Interaction between the TBC1D24 TLDc domain and the KIBRA C2 domain is disrupted by two epilepsy-associated TBC1D24 missense variants.

Mutations of human TBC1D24 are associated with deafness, epilepsy, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, cognitive disability, and seizures). The causal relationships between TBC1D24 variants and the different clinical phenotypes are not understood. Our hypothesis is that phenotypic heterogeneity of missense mutations of TBC1D24 results, in part, from perturbed binding of different protein partners. To discover novel protein partners of TBC1D24, we conducted yeast two-hybrid (Y2H) screen using mouse full-length TBC1D24 as bait. Kidney and brain protein (KIBRA), a scaffold protein encoded by Wwc1, was identified as a partner of TBC1D24. KIBRA functions in the Hippo signaling pathway and is important for human cognition and memory. The TBC1D24 TLDc domain binds to KIBRA full-length and to its C2 domain, confirmed by Y2H assays. No interaction was detected with Y2H assays between the KIBRA C2 domain and TLDc domains of NCOA7, MEAK7, and OXR1. Moreover, the C2 domains of other WWC family proteins do not interact with the TLDc domain of TBC1D24, demonstrating specificity. The mRNAs encoding TBC1D24 and KIBRA proteins in mouse are coexpressed at least in a subset of hippocampal cells indicating availability to interact in vivo. As two epilepsy-associated recessive variants (Gly511Arg and Ala515Val) in the TLDc domain of human TBC1D24 disrupt the interaction with the human KIBRA C2 domain, this study reveals a pathogenic mechanism of TBC1D24-associated epilepsy, linking the TBC1D24 and KIBRA pathways. The interaction of TBC1D24-KIBRA is physiologically meaningful and necessary to reduce the risk of epilepsy.

Unbalanced bidirectional radial stiffness gradients within the organ of Corti promoted by TRIOBP.

Hearing depends on intricate morphologies and mechanical properties of diverse inner ear cell types. The individual contributions of various inner ear cell types into mechanical properties of the organ of Corti and the mechanisms of their integration are yet largely unknown. Using sub-100-nm spatial resolution atomic force microscopy (AFM), we mapped the Young's modulus (stiffness) of the apical surface of the different cells of the freshly dissected P5-P6 cochlear epithelium from wild-type and mice lacking either Trio and F-actin binding protein (TRIOBP) isoforms 4 and 5 or isoform 5 only. Variants of TRIOBP are associated with deafness in human and in Triobp mutant mouse models. Remarkably, nanoscale AFM mapping revealed unrecognized bidirectional radial stiffness gradients of different magnitudes and opposite orientations between rows of wild-type supporting cells and sensory hair cells. Moreover, the observed bidirectional radial stiffness gradients are unbalanced, with sensory cells being stiffer overall compared to neighboring supporting cells. Deafness-associated TRIOBP deficiencies significantly disrupted the magnitude and orientation of these bidirectional radial stiffness gradients. In addition, serial sectioning with focused ion beam and backscatter scanning electron microscopy shows that a TRIOBP deficiency results in ultrastructural changes of supporting cell apical phalangeal microfilaments and bundled cortical F-actin of hair cell cuticular plates, correlating with messenger RNA and protein expression levels and AFM stiffness measurements that exposed a softening of the apical surface of the sensory epithelium in mutant mice. Altogether, this additional complexity in the mechanical properties of the sensory epithelium is hypothesized to be an essential contributor to frequency selectivity and sensitivity of mammalian hearing.

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.

Noncoding Microdeletion in Mouse Hgf Disrupts Neural Crest Migration into the Stria Vascularis, Reduces the Endocochlear Potential, and Suggests the Neuropathology for Human Nonsyndromic Deafness DFNB39.

Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, cell dispersion, neuronal survival, and wound healing. In the inner ear, levels of HGF must be fine-tuned for normal hearing. In mice, a deficiency of HGF expression limited to the auditory system, or an overexpression of HGF, causes neurosensory deafness. In humans, noncoding variants in HGF are associated with nonsyndromic deafness DFNB39 However, the mechanism by which these noncoding variants causes deafness was unknown. Here, we reveal the cause of this deafness using a mouse model engineered with a noncoding intronic 10 bp deletion (del10) in Hgf Male and female mice homozygous for del10 exhibit moderate-to-profound hearing loss at 4 weeks of age as measured by tone burst auditory brainstem responses. The wild type (WT) 80 mV endocochlear potential was significantly reduced in homozygous del10 mice compared with WT littermates. In normal cochlea, endocochlear potentials are dependent on ion homeostasis mediated by the stria vascularis (SV). Previous studies showed that developmental incorporation of neural crest cells into the SV depends on signaling from HGF/MET. We show by immunohistochemistry that, in del10 homozygotes, neural crest cells fail to infiltrate the developing SV intermediate layer. Phenotyping and RNAseq analyses reveal no other significant abnormalities in other tissues. We conclude that, in the inner ear, the noncoding del10 mutation in Hgf leads to developmental defects of the SV and consequently dysfunctional ion homeostasis and a reduction in the EP, recapitulating human DFNB39 nonsyndromic deafness.SIGNIFICANCE STATEMENT Hereditary deafness is a common, clinically and genetically heterogeneous neurosensory disorder. Previously, we reported that human deafness DFNB39 is associated with noncoding variants in the 3'UTR of a short isoform of HGF encoding hepatocyte growth factor. For normal hearing, HGF levels must be fine-tuned as an excess or deficiency of HGF cause deafness in mouse. Using a Hgf mutant mouse with a small 10 bp deletion recapitulating a human DFNB39 noncoding variant, we demonstrate that neural crest cells fail to migrate into the stria vascularis intermediate layer, resulting in a significantly reduced endocochlear potential, the driving force for sound transduction by inner ear hair cells. HGF-associated deafness is a neurocristopathy but, unlike many other neurocristopathies, it is not syndromic.

Variants of human CLDN9 cause mild to profound hearing loss.

Hereditary deafness is clinically and genetically heterogeneous. We investigated deafness segregating as a recessive trait in two families. Audiological examinations revealed an asymmetric mild to profound hearing loss with childhood or adolescent onset. Exome sequencing of probands identified a homozygous c.475G>A;p.(Glu159Lys) variant of CLDN9 (NM_020982.4) in one family and a homozygous c.370_372dupATC;p.(Ile124dup) CLDN9 variant in an affected individual of a second family. Claudin 9 (CLDN9) is an integral membrane protein and constituent of epithelial bicellular tight junctions (TJs) that form semipermeable, paracellular barriers between inner ear perilymphatic and endolymphatic compartments. Computational structural modeling predicts that substitution of a lysine for glutamic acid p.(Glu159Lys) alters one of two cis-interactions between CLDN9 protomers. The p.(Ile124dup) variant is predicted to locally misfold CLDN9 and mCherry tagged p.(Ile124dup) CLDN9 is not targeted to the HeLa cell membrane. In situ hybridization shows that mouse Cldn9 expression increases from embryonic to postnatal development and persists in adult inner ears coinciding with prominent CLDN9 immunoreactivity in TJs of epithelia outlining the scala media. Together with the Cldn9 deaf mouse and a homozygous frameshift of CLDN9 previously associated with deafness, the two bi-allelic variants of CLDN9 described here point to CLDN9 as a bona fide human deafness gene.

The phenotypic landscape of a Tbc1d24 mutant mouse includes convulsive seizures resembling human early infantile epileptic encephalopathy.

Epilepsy, deafness, onychodystrophy, osteodystrophy and intellectual disability are associated with a spectrum of mutations of human TBC1D24. The mechanisms underlying TBC1D24-associated disorders and the functions of TBC1D24 are not well understood. Using CRISPR-Cas9 genome editing, we engineered a mouse with a premature translation stop codon equivalent to human S324Tfs*3, a recessive mutation of TBC1D24 associated with early infantile epileptic encephalopathy (EIEE). Homozygous S324Tfs*3 mice have normal auditory and vestibular functions but show an abrupt onset of spontaneous seizures at postnatal day 15 recapitulating human EIEE. The S324Tfs*3 variant is located in an alternatively spliced micro-exon encoding six perfectly conserved amino acids incorporated postnatally into TBC1D24 protein due to a micro-exon utilization switch. During embryonic and early postnatal development, S324Tfs*3 homozygotes produce predominantly the shorter wild-type TBC1D24 protein isoform that omits the micro-exon. S324Tfs*3 homozygotes show an abrupt onset of seizures at P15 that correlates with a developmental switch to utilization of the micro-exon. A mouse deficient for alternative splice factor SRRM3 impairs incorporation of the Tbc1d24 micro-exon. Wild-type Tbc1d24 mRNA is abundantly expressed in the hippocampus using RNAscope in situ hybridization. Immunogold electron microscopy using a TBC1D24-specific antibody revealed that TBC1D24 is associated with clathrin-coated vesicles and synapses of hippocampal neurons, suggesting a crucial role of TBC1D24 in vesicle trafficking important for neuronal signal transmission. This is the first characterization of a mouse model of human TBC1D24-associated EIEE that can now be used to screen for antiepileptogenic drugs ameliorating TBCID24 seizure disorders.

Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome.

KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal-hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano-Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss-of-function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants.

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.

[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.

Genomic analysis of childhood hearing loss in the Yoruba population of Nigeria.

Although variant alleles of hundreds of genes are associated with sensorineural deafness in children, the genes and alleles involved remain largely unknown in the Sub-Saharan regions of Africa. We ascertained 56 small families mainly of Yoruba ethno-lingual ancestry in or near Ibadan, Nigeria, that had at least one individual with nonsyndromic, severe-to-profound, prelingual-onset, bilateral hearing loss not attributed to nongenetic factors. We performed a combination of exome and Sanger sequencing analyses to evaluate both nuclear and mitochondrial genomes. No biallelic pathogenic variants were identified in GJB2, a common cause of deafness in many populations. Potential causative variants were identified in genes associated with nonsyndromic hearing loss (CIB2, COL11A1, ILDR1, MYO15A, TMPRSS3, and WFS1), nonsyndromic hearing loss or Usher syndrome (CDH23, MYO7A, PCDH15, and USH2A), and other syndromic forms of hearing loss (CHD7, OPA1, and SPTLC1). Several rare mitochondrial variants, including m.1555A>G, were detected in the gene MT-RNR1 but not in control Yoruba samples. Overall, 20 (33%) of 60 independent cases of hearing loss in this cohort of families were associated with likely causal variants in genes reported to underlie deafness in other populations. None of these likely causal variants were present in more than one family, most were detected as compound heterozygotes, and 77% had not been previously associated with hearing loss. These results indicate an unusually high level of genetic heterogeneity of hearing loss in Ibadan, Nigeria and point to challenges for molecular genetic screening, counseling, and early intervention in this population.

Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness.

Human pathogenic variants of TBC1D24 are associated with clinically heterogeneous phenotypes, including recessive nonsyndromic deafness DFNB86, dominant nonsyndromic deafness DFNA65, seizure accompanied by deafness, a variety of isolated seizure phenotypes and DOORS syndrome, characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability and seizures. Thirty-five pathogenic variants of human TBC1D24 associated with deafness have been reported. However, functions of TBC1D24 in the inner ear and the pathophysiology of TBC1D24-related deafness are unknown. In this study, a novel splice-site variant of TBC1D24 c.965 + 1G > A in compound heterozygosity with c.641G > A p.(Arg214His) was found to be segregating in a Pakistani family. Affected individuals exhibited, either a deafness-seizure syndrome or nonsyndromic deafness. In human temporal bones, TBC1D24 immunolocalized in hair cells and spiral ganglion neurons, whereas in mouse cochlea, Tbc1d24 expression was detected only in spiral ganglion neurons. We engineered mouse models of DFNB86 p.(Asp70Tyr) and DFNA65 p.(Ser178Leu) nonsyndromic deafness and syndromic forms of deafness p.(His336Glnfs*12) that have the same pathogenic variants that were reported for human TBC1D24. Unexpectedly, no auditory dysfunction was detected in Tbc1d24 mutant mice, although homozygosity for some of the variants caused seizures or lethality. We provide some insightful supporting data to explain the phenotypic differences resulting from equivalent pathogenic variants of mouse Tbc1d24 and human TBC1D24.

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.

Audio-visual speech perception in prelingually deafened Japanese children following sequential bilateral cochlear implantation.

OBJECTIVES: An effect of audio-visual (AV) integration is observed when the auditory and visual stimuli are incongruent (the McGurk effect). In general, AV integration is helpful especially in subjects wearing hearing aids or cochlear implants (CIs). However, the influence of AV integration on spoken word recognition in individuals with bilateral CIs (Bi-CIs) has not been fully investigated so far. In this study, we investigated AV integration in children with Bi-CIs. METHODS: The study sample included thirty one prelingually deafened children who underwent sequential bilateral cochlear implantation. We assessed their responses to congruent and incongruent AV stimuli with three CI-listening modes: only the 1st CI, only the 2nd CI, and Bi-CIs. The responses were assessed in the whole group as well as in two sub-groups: a proficient group (syllable intelligibility ≥80% with the 1st CI) and a non-proficient group (syllable intelligibility < 80% with the 1st CI). RESULTS: We found evidence of the McGurk effect in each of the three CI-listening modes. AV integration responses were observed in a subset of incongruent AV stimuli, and the patterns observed with the 1st CI and with Bi-CIs were similar. In the proficient group, the responses with the 2nd CI were not significantly different from those with the 1st CI whereas in the non-proficient group the responses with the 2nd CI were driven by visual stimuli more than those with the 1st CI. CONCLUSION: Our results suggested that prelingually deafened Japanese children who underwent sequential bilateral cochlear implantation exhibit AV integration abilities, both in monaural listening as well as in binaural listening. We also observed a higher influence of visual stimuli on speech perception with the 2nd CI in the non-proficient group, suggesting that Bi-CIs listeners with poorer speech recognition rely on visual information more compared to the proficient subjects to compensate for poorer auditory input. Nevertheless, poorer quality auditory input with the 2nd CI did not interfere with AV integration with binaural listening (with Bi-CIs). Overall, the findings of this study might be used to inform future research to identify the best strategies for speech training using AV integration effectively in prelingually deafened children.

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.

Audio-visual integration during speech perception in prelingually deafened Japanese children revealed by the McGurk effect.

OBJECTIVE: To investigate the McGurk effect in profoundly deafened Japanese children with cochlear implants (CI) and in normal-hearing children. This was done to identify how children with profound deafness using CI established audiovisual integration during the speech acquisition period. METHODS: Twenty-four prelingually deafened children with CI and 12 age-matched normal-hearing children participated in this study. Responses to audiovisual stimuli were compared between deafened and normal-hearing controls. Additionally, responses of the children with CI younger than 6 years of age were compared with those of the children with CI at least 6 years of age at the time of the test. RESULTS: Responses to stimuli combining auditory labials and visual non-labials were significantly different between deafened children with CI and normal-hearing controls (p<0.05). Additionally, the McGurk effect tended to be more induced in deafened children older than 6 years of age than in their younger counterparts. CONCLUSIONS: The McGurk effect was more significantly induced in prelingually deafened Japanese children with CI than in normal-hearing, age-matched Japanese children. Despite having good speech-perception skills and auditory input through their CI, from early childhood, deafened children may use more visual information in speech perception than normal-hearing children. As children using CI need to communicate based on insufficient speech signals coded by CI, additional activities of higher-order brain function may be necessary to compensate for the incomplete auditory input. This study provided information on the influence of deafness on the development of audiovisual integration related to speech, which could contribute to our further understanding of the strategies used in spoken language communication by prelingually deafened children.

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.

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.

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.