Uncovering the WWTR1::NCOA2 Gene fusion in low-grade myoepithelial-rich neoplasm with HMGA2 expression: A case report.

We describe a case of a pleomorphic adenoma (PA) arising from the para-tracheal accessory salivary gland in a 44-year-old male harboring a novel WWTR1::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in salivary gland tumors. The patient presented with hoarseness of voice. The radiological exam revealed a mass in the upper third of the trachea involving the larynx. Histologically, the tumor consisted of bland-looking monocellular eosinophilic epithelial cells arranged in cords and sheets separated by thin fibrous stroma, focally forming a pseudo-tubular pattern. In immunohistochemistry, the tumor cells demonstrated positivity for CK7, PS100, SOX10, and HMGA2; and negativity for CK5/6, p40 p63, and PLAG1. In addition, the clustering analysis clearly demonstrates a clustering of tumors within the PA group. In addition to reporting this novel fusion in the PA spectrum, we discuss the relevant differential diagnoses and briefly review of NCOA2 and WWTR1 gene functions in normal and neoplastic contexts.

Peculiar nuclear atypia associated with MDM2 gene amplification in carcinoma ex-pleomorphic adenoma harbouring an alteration of HMGA2.

AIMS: Salivary gland neoplasms (SGN) exhibiting the HMGA2::WIF1 fusion are recognized by their resemblance to histology found in canalicular adenoma. Recently, ~20% of cases among 28 HMGA2::WIF1-rearranged-SGN showed malignancy and adverse outcomes (recurrence, distant metastasis, and disease-specific mortality). Among them, MDM2/CDK4 amplifications were identified in one case. This outcome suggests that the MDM2/CDK4 amplifications could be useful to predict an aggressive course of carcinoma ex-pleomorphic adenoma (CEPA). METHODS AND RESULTS: We investigated the correlation between HMGA2 fusion and MDM2 amplification in four salivary gland neoplasms, providing detailed clinicopathological features and outcomes. Cases were selected from different institutions. Histological examination, immunohistochemistry, fluorescence in situ hybridization (FISH), RNA sequencing, and whole-exome capture were performed. The cohort included four CEPA cases, all female, aged between 32 and 89 years. Tumours arose from the parotid gland with an average size of 24.5 mm. None exhibited recurrence or distant metastases during the 4-5 months of follow-up. Pathologically, all cases displayed a peculiar atypical nuclei with 'gear-like appearance'. Immunohistochemically, tumours exhibited a biphasic pattern with myoepithelial and ductal differentiation markers. All cases showed HMGA2 overexpression and MDM2 amplification by FISH and RNA sequencing. In a control cohort of MDM2 nonamplified CEPA cases, not exhibiting the peculiar nuclear atypia. CONCLUSIONS: Our findings suggest a strong correlation between HMGA2 alteration/MDM2 amplification and a peculiar nuclear atypia, advocating for their evaluation in biphasic tumours to facilitate accurate diagnosis and tailored posttumour removal monitoring. Further studies are warranted to validate these observations and elucidate their prognostic implications.

Peri-operative management of endoscopic endonasal cerebrospinal fluid leak repair: an international survey.

PURPOSE: Peri-operative management of nasal cerebrospinal fluid (CSF) leaks is not consensual due to limited evidence. The main aim of this study was to identify key factors in peri-operative management of endoscopic endonasal CSF leak repair among international experts. METHODS: A 60-item survey questionnaire collected opinions of members of international learned societies of ENT surgeons and neurosurgeons on nasal packing, post-operative instructions, antibiotic prophylaxis, and CSF volume depletion. RESULTS: The survey had 153 respondents (124 otorhinolaryngologists and 29 neurosurgeons). A resting position was recommended by 85% (130/151) of respondents for extended CSF leak of the anterior skull base, mainly in Fowler's position (72% (110/153)). Nasal packing was used by 85% (130/153) of respondents; 33.3% (51/153) used it to stabilize the reconstruction, and 22.2% (34/153) to prevent bleeding. It was usually removed after 48 h in 44.4% of cases (68/153). CSF depletion was considered by 47.1% (72/153) of respondents in case of CSF leak recurrence and by 34.6% (53/153) in cases of increased intracranial pressure. All respondents gave specific postoperative instructions to patients including driving, running, swimming, diving restrictions and flighting restrictions. In subgroup analysis, ENT surgeons more often recommended a resting position than neurosurgeons (71% vs. 37.9% ; p = 0.0008) and prescribed more antibiotics (82.3% vs. 21.4% ; p < 0.0001). CONCLUSION: Although postoperative management after CSF closure remains challenging and not codified, this international survey revealed some points of consensus concerning resting position and restriction of post-operative activities. Prospective clinical studies must be undertaken to evaluate their efficiency.

Internal Nasal Valve Collapse Treatment by Endonasal Hyaluronic Acid Injection.

OBJECTIVE: Internal nasal valve collapse (IVC) is a common functional complication of rhinoplasty and injecting hyaluronic acid is one of the treatment options available, but its effectiveness has never been evaluated. The objective of this study was to assess the evolution of IVC after injection of hyaluronic acid using objective and subjective measures of nasal obstruction. STUDY DESIGN: A prospective interventional study was conducted. METHODS: Adult patients consulting for nasal obstruction after (septo)rhinoplasty and diagnosed with IVC were included. Patients underwent 4-phase rhinomanometry, completed nasal obstruction symptoms evaluation (NOSE) and visual analog scale (VAS) questionnaires and received hyaluronic acid injections. Measurements were repeated immediately, one month and one year later. The primary outcome measure was the proportion of patients below the rhinomanometric diagnostic threshold for IVC at one month. RESULTS: Among the 22 patients included, 20 (91%) had rhinomanometry measurements below the diagnostic threshold for IVC one month after injection. It decreased to 53% (8/15 patients) at one year post injection. The mean NOSE score decreased from 74.5 (± 18.0) before injection to 35.2 (± 23.3) after injection (p < 0.0001). The mean VAS score decreased from 7.0 (± 1.4) before injection to 3.4 (± 1.9) after injection (p < 0.0001). In these patients with post-(septo)rhinoplasty IVC, hyaluronic acid injection into the internal nasal valve substantially improved subjective and objective measures of nasal obstruction. CONCLUSION: These results suggest hyaluronic acid injection (performed as described) is an effective treatment for IVC and is an excellent alternative to surgical treatment. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/00266 .

Oncostatin M Contributes to Airway Epithelial Cell Dysfunction in Chronic Rhinosinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a typical type-2 inflammation involving several cytokines and is associated with epithelial cell dysfunction. Oncostatin M (OSM) (belonging to the interleukin(IL)-6 family) could be a key driver of epithelial barrier dysfunction. Therefore, we investigated the presence of OSM and IL-6 and the expression pattern of tight junctions (TJs) in the nasal tissue of CRSwNP patients and controls using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Then, their potential role in the epithelial barrier was evaluated in vitro in 27 different primary cultures of human nasal epithelial cells (HNECs) by measuring TJ expression and transepithelial electric resistance (TEER) with or without OSM or IL-6 (1, 10, and 100 ng/mL). The effect on ciliary beating efficiency was evaluated by high-speed videomicroscopy and on repair mechanisms with a wound healing model with or without OSM. OSM and IL-6 were both overexpressed, and TJ (ZO-1 and occludin) expression was decreased in the nasal polyps compared to the control mucosa. OSM (100 ng/mL) but not IL-6 induced a significant decrease in TJ expression, TEER, and ciliary beating efficiency in HNECs. After 24 h, the wound repair rate was significantly higher in OSM-stimulated HNECs at 100 ng/mL. These results suggest that OSM could become a new target for monoclonal antibodies.

Pre-referral intranasal artesunate powder for cerebral malaria: a proof-of-concept study.

BACKGROUND: Malaria still kills young children in rural endemic areas because early treatment is not available. Thus, the World Health Organization recommends the administration of artesunate suppositories as pre-referral treatment before transportation to the hospital in case of severe symptoms with an unavailable parenteral and oral treatment. However, negative cultural perception of the rectal route, and limited access to artesunate suppositories, could limit the use of artesunate suppositories. There is, therefore, a need for an alternative route for malaria pre-referral treatment. The aim of this study was to assess the potential of intranasal route for malaria pre-referral treatment. METHODS: The permeability of artesunate through human nasal mucosa was tested in vitro. The Transepithelial Electrical Resistance (TEER) of the nasal mucosa was followed during the permeation tests. Beside, regional deposition of artesunate powder was assessed with an unidose drug delivery device in each nostril of a nasal cast. Artesunate quantification was performed using Liquid Chromatography coupled to tandem Mass Spectrometry. RESULTS: The experimental model of human nasal mucosa was successfully implemented. Using this model, artesunate powder showed a much better passage rate through human nasal mucosa than solution (26.8 ± 6.6% versus 2.1 ± 0.3%). More than half (62.3%) of the artesunate dose sprayed in the nostrils of the nasal cast was recovered in the olfactory areas (44.7 ± 8.6%) and turbinates (17.6 ± 3.3%) allowing nose-to-brain and systemic drug diffusion, respectively. CONCLUSION: Artesunate powder showed a good permeation efficiency on human nasal mucosa. Moreover it can be efficiently sprayed in the nostrils using unidose device to reach the olfactory area leading to a fast nose-to-brain delivery as well as a systemic effect. Taken together, those results are part of the proof-of-concept for the use of intranasal artesunate as a malaria pre-referral treatment.

Feasibility of day-case pediatric cochlear implantation.

PURPOSE: Pediatric cochlear implantation is performed on an outpatient basis in an inconstant way. The aim of this study is to assess the feasibility of day-case pediatric cochlear implantation by determining the acceptability of outpatient-to-inpatient conversion rate (acceptability threshold of 5%) and to assess the safety by comparing outpatient and inpatient postoperative events. We also want to identify conversion predictive factors. METHODS: We conducted a monocentric retrospective study including 267 cases aged 6 months to 18 years who underwent unilateral cochlear implantation between 2016 and 2020. This population was divided into two groups: outpatient group (190 cases) and inpatient group (77 cases). RESULTS: Among the 190 cases scheduled as day surgery, 9 cases required conversion to conventional hospitalization which leads to an outpatient-to-inpatient conversion rate of 4.7%. Postoperative nausea and vomiting (PONV) were involved in all cases of conversion. Conversion predictive factors were the presence of an inner ear malformation at risk of gusher (OR 32.51, 95% CI [4.98-370.27], p 0.001) and the intraoperative administration of morphine (OR 8.52, 95% CI [1.38-86.84], p 0.035). There was no statistically significant difference in immediate postoperative complications (outpatient 14.2% vs inpatient 16.9% p 0.715), early-stage complications (outpatient 12.6% vs inpatient 10.4% p 0.812) and early-stage unplanned consultations (outpatient 4.7% vs inpatient 3.9% p 0.748) between outpatient and inpatient groups. Unplanned readmissions were found only in the outpatient group. CONCLUSION: Day-case pediatric cochlear implantation is a feasible and safe procedure even in infants. The outpatient-to-inpatient conversion rate of 4.7% is considered acceptable but requires anticipation of human and accommodation needs. No causes of conversion were life-threatening. The risk of postoperative complications and unplanned consultations are not influenced by the mode of hospitalization. Special attention should be paid to the prevention of PONV and the presence of inner ear malformations.

Multi-operated cholesteatoma: when two surgeries are not enough.

PURPOSE: Most studies regarding residual and recurrent cholesteatoma focus on single relapse. This study examines patients who had to undergo at least three surgeries for complete eradication of their cholesteatoma, with the aim of bringing to light risk factors and assessing the functional impact of multiple surgeries on hearing. METHOD: We include 27 patients who underwent 3 consecutive surgeries for cholesteatoma between 2006 and 2016. This population represented 3.1% of all cholesteatoma operated on during that same period (868 patients). RESULTS: Cases of multi-residual and/or recurrent cholesteatoma (RRC) were significantly younger (13.1 years old), than single-RRC or cases with No-RRC (respectively, 28.0 and 38.5 years old) (p < 0.01). Furthermore, there was a significant difference in cholesteatoma location especially for combined attical and mesotympanic location between the three groups (no-RCC 26%; single-RRC 34% and multi-RRC 66%) (p < 0.01). There was also a significant difference in ossicular erosion of the malleus, incus and stapes between the three groups (p < 0.01). In our study, the type of surgery did not influence multi-RRC rates. We did not observe any significant impact on hearing between the first and third surgeries. Mean duration between the first and second surgeries was significantly shorter for multi-RRC (14.5 months SD 8.3) than for single-RRC (23.3 months SD 18.1) (p < 0.05). CONCLUSION: Special care should be given in case of combined attical and mesotympanic extension, ossicular erosion and young children. Delaying the realization of MRI, and/or of second-look surgery, could decrease the risk of multi-RRC.

Otoskills training during covid-19 pandemic: a before-after study.

BACKGROUND: The ongoing COVID-19 pandemic has disrupted the surgical training of residents. There is a real concern that trainees will not be able to meet their training requirements. Low-fidelity surgical simulation appears to be an alternative for surgical training. The educational benefits of repeating ossiculoplasty simulations under a microscope have never been evaluated. With this study we aimed to evaluate the differences in performance scores and on a global rating scale before and after training on an ossiculoplasty simulator. METHODS: In this quasi-experimental, prospective, single-centre, before-after study with blinded rater evaluation, residents performed five microscopic ossiculoplasty tasks with a difficulty gradient (sliding beads onto rods, the insertion of a partial prosthesis, the insertion of a total prosthesis, and the insertion of a stapedotomy piston under microscopic or endoscopic surgery) before and after training on the same simulator. Performance scores were defined for each task, and total performance scores (score/min) were calculated. All data were collected prospectively. RESULTS: Six out of seven intermediate residents and 8/9 novices strongly agreed that the simulator was an effective training device and should be included in the ENT residency program. The mean effect of training was a significant increase in the total performance score (+ 0.52 points/min, [95 % CI, 0.40-0.64], p < 0.001), without a significant difference between novice and intermediate residents. CONCLUSIONS: This preliminary study shows that techniques for middle-ear surgery can be acquired using a simulator, avoiding any risk for patients, even under lockdown measures.

FcRn as a Transporter for Nasal Delivery of Biologics: A Systematic Review.

FcRn plays a major role in regulating immune homeostasis, but it is also able to transport biologics across cellular barriers. The question of whether FcRn could be an efficient transporter of biologics across the nasal epithelial barrier is of particular interest, as it would allow a less invasive strategy for the administration of biologics in comparison to subcutaneous, intramuscular or intravenous administrations, which are often used in clinical practice. A focused systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was registered on the international prospective register of systematic reviews PROSPERO, which helped in identifying articles that met the inclusion criteria. Clinical and preclinical studies involving FcRn and the nasal delivery of biologics were screened, and the risk of bias was assessed across studies using the Oral Health Assessment Tool (OHAT). Among the 12 studies finally included in this systematic review (out of the 758 studies screened), 11 demonstrated efficient transcytosis of biologics through the nasal epithelium. Only three studies evaluated the potential toxicity of biologics' intranasal delivery, and they all showed that it was safe. This systematic review confirmed that FcRn is expressed in the nasal airway and the olfactory epithelium, and that FcRn may play a role in IgG and/or IgG-derived molecule-transcytosis across the airway epithelium. However, additional research is needed to better characterize the pharmacokinetic and pharmacodynamic properties of biologics after their intranasal delivery.

Tolerance and safety of 45S5 bioactive glass used in obliteration procedures during middle ear surgery: Preliminary results.

OBJECTIVE: Otologists face many disadvantages after extensive mastoid drilling and canal wall down technique in cholesteatoma surgery. Mastoid and epitympanic cavity obliterations or reconstructions after canal wall down procedure using bioactive glass seem to be an interesting solution to overcome some of these disadvantages. Bioactive glass offers many benefits including the availability when there are no sufficient autologous materials for obliteration, its antibacterial activity in chronic infected ear and decreasing the recidivism of cholesteatoma. The objective of this study is to evaluate the tolerance and safety of 45S5 bioactive glass as a filing bone-synthetic material by clinical, audiological and radiological examinations. METHODOLOGY: A retrospective study of 42 patients who had undergone obliteration of mastoid or/and epitympanic cavity with 45S5 bioactive glass between, November 2017 to January 2019. Data from clinical follow-ups, audiological assessment, CT-scan and MRI were analyzed. RESULT: The patients' mean age was 49.8 years old. Microscopic examinations showed dry well-healed tympanic membranes and external auditory canals for 95.2% of the patients after 1 year. Inner ear injuries after obliteration were not observed by comparing pre and post-operative bone conduction audiometry (p value 0.457). No facial palsy was reported post-operatively. One-year postoperative radiological assessments did not reveal any silent implantation of cholesteatoma or residual disease. CONCLUSION: Mastoid and epitympanic obliterations with 45S5 bioactive glass seem to be a tolerable and safe option in cholesteatoma surgery with favorable outcomes similar to other member of bioactive glass especially the S53P4.

Is one of these two techniques: CO2 laser versus microdrill assisted stapedotomy results in better post-operative hearing outcome?

OBJECTIVE: To evaluate hearing results and outcome using two different surgical techniques (microdrill and CO2 Laser fenestration) in the treatment of conductive hearing loss in patients with otosclerosis. STUDY DESIGN: Retrospective audiometric database and chart review from January 2005 until December 2016. SETTING: Two tertiary referral hospitals MATERIALS AND METHODS: Seven-hundred forty-two primary stapedotomy have been reviewed retrospectively in two referral hospitals. This multicenter study compared 424 patients operated for otosclerosis with microdrill technique and 318 patients operated with CO2 laser assisted stapedotomy. Preoperative and postoperative audiological assessment (following the recommendations of the Committee on Hearing and Equilibrium) were compared between the two groups at least 6 weeks and at 1 year or more. Measure of overclosure and hearing damage have been analyzed and compared between the groups. RESULTS: There were no statistically significant differences in demographic data between the two groups and no statistically significant difference in hearing outcome between the two groups. CO2 Laser with 0.4 piston showed slightly better results to close the air-bone gap postoperatively to ≤ 10 dB (84% as compared with the 80% of patients operated with microdrill technique). Patients operated with microdrill technique and 0.6 piston have less damage to hearing at 4 kHz. CONCLUSION: The use of CO2 laser seems associated with better postoperative air-bone gap closure. However, it carries more risk of hearing damage at 4 kHz at it is the case for the microdrill at 1 kHz. In general, postoperative hearing outcome using these two surgical techniques is comparable.

Vestibular Assessment with the vHIT and Skull Vibration-Induced Nystagmus Test in Patients with Nonprogressive Vestibular Schwannoma.

Background: Our primary objective was to monitor nonprogressive unilateral vestibular schwannomas (VSs) to assess the efficiency of rapid bedside examinations, such as the video head impulse test (vHIT) and skull vibration-induced nystagmus test (SVINT), in identifying vestibular damage. Methods: An observational study was conducted from March 2021 to March 2022 on all adult patients (>18 years old) with a confirmed nonprogressive VS (no active treatment). The SVINT (using a 100 Hz vibrator with two (SVINT2) or three (SVINT3) stimulation locations) and vHIT (for the six semicircular canals (SCCs)) were performed on all patients. The asymmetry of function between the vestibules was considered significant when the gain asymmetry was greater than 0.1. Rapid and repeatable assessment of VSs using two- and three-stimulation SVINT plus vHIT was performed to quantify intervestibular asymmetry. Results: SVINT3 and SVINT2 triggered VIN in 40% (24/60) and 65% (39/60) of patients, respectively. There was significant asymmetry in the vestibulo-ocular reflex (VOR), as shown by a VS-side gain < healthy-side gain in 58% (35/60) of the patients. Among the patients with significant gain asymmetry between the two vestibules according to the vHIT (VS-side gain < healthy-side gain), the proportion of patients expressing vestibular symptomatology was significantly greater than that of patients without any symptoms [67% (29/43) vs. 35% (6/17), respectively; p = 0.047]. Conclusions: The SVINT2 can be combined with the vHIT to form an interesting screening tool for revealing vestibular asymmetry. This work revealed the superiority of mastoid stimulation over vertex stimulation for SVINT in patients with unilateral vestibular loss.

Interpretability of operative and pathological reports for radiotherapy planning of sinonasal carcinomas: An ancillary study of the GORTEC 2016-02 SANTAL trial.

KEY POINTS: Interpretation of surgical mapping is essential for postoperative radiotherapy planning. Operative and pathological reports lack comprehensive information on margins quality and tissue block mapping. Standardizing reports is essential to reduce uncertainties, aiming for less morbid poRT.

Artificial Intelligence for Otosclerosis Detection: A Pilot Study.

The gold standard for otosclerosis diagnosis, aside from surgery, is high-resolution temporal bone computed tomography (TBCT), but it can be compromised by the small size of the lesions. Many artificial intelligence (AI) algorithms exist, but they are not yet used in daily practice for otosclerosis diagnosis. The aim was to evaluate the diagnostic performance of AI in the detection of otosclerosis. This case-control study included patients with otosclerosis surgically confirmed (2010-2020) and control patients who underwent TBCT and for whom radiological data were available. The AI algorithm interpreted the TBCT to assign a positive or negative diagnosis of otosclerosis. A double-blind reading was then performed by two trained radiologists, and the diagnostic performances were compared according to the best combination of sensitivity and specificity (Youden index). A total of 274 TBCT were included (174 TBCT cases and 100 TBCT controls). For the AI algorithm, the best combination of sensitivity and specificity was 79% and 98%, with an ideal diagnostic probability value estimated by the Youden index at 59%. For radiological analysis, sensitivity was 84% and specificity 98%. The diagnostic performance of the AI algorithm was comparable to that of a trained radiologist, although the sensitivity at the estimated ideal threshold was lower.

SimLife®: A New Dynamic Model for Head and Neck Surgical Oncology Simulation.

The SimLife® model consists in a human cadaver dynamized by pulsatile vascularization. The objective was to evaluate the face, contents, and constructs validity of the SimLife® model in head and neck surgical oncology simulation. Head and neck surgical oncology simulation sessions on SimLife® models were organized with lateral neck dissection and total laryngectomy. Face and contents validity were addressed by questionnaires. Constructs validity was assessed by objective structured assessment of technical skills (OSATS) score. High realism was demonstrated for consistency of tissues (7.1 ± 1.4), color of arteries and veins (7.3 ± 1.9, 8.5 ± 1.1, respectively), and vein consistency (8.5 ± 1.2). The mean OSATS score was 19.7 ± 5.4 for residents and 32.7 ± 1.9 for senior surgeon (P = .0022). SimLife® is a hyperrealistic model for head and neck surgical oncology simulation and it might become a core component of the surgical resident curriculum.