The impact of multidisciplinary approaches on the outcomes of olfactory neuroblastoma treated with postoperative radiotherapy.

BACKGROUND: We investigated the outcomes of postoperative radiation therapy for olfactory neuroblastoma (ONB) and our cross-departmental collaboration to enhance the effectiveness of cancer treatment. METHODS: We retrospectively evaluated 22 patients with ONB who underwent postoperative radiotherapy after tumor resection. En bloc resection was performed; pathology specimens were prepared in coronal sections; and irradiation fields were determined after discussion with radiation oncologists, head and neck surgeons, and pathologists. RESULTS: The overall survival and local control rates were 95.5% and 100%, respectively, at a median 37-month follow-up. The 3- and 5-year disease-free survival (DFS) rates were 64.4% and 56.3%, respectively. Of the 22 patients, 9 (8 Kadish C and 1 Kadish B) had disease recurrence. Of the nine patients, five had positive margins and two had closed margins; cervical lymph node recurrence occurred in six, and distant metastasis with or without cervical lymph node recurrence occurred in three. DFS analysis of risk factors showed no statistically significant differences, but positive margins were a significant recurrence factor in multivariate analysis. CONCLUSIONS: The local control rate of ONB treated with postoperative radiation therapy was 100%. This may be attributed to cross-departmental cooperation between head and neck surgeons, pathologists, and radiation oncologists, which resulted in accurate matching of CT images for treatment planning with the location of the tumor and positive margins. Longer follow-up periods are required to evaluate the effectiveness of our strategy.

Safety of cricotracheostomy with skin and tracheal membrane flaps for severe COVID-19 patients.

OBJECTIVE: Airway surgery is performed for COVID-19 patients who require long-term tracheal intubation and mechanical ventilation. Tracheostomy sometimes causes postoperative complications represented by bleeding at a relatively high rate in COVID-19 patients. As an alternative surgical procedure to tracheostomy, cricotracheostomy may reduce these complications, but few studies have examined its safety. METHODS: Data were retrospectively collected for sixteen COVID-19 patients (11 underwent tracheostomy, 5 underwent modified cricotracheostomy). In addition to patients' backgrounds and blood test data, the frequency of complications and additional care required for postoperative complications were collected. Statistical analysis was conducted by the univariate analysis of Fischer analysis and Mann-Whitney U test. RESULTS: Five cases experienced postoperative bleeding, four cases experienced peristomal infection, and one case experienced subcutaneous emphysema in the tracheostomy patients. These complications were not observed in the cricotracheostomy patients. The number of additional cares for postoperative complications was significantly lower in cricotracheostomy than in tracheostomy patients (p < 0.05). CONCLUSIONS: Modified cricotracheostomy could be a safe procedure in airway surgery for patients with COVID-19 from the point of fewer postoperative complications and additional care. It might be necessary to select the cricotracheostomy depending on patients' background to reduce postoperative complications.

Augmented Reality-Assisted Transcanal Endoscopic Ear Surgery for Middle Ear Cholesteatoma.

Background: The indications for transcanal endoscopic ear surgery (TEES) for middle ear cholesteatoma have expanded for cases involving mastoid extension. However, TEES is not indicated for all cases with mastoid extension. In addition, predicting the extent of external auditory canal (EAC) removal needed for cholesteatoma resection is not always easy. The purpose of this study was to use augmented reality (AR) to project the lesion onto an intraoperative endoscopic image to predict EAC removal requirements and select an appropriate surgical approach. Methods: In this study, patients showing mastoid extension were operated on using a navigation system with an AR function (Stryker). Results: The results showed that some cases with lesions slightly extending into the antrum required extensive resection of the EAC, while cases with lesions extending throughout the antrum required smaller resection of the EAC, indicating TEES. Conclusions: By predicting the extent of the needed EAC removal, it is possible to determine whether TEES (a retrograde approach) or canal wall-up mastoidectomy, which preserves as much of the EAC as possible, should be performed. We believe that our findings will contribute to the success of middle ear surgeries and the implementation of robotic surgery in the future.

Effect of basic fibroblast growth factor with collagen/gelatin fixture in a rabbit model of nasal septum perforation.

Introduction: The treatment of nasal septum perforation solely by surgical intervention presents significant challenges. This study evaluated the effect of basic fibroblast growth factor (bFGF) in combination with collagen/gelatin on wound healing of nasal septum perforation in a rabbit animal model. Methods: A nasal septum perforation rabbit model was created. bFGF was added to a collagen/gelatin fixture and placed adjacent to the perforation, which is a complete defect. The rabbits were divided into three groups: the sham group that underwent the surgical procedure only, bFGF (-) group that received collagen/gelatin fixture without bFGF, and bFGF(+) group that received collagen/gelatin fixture with bFGF. The dimensions of the perforations were measured after 4 weeks, and the septum was subjected to histological examination. Results: All perforations remained open in the sham group (closure rate: 20.4%-83.1%). The closure rates of the bFGF(-) and bFGF(+) groups were 49.4%-68.8% and 72.7%-100%, respectively. No significant difference was noted in the closure rates between the sham and bFGF(-) groups; however, significant differences were observed between the sham and bFGF(+) groups, and the bFGF(-) and bFGF(+) groups (p < 0.05), indicating that bFGF promoted perforation closure. Conclusions: The study demonstrated that bFGF with collagen/gelatin carrier promoted wound healing in a rabbit model of nasal septum perforation.

Loss of Pax3 causes reduction of melanocytes in the developing mouse cochlea.

Cochlear melanocytes are intermediate cells in the stria vascularis that generate endocochlear potentials required for auditory function. Human PAX3 mutations cause Waardenburg syndrome and abnormalities of skin and retinal melanocytes, manifested as congenital hearing loss (~ 70%) and hypopigmentation of skin, hair and eyes. However, the underlying mechanism of hearing loss remains unclear. Cochlear melanocytes in the stria vascularis originated from Pax3-traced melanoblasts and Plp1-traced Schwann cell precursors, both of which derive from neural crest cells. Here, using a Pax3-Cre knock-in mouse that allows lineage tracing of Pax3-expressing cells and disruption of Pax3, we found that Pax3 deficiency causes foreshortened cochlea, malformed vestibular apparatus, and neural tube defects. Lineage tracing and in situ hybridization show that Pax3+ derivatives contribute to S100+, Kir4.1+ and Dct+ melanocytes (intermediate cells) in the developing stria vascularis, all of which are significantly diminished in Pax3 mutant animals. Taken together, these results suggest that Pax3 is required for the development of neural crest cell-derived cochlear melanocytes, whose absence may contribute to congenital hearing loss of Waardenburg syndrome in humans.

Preoperative prediction of sinonasal papilloma by artificial intelligence using nasal video endoscopy: a retrospective study.

Sinonasal inverted papilloma (IP) is at risk of recurrence and malignancy, and early diagnosis using nasal endoscopy is essential. We thus developed a diagnostic system using artificial intelligence (AI) to identify nasal sinus papilloma. Endoscopic surgery videos of 53 patients undergoing endoscopic sinus surgery were edited to train and evaluate deep neural network models and then a diagnostic system was developed. The correct diagnosis rate based on visual examination by otolaryngologists was also evaluated using the same videos and compared with that of the AI diagnostic system patients. Main outcomes evaluated included the percentage of correct diagnoses compared to AI diagnosis and the correct diagnosis rate for otolaryngologists based on years of practice experience. The diagnostic system had an area under the curve of 0.874, accuracy of 0.843, false positive rate of 0.124, and false negative rate of 0.191. The average correct diagnosis rate among otolaryngologists was 69.4%, indicating that the AI was highly accurate. Evidently, although the number of cases was small, a highly accurate diagnostic system was created. Future studies with larger samples to improve the accuracy of the system and expand the range of diseases that can be detected for more clinical applications are warranted.

Pax3 deficiency diminishes melanocytes in the developing mouse cochlea.

Cochlear melanocytes are intermediate cells in the stria vascularis that generate endocochlear potentials required for auditory function. Human PAX3 mutations cause Waardenburg syndrome and abnormalities of melanocytes, manifested as congenital hearing loss and hypopigmentation of skin, hair and eyes. However, the underlying mechanism of hearing loss remains unclear. During development, cochlear melanocytes in the stria vascularis are dually derived from Pax3-Cre+ melanoblasts migrating from neuroepithelial cells including neural crest cells and Plp1+ Schwann cell precursors originated from also neural crest cells, differentiating in a basal-apical manner. Here, using a Pax3-Cre mouse line, we found that Pax3 deficiency causes foreshortened cochlea, malformed vestibular apparatus, and neural tube defects. Lineage tracing and in situ hybridization show that Pax3-Cre derivatives contribute to S100+ , Kir4.1+ and Dct+ melanocytes (intermediate cells) in the developing stria vascularis, all significantly diminished in Pax3 mutant animals. Taken together, these results suggest that Pax3 is required for the development of neural crest cell-derived cochlear melanocytes, whose absence may contribute to congenital hearing loss of Waardenburg syndrome in human.

Time Analysis of Recidivism in Acquired Cholesteatoma Using the Kaplan-Meier Method.

OBJECTIVE: To analyze the time trends of recidivism of acquired cholesteatoma using the Kaplan-Meier method. STUDY DESIGN: We conducted a retrospective, observational study of 256 patients having their first cholesteatoma surgery. The cumulative recidivism-free rate was calculated using Kaplan-Meier survival analysis related to the follow-up period, pathophysiology, the extent of the disease, and recidivism pathologies. RESULTS: Pars flacida cholesteatoma with tympanic cavity progression had a high likelihood of recurrence disease. Pars tensa cholesteatoma led to more recurrence of the disease than the residual disease. In both pars flacida and pars tensa cholesteatoma, the incidence of disease recurrence increased even 3 years after surgery. On the contrary, the incidence of residual disease peaked within 3 years after surgery, and thereafter, the incidence of residual disease tended to be small. In particular, pars flacida cholesteatoma extending into the mastoid cavity or tympanic cavity tended to recur up to 5 years postoperatively. CONCLUSIONS: We calculated the cumulative recidivism-free rates of 256 patients with cholesteatoma using Kaplan-Meier survival analysis. These results can lead to better estimates of the length of the follow-up period. LEVEL OF EVIDENCE: Level IV evidence from case-control studies.

Analysis of the potential of human cultured nasal epithelial cell sheets to differentiate into airway epithelium.

Understanding the expected efficacy and safety of a new regenerative therapy requires analysis of the fate of the transplanted cell graft. We have shown that transplantation of autologous cultured nasal epithelial cell sheets onto the middle ear mucosa can improve middle ear aeration and hearing. However, it remains unknown whether cultured nasal epithelial cell sheets have the potential to gain mucociliary function in the environment of the middle ear because sampling cell sheets after transplantation is challenging. The present study re-cultured cultured nasal epithelial cell sheets in different culture media and evaluated whether the sheets have the potential to differentiate into airway epithelium. Before re-cultivation, cultured nasal epithelial cell sheets fabricated in keratinocyte culture medium (KCM) contained no FOXJ1-positive and acetyl-α-tubulin-positive multiciliated cells or MUC5AC-positive mucus cells. Interestingly, multiciliated cells and mucus cells were observed when the cultured nasal epithelial cell sheets were re-cultured in conditions that promote differentiation of airway epithelium. However, multiciliated cells, mucus cells and CK1-positive keratinized cells were not observed when cultured nasal epithelial cell sheets were re-cultured in conditions that promote epithelial keratinization. These findings support the suggestion that cultured nasal epithelial cell sheets have the ability to differentiate and gain mucociliary function in response to an appropriate environment (possibly including the environment found in the middle ear) but are unable to develop into an epithelial type that differs from its origins.

Radiological and audiological predictors of stapes destruction in adherent pars tensa.

PURPOSE: Progressive adherent pars tensa occasionally induces ossicular erosion. Specifically, stapes discontinuity adversely affects postoperative hearing. However, this irretrievable sequela is challenging to prove preoperatively, partly because perimatrix inflammation on the pars tensa can obscure the visibility of the ossicles or the partial volume effect of computed tomography (CT) imaging can hamper detailed ossicular visualization. Therefore, there is no consensus regarding the ideal timing for switching from a wait-and-see approach to a surgical one. Herein, we aimed to explore the potential predictors of stapes superstructure destruction in adherent pars tensa. METHODS: This retrospective cohort study enrolled consecutive patients who underwent primary tympanoplasty for adherent pars tensa categorized as grade IV on Sadé's grading scale between April 2016 and September 2021. The impact of features on otoscopy and CT and air-bone gap (ABG) on stapes superstructure destruction was assessed using uni- and multivariable logistic regression analyses. RESULTS: Sixty-four ears were included. Multivariate analysis revealed the presence of debris on the adherent pars tensa (odds ratio [OR] [95% confidence interval {CI}]): 4.799 [1.063-21.668], p = 0.0415), presence of soft-tissue density occupying the oval window (OR [95% CI]: 13.876 [3.084-62.437], p = 0.0006), and a ≥ 20-dB preoperative ABG at 3 kHz (OR [95% CI]: 7.595 [1.596-36.132], p = 0.0108) as independent predictors for stapes superstructure destruction. CONCLUSION: High preoperative awareness of the possibility of destruction of the stapes superstructure would enable the surgeon to make a timely decision to provide surgical intervention before progression to severe stapes destruction, thereby maintaining long-term satisfactory hearing.

Epigenetic Regulation as a New Therapeutic Target for Middle Ear Cholesteatoma.

HYPOTHESIS: To evaluate the effectiveness of the menin-MLL inhibitor, MI503, as a conservative treatment of middle ear cholesteatoma (cholesteatoma) in a mouse model and to confirm its safety profile regarding auditory function in vivo. BACKGROUND: Cholesteatoma is a mass formed by the keratinizing squamous epithelium in the tympanic cavity and/or mastoid and subepithelial connective tissue and by the progressive accumulation of keratin debris with/without a surrounding inflammatory reaction. Although the main treatment is surgical therapy, the techniques to prevent recurrence remain a critical area of research. Recently, the use of MI503 in experiments resulted in the inhibition of the growth of cholesteatoma in vivo under histone modification. METHODS: After cholesteatoma was induced in ICR mice (n = 7) by keratinocyte growth factor expression vector transfection, MI503 (50 µM) or phosphate-buffered saline was topically injected for 14 days. The effects of MI503 against cholesteatoma were analyzed by micro-computed tomography images. For the in vivo ototoxicity study, a single intratympanic injection of MI503 (50 or 500 µM) or phosphate-buffered saline (n = 4 each) was done in the ICR mice. An auditory brainstem response was performed at days 0, 1, and 14. For morphological analysis, immunostaining for Phalloidin/F-actin and Myo7a was performed. RESULTS: MI503 reduced keratinocyte growth factor-induced cholesteatoma in vivo (4 of 4 [100%]). No difference was found in the mean variation of the average of the auditory brainstem response thresholds between the three groups in the in vivo ototoxicity study, thus confirming its safety profile regarding auditory function. MI503 does not demonstrate any deleterious effects on murine hair cells when assessed by immunostaining. CONCLUSION: These findings demonstrate an encouraging safety profile for the use of menin-MLL inhibitor for the conservative treatment of cholesteatoma.

Imaging analysis of dural exposure in cholesteatomas with a skull base defect.

PURPOSE: Dural exposure during cholesteatoma surgery can pose a risk of cerebrospinal fluid leakage or residual disease. Therefore, delicate handling of the area surrounding the bone defect in the cranial fossa is required. However, in small-sized defects, preoperative prediction of dural exposure can be challenging. This study aimed to evaluate the diagnostic value of computed tomography (CT) for preoperative prediction of cholesteatoma-related dural exposure in bone discontinuities in the skull base. METHODS: We evaluated serial high-resolution CT images showing bone density discontinuities in the middle cranial fossa (MCF) requiring mastoidectomy for cholesteatoma. The CT and intraoperative findings were analyzed retrospectively. We evaluated the length between the superior margins of the bone density discontinuities using coronal CT planes. Receiver operating characteristic (ROC) curves were constructed to determine the optimal cut-off values. RESULTS: We extracted data from 107 bone density discontinuities, among which 54 (50.5%) showed dural exposure intraoperatively. Discontinuities with dural exposure (n = 54) had significantly greater lengths than did those without (n = 53) (p < 0.001, Wilcoxon rank-sum test). The area under the curve was 0.9780 according to the ROC analysis, and the optimal cut-off value was determined to be 2.99 mm (sensitivity 92.59%; specificity 94.34%). CONCLUSION: A bone density discontinuity length of > 2.99 mm in the MCF on coronal CT plane is a reliable diagnostic marker for cholesteatoma-related dural exposure. Thus, preoperative high-resolution CT analysis can inform optimal surgical preparation and planning before manipulating the area surrounding the osteolytic lesion in the MCF.

Radiological and audiological prediction for hearing outcome in cholesteatoma recidivism surgery.

PURPOSE: In cholesteatoma recidivism, achieving satisfactory hearing outcome after revision surgery remains challenging. The presence of concomitant recidivism pathology or related anatomical abnormalities can impact revision reconstruction of the sound transmission system. The current study aimed to identify prognostic factors affecting hearing outcomes after surgery for cholesteatoma recidivism. METHODS: This retrospective cohort study included consecutive patients whose ears required initial surgery for recidivism between January 2016 and December 2021. Patients followed up for < 6 months and those not indicated for ossiculoplasty were excluded. The impact of preoperative otoscopic findings, computed tomography (CT) features, and hearing levels on the prediction of satisfactory hearing (postoperative air-bone gap [ABG] ≤ 20 dB) was evaluated using univariate and multivariate logistic regression analyses. RESULTS: Overall, 102 patients were included, with a mean follow-up of 24.8 months. Multivariate logistic regression analysis revealed the following independent predictive factors for satisfactory hearing: presence of aeration in the tympanic cavity (odds ratio [OR] [95% confidence interval {CI}]: 13.287 [1.113-158.604], p = 0.0409), absence of soft-tissue density occupying the oval window (OR [95% CI]: 13.445 [3.178-56.887], p = 0.0040), and ≤ 22.5 dB preoperative ABG in four-frequency average (OR [95% CI]: 9.339 [2.026-43.050], p = 0.0042). CONCLUSIONS: For cholesteatoma recidivism, reliable preoperative prediction based on CT and ABG would facilitate decision-making regarding the probability of efficient revision ossiculoplasty or appropriate preoperative counseling, including early hearing rehabilitation using hearing aids or implementation of simultaneous implantable hearing equipment during surgery for recidivism.

Endoscopic-assisted total maxillectomy with precise surgical margins.

In traditional open maxillectomy, identifying the posterior margin is difficult because of its deep location and bleeding from the pterygoid venous plexus. Here, we present our endoscope-assisted total en bloc maxillectomy technique and discuss its merits and demerits compared to previously reported methods. We developed an endoscope-assisted total en bloc maxillectomy procedure. We reviewed a series of total maxillectomies performed with and without endoscopic assistance to verify the advantages of endoscopic assistance over conventional total maxillectomy. We analyzed (1) the precision using the distance of the remaining pterygoid process, (2) the operation time, and (3) blood loss. The length of the remnant pterygoid process was significantly shorter in the endoscopic assistance group. The operation time and blood loss were not significantly different between the two groups. Endoscopic assistance makes total maxillectomy more precise without requiring additional time and is a reasonable option for total maxillectomies.

Mucosal Epithelial Preservation of Free Nasal Grafts Depending on the Recipient Site.

OBJECTIVES/HYPOTHESIS: Reconstruction of mucosal defects using free mucosal grafts has become a common procedure during endoscopic sinus surgery. Epithelialization of mucosal grafts affects postoperative complications and outcomes, which could be influenced by different recipient tissue. However, morphological changes occurring in the grafts transplanted over different tissues remain unexplored. STUDY DESIGN: An animal study. METHODS: Free mucoperichondrial grafts were prepared from the nasal septum of rabbits; the cartilage group had reconstruction on the nasal septal cartilage, and the perichondrium group had reconstruction on the contralateral perichondrium. The nasal septum was removed after 1 and 4 weeks of reconstruction, and the graft was histologically evaluated. RESULTS: After 1 week of reconstruction, the mucosal epithelium of grafts in the cartilage group disappeared, whereas the columnar epithelium of grafts was preserved in the perichondrium group. After 4 weeks of reconstruction, the mucosal defect site was covered with mucosal epithelium in both groups. However, while squamous epithelium was mostly observed in the cartilage group, columnar epithelium containing the healthy ciliary and goblet cells was observed in the perichondrium group. Statistically significant differences were detected in the parameters of epithelial morphology between the two groups, which were higher in the perichondrium group. CONCLUSIONS: In the reconstruction of mucosal defects using free mucosal grafts, difference in recipient tissue affects the graft epithelial morphology. LEVEL OF EVIDENCE: NA Laryngoscope, 132:2301-2306, 2022.

Endoscopic tympanoplasty type I using interlay technique.

BACKGROUND: Tympanoplasty using the interlay technique has rarely been reported in transcanal endoscopic ear surgery, unlike the underlay technique. This is because many surgeons find it challenging to detach the epithelial layer of the tympanic membrane using only one hand. However, the epithelial layer can be easily detached from the inferior part of the tympanic membrane. Another key point is to actively improve anteroinferior visibility even if the overhang is slight because most perforations and postoperative reperforations are found in the anteroinferior quadrant of the tympanic membrane. We report the application of the interlay technique in endoscopic tympanoplasty type I for tympanic perforations. METHODS: We retrospectively reviewed the medical records of 51 patients who had undergone tympanoplasty using the interlay technique without ossiculoplasty between 2017 and 2020. We then compared the data with those of patients who underwent microscopic surgery (MS) using the underlay technique between 1998 and 2009 (n = 104). No other technique was used in each group during this period. Repair of tympanic membrane perforation and hearing outcomes were assessed for > 1 year postoperatively. RESULTS: The perforation sites were limited to the anterior, posterior, and anterior-posterior quadrants in 23, 1, and 27 ears, respectively. Perforations were closed in 50 of the 51 ears (98.0%), and the postoperative hearing was good (average air-bone [A-B] gap was 6.8 ± 5.8 dB). The surgical success rate for the repair of tympanic membrane perforation was not significantly different from the MS group (93.3%, P = 0.15). The average postoperative average A-B gap in the group that underwent the interlay technique was significantly different from that in the MS group (10.1 ± 6.6 dB, P < 0.01). CONCLUSION: The interlay technique should be considered as one of the treatment methods in endoscopic surgery for tympanic perforations. Further study of the postoperative outcomes of this procedure should be conducted to establish the optimal surgical procedure for tympanic perforations. TRIAL REGISTRATION: This study was retrospectively approved by the Institutional Review Board of the Jikei University, Tokyo, Japan (approval number: 32-205 10286). Video abstract.

Preoperative prediction by artificial intelligence for mastoid extension in pars flaccida cholesteatoma using temporal bone high-resolution computed tomography: A retrospective study.

Cholesteatoma is a progressive middle ear disease that can only be treated surgically but with a high recurrence rate. Depending on the extent of the disease, a surgical approach, such as microsurgery with a retroarticular incision or transcanal endoscopic surgery, is performed. However, the current examination cannot sufficiently predict the progression before surgery, and changes in approach may be made during the surgery. Large amounts of data are typically required to train deep neural network models; however, the prevalence of cholesteatomas is low (1-in-25, 000). Developing analysis methods that improve the accuracy with such a small number of samples is an important issue for medical artificial intelligence (AI) research. This paper presents an AI-based system to automatically detect mastoid extensions using CT. This retrospective study included 164 patients (80 with mastoid extension and 84 without mastoid extension) who underwent surgery. This study adopted a relatively lightweight neural network model called MobileNetV2 to learn and predict the CT images of 164 patients. The training was performed with eight divided groups for cross-validation and was performed 24 times with each of the eight groups to verify accuracy fluctuations caused by randomly augmented learning. An evaluation was performed by each of the 24 single-trained models, and 24 sets of ensemble predictions with 23 models for 100% original size images and 400% zoomed images. Fifteen otolaryngologists diagnosed the images and compared the results. The average accuracy of predicting 400% zoomed images using ensemble prediction model was 81.14% (sensitivity = 84.95%, specificity = 77.33%). The average accuracy of the otolaryngologists was 73.41% (sensitivity, 83.17%; specificity, 64.13%), which was not affected by their clinical experiences. Noteworthily, despite the small number of cases, we were able to create a highly accurate AI. These findings represent an important first step in the automatic diagnosis of the cholesteatoma extension.

Keratinocyte Growth Factor Stimulates Growth of p75+ Neural Crest Lineage Cells During Middle Ear Cholesteatoma Formation in Mice.

During development, cranial neural crest (NC) cells display a striking transition from collective to single-cell migration and undergo a mesenchymal-to-epithelial transformation to form a part of the middle ear epithelial cells (MEECs). While MEECs derived from NC are known to control homeostasis of the epithelium and repair from otitis media, paracrine action of keratinocyte growth factor (KGF) promotes the growth of MEECs and induces middle ear cholesteatoma (cholesteatoma). The animal model of cholesteatoma was previously established by transfecting a human KGF-expression vector. Herein, KGF-inducing cholesteatoma was studied in Wnt1-Cre/Floxed-enhanced green fluorescent protein (EGFP) mice that conditionally express EGFP in the NC lineages. The cytokeratin 14-positive NC lineage expanded into the middle ear and formed cholesteatoma. Moreover, the green fluorescent protein-positive NC lineages comprising the cholesteatoma tissue expressed p75, an NC marker, with high proliferative activity. Similarly, a large number of p75-positive cells were observed in human cholesteatoma tissues. Injections of the immunotoxin murine p75-saporin induced depletion of the p75-positive NC lineages, resulting in the reduction of cholesteatoma in vivo. The p75 knockout in the MEECs had low proliferative activity with or without KGF protein in vitro. Controlling p75 signaling may reduce the proliferation of NC lineages and may represent a new therapeutic target for cholesteatoma.

MRI tractography reveals the human olfactory nerve map connecting the olfactory epithelium and olfactory bulb.

The olfactory nerve map describes the topographical neural connections between the olfactory epithelium in the nasal cavity and the olfactory bulb. Previous studies have constructed the olfactory nerve maps of rodents using histological analyses or transgenic animal models to investigate olfactory nerve pathways. However, the human olfactory nerve map remains unknown. Here, we demonstrate that high-field magnetic resonance imaging and diffusion tensor tractography can be used to visualize olfactory sensory neurons while maintaining their three-dimensional structures. This technique allowed us to evaluate the olfactory sensory neuron projections from the nasal cavities to the olfactory bulbs and visualize the olfactory nerve maps of humans, marmosets and mice. The olfactory nerve maps revealed that the dorsal-ventral and medial-lateral axes were preserved between the olfactory epithelium and olfactory bulb in all three species. Further development of this technique might allow it to be used clinically to facilitate the diagnosis of olfactory dysfunction.