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• Proposed photoacoustic imaging enabled depth profiling of sensitizer and vessels. • Pharmacokinetics in PDT with indocyanine green-lactosome was revealed. • Vascular shutdown effect was shown in PDT with indocyanine green-lactosome. Indocyanine green lactosome (ICG-lactosome) is an attractive new-generation agent for photodynamic therapy (PDT) that is characterized by a near-infrared excitation wavelength and high stability in the bloodstream. Fluorescence imaging has been used to examine its pharmacokinetics in vivo , but no depth-resolved information can be obtained with this method. In this study, we applied photoacoustic (PA) imaging to visualize the depth distribution of ICG-lactosome in a mouse subcutaneous tumor model. With this method, the depth distribution of blood vessels can also be visualized, enabling detection of vascular shutdown effects due to PDT. We performed PA imaging of both the distributions of ICG-lactosome and blood vessels in a tumor before and after PDT, and we found that PA signals originating from ICG-lactosome were greatly increased at 18 h after drug injection but rapidly decreased after PDT. These results indicate efficient accumulation of ICG-lactosome and rapid photobleaching due to the PDT reaction in the tumor, respectively. After PDT, PA amplitudes of hemoglobin were significantly decreased, being attributable to vascular shutdown effects. These results show the usefulness of PA imaging for monitoring not only photosensitizer accumulation and bleaching but also vascular responses in PDT with ICG-lactosome. This method can be applied to the diagnosis of many types of PDT processes. [ABSTRACT FROM AUTHOR]

Transoral surgery is a less invasive treatment that is becoming a major strategy in the treatment of laryngo-pharyngeal cancer. It is a minimally invasive approach that has no skin incision and limits the extent of tissue dissection, disruption of speech and swallowing muscles, blood loss, damage to major neurovascular structures, and injury to normal tissue. Transoral approaches to the laryngo-pharynx, except for early glottis cancer, had been limited traditionally to tumors that can be observed directly and manipulated with standard instrumentation and lighting. Since the 1990s, transoral laser microsurgery (TLM) has been used as an organ preservation strategy with good oncological control and good functional results, although it has not been widely used because of its technical difficulty. Recently, transoral robotic surgery (TORS) is becoming popular as a new treatment modality for laryngo-pharyngeal cancer, and surgical robots are used widely in the world since United States FDA approval in 2009. In spite of the global spread of TORS, it has not been approved by the Japan FDA, which has led to the development of other low-cost transoral surgical techniques in Japan. Transoral videolaryngoscopic surgery (TOVS) was developed as a new transoral surgery system for laryngo-pharyngeal lesions to address the problems of TLM. In TOVS, a rigid endoscope is used to visualize the surgical field instead of a microscope and the advantages of TOVS include the wide operative field and working space achieved using the distending laryngoscope and videolaryngoscope. Also, with the spread of narrow band imaging (NBI), endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), which are widely used for superficial cancers in the gastrointestinal tract, have been applied for the superficial laryngo-pharyngeal cancer. Both EMR and ESD are performed mainly by gastroenterologists with a sharp dissector and magnifying endoscopy (ME)-NBI with minimal surgical margin. Endoscopic laryngo-pharyngeal surgery (ELPS) was developed to treat laryngo-pharyngeal superficial cancer by modifying the ESD procedure. The concept of ELPS is the same as that of ESD, however, the resection procedure is performed by a head and neck surgeon with both hands using a ME-NBI and rigid curved laryngo-pharyngoscope. These four procedures are low cost with similar oncological and functional outcomes to TORS. TORS may be less expensive than chemoradiotherapy, but the number of hospitals that can afford da Vinci surgical systems is limited. Even in the era of robotic surgery, these four procedures will be good options for laryngo-pharyngeal cancer. [ABSTRACT FROM AUTHOR]

Pyriform sinus fistula is a rare branchial anomaly that manifests as recurrent cervical infection resulting from contamination of the fistula internal orifice in the pyriform sinus. Although open neck surgery to resect the fistula has been recommended as a definitive treatment, identifying the fistula within the scar is difficult and occasionally results in recurrence. Here, we describe a novel transoral surgical technique for pyriform sinus fistula using transoral videolaryngoscopic surgery (TOVS) as a definitive treatment to resect and close the fistula without skin incision. Needle cautery enables fine excision and delicate dissection of the fistula tract. TOVS is a safe, easy, and reliable treatment and is a suitable first line treatment. [ABSTRACT FROM AUTHOR]

Abstract: Nestin is an intermediate filament expressed in immature cells in the CNS including neural stem/progenitor cells, reactive astrocytes and immature neurons in lesser amounts after injury. Nestin expression in the nucleus ambiguus following vagal nerve injury was studied using nestin-EGFP transgenic rats. We confirmed that EGFP immunoreactivity was evident at 6h to 8 days in ipsilateral nucleus ambiguus after nerve transection. Properties of these cells were examined immunohistochemically. These EGFP-immunoreactive cells were immunoreactive for Tuj1 and Hu, and exhibited ChAT activity. However, no immunoreactivity for GFAP or CNPase was observed. In normal development, the level of KCC2 expression is known to increase with maturation of neurons. In our study, decreased KCC2 expression was observed in nestin-EGFP-positive cells within the nucleus ambiguus on the lesioned side compared with the contralateral side. These EGFP-immunoreactive cells were immunonegative for BrdU. This is the first study to demonstrate the expression of a neural stem/progenitor cell-enriched marker, Nestin, in the nucleus ambiguus after vagal nerve injury. The present findings suggest that mature motoneurons are an origin of these Nestin-positive cells, which are induced after injury. Mature neurons in the nucleus ambiguus may thus have the potential to juvenilize after vagal/recurrent laryngeal nerve injury. [Copyright &y& Elsevier]

Abstract: Oxidative stress, including reactive oxygen species and other free radicals, is thought to play an important role in neuronal cell death, including noise-induced hearing loss. 1-{3-[2-(1-Benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate (T-817MA), a novel neurotrophic agent, protects against oxidative stress-induced neurotoxicity. This study examines the effects of T-817MA in noise-induced ototoxicity in the cochlea. Guinea pigs received treatment with T-817MA-enhanced water (0.2, 0.7mg/ml) or untreated water (control) beginning 10 days prior to noise exposure and continuing through this study. All subjects were exposed to 4-kHz octave-band noise at 120-dB SPL for 5h. Auditory thresholds were assessed by sound-evoked auditory brainstem response at 4, 8, and 16kHz, prior to and 10 days following noise exposure. Hair cell damage was analyzed by quantitative histology. T-817MA significantly reduced threshold deficits and hair cell death. These results suggest T-817MA reduces noise-induced hearing loss and cochlear damage, suggesting functional and morphological protection. [Copyright &y& Elsevier]

Abstract: We have previously shown that neuroprotective effects of an adenoviral glial cell line-derived neurotrophic factor (GDNF) gene transfer on the lesioned adult rat motoneurons in the nucleus ambiguus. In the present study, we examined neuroprotective effects of adenoviral gene transfer of brain-derived neurotrophic factor (BDNF) or/and GDNF to motoneurons in nucleus ambiguus using an adult rat vagal nerve avulsion model. The animals avulsed and inoculated with adenoviral vectors encoding BDNF (AxCAmBDNFME) or/and GDNF (AxCAhGDNF) showed immunolabeling for BDNF or/and GDNF in the nucleus ambiguus on the treated side, respectively, and expression of virus-induced BDNF or/and GDNF mRNA transcripts in the brainstem tissue that contained the nucleus ambiguus of the treated side. The treatment with AxCAhGDNF or AxCAmBDNFME significantly prevented the loss of vagal motoneurons in comparison to the control; the protective effect of AxCAmBDNFME was greater than that of AxCAhGDNF. The combined treatment with AxCAmBDNFME and AxCAhGDNF acted synergistically and significantly larger number of vagal motoneurons was preserved as compared to either AxCAmBDNFME treatment or AxCAhGDNF treatment. The treatment with AxCAmBDNFME or/and AxCAhGDNF after avulsion also suppressed the activity of nitric oxide synthase in lesioned motoneurons in the nucleus ambiguus. These results indicate that adenovirus-mediated BDNF and GDNF gene transfer may prevent the degeneration of motoneurons in humans after either vagal nerve injury or recurrent laryngeal nerve injury. [Copyright &y& Elsevier]

We examined neuroprotective effects of an adenoviral vector encoding glial cell line-derived neurotrophic factor (AxCAhGDNF) on the lesioned adult rat motoneurons in the nucleus ambiguus. After vagal nerve avulsion, AxCAhGDNF, AxCALacZ (adenovirus encoding β-galactosidase gene) or PBS was inoculated into the jugular foramen. Four days after the avulsion and treatment with AxCALacZ, the animals expressed β-galactosidase activity in the lesioned motoneurons in the nucleus ambiguus. The animals avulsed and inoculated with AxCAhGDNF showed immunolabeling for GDNF in the nucleus ambiguus on the treated side and expression of virus-induced human GDNF mRNA transcripts in the brainstem tissue that contained the nucleus ambiguus of the treated side. The treatment with AxCAhGDNF after avulsion prevented the loss of lesioned motoneurons in the nucleus ambiguus, ameliorated the choline acetyltransferase immunoreactivity, and also suppressed the activity of nitric oxide synthase in these neurons. These results indicate that adenovirus-mediated GDNF gene transfer may prevent the degeneration of motoneurons in humans after either vagal nerve injury or recurrent laryngeal nerve injury. [Copyright &y& Elsevier]

Abstract: Laryngeal carcinoma presenting as a cervical abscess is rare, so that its diagnosis is not easy. We described a case of laryngeal squamous cell carcinoma presenting as a prelaryngeal large abscess. Markedly swollen false vocal fold inhibited fiberscopic examination of the vocal folds. CT scan indicated destruction of the thyroid cartilage. Although biopsies from the abscess did not reveal malignancy, laryngeal squamous cell carcinoma was confirmed by laryngomicrosurgery with laryngeal vestibulectomy. The patient was treated by total laryngectomy with neck dissection followed by radiotherapy. The abscess was thought to be formed not by direct extension and necrosis of the tumor, but by the leakage of air and mucus through the fistula on the destroyed thyroid cartilage. Precise observation and biopsy under directscopic vestibulectomy played an important role in diagnosis of malignancy inherent in severe inflammatory tissues. [Copyright &y& Elsevier]

Transoral surgery preserves good swallowing function in most cases, however, postoperative dysphagia sometimes leads to fatal complication such as aspiration pneumonia. We investigated the chronological changes in swallowing function have not been revealed relationship with dysphagia. The primary aim of this study was to reveal the mechanism of dysphagia following transoral surgery by analyzing chronological videofluorography (VF) findings. Moreover, the secondary aim of this study was to evaluate the relationship between mechanism of dysphagia and risk factors of patients to clarify the risk for dysphagia lead to prevention of postoperative complications. 22 patients who underwent transoral videolaryngoscopic surgery (TOVS) for either supraglottic or hypopharyngeal cancer were evaluated swallowing function. We performed VF during the preoperative, postoperative acute, and stable phases and investigated the chronological changes in the VF findings. The following parameters were evaluated by VF: horizontal distance of laryngeal movement, vertical distance of laryngeal elevation, laryngeal elevation delay time (LEDT), Bolus Residue Scale (BRS) scores, and Penetration Aspiration Scale (PAS) scores. Additionally, we evaluated risk factors for postoperative aspiration by investigating relationships between preoperative VF parameters, age of patients, history of radiation therapy, resection area, tumor (T) stage, postoperative Numeric Rating Scale (NRS), and PAS and BRS scores. The median time at which oral feeding was resumed in this study was 9 (2–200) days. The patients who had postoperative acute PAS scores of 4 and above exhibited delays in resuming oral ingestion after surgery. TOVS did not impair laryngeal elevation and LEDT; however, the BRS and PAS scores temporarily worsened in the acute phase compared to the preoperative scores. These scores almost recovered to their preoperative states in the stable phase, and both the BRS and PAS scores worsened and recovered concurrently. Patients who exhibited poor vertical distance in laryngeal elevation as observed via preoperative VF or who had histories of radiation therapy had worse PAS scores in postoperative acute phase VF. Patients with broad resection areas had worse BRS scores in postoperative acute phase VF. TOVS didn't impair the function of laryngeal elevation and elicitation of the swallowing reflex whereas pharyngeal bolus clearance, laryngeal penetration, and aspiration temporarily deteriorated concurrently but eventually almost recovered to their baseline values. Patients with histories of radiotherapy, poor laryngeal elevation, and broad resection areas are at the risk of postoperative dysphagia after TOVS. Patients with these risk factors need appropriate evaluation before resuming postoperative oral intake. [ABSTRACT FROM AUTHOR]

Objective: The localization pattern of metastatic sentinel lymph node (SN) and non-SNs and pathologic analysis of metastatic lymph nodes in SN lymphatic basin dissection (SLBD) were investigated in patients with cT2/T3cN0 oral squamous cell carcinoma (OSCC).Methods: This prospective multicenter trial involved 10 institutions nationwide in Japan. A total of 57 patients were enrolled. The lateral neck was divided into 5 lymphatic basins. The lymphatic basin containing SNs was defined as the SN lymphatic basin. All patients underwent SLBD with backup selective neck dissection (I-III) combined with primary tumor removal. When SNs were found outside of levels I-III, including in the contralateral neck, SLBD was performed by removing the compartments containing SNs separately. SN metastasis was classified as isolated tumor cells (ITCs), micrometastasis, or macrometastasis. ITCs are defined as a lesion no larger than 0.2 mm in largest dimension and are classified as pN0.Results: SN metastasis was observed in 22 cases. All metastatic lymph nodes, including false-negative cases, were detected in the SN lymphatic basin. Isolated tumor cells in the SNs did not affect prognosis, whereas micrometastasis tended to have poor prognosis. After adjusting for other risk factors, a positive SN remained a significant predictor of poor 5-year overall survival in pT2-4 OSCC.Conclusion: SLBD for intraoperative SN biopsy is a sufficient therapeutic procedure and is valuable for determining pathologic nodal stage in OSCC. SN positivity was demonstrated to be an independent predictor of poor prognosis in patients with pT2-4 disease undergoing SLBD with backup selective neck dissection (I-III). [ABSTRACT FROM AUTHOR]

Objective: Tinnitus is a phantom auditory sensation, which is mainly triggered by dysfunction of the peripheral auditory organ, such as cochlear disorders. Additionally, the central nervous system, specifically the limbic system, plays a crucial role in the generation and exacerbation of tinnitus. Therefore, to analyze the hypothesis that tinnitus has strong and specific association with the plastic changes in the limbic system, we assessed the neuronal plastic changes in the limbic system, including the hippocampus and the amygdala, in rats with single-sided tinnitus.Methods: The cochlear damage was achieved by irradiating the cochlea with laser-induced shock wave (LISW). While both hearing loss and tinnitus were confirmed after exposure of rats to LISW, the degree of tinnitus was objectively measured using gap detection behavioral tests. Following the generation of hearing loss and tinnitus, plastic changes in the neurons of the limbic system were confirmed using a molecular marker (activity regulated cytoskeleton-associated protein; Arc).Results: While the expression level of Arc-positive cells in the hippocampal CA1 showed an obvious increase in the hearing loss and tinnitus groups, a significant difference was found between the tinnitus and the control groups. In the dentate gyrus, although the largest number of Arc-positive cells was observed in the tinnitus group, there were no significant differences between the numbers of cells in the hearing loss and tinnitus groups compared to that in the control group.Conclusion: Although a significant increase of Arc-positive cells in the hippocampal CA1 was observed between the tinnitus group and control, no obvious tendencies of Arc-positive cells in the limbic system were observed between the rats with and without tinnitus behavior. [ABSTRACT FROM AUTHOR]

Objectives: Hearing loss is one of the biggest health problems in the world and occupational noise-induced hearing loss is recognized as the most common work-related illness. However, many factors that result in hearing loss make it difficult to define the specific factor that induces noise-induced hearing loss. To access the exact effect of occupational noise exposure on hearing, we conducted a cross-sectional cohort study of the relationship between noise exposure and hearing impairment in 50-year-old male Japanese Self-Defense Force (JSDF) personnel who work in a noisy environment. This population is ideal for the detection of noise-induced hearing impairments due to the homogeneity of genetic and social backgrounds.Methods: The data utilized in this study were collected from a "50-year-old milestone health examination" of the JSDF from July 2013 to October 2015. One thousand sixty-seven male personnel were enrolled in the study. Pure-tone audiometry was conducted with an audiometer. A survey questionnaire asked participants to self-report occupational noise exposure.Results: This cohort revealed that noise-exposed personnel had a higher hearing threshold and a higher odds ratio in 1) the average threshold of 4 frequencies (500 + 1000 + 2000 + 4000 Hz / 4), 2) the average threshold of higher 3 frequencies (2000 + 4000 + 8000 Hz / 3), and 3) the threshold of 4 kHz compared to no noise-exposed control personnel. The prevalence of tinnitus was also significantly higher in the noise-exposed group.Conclusions: This study provides specific evidence for the relationship between noise exposure and noise-induced hearing impairments. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the efficacy and safety of local steroid injections to prevent scar contracture after transoral videolaryngoscopic surgery (TOVS) in hypopharyngeal cancer patients.Methods: Patients were enrolled in this study if they had received a local steroid injection during TOVS and had attended an outpatient clinic after at least three months. All patients were being treated for hypopharyngeal cancer and received a single session of triamcinolone acetonide, injected using a 21-gage needle. Retrospective chart reviews were performed, and the degree of scar contracture, pharyngeal stenosis, vocal fold movements, and adverse events were evaluated. Scar contracture was assessed using a scoring system, which compared the endoscopic findings of treatment and matched pair control groups.Results: A total of 20 patients received local steroid injections during TOVS and were enrolled in the treatment. Scar contracture was seen in 14 patients (70%); however, the degree of scar contracture was significantly decreased when compared to control cases. Vocal fold immobility was observed in five patients, but no pharyngeal stenosis was noted. Adverse effects, such as postoperative laryngeal chondritis or cervical spondylitis, were seen in three patients who had previously been treated with resection to the muscularis propria or definitive irradiation.Conclusion: Local steroid injection during TOVS significantly reduced the degree of postoperative scar contracture. However, caution should be used when treating with local steroid injection during TOVS, as this may complicate wound healing in patients who have already received treatment. [ABSTRACT FROM AUTHOR]

Objective: Transoral videolaryngoscopic surgery (TOVS) was developed as a non-robotic procedure for en bloc laryngo-hypopharyngeal cancer resection. Straight devices had been used for this procedure, however, some cases had difficulty to reach the lesions especially in hypopharyngeal area. To overcome this problem, technical updates to facilitate transoral manipulation were developed and long term oncological and functional results were analyzed.Methods: Surgical indications were Tis, T1, T2 and selected T3 cases. In advanced T3 or T4 lesions, neoadjuvant chemotherapy was performed before surgery. Radiation failure cases (rT1 and rT2) were also indicated for TOVS. Resectable nodal involvement can be managed by combination of neck dissection. Ninety hypopharyngeal and 25 supraglottic cancer cases were retrospectively reviewed for survival analyses. In fresh hypopharyngeal cancer, 51 Stage 0-II disease and 32 Stage III-IV disease were included. In supraglottic cancer, 11 Stage I-II disease and 9 Stage III-IV disease were included. Twelve radiation failure cases were analyzed separately. As new devices, malleable forceps and malleable suction coagulator were introduced to reach the whole laryngo-hypopharynx. New curved blades for the FKWO retractor were developed and these were applied for difficult hypopharyngeal exposure cases by conventional blades. Swallowing functional outcome and risk factors for postoperative dysphagia were evaluated by univariate analysis.Results: The 5-year overall survival, disease-specific survival and larynx preservation rate of fresh hypopharyngeal cancer cases were 83.2%, 94.3% and 94.6%, respectively. Those of supraglottic cancer cases were 80%, 95% and 94.7%, respectively. Those of salvage cases were 87.5%, 87.5% and 82.5%, respectively. Those of T3 and T4 hypopharyngeal cancer treated by neoadjuvant chemotherapy with TOVS were 75.0%, 82.5% and 100% respectively. Surgical complication included bleeding (2.6%) and emergency tracheostomy (3.4%). Oral intake was maintained in 94.8% cases. By univariate analysis, patient's age (especially 80 years of age or older), larger resected area, arytenoid resection and tracheostomy were regarded as risk factors for postoperative dysphagia. Among 31 recent cases, 5 cases had difficulty in exposing hypopharyngeal lesions by conventional blades. These exposure problems were solved by curved blades.Conclusion: Using malleable devices and new curved blades for the FKWO retractor, exposure problems in the hypopharynx could be solved and TOVS could be applied in more cases. Although oncological outcomes and functional outcomes were good, patients with risk factors for dysphagia should be carefully indicated. [ABSTRACT FROM AUTHOR]

Objective: To develop a summary of the first version of the Clinical Practice Guideline of Voice Disorders for Diagnosis, Management, and Treatment in Japan by the Clinical Practice Guideline Committee of the Japan Society of Logopedics and Phoniatrics and The Japan Laryngological Association. The 2018 recommendations, based on a review of the scientific literature, are intended to serve as clinical practice guidelines for the diagnosis, management, and treatment of voice disorders in Japan.Methods: A summary of the original version of the Clinical Practice Guideline of Voice Disorders for Diagnosis, Management, and Treatment in Japan was described. Recommendations for the diagnosis, management, and treatment of voice disorders were prepared. Twelve clinical questions (CQs) regarding the diagnosis, management, treatment, and effectiveness of therapy for voice disorders were also prepared.Results: A summary of the first version of the clinical practice guidelines for the diagnosis, management, and therapy of voice disorders was prepared and is presented. Additionally, answers to the 12 CQs on the diagnosis, management, treatment, and effectiveness of voice disorder therapy were prepared, and include evidence-based recommendations.Conclusion: These guidelines present a summary of the standard approaches for the diagnosis and treatment of voice disorders and relevant CQs that consider the medical environments in Japan. We hope that the guidelines will assist physicians in clinical settings for patients with voice disorders. [ABSTRACT FROM AUTHOR]

Objective: The fiber-guided carbon dioxide (CO2) laser is a useful device for laryngopharyngeal surgery. The flexible CO2 wave-guide laser has been developed and commercially available for several years. However, the transnasal use of CO2 flexible wave-guided laser surgery through the instrument channel of a flexible endoscope (CO2 TNFLS) is not permitted in Japan. This feasibility study aimed to assess the value and the safety of an in-office CO2 TNFLS procedure.Methods: Patients with small laryngopharyngeal diseases were enrolled from June 2015. Eligible patients had indications with lesions generally localized superficial lesions such as the benign tumor, leukoplakia, and premalignant lesion-like carcinoma in situ (CIS). Patients were locally well anesthetized using xylocaine. After removing as much of the lesion(s) as possible with flexible forceps, the remainder of the lesions were evaporated using CO2 TNFLS through the instrument channel of a flexible endoscope under local anesthesia.Results: Eighteen surgeries involving 13 patients, including 9 papilloma (7 recurrent respiratory papilloma [RRP]), 2 carcinoma in situ, 1 leukoplakia, and 1 large epiglottic cyst), were performed. Four patients with RRP required multiple surgeries. Except for 3 patients with RRP, all patients achieved disease control without additional intervention. All procedures were completed with no severe adverse events.Conclusion: Office-based CO2 TNFLS is safe and feasible for patients with laryngopharyngeal pathologies. It is especially valuable for RRP patients with small lesions to avoid surgery under general anesthesia. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility of Transoral Videolaryngoscopic Surgery (TOVS) for radiorecurrent supraglottic and hypopharyngeal cancer, and to compare survival and complications between primary and radiorecurrent cases.Methods: Twelve cases of salvage TOVS for radiorecurrent cancer and 53 cases of TOVS as an initial treatment (primary cases) were evaluated. Days to resume soft diet, Functional Outcomes of Swallowing Scale (FOSS), postoperative complications, epithelization days and survival outcomes were assessed by retrospective chart review.Results: FOSS score was significantly worse in salvage cases compared with primary cases. Bleeding and airway compromise was slightly greater in salvage cases than in primary cases; however, this was not statistically significant. Wound healing was significantly delayed in salvage cases compared with primary cases (P<0.001). In primary cases, wounds were re-epithelized within 60 days in 83% of patients and within 90 days in almost all patients, while in salvage cases 42% of patients required more than 90 days for wound healing. In salvage cases, the 5-year overall survival, disease specific survival rate, local control rate, and laryngeal preservation rate was 85.7%, 85.7%, 62.5%, and 78.0%, respectively, and 85.7%, 98.0%, 91.3%, and 97.8%, respectively, for primary cases. Local control rate was significantly better in primary cases than in salvage cases.Conclusion: Salvage TOVS was feasible in highly selected cases. After serial transoral surgery, the final laryngeal preservation rate was satisfactory. Swallowing function in salvage cases tended to be worse than in primary cases, and a significantly longer time was required for wound healing. [ABSTRACT FROM AUTHOR]

Objective: A recent study identified a survival benefit with prophylactic neck dissection (ND) at the time of primary surgery as compared with watchful waiting followed by therapeutic neck dissection for nodal relapse, in patients with cN0 oral squamous cell carcinoma (OSCC). Alternative management of cN0 neck cancer is recommended to minimize the adverse effects of ND, indicating the need for sentinel node biopsy (SNB) and limited neck dissection. We conducted a multicenter Phase II study to examine the feasibility of SNB for clinically N0 OSCC.Methods: Previously untreated N0 OSCC patients (n=57) with clinical late-T2 or T3 tumors were enrolled across 10 institutions. SNB navigated with multislice frozen section analysis of sentinel nodes (SNs) and SNB supported sentinel node lymphatic basin dissection (SN basin dissection) were performed in a one-stage procedure. The endpoint was to investigate the rate of false-negative metastases after SN basin dissection and SNB alone.Results: Most tumors were late-T2 lesions (n=50; 87.7%). SNs were identified in all patients. A total of 196 SNs were detected. Among these SNs, 35 (17.8%) were positive for metastasis (9 in level I, 12 in level II, 12 in level III, 1 in level V and 2 in the contralateral region of the neck). The false-negative rate of SNB supported by SN basin dissection and SNB alone was 4.5% and 9.1%, respectively. The concordance of the SN status in intraoperative frozen sections with the permanent histopathology was 97.4% (191/196). The sensitivity and specificity of intraoperative pathological evaluation were 85.7% (30/35) and 100% (30/30), respectively. The 3-year overall survival (OS) and disease-free survival was 89.5% and 82.5%, respectively. The OS of SN-negative patients was significantly longer than that of SN-positive patients (P=0.047).Conclusion: The current study verified that SN basin dissection was a useful back-up procedure for SNB performed as a one-stage procedure, showing a low false-negative rate. SNB alone is an appropriate staging method for patients with clinical N0 staging, and a reliable procedure to determine the appropriate levels for neck dissection. [ABSTRACT FROM AUTHOR]

Objective: Ototoxic damage caused by aminoglycosides (AG) leads to the loss of cochlear hair cells (HCs). In mammals, mature cochlear HCs are unable to regenerate, and their loss results in permanent hearing deficits. Our objective was to protect the inner ear from damage after an AG challenge. The generation of reactive oxygen species (ROS), one of the earliest events in the process of AG ototoxicity, is considered to play a key role in the initiation of HC death. We examined whether Hangesha-shin-to (TJ-014), a traditional Japanese Kampo medicine considered to be a potent antioxidant, protects HCs from gentamicin (GM)-induced damage.Methods: Organ of Corti explants removed from postnatal day 3-5 rats were maintained in tissue culture and exposed to 50μM GM for up to 48h. The effects of TJ-014 on GM-induced ototoxicity were assessed by HC counts and immunohistochemistry against cleaved caspase-3, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and a probe reacting to mitochondrial function changes.Results: TJ-014 treatments significantly reduced GM-induced HC loss and immunoreactivities for cleaved caspase-3 and 8-OHdG; these effects were correlated with increasing TJ-014 concentrations. Moreover, TJ-014 protected the mitochondrial membrane potential from GM ototoxicity.Conclusion: These findings indicate the potential of TJ-014 to prevent GM-induced cochlear damage involving ROS. [ABSTRACT FROM AUTHOR]

Photobiomodulation (PBM) is a noninvasive treatment that can be neuroprotective, although the underlying mechanisms remain unclear. In the present study, we assessed the mechanism of PBM as a novel treatment for noise-induced hearing loss, focusing on the nuclear factor (NF)-κB signaling pathway. Sprague–Dawley rats were exposed to 1-octave band noise centered at 4 kHz for 5 h (121 dB). After noise exposure, their right ears were irradiated with an 808 nm diode laser beam at an output power density of 165 mW/cm 2 for 30 min a day for 5 consecutive days. Measurement of the auditory brainstem response revealed an accelerated recovery of auditory function in the groups treated with PBM compared with the non-treatment group at 4, 7, and 14 days after noise exposure. Immunofluorescent image analysis for inducible nitric oxide synthase and cleaved caspase-3 showed lesser immunoreactivities in outer hair cells in the PBM group compared with the non-treatment group. However, immunofluorescent image analysis for NF-κB, an upstream protein of inducible nitric oxide synthase, revealed greater activation in the PBM group compared with the naïve and non-treatment groups. Western blot analysis for NF-κB also showed stronger activation in the cochlear tissues in the PBM group compared with the naïve and non-treatment groups (p<0.01, each). These data suggest that PBM activates NF-κB to induce protection against inducible nitric oxide synthase-triggered oxidative stress and caspase-3-mediated apoptosis that occur following noise-induced hearing loss. [ABSTRACT FROM AUTHOR]

Antiresorptive drugs have been widely used to treat patients with hypercalcemia caused by malignancy, bone metastasis, multiple myeloma, and osteoporosis. However, it is well known that antiresorptive drugs can cause osteonecrosis of the jaw (ONJ). Herein, we report a rare case of nasal septal abscess caused by medication related osteonecrosis of the jaw (MRONJ) in a breast cancer patient. A 69-year-old woman was referred to our clinic for evaluation of nasal obstruction. Physical examination revealed a cherry-like swelling of the nasal mucosa emanating from the septum that obstructed both nasal cavities and a fistulous tract showing pus discharge after extraction of the bilateral maxillary central incisors (MCI) and the right maxillary lateral incisor (MLI). Computed tomography and panoramic radiography revealed extensive osteonecrosis of the maxilla and swelling of the nasal mucosa. The clinical diagnosis was nasal septal abscess caused by osteonecrosis of the maxilla. Surgical procedure was undertaken for this case. An indwelling drain was placed in the oral cavity, and sequestrectomy was performed with incision and drainage of the anterior portion of left nasal septum. The patient was doing well at the 7-month follow-up. The patient had a medical history of breast cancer with bone, lung, liver metastases, and had received intravenous bisphosphonate, which is one of the antiresorptive medicines, over the past 4 years. We suspect that this history played an important role in MRONJ induced nasal septal abscess. [ABSTRACT FROM AUTHOR]

Noninvasive low-level laser therapy (LLLT) is neuroprotective, but the mechanism of this effect is not fully understood. In this study, the use of LLLT as a novel treatment for noise-induced hearing loss (NIHL) is investigated. Sprague–Dawley rats were exposed to intense noise and their right ears were irradiated with an 808 nm diode laser at an output power density of 110 or 165 mW/cm 2 for a 30 min period for 5 consecutive days. Measurement of the auditory brainstem response revealed an accelerated recovery of auditory function in the groups treated with LLLT compared with the non-treatment group at days 2, 4, 7 and 14 after noise exposure. Morphological observations also revealed a significantly higher outer hair cell survival rate in the LLLT groups. Immunohistochemical analyses for inducible nitric oxide synthase (iNOS) and cleaved caspase-3 were used to examine oxidative stress and apoptosis. Strong immunoreactivities were observed in the inner ear tissues of the non-treatment group, whereas these signals were decreased in the LLLT group at 165 mW/cm 2 power density. Our findings suggest that LLLT has cytoprotective effects against NIHL via the inhibition of iNOS expression and apoptosis. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) that form in the inner ear play an important role in noise-induced hearing loss (NIHL). Recent studies have revealed that molecular hydrogen (H 2 ) has great potential for reducing ROS. In this study, we examined the potential of hydrogen gas to protect against NIHL. We tested this hypothesis in guinea pigs with 0.5%, 1.0% and 1.5% H 2 inhalation in air for 5 h a day after noise exposure, for five consecutive days. All animals underwent measurements for auditory brainstem response after the noise exposure; the results revealed that there was a better improvement in the threshold shift for the 1.0% and 1.5% H 2 -treated groups than the non-treated group. Furthermore, outer hair cell (OHC) loss was examined 7 days after noise exposure. A significantly higher survival rate of OHCs was observed in the 1.0% and 1.5% H 2 -treated group as compared to that of the non-treated group in the basal turn. Immunohistochemical analyses for 8-hydroxy-2′-deoxyguanosine (8-OHdG) were performed to examine the amount of oxidative DNA damage. While strong immunoreactivities against 8-OHdG were observed of the non-treated group, the H 2 -treated group showed decreased immunoreactivity for 8-OHdG. These findings strongly suggest that inhaled hydrogen gas protects against NIHL. [ABSTRACT FROM AUTHOR]

Objective The introduction of minimally invasive surgical procedures using sialendoscopy has significantly reduced the rate of major salivary gland removal due to sialolithiasis. The present study assessed the utility of sialendoscopy and identified potential factors influencing successful sialendoscopic salivary stone retrieval. Methods Medical records of sialendoscopic procedures performed at the Department of Otolaryngology of the National Defense Medical College in Japan from November 2007 to January 2014 were retrospectively reviewed. We identified 78 patients diagnosed with sialolithiasis and treated with sialendoscopy (SE). Factors analyzed included stone location, size, symptom duration, surgical methods, and complications. Results The mean age at presentation was 41 years (range, 11–76 years) with a male-to-female gender ratio of 1:1.89. In total, 73 submandibular and 5 parotid endoscopies were performed. Stone size ranged from 2 to 20 mm in diameter. Submandibular stones were removed either by SE alone (9.6%), by transoral stone removal (19.2%), or a combined approach (57.5%). Only 13.7% (10/73) of the cases required submandibular gland removal. Stone size and shape were significant predictors for successful endoscopic stone removal, and stone size and location were significant predictors for submandibular gland removal. Conclusion Sialendoscopy is a reasonable, minimally invasive treatment option for sialolithiasis that avoids salivary gland removal. The present results indicate that sialendoscopy is the first treatment of choice for submandibular gland sialolithiasis. Complete surgical excision is becoming uncommon as a first-line treatment, but it remains indispensable in certain cases. [ABSTRACT FROM AUTHOR]

Activated protein C (APC) is a serine/threonine protease and a physiological anticoagulant that exerts anti-inflammatory and anti-apoptotic effects. Although recent studies have revealed that APC has the potential to protect endothelial cells from apoptosis, the mechanisms of its cytoprotective effect are not fully understood. We examined the potential of APC to protect against noise-induced hearing loss (NIHL) and investigated phosphorylation of serine-threonine kinase (Akt) and inhibition of apoptosis as possible cytoprotective mechanisms. We administered intraperitoneal injections of APC (150, 300 U/kg) or normal saline to rats 30 min before exposure to a sound pressure level (SPL) of 126 dB and 4-kHz octave band noise for 5 h. The auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) were measured before and after exposure. ABR and DPOAE measurements revealed greater improvement in the APC group than in the control group 28 days after exposure. Our examination of outer hair cells (OHCs) at 28 days after noise exposure revealed a significantly higher OHC survival rate in the APC group than in the control group. Immunohistochemical analyses for cleaved-caspase 3, phospho-p38 (p-p38), TUNEL, and phospho-Akt (p-Akt) revealed strong immunoreactivities against cleaved-caspase 3, p-p38, and TUNEL in the inner ear tissues of the control group; however, these signals were decreased in the APC group. Moreover, APC significantly induced activation of p-Akt in the cochlea. These findings suggest that APC has a novel protective effect on the cochlea against NIHL that is mediated by p-Akt and the anti-apoptotic signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Sentinel node (SN) biopsy in the head and neck region has not been widely used in Japan, except at a few facilities. However, almost all these facilities perform preoperative localization and intraoperative diagnosis by frozen section analysis of SN to select patients who must undergo neck dissection in a one-stage procedure. The objective of this study was to determine the actual status of SN biopsy at those facilities in Japan that have actively conducted this procedure, and to elucidate the usefulness and drawbacks of this technique in head and neck cancer. Methods: We retrospectively reviewed 177 patients who had undergone SN biopsy at 7 facilities. The underlying pathology was laryngeal or hypopharyngeal cancer in 20 patients from one hospital, while the remaining 157 patients had oral cancer. Preoperative localization of SN was determined using conventional lymphoscintigraphy with or without single photon emission computed tomography with CT (SPECT-CT). Intraoperative localization and diagnosis of SN were performed by gamma probe and frozen section analysis. Results: Conventional lymphoscintigraphy detected a mean of 2.6 SNs per patient in 137 patients with oral cancer, compared to 2.7 in 71 patients using SPECT-CT and 2.9 in 154 patients using the gamma probe. No significant differences were apparent between techniques. Forty of the 520 SNs (7.7%; 33 in oral cancer and 7 in laryngeal or hypopharyngeal cancer) were pathologically positive in the final diagnosis. Of these, 3 were not processed for frozen sectioning and were diagnosed only with hematoxylin and eosin staining. Among the others, 32 (86.5%) were diagnosed intraoperatively as showing metastasis. In terms of the false-negative rate, 144 patients were determined by SN biopsy to have no positive SNs. Of these, 2 patients had non-SN metastases found in their dissected neck and 8 patients without neck dissection showed late nodal recurrence. The false-negative rate was thus 6.9%. Conclusion: Frozen section analysis, particularly multislice sectioning, offers a relatively reliable intraoperative diagnostic method. We were able to perform immediate neck dissection based on the results of multislice sectioning as a single-stage procedure. [Copyright &y& Elsevier]

Purpose: To retrospectively assess the efficacy, toxicity, and prognostic factors of weekly low-dose docetaxel–based chemoradiotherapy for Stage III/IV oropharyngeal or hypopharyngeal carcinoma. Methods and Materials: Between 2001 and 2005, 72 consecutive patients with locally advanced oropharyngeal or hypopharyngeal carcinoma were treated with concurrent chemoradiotherapy (CCR; radiation at 60 Gy plus weekly docetaxel [10 mg/m2]). Thirty of these patients also received neoadjuvant chemotherapy (NAC; docetaxel, cisplatin, and 5-fluorouracil) before concurrent chemoradiotherapy. Survival was calculated according to the Kaplan-Meier method. The prognostic factors were evaluated by univariate and multivariate analyses. Results: The median follow-up was 33 months, with overall survival, disease-free survival, and locoregional control rates at 3 years of 59%, 45%, and 52%, respectively. Thirty-six patients (50%) experienced more than one Grade 3 to 4 acute toxicity. Grade 3 mucositis occurred in 32 patients (44%), Grade 4 laryngeal edema in 1 (1%). Grade ≥3 severe hematologic toxicity was observed in only 2 patients (3%). Grade 3 dysphagia occurred as a late complication in 2 patients (3%). Multivariate analyses identified age, T stage, hemoglobin level, and completion of weekly docetaxel, but not NAC, as significant factors determining disease-free survival. Conclusions: Docetaxel is an active agent used in both concurrent and sequential chemoradiotherapy regimens. Mucositis was the major acute toxicity, but this was well tolerated in most subjects. Anemia was the most significant prognostic factor determining survival. Further studies are warranted to investigate the optimal protocol for integrating docetaxel into first-line chemoradiotherapy regimens, as well as the potential additive impact of NAC. [Copyright &y& Elsevier]

Abstract: Inner ear barotrauma (IEB) that is caused by acute pressure changes can often lead to permanent severe sensorineural hearing loss (SNHL). However, the mechanism that causes IEB is still unknown. In the current study, we assessed the involvement of reactive oxygen species (ROS) in IEB and the therapeutic effect of 3-methyl 1-phenyl-2-pyrazolin-5-one (edaravone), which is a free radical scavenger. To create the IEB model, guinea pigs were subjected to quick pressure changes that resulted in acute SNHL. The animals were then divided into two groups, an edaravone-treated IEB group and a non-treated IEB group that only received normal saline. Immunohistochemical analyses for 8-hydroxy-2-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) were performed to examine the amount of oxidative DNA damage and lipid peroxidation that occurred in guinea pig cochlea. To assess the curative efficacy of edaravone, auditory brainstem response (ABR) testing was performed to evaluate auditory function. Strong immunoreactivities against 8-OHdG and 4-HNE were observed in the inner ear tissues of the non-treated IEB group. Lesser amounts of immunoreactivity were observed in the same region of the edaravone-treated IEB group as compared to the non-treated IEB group. Furthermore, ABR measurement revealed that there was a faster improvement in the threshold shift for the edaravone-treated IEB group as compared to that of the non-treated IEB group. At the final 7-week time point, the threshold shift for the edaravone-treated IEB group was significantly smaller as compared to the non-treated IEB group. These results strongly suggest that ROS is produced in the cochlea in response to acute pressure changes and that ROS plays an important role in the pathophysiology of IEB. Furthermore, edaravone treatment had a therapeutic effect on IEB-induced acute SNHL and thus, edaravone might possibly be able to be used as a therapeutic treatment for IEB. [Copyright &y& Elsevier]