 status. No HER2 overexpression/amplification was detected. Contrary to previous studies, our findings seem to rule out any oncogenetic role of HER2 in ITAC pathogenesis.

Peak nasal inspiratory flow measurement and visual analogue scale in a large adult population.

OBJECTIVES: Nasal obstruction is the most common symptom in nasal diseases. It can be evaluated objectively, that is by means of peak nasal inspiratory flow (PNIF) measures and/or subjectively by means of validated questionnaires. However, it has been reported that there is a lack of reliable correlation between subjective and objective measurements of nasal obstruction. The aim of the present study was to evaluate the correlation between PNIF measurements and the subjective sensation of nasal obstruction measured by means of a visual analogue scale (VAS) in a large population of consecutive rhinologic patients. DESIGN: Prospective clinical study. SETTING: Tertiary rhinological referral centre. PARTICIPANT MAIN OUTCOME MEASURES: A total of 641 consecutive subjects were enrolled. Visual analogue scale and PNIF were performed to assess nasal obstruction. Nasal septal deviation was classified according to Mladina classification, and its severity was assessed using three levels of severity. RESULTS: Although weak, there was a significant negative correlation (r = -0.13, P = 0.001) between PNIF and VAS. Dividing the population in those affected by nasal septal deviation (NSD) and those affected by chronic rhinosinusitis (CRS), a week negative correlation between PNIF and VAS was again confirmed in both groups (r = -0.208, P = 0.006 for NSD and r = -0.13, P = 0.04 for CRS). Peak nasal inspiratory flow and VAS were also evaluated according to the grade of polyps and the type and level of septal deviation. CONCLUSIONS: Visual analogue scale and PNIF significantly correlated, although with a low degree, in a large population of rhinologic patients. Peak nasal inspiratory flow, being cheap and simple to use, could be a good candidate to assist clinicians dealing with "airway" diseases in their daily clinical practice in order to provide comprehensive information on nasal function. Peak nasal inspiratory flow can in fact give some important rough insights on VAS, but these measurements cannot be alternative to each other.