Complications including dysphagia following transoral non-robotic surgery for pharyngeal and laryngeal squamous cell carcinoma: A retrospective multicenter study.

OBJECTIVE: Transoral surgery is a minimally invasive treatment but may cause severe dysphagia at a lower rate than chemoradiotherapy. METHODS: We compared clinical information, surgical complications, and swallowing function in patients who underwent transoral nonrobotic surgery for laryngo-pharyngeal squamous cell carcinoma between 2015 and 2021 in a multicenter retrospective study. RESULTS: Six hundred and forty patients were included. Postoperative bleeding was observed in 20 cases (3.1%), and the risk factor was advanced T category. Postoperative laryngeal edema was observed in 13 cases (2.0%), and the risk factors were prior radiotherapy, advanced T stage, and concurrent neck dissection in patients with resected HPC. Dysphagia requiring nutritional support was observed in 29 cases (4.5%) at 1 month postoperatively and in 19 cases (3.0%) at 1 year postoperatively, respectively. The risk factors for long-term dysphagia were prior radiotherapy and advanced T category. Short-term risk factors for dysphagia were prior radiotherapy, advanced T category, and concurrent neck dissection, while long-term risk factors for dysphagia were only prior radiotherapy and advanced T category. CONCLUSION: Prior radiotherapy, advanced T stage, and concurrent neck dissection increased the incidence of postoperative laryngeal edema and short-term dysphagia, but concurrent neck dissection did not affect long-term dysphagia. Such features should be considered when considering the indication for transoral surgery and postoperative management.

Impact of cervical lymph node metastasis on transoral surgery for hypopharyngeal squamous cell carcinoma: A retrospective multicenter study.

BACKGROUND: Hypopharyngeal carcinoma is likely to spread to the lymph nodes, but there is no established strategy for management in transoral surgery. METHODS: We compared oncologic and functional outcomes in a retrospective multicenter study of patients who underwent transoral surgery for hypopharyngeal carcinoma between 2015 and 2021. RESULTS: Two-hundred and thirty-two patients were included. Comparing patients with and without adjuvant radiotherapy, 3-year regional recurrence-free survival (RRFS) was not significantly different in pN2b and pN2c, but was significantly worse in pN3b without adjuvant radiotherapy. In patients without neck dissection, the 3-year RRFS was 85.6%, 76.8%, and 70.0% for T1, T2, and T3 primary lesions, respectively, and was significantly worse for T2 or higher (p = 0.035). CONCLUSIONS: In the absence of extracapsular invasion, regional control did not deteriorate without adjuvant therapy. If prophylactic neck dissection is not performed, careful follow-up is necessary if the primary lesion is T2 or greater.

Local recurrence and metachronous multiple cancers after transoral nonrobotic surgery for pharyngeal and laryngeal squamous cell carcinoma: A retrospective multicenter study.

BACKGROUND: Late laryngopharyngeal cancers after transoral surgery include not only local recurrences but also metachronous multiple cancers. METHODS: We compared clinical information, surgical outcomes, and late laryngopharyngeal cancers in patients who underwent transoral nonrobotic surgery for laryngopharyngeal squamous cell carcinoma without lymph node metastases between 2015 and 2021 in a multicenter retrospective study. RESULTS: Four hundred and fifty-seven patients were included. Positive surgical margins were found in 121 patients (26.5%). Twenty-two patients (4.8%) received additional treatment. Positive horizontal margins of invasive carcinoma (p = 0.003) and positive horizontal margins of carcinoma in situ only (p = 0.032) were independent risk factors for local recurrence, and prior radiotherapy (p = 0.001) for metachronous multiple cancers. Local control was significantly worse without additional treatment (p = 0.049), but there was no significant difference in survival. CONCLUSIONS: Patients with positive margins had an increased frequency of local recurrence, but salvage therapy was effective.

Characteristics of oral squamous cell carcinoma focusing on cases unaffected by smoking and drinking: A multicenter retrospective study.

BACKGROUND: Some oral squamous cell carcinoma (OSCC) cases are unaffected by smoking or drinking. This study aimed to clarify distinctive groups among OSCC patients and examine the characteristics of multiple primary carcinomas (MPCs). METHODS: We analyzed data from 970 patients. The patients were divided into three groups: all individuals <45 years (<45 y), smokers/drinkers ≥45 years (SD ≥45 y), and non-smokers/non-drinkers ≥45 years (NSND ≥45 y). RESULTS: Tongue cancers were more common in the <45 y group than in the other groups (p < 0.001). The NSND ≥45 y group was significantly older and more likely to be female than the SD ≥45 y group (p < 0.001). MPCs in the upper aerodigestive tract were more common in men and smokers/drinkers, whereas women were at risk for multiple primary OSCCs (p = 0.022). CONCLUSIONS: The "young tongue" and "elderly female" subgroups and characteristics of MPCs suggest carcinogenic factors of OSCC other than smoking and drinking.

Effects of COVID-19 pandemic on hospital visit of head and neck cancer patients.

OBJECTIVE: Head and neck cancer (HNC) often causes respiratory symptoms, so diagnostic delays due to COVID-19 are anticipated. Especially, our institute is a designated medical institute for Class 1 specified infectious diseases, and most of the severe COVID-19 patients in this region were preferentially admitted or transferred. Hereby, we evaluated the trends of the numbers, primary sites and clinical stages of HNC patients before and after COVID-19 pandemic. METHODS: A retrospective analysis of all patients diagnosed and treated for HNC from 2015 to 2021 was performed. Especially, 309 cases between 2018 and 2021 were extracted in order to examine a direct impact of COVID-19 pandemic, which were dichotomized into "Pre" group in 2018-2019 and "COVID" group in 2020-2021. They were compared about the distribution of clinical stage, the period between onset of symptom and hospital visit. RESULTS: HNC patients decreased by 38% in 2020 and by 18% in 2021 compared to average number of patients from 2015 to 2019. Patients of stage 0 and 1 in "COVID" group significantly decreased compared to that in "Pre" group. Cases performed emergent tracheostomy in hypopharyngeal cancer and laryngeal cancer increased in "COVID" group (10.5% vs 1.3%). CONCLUSION: Patients with slight symptoms would hesitated to visit hospital after COVID-19, and only a few delays of HNC diagnosis could have increased tumor burden and caused narrowed airway, especially in advanced HPC and LC.

Clinicopathological Characteristics and Survival Outcomes of Patients with Buccal Squamous Cell Carcinoma: Results of a Multi-Institutional Study.

Background and Objectives: To investigate clinicopathological characteristics and survival outcomes of patients with buccal cancer in Japan. Materials and Methods: This study was conducted using a database of 1055 patients with oral cancers treated between 2010 and 2017 at 12 institutions in Japan. Ninety-two patients (8.7%) with primary buccal cancer were extracted and clinicopathological characteristics and survival outcomes were compared between patients with buccal cancers and patients with other oral cancers. Results: Ages were significantly higher in the patients with buccal cancer (73 years old vs. 69 years old). Buccal cancer had less advanced cT stage and cN stage than other oral cancers. Overall 5-year survival (OS) was 80.6%, and recurrence-free 5-year survival (RFS) of buccal cancers was 67.8%, and there were no significant differences in survival compared with other oral cancers in terms OS or RFS (5y-OS: 82.5%, 5y-RFS: 74.4%). However, patients with stage IV buccal cancer showed poorer prognosis in terms of OS and RFS compared with the same stage patients with other oral cancer. Advanced T stage was the only factor independently associated with both OS and RFS of patients with buccal cancer in this study. Conclusions: Postoperative radiotherapy or chemoradiotherapy should be considered to improve survival outcome of buccal cancer patients, especially for the patients with advanced primary site disease or a higher cancer stage.

Concurrent Chemoradiotherapy With Weekly Low-Dose Cisplatin for Japanese Patients With Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) with tri-weekly high-dose cisplatin (HDC) is considered the standard regimen. However, due to significant toxicity, various weekly low-dose schedules have been increasingly used. We investigated the tolerability and survival of patients with head and neck squamous cell carcinoma (HNSCC) who underwent CCRT with low-dose weekly cisplatin (LDC) for Japanese population. METHODS: A retrospective review was conducted among patients with HNSCC who were treated with CCRT/LDC in our institute. Ninety-five patients who met the criteria were enrolled in this study. We evaluated the cycle and cumulative cisplatin dose, completion rate of radiotherapy, adverse events, and survival outcome. RESULTS: The mean cycles and cumulative cisplatin dose were 4.7 cycles and 187 mg/m2. All patients completed planned dose of radiation without prolonged breaks. Leucopoenia was the most frequent dose-limiting factor and 44% patients developed grade 3 or 4 toxicity. The 2-year overall survival and recurrence-free survival were 93% and 74%, respectively. The significant differences of survival outcomes between the patients with total cisplatin dose (⩾200 mg and <200 mg) or among age distribution (35-55, 56-75, and ⩾76) were not observed. CONCLUSIONS: Concurrent chemoradiotherapy/LDC can be safely administered with acceptable toxicity and survival outcome even if the patients with higher age, lower eGFR, and so on.

Discordant Immune Marker Expression Between Preoperatively Biopsied and Matched Surgically Resected Specimens in Patients With Oral Squamous Cell Carcinoma.

Programmed cell death ligand 1 (PD-L1) expression and tumor-associated immune cell (TAIC) density can be the biomarkers of survival outcome and for predicting the efficacy of immune checkpoint inhibitors in oral squamous cell carcinoma (OSCC), but whether single biopsy accurately reflects the values of these parameters in resected specimens is unclear. To clarify this, we evaluated the concordance of immune marker expression (PD-L1, PD-1, CD3, CD4, CD8, and CD68) between 39 paired biopsied and surgically resected specimens obtained from patients with OSCC at Kobe City Medical Center General Hospital between July 2011 and January 2016. Immune marker expression was assessed using immunohistochemistry. PD-L1 expression was consistent between the biopsied and surgically resected specimens in only 76.9% of cases. TAIC density was significantly lower in biopsied than in surgically resected specimens. There was considerable discordance in immune marker expression between biopsied and surgically resected specimens. We should take into consideration that PD-L1 positivity and TAIC density would be underestimated by single small biopsies compared to the estimations by surgically resected specimens.

Lingual Lymph Node Metastases as a Prognostic Factor in Oral Squamous Cell Carcinoma-A Retrospective Multicenter Study.

Backgrounds and Objectives: The epidemiology and prognostic role of lingual lymph node (LLN) metastasis in patients with oral squamous cell carcinoma (OSCC) remain unclear. Here, we aimed to analyze the clinicopathological features, risk factors, and prognostic role of LLN metastasis in patients with OSCC. Materials and Methods: In total, 945 patients with OSCC were retrospectively analyzed. Clinicopathological features were compared between patients with and without LLN metastasis. The risk factors of LLN metastasis and its effects on survival outcomes were evaluated using multi-variate analysis. Results: LLN metastasis was noted in 67 patients (7.1%). Habitual alcohol consumption and clinical neck node metastasis were independent risk factors for LLN metastasis. LLN metastasis was an independent prognostic factor for disease-free and overall survival, although LLN dissection did not improve survival outcomes. Conclusion: LLN metastasis is an independent adverse prognostic factor. Further prospective studies are needed to fully assess the extent of LLN dissection required in OSCC patients.

Clinical significance of tumor-associated immune cells in patients with oral squamous cell carcinoma.

BACKGROUND: The expression of PD-L1 in tumor cells and infiltration of tumor-associated immune cells (TAICs) might reflect the tumor biology of head and neck cancer. We aimed to characterize their prognostic roles in oral squamous cell carcinomas (OSCCs). METHODS: We enrolled 103 OSCC patients who underwent definitive surgery. Immune expression levels of PD-L1, PD-1, CD3, CD4, CD8, and CD68 were assessed in surgically resected specimens. We evaluated the effects of immune marker expression and localization on survival outcomes. RESULTS: Multivariate analysis results adjusted by the pathological stage, resection margin, and extracapsular extension showed that a high number of PD-1+ TAICs and intratumoral CD68+ TAICs were independent positive and negative prognostic markers (hazard ratio: 0.20 and 4.15, respectively; P = .02 and .01, respectively). CONCLUSION: PD-1+ TAICs in the tumor microenvironment and CD68+ TAICs in the intratumoral area could act as novel biomarkers for predicting overall survival outcomes in OSCC patients.

Neck Dissection for Cervical Lymph Node Metastases from Remote Primary Malignancies.

Background and Objectives: Patients with cervical lymph node metastases from remote primary tumours have poor prognoses because of the advanced stage of their cancer. Owing to recent progress in the nonsurgical management of various cancer types, options for surgical treatment to reduce tumour volume are increasing, and may help improve survival rates. For example, neck dissection may be a good option as a definitive therapy for some patients with resectable cervical metastases. We assessed patients who underwent neck dissection with curative intent and discuss the effectiveness of this approach for cervical metastases from remote malignancies. Material and Methods: We retrospectively reviewed the data of 18 patients (10 males and 8 females in an age range of 30-79 years) who underwent neck dissections for neck lymph node metastases from a remote primary tumour between 2010 and 2019. Patient clinical characteristics, preoperative accuracy of positive node localisation using fluorodeoxyglucose positron emission tomography-computed tomography (FDG/PET-CT), and patient survival rates were estimated. Results: Primary sites included ten lungs, two mammary glands, one thymus, one thoracic oesophagus, one stomach, one uterine cervix, one ovary, and one testis per patient. There were 19 levels with FDG/PET-CT positive nodes in 17 out of 18 patients. Conversely, there were 28 pathological positive levels out of 50 dissected levels. The sensitivity, specificity, positive and negative predictive values, and accuracy of FDG-PET/CT in predicting positive nodes were 69%, 88%, 95%, 47%, and 74%, respectively. The three-year overall survival (OS) rate for all patients was 70%. The three-year OS rate of the group with zero or one pathological positive nodes was 81%, which was significantly higher than that of the group with more than two positive nodes (51%) (p = 0.03). Conclusions: Neck dissection for cervical lymph node metastases from remote primary malignancies may improve prognoses, especially considering anticancer agents and radiotherapy advancements.

Real-time imaging of head and neck squamous cell carcinomas using confocal micro-endoscopy and applicable dye: A preliminary study.

OBJECTIVES: Confocal laser endomicroscopy (CLE) is a technology that enables microscopic visualization of lesions in real-time (optical biopsy) and has been successfully applied for clinical use in gastroenterology. Recently, it was also introduced for head and neck squamous cell carcinoma (HNSCC) diagnostics. We previously designed a self-made CLE, which can provide bichrome images, with topical contrast agents that are safe for use in patients. Herein, we report findings of a pilot study using our self-made CLE to image pairs of normal and cancerous tissues. This study aimed to characterize the features of HNSCC compared with normal mucosa and to establish a methodology of in vivo real-time optical biopsy of HNSCCs. METHODS: HNSCC tissues were acquired from 10 patients who underwent surgical resection. Dissected specimens were first evaluated for their auto-fluorescence spectral profiles with 473 nm laser excitation and further optical observation. While obtaining the image, auto-fluorescence spectrum and intensity of the reflectance fluorescent signals were measured in real-time by a spectrometer. Subsequently, acriflavine was applied to the specimen to fluorescently label the nuclei and observe the difference between normal and cancerous tissues with 473 nm laser excitation. Finally, double staining with acriflavine and edible Food Red No.106 was performed to observe both nuclei and the cytoplasm of normal and cancerous tissues at 473 nm and 561 nm laser excitation. RESULTS: Lower signals were detected from auto-fluorescence images of cancer tissues than normal tissues with 473 nm laser excitation. After acriflavine application, there was a clear difference between cancer and normal mucosa in the uniformity of nuclear size and shape. In normal mucosa, cells were arranged in an orderly manner, with each cell resembling a frog's egg. By contrast, in cancer tissues, the cell density was higher, and the cellular arrangement was less orderly. Using both acriflavine and Food Red No.106, images became more vivid, but more complicated because red dye staining of the cytoplasm emerged as fluorescence at different wavelengths. CONCLUSIONS: Real-time in vivo imaging using the newly developed CLE and conditions may be used to distinguish cancer tissue from normal mucosa without invasive biopsy.

Bone Marrow Stromal Cells Accelerate Hearing Recovery via Regeneration or Maintenance of Cochlear Fibrocytes in Mouse Spiral Ligaments.

Mammalian cochleae have limited capacity for regeneration, which is one of the major difficulties in the treatment of sensorineural hearing loss. In the current study, we examined the potential of bone marrow-derived stromal cells (BMSCs) for functional restoration of mouse cochleae through regeneration or maintenance of cochlear fibrocytes in the spiral ligament (SL). We used a mouse model of degeneration of cochlear fibrocytes in the SL using local application of 3-nitropropionic acid (3-NP), in which disruption of the gap junction network in the SL resulted in the reduction of the endocochlear potential (EP). Mouse BMSCs were infused into the posterior semicircular canal 7 days after 3-NP application. Transplanted BMSCs were frequently observed in the cochlear fluid space 4 weeks after transplantation, although a few transplants had migrated into the cochlear tissues including the SL. BMSC-treated cochleae exhibited higher cell densities in the SL and greater EP levels than the control ones. Immunohistochemistry further demonstrated the restoration of functional proteins in the SL. Significant recovery in thresholds of auditory brainstem responses following BMSC transplantation was found only at 40 kHz in a mild degeneration model. Our cumulative findings indicated that BMSCs accelerated regeneration or maintenance of fibrocytes in damaged SLs, leading to partial functional restoration of the mouse cochleae. Anat Rec, 303:478-486, 2020. © 2019 American Association for Anatomy.

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration.

Cell transplantation therapy has long been investigated as a therapeutic intervention for neurodegenerative disorders, including spinal cord injury, Parkinson's disease, and amyotrophic lateral sclerosis. Indeed, patients have high hopes for a cell-based therapy. However, there are numerous practical challenges for clinical translation. One major problem is that only very low numbers of donor cells survive and achieve functional integration into the host. Glial scar tissue in chronic neurodegenerative disorders strongly inhibits regeneration, and this inhibition must be overcome to accomplish successful cell transplantation. Intraneural cell transplantation is considered to be the best way to deliver cells to the host. We questioned this view with experiments in vivo on a rat glial scar model of the auditory system. Our results show that intraneural transplantation to the auditory nerve, preceded by chondroitinase ABC (ChABC)-treatment, is ineffective. There is no functional recovery, and almost all transplanted cells die within a few weeks. However, when donor cells are placed on the surface of a ChABC-treated gliotic auditory nerve, they autonomously migrate into it and recapitulate glia- and neuron-guided cell migration modes to repair the auditory pathway and recover auditory function. Surface transplantation may thus pave the way for improved functional integration of donor cells into host tissue, providing a less invasive approach to rescue clinically important neural tracts.

Therapeutic potential of a gamma-secretase inhibitor for hearing restoration in a guinea pig model with noise-induced hearing loss.

BACKGROUND: Notch signaling plays a crucial role in the fate determination of cochlear progenitor cells, hair cells, and supporting cells in the developing cochlea. Recent studies have demonstrated the temporal activation of Notch signaling in damaged mature cochleae, and have demonstrated the induction of new hair cells by pharmacologically inhibiting Notch signaling. The present study aimed to illustrate the feasibility of pharmacologically inhibiting Notch signaling by using a gamma-secretase inhibitor for treating sensorineural hearing loss. RESULTS: The effect of the sustained local delivery of MDL28170, a gamma-secretase inhibitor, on hearing and hair cell induction was tested in a guinea pig model with noise-induced hearing loss. MDL28170 was directly delivered into the cochlear fluids via a micro-osmotic pump. Drug application was initiated 7 days after noise exposure. Measurements of auditory brainstem responses revealed better hearing in the MDL28170-treated animals than in the vehicle controls. Histological analysis demonstrated a higher number of outer hair cells in the MDL28170-treated cochleae than the vehicle-treated cochleae. CONCLUSION: These findings strongly suggest that local sustained delivery of a gamma-secretase inhibitor into the cochlea could be a novel strategy for treating acute hearing loss that is refractory to conventional treatment.

In vivo imaging of mouse cochlea by optical coherence tomography.

HYPOTHESIS: Cochlear pathology can be evaluated in living animals using optical coherence tomography (OCT). BACKGROUND: The current imaging methods available for the detailed analysis of cochlear pathology in a clinical setting provide only limited information. Thus, a cochlear imaging modality with high definition is needed for improving the diagnosis of cochlear pathology. OCT has been used in other fields for obtaining high-resolution subsurface images, and its use could potentially be extended to the analysis of cochlear pathogenesis. METHODS: Slc26a4(-/-) mice, which generate endolymphatic hydrops, and their littermates were used in this study. Auditory function was monitored by the auditory brainstem responses (ABR). After the mice were placed under general anesthesia, OCT images of the cochlea were captured. The cochlea was subsequently dissected out and histologically evaluated. Three or 7 days later, the wild-type mice cochleae were visualized again. RESULTS: In ABR assessments, Slc26a4(-/-) mice showed severe hearing loss, while no significant hearing loss was found in Slc26a4(+/-) or Slc26a4(+/+) mice. OCT demonstrated normal morphology in the cochlea of both Slc26a4(+/-) and Slc26a4(+/+) mice, including the location of Reissner's membrane. Meanwhile, in Slc26a4(-/-) mice, obvious dislocation of Reissner's membrane was observed, indicating severe endolymphatic hydrops. These findings in the OCT images were consistent with the histologic results for the cochlear morphology, as observed with hematoxylin and eosin staining. Three or 7 days later, wild-type cochleae were successfully visualized using OCT, and no otitis media or labyrinthitis was observed. CONCLUSION: OCT can be applied in the detection of endolymphatic hydrops in living mice, indicating the potential of OCT for cochlear imaging analyses for clinical use in the near future.

[Parotidectomy for parotid gland tumor using a retrograde approach from the peripheral branches of the facial nerve].

There are two techniques for excising a parotid gland tumor. The first technique is the anterograde approach, and the second is the retrograde approach. Although the anterograde approach has generally been adopted, the retrograde approach may be useful depending on the identification and dissection of the facial nerve and the localization of the tumor. We reviewed 35 patients who were surgically treated with a parotidectomy using the retrograde approach between 2002 and 2012 at Tenri Hospital. We also reviewed the clinical records for evidence of temporary or definitive injury to the facial nerve. In cases where the identification of the main nerve trunk was expected to be difficult, the parotidectomy was performed using the retrograde approach guided by the mandibular branch. In cases where a tumor was located in the marginal region of the parotid gland, the retrograde approach was guided by the mandibular branch or the zygomatic branch. Of the 35 patients, 17 underwent the retrograde approach guided by the mandibular branch and 18 underwent this approach guided by the zygomatic branch. The mean surgical time and amount of bleeding using the retrograde approach were 70.7 minutes and 33.9 g, respectively. Two of the 35 patients in the retrograde group exhibited a temporary facial deficit.

Four-dimensional computed tomographic angiography of an arteriovenous fistula in the neck.

Arteriovenous fistula (AVF), a type of vascular anomaly, is a relatively uncommon disease characterized by abnormal connections between the arterial and venous systems. Recently, remarkable advances in four-dimensional computed tomographic angiography (4D-CTA) have enabled detailed analysis of the hemodynamic features of vascular anomalies, which cannot be achieved by conventional imaging modalities. We report a case of AVF in a 59-year-old female presenting as a right neck mass. Using reconstructed animations from various viewing angles, 4D-CTA could clearly visualize not only a mass but the feeding artery and draining vein from the mass. 4D-CTA was useful for the diagnosis of AVF and to determine the surgical strategy preoperatively.

Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea.

Mechanosensory hair cells and supporting cells develop from common precursors located in the prosensory domain of the developing cochlear epithelium. Prosensory cell differentiation into hair cells or supporting cells proceeds from the basal to the apical region of the cochleae, but the mechanism and significance of this basal-to-apical wave of differentiation remain to be elucidated. Here, we investigated the role of Hedgehog (Hh) signaling in cochlear development by examining the effects of up- and downregulation of Hh signaling in vivo. The Hh effector smoothened (Smo) was genetically activated or inactivated specifically in the developing cochlear epithelium after prosensory domain formation. Cochleae expressing a constitutively active allele of Smo showed only one row of inner hair cells with no outer hair cells (OHCs); abnormal undifferentiated prosensory-like cells were present in the lateral compartment instead of OHCs and their adjacent supporting cells. This suggests that Hh signaling inhibits prosensory cell differentiation into hair cells or supporting cells and maintains their properties as prosensory cells. Conversely, in cochlea with the Smo conditional knockout (Smo CKO), hair cell differentiation was preferentially accelerated in the apical region. Smo CKO mice survived after birth, and exhibited hair cell disarrangement in the apical region, a decrease in hair cell number, and hearing impairment. These results indicate that Hh signaling delays hair cell and supporting cell differentiation in the apical region, which forms the basal-to-apical wave of development, and is required for the proper differentiation, arrangement and survival of hair cells and for hearing ability.

Prostaglandin E receptor subtype EP4 agonist serves better to protect cochlea than prostaglandin E1.

OBJECTIVE: The present study aimed to examine whether an E-prostanoid receptor 4 (EP4) agonist has superior protective effects to those of prostaglandin E1 (PGE1) in a guinea pig model of noise trauma. METHODS: Drugs were locally applied on the round window membrane of guinea pig cochleae, followed by exposure of the test animals to intense noise. Protective effects mediated by an EP4 agonist were compared with those mediated by PGE1. Auditory function was monitored by measurements of the auditory brainstem response (ABR), and histological damage was assessed by immunohistochemical analysis of cochlear specimens. RESULTS: Animals treated with an EP4 agonist exhibited significantly better hearing recovery than those pretreated with PGE1. Histologically, the numbers of remaining outer hair cells in cochleae treated with the EP4 agonist were significantly higher than in those treated with PGE1. CONCLUSION: The selective activation of EP4 has a stronger protective effect on cochleae against noise trauma than does the broad activation of EPs by PGE1.