Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing.

TRIOBP remodels the cytoskeleton by forming unusually dense F-actin bundles and is implicated in human cancer, schizophrenia, and deafness. Mutations ablating human and mouse TRIOBP-4 and TRIOBP-5 isoforms are associated with profound deafness, as inner ear mechanosensory hair cells degenerate after stereocilia rootlets fail to develop. However, the mechanisms regulating formation of stereocilia rootlets by each TRIOBP isoform remain unknown. Using 3 new Triobp mouse models, we report that TRIOBP-5 is essential for thickening bundles of F-actin in rootlets, establishing their mature dimensions and for stiffening supporting cells of the auditory sensory epithelium. The coiled-coil domains of this isoform are required for reinforcement and maintenance of stereocilia rootlets. A loss of TRIOBP-5 in mouse results in dysmorphic rootlets that are abnormally thin in the cuticular plate but have increased widths and lengths within stereocilia cores, and causes progressive deafness recapitulating the human phenotype. Our study extends the current understanding of TRIOBP isoform-specific functions necessary for life-long hearing, with implications for insight into other TRIOBPopathies.

Regenerative treatment for tympanic membrane perforation using gelatin sponge with basic fibroblast growth factor.

OBJECTIVE: The objective of this study was to evaluate safety and efficacy of regenerative treatment using gelatin sponge with basic fibroblast growth factor (bFGF) in patients with tympanic membrane perforation (TMP). METHODS: The current study was a prospective, multicenter, open-label, single-arm, and exploratory clinical trial to evaluate the safety and efficacy of the TM regeneration procedure (TMRP). Myringotomy was used to mechanically disrupt the edge of the TMP, and a gelatin sponge immersed in bFGF was then placed over the perforation. Fibrin glue was dripped over the sponge as a sealant. TMP closure was examined 4 weeks later and, if insufficient, TMRP was repeated a maximum of three more times. TMP closure and hearing improvement 12 weeks after the final TMRP as well as safety were evaluated. RESULTS: Of the 11 patients with TMP who participated in this study, one who fulfilled the exclusion criteria and did not undergo TMRP and one with cholesteatoma were excluded from the efficacy analysis. TMP closure and hearing improvement 12 weeks after the final TMRP were achieved in eight out of nine patients (88.9%). Mean bone conduction threshold significantly improved 12 weeks after the TMRP compared with baseline (35.7±20.3 vs 29.4±21.0dB, P=0.015). Six out of ten patients receiving TMRP experienced temporary adverse events: appendicitis (serious, severe), otorrhea (mild), otitis media (mild), and sudden hearing loss (mild). However, none were related to the protocol treatment. CONCLUSION: TMP closure and hearing improvement were frequently confirmed following the TMRPs which were safely performed. These favorable outcomes were accompanied with significant improvement of the bone conduction threshold. These promising outcomes would encourage a large-scaled, randomized and pivotal clinical trial in the future. This trial is registered at http://www.umin.ac.jp/ctr/index.htm (identifier: UMIN000006585).

Detection of subclinical recurrence or second primary cancer using (18) F-FDG PET/CT in patients treated curatively for head and neck squamous cell carcinoma.

BACKGROUND: The efficacy of posttreatment surveillance (18) F-fluorodeoxyglucose positron emission tomography ((18) F-FDG PET)/CT was evaluated in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: The subjects were 158 patients with HNSCC who underwent PET/CT after definitive treatment. PET/CT detection of subclinical recurrence or a second primary cancer and the effect of timing of PET/CT scans on survival were analyzed. RESULTS: Recurrence or a second primary cancer occurred in 70 patients, and 67% of these cases were detected by PET/CT. Detection rates were 17%, 9%, 5%, and 5% in the first, second, third, and fourth scans at 4, 9, 15, and 21 months, respectively. In multivariate analysis, patients who underwent early first scans had significantly better disease-specific (hazard ratio [HR] = 0.37; p = .031) and overall (HR = 0.45; p = .040) survival compared with those who underwent late first scans. CONCLUSION: Earlier detection of subclinical lesions by surveillance PET/CT within 4 months after treatment may improve survival in patients with HNSCC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E511-E518, 2016.

A case of angiosarcoma arising from internal jugular vein.

Primary angiosarcoma is a rare disease with a poor prognosis. It most commonly arises in the head and neck region; localization in the deep soft tissue of the neck is extremely rare. We herein present a case of angiosarcoma derived from the right internal jugular vein. A 79-year-old man presented with a 1-month history of a growing right neck mass. Computed tomography, magnetic resonance imaging, positron emission tomography-computed tomography, and fine-needle aspiration cytology revealed a malignant tumor of unknown origin. Right neck dissection was performed for both diagnosis and therapy. Immunostaining of the resected tumor cells revealed positivity for CD31, CD34, factor VIII-related antigen, and D2-40, which allowed for a definitive diagnosis of angiosarcoma. Postoperative radiotherapy (66Gy) was performed on the right neck, including the surgical bed and upper mediastinum. The patient was followed up for 10 months with no recurrence. Only six cases of angiosarcoma arising in the deep soft tissue of the neck have been reported in the English-language literature. The present report is the first to describe angiosarcoma arising from the internal jugular vein.

Prognostic value of pretreatment 18F-fluorodeoxyglucose positron emission tomography/CT volume-based parameters in patients with oropharyngeal squamous cell carcinoma with known p16 and p53 status.

BACKGROUND: The purpose of this study was to determine whether pretreatment 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET/CT) volume-based parameters, such as metabolic tumor volume and total lesion glycolysis, add more prognostic information in patients with oropharyngeal squamous cell carcinoma (SCC). METHODS: The subjects were 47 patients with oropharyngeal SCC who underwent 18F-FDG PET/CT before any treatment and followed by definitive therapy. PET parameters (metabolic tumor volume and total lesion glycolysis) and tumor p16/p53 status were evaluated retrospectively. Univariate and multivariate analyses were performed for disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). RESULTS: All volume-based PET parameters were found to be significant prognostic factors for DFS, DSS, and OS in univariate analysis. In multivariate analysis, only metabolic tumor volume for total tumor lesions (cutoff 65) retained an independent association with DFS, DSS, and OS. CONCLUSION: Metabolic tumor volume for total tumor lesions may be a predictive marker for survival outcomes in patients with oropharyngeal SCC with known p16/p53 status.

Prognostic impact of p16 and p53 expression in oropharyngeal squamous cell carcinomas.

BACKGROUNDS: A p16 protein is known to be overexpressed in human papillomavirus-positive head and neck squamous cell carcinoma specimens. p53 is a tumor suppressor protein detectable by immunohistochemistry in carcinogen-associated head and neck squamous cell carcinoma as a result of gene mutations. The purpose of this study is to investigate the prognostic impact of p16 and p53 expression in oropharyngeal squamous cell carcinomas. METHODS: We retrospectively examined the relationship between prognosis, and p16 and p53 expression levels of oropharyngeal squamous cell carcinoma specimens in 53 patients using immunohistochemistry. RESULTS: Overall, 55% of patients were p16 positive and 45% p16 negative, while 28% were p53 positive and 72% p53 negative. The p16 status showed an inverse relationship with the p53 status. A survival analysis by p16 status, p53 status, Union for International Cancer Control stage and main treatment modality demonstrated that only p16 status was related to better prognosis in terms of overall survival and disease-specific survival (3-year overall survival, 87 vs. 62%, P = 0.02; 3-year disease-specific survival, 90 vs. 62%, P = 0.02). To evaluate the practical prognostic factors in oropharyngeal squamous cell carcinoma patients, we classified patients as either p16-positive or p53-negative oropharyngeal squamous cell carcinomas, representing human papillomavirus-related oropharyngeal squamous cell carcinoma with wild-type p53 or the remaining patients with p16-negative or p53-positive OPSCCs, respectively. The former group showed survival advantages in terms of overall survival and disease-specific survival by log-tank test compared with the latter group (3-year overall survival, 96 vs. 58%, P = 0.005; 3-year disease-specific survival, 96 vs. 63%, P = 0.02). CONCLUSIONS: A group of patients who were p16 positive/p53 negative had better prognoses in terms of overall survival and disease-specific survival than that who were p16-positive alone.

Intra-arterial administration of antibiotics for refractory skull base osteomyelitis.

We report two cases of elderly diabetic men with skull base osteomyelitis (SBO) originating from malignant external otitis (MEO). In both, a devastating infection and neural paralysis deteriorated after conventional therapy, including long-term intravenous administration of culture-directed antibiotics with strict control of blood sugar levels and surgical debridement of infectious granulation tissue. Since poor perfusion of antibiotics in the lesion may be associated with serious nature of MEO/SBO, we administered antibiotics intra-arterially via a retrograde catheter with the tip set at the proximal point of the external carotid artery to increase the tissue drug concentration in the maxillary artery (MA) and ascending pharyngeal artery (APA) supply areas, in which intense inflammation was observed. This intra-arterial administration of antibiotics (IA therapy) followed by long-term intravenous and oral antibiotic treatments eliminated their infection and no recurrence was observed in 2 years follow-up period. Interestingly, CT images of angiography via the catheter demonstrated stronger enhancement in the MA supply area compared to the APA supply area and IA therapy was more effective in the former. These results suggest that IA therapy, which might achieve high antibiotic concentration at the site of infection, is effective in patients with MEO/SBO refractory to conventional treatments.

Clinical features of rapidly progressive bilateral sensorineural hearing loss.

CONCLUSION: Rapidly progressive bilateral sensorineural hearing loss (SNHL) often develops as a symptom of intracranial diseases or systemic vasculitis. For early diagnosis and treatment of these potentially fatal diseases, a history of hearing deterioration within 2 months and associated symptoms may be important. OBJECTIVES: To reveal clinical features and causative diseases for rapidly progressive bilateral SNHL. METHODS: The inclusion criterion was patients with bilateral progressive SNHL, who had experienced difficulty in daily conversation within 4 days to 1 year after the onset of hearing loss awareness. This study was a retrospective evaluation of 12 patients with rapidly progressive bilateral SNHL who visited our hospital between 2007 and 2011. RESULTS: The causative disease for hearing loss was identified in 11 of 12 patients; intracranial lesions including nonbacterial meningitis, meningeal metastasis of lymphoma, and superficial siderosis in 4 patients, systemic vasculitis in 2, auditory neuropathy spectrum disorder in 1, and an isolated inner ear disorder in 4. Relatively rapid hearing deterioration within 2 months showed a significant association in six patients with an intracranial lesion or systemic vasculitis. Moreover, all these six patients complained of dizziness and/or non-cochleovestibular symptoms such as fever, headache, and/or altered mental state in addition to hearing loss.

Predictive value of middle ear aeration before second-stage operation in staged tympanoplasty with soft-wall reconstruction.

CONCLUSION: The extent of middle ear aeration before second-stage canal wall-down (CWD) tympanoplasty was correlated with postoperative middle ear stability. OBJECTIVE: To evaluate middle ear aeration before second-stage CWD tympanoplasty as a predictor of postoperative re-aeration potential and external auditory canal (EAC) stability in staged CWD tympanoplasty with soft-wall reconstruction (SWR). METHODS: Middle ear aeration was evaluated before and at 1 year after the second-stage operation in patients who underwent staged CWD tympanoplasty with SWR for middle ear cholesteatoma. Based on the computed tomography (CT) findings, middle ear aeration was graded as A when the mastoid and tympanic cavities were aerated, B when only the tympanic cavity was aerated, and C in cases with no aeration in the tympanic cavity. We also examined postoperative EAC stability. RESULTS: Forty-one ears were included. In all, 17 of 19 ears (89.5%) with grade A aeration preoperatively maintained grade A aeration postoperatively, while 5 of 18 ears (27.8%) with grade B aeration had grade A aeration, and no ear with grade C aeration had recovered grade A aeration. All ears with grade A aeration preoperatively maintained smooth EACs. EAC retraction requiring additional treatment occurred in five ears with grade B aeration and all ears with grade C aeration.

[A case of intraorbital solitary fibrous tumor resected successfully with preoperative arterial embolization].

The solitary fibrous tumor (SFT) is a rare spindle cell neoplasm derived from mesenchymal cells. It sometimes recurs clinically, and is categorized as an 'intermediate malignancy' tumor under the WHO (World Health Organization) classification of soft tissue tumors. Several studies have reported on intraorbital SFTs, but none of them has pointed out the utility of preoperative arterial embolization in the case of an intraorbital SFT. A 75-year-old man, who had received a dacryocystectomy for a benign tumor in the right lacrimal sac 30 years previously, visited our hospital complaining of lower eyelid swelling and lachrymation that had persisted for a year. CT and MRI revealed an intraorbital lesion, and the open biopsy specimen showed dense growth of spindle cells, which turned out to be an SFT by immunohistochemistry based on the findings. After preoperative embolization of the infraorbital artery, we removed the tumor with a skin incision on the lower rim of the orbit with little bleeding. The surgical specimen revealed that the tumor was close to a lacrimal canaliculus, which suggested the tumor originated from the lacrimal apparatus considering the patient's past history. He was followed up for three months without recurrences.