Botulinum toxin injection into the intrinsic laryngeal muscles to treat spasmodic dysphonia: A multicenter, placebo-controlled, randomized, double-blinded, parallel-group comparison/open-label clinical trial.

BACKGROUND AND PURPOSE: Botulinum toxin (BT) injection into the laryngeal muscles has been a standard treatment for spasmodic dysphonia (SD). However, few high-quality clinical studies have appeared, and BT is used off-label in most countries. METHODS: We performed a multicenter, placebo-controlled, randomized, double-blinded, parallel-group comparison/open-label clinical trial to obtain approval for BT (Botox) therapy in Japan. Twenty-four patients (22 with adductor SD and two with abductor SD) were enrolled. The primary end point was the change in the number of aberrant morae (phonemes) at 4 weeks after drug injection. The secondary end points included the change in the number of aberrant morae, GRBAS scale, Voice Handicap Index (VHI), and visual analog scale (VAS) over the entire study period. RESULTS: In the adductor SD group, the number of aberrant morae at 4 weeks after injection was reduced by 7.0 ± 2.30 (mean ± SE) in the BT group and 0.2 ± 0.46 in the placebo group (p = 0.0148). The improvement persisted for 12 weeks following BT injections. The strain element in GRBAS scale significantly reduced at 2 weeks after BT treatment. The VHI and VAS scores as subjective parameters also improved. In the abductor SD group, one patient responded to treatment. Adverse events included breathy hoarseness (77.3%) and aspiration when drinking (40.9%) but were mild and resolved in 4 weeks. CONCLUSIONS: Botulinum toxin injection was safe and efficacious for the treatment of SD. Based on these results, BT injection therapy was approved as an SD treatment in Japan.

Effects of a Cloth Panel Containing a Specific Ore Powder on Patients with Chamaecyparis obtusa (Cypress) Pollen Allergy.

Pollen allergy to Japanese cedar and cypress is a serious illness that impairs daily life and sleep, especially during pollen season. We have reported that placing a cloth panel containing a specific natural ore powder (CCSNOP) in a room may alleviate the symptoms of hay fever and may also benefit the immune system. This ore is from the Aso mountain range, a volcano on Kyushu Island in the southwestern part of Japan. The purpose of this study was to verify the effect of CCSNOP on cypress pollen. Thirty-one double-blind tests, which investigated cedar pollen allergies, were conducted from February to March 2018 and have already been reported. After this, in early April, 10 of these cases were recruited and all had CCSNOP installed in their bedrooms. Before that, various symptoms and changes in medication were recorded in a "Symptom Diary" and included a mood survey by a questionnaire, stress test using saliva amylase, changes in cypress-specific immunoglobulins IgE and IgG4 by blood sampling, and eosinophil changes. In addition, changes in 29 types of cytokines were investigated. Exposure to CCSNOP relieved symptoms and subjects decreased their intake of medication. There was no change in mood or stress, but eosinophil levels tended to decrease. Although there were no statistical changes in cypress-specific IgE or IgG4, an increase in the former and a decrease in the latter were observed in some individuals during the period of pollen dispersal. Furthermore, levels of GM-CSF and IL8 decreased significantly after use of CCSNOP. The CCSNOP was shown to be effective against cypress pollen allergy, and future investigations will be necessary to observe the long-term effects of CCSNOP.

Obstructive sleep apnea in Asian primary school children.

PURPOSE: The objectives of this study were to examine the prevalence of obstructive sleep apnea (OSA) in primary school children, relationships between OSA and tonsillar hypertrophy, adenoid, and patency of the nasal cavity, and the effects of the tonsillar hypertrophy and adenoid on the nasal patency. METHODS: An examination of the palatine tonsils and anterior rhinoscopy, completion of a questionnaire survey, a measurement of nasal resistance, an examination for sleep apnea at home using portable polysomnography device, and radiography of pharyngeal tonsil were performed in 152 primary school children. RESULTS: The obstructive apnea hypopnea index (O-AHI) increased with enlargements in the palatine tonsils. The adenoidal nasopharyngeal ratio (A/N ratio) decreased with advances in grade. A significant difference was observed in the O-AHI between those with and without adenoid. The median value of the O-AHI increased with advances in grade. The nasal resistance was significantly higher in the group with adenoid compared as in the group without. It was also higher in the nasal disease group with OSA than in the group without. Full polysomnography(PSG) was recommended in 16 (10.5%) of 152 who underwent the examination using the portable polysomnography device, and of the eight who underwent PSG, six (75%) were confirmed to have OSA, while its prevalence in all subjects was estimated as 7.9%. CONCLUSIONS: Disturbances in nasal respiration as well as tonsillar hypertrophy and adenoid were found to be a risk factor of OSA in primary school children.

Human laryngitis caused by Clinostomum complanatum.

A 64-year-old Japanese man visited our outpatient department complaining of an irritable sensation in the throat, occurring two days after eating raw freshwater fish (carp sashimi) at a Japanese-style inn. During laryngeal endoscopy, a slow-moving worm (fluke) was found attached to the surface of the right aryepiglottic fold. After inhalation of 4% lidocaine, the fluke was removed using endoscopic forceps. Patient's throat symptoms immediately improved. The worm was microscopically identified as Clinostomum complanatum. C. complanatum is a digenetic trematode that usually infects fish-eating water birds. Clinostomum infections in humans are rare, and only 21 cases have been described in Japan and Korea. C. complanatum infection is known to occur after eating raw freshwater fish, which is a secondary intermediate host. In humans, the metacercariae are released into the stomach and migrate through the esophagus before lodging in the throat. Primary therapy involves endoscopic removal of the worm.

Correction: Effectiveness and safety of weekly paclitaxel and cetuximab as a salvage chemotherapy following immune checkpoint inhibitors for recurrent or metastatic head and neck squamous cell carcinoma: a multicenter clinical study.

[This corrects the article DOI: 10.1371/journal.pone.0271907.].

Protease-Activated Receptor 1 (PAR1) Expression Contributes to HPV-Associated Oropharyngeal Cancer Prognosis.

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer occasionally has a poor prognosis, making prognostic risk stratification crucial. Protease-activated receptor-1 (PAR1) is involved in carcinogenesis, and its expression is regulated by alpha-arrestin domain-containing protein 3 (ARRDC3). It is also involved in the tumor microenvironment. We sought to evaluate the predictive ability of PAR1, ARRDC3, and tumor-infiltrating lymphocyte (TIL) scores in patients with oropharyngeal, hypopharyngeal, and uterine cervical cancers, serving as comparators for HPV-associated oropharyngeal cancer. METHODS: Immunohistochemical analysis of p16, ARRDC3, and PAR1 expression was performed on 79 oropharyngeal, 44 hypopharyngeal, and 42 uterine cervical cancer samples. The TIL scores were assessed and classified into the following groups based on invasion: low: 0-10%, medium: 20-40%, and high: > 50%. For prognostic analysis, the three groups were evaluated by dividing them into low, medium, and high categories, or alternatively into two groups using the median value as the cutoff. RESULTS: p16 was expressed in 44 (56%) oropharyngeal, 8 (18%) hypopharyngeal, and all uterine cervical cancer samples. ARRDC3 was detected in 39 (49%) oropharyngeal, 25 (57%) hypopharyngeal, and 23 (55%) uterine cervical cancer samples. PAR1 was expressed in 45 (57%) oropharyngeal, 22 (50%) hypopharyngeal, and 22 (50%) uterine cervical cancer samples. Patients diagnosed with p16-positive oropharyngeal cancer had a substantially improved prognosis compared to those diagnosed with p16-negative cancer. The PAR1-negative cases had a considerably improved prognosis compared to the positive cases (disease-specific survival [DSS] and -negative cases (disease-free survival [DFS]). Multivariate analysis revealed that ARRDC3-positive cases had an appreciably better DSS prognosis than patients with p16-negative oropharyngeal cancers. PAR1-positive patients among patients with p16-positive oropharyngeal cancer had a poor prognosis. With respect to DFS, patients with PAR1-positive and p16-negative oropharyngeal cancer had a 35-fold higher recurrence rate than those with PAR1-negative and p16-negative oropharyngeal cancer. CONCLUSION: Our results suggest that PAR1 expression affects the prognosis and recurrence rate of HPV-associated oropharyngeal cancer.

[Clinical evaluation of a novel multiplex HPV genotyping reagent using the luminex xMAP technology].

Of the more than 100 strains of human papillomavirus (HPV) reported to date, 13 strains are clinically significant due to the highly associated risk of cervical cancer. HPV test reagents are currently being developed to aid detection of these strains. The present study compared a novel HPV genotyping reagent using a Luminex device, which enables simultaneous quantitation of multiple targets using fluorescent beads, and gene-specific multiplex polymerase chain reaction (Luminex method) with approved in vitro diagnostics. Subjects comprised 256 patients examined at our hospital for either secondary cervical cancer testing or follow-up (mean age, 40 years; age range, 20-85 years) and specimens were obtained using a cervical brush and lavage fluid. The HPV-positive rate with the Luminex method was 51.4%(132/256), of which single and multiple strain infections constituted 65.9% (87/132) and 34.1% (45/132), respectively. Correlation testing of 50 positive and 50 negative Luminex method specimens was conducted using the HPV DNA Hybrid Capture II (HCII), revealing high overall (97%[97/100]), positive(100% [47/47]) and negative(94.3% [50/53]) concordance rates. Correlation was also high for the Clinichip HPV (Clinichip), with overall, positive and negative concordance rates of 98% (98/100), 100%(48/48) and 96.2%(50/52), respectively. Furthermore, the detection concordance rate with the Clinichip was 95.8% (46/48). Sequencing of the seven specimens showing result discrepancies (HCII, n = 3; Clinichip, n = 4) confirmed concordance with the Luminex method results in all cases, indicating the validity of the present method. The present findings suggest that the Luminex method has sufficient response capability for clinical application.

Effectiveness and safety of weekly paclitaxel and cetuximab as a salvage chemotherapy following immune checkpoint inhibitors for recurrent or metastatic head and neck squamous cell carcinoma: A multicenter clinical study.

OBJECTIVES: The benefit of sequential therapy after immune checkpoint inhibitor (ICI) treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) has been recently reported. Furthermore, there is a growing interest in the impact of cetuximab (Cmab)-containing salvage chemotherapy (SCT) and the therapeutic efficacy and adverse events (AEs) of Cmab administration prior to ICI administration. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 52 patients with R/M HNSCC treated with SCT (weekly paclitaxel [PTX], n = 7, or weekly PTX and Cmab [PC], n = 45). RESULTS: The objective response rate (ORR) and a disease control rate (DCR) was 53.3% and 91.1% in the PC group and 42.9% and 57.1% in the PTX group, respectively. There was a significant difference in the DCR between the PC and PTX groups (p = 0.0143). The overall survival (OS) and progression-free survival were significantly better in the PC group than in the PTX group. On the other hand, the incidence of drug-induced interstitial pneumonia (DI-IP) in R/M HNSCC patients who received SCT was 21.2%. Patients in the PC group were divided according to whether they received Cmab (Group A) or did not receive Cmab (Group B) as palliative therapy prior to ICIs. Group B had a significantly better OS than Group A. Furthermore, our findings suggest that the incidence rate of DI-IP during SCT might be higher in Group B. CONCLUSION: Although PC following ICIs shows dramatic efficacy, careful monitoring of AEs, including DI-IP, is recommended.

[High-throughput screening method of KRAS mutations at codons 12 and 13 in formalin-fixed paraffin-embedded tissue specimens of metastatic colorectal cancer].

Clinical studies overseas using the therapeutic anti-EGFR monoclonal antibodies, cetuximab or panitumumab against metastatic colorectal cancer(mCRC), have revealed KRAS mutations as a negative predictive marker of response. Accordingly, the Ministry of Health, Labour and Welfare in Japan approved medical reimbursement of the KRAS mutation test in April 2010. Anti-EGFR monoclonal antibody therapies are now used as first-line treatment for patients with mCRC. To advance the simple high-throughput KRAS mutation test, we established a high-throughput screening system for detecting KRAS mutations utilizing Luminex(xMAP)technology(the fluorescent bead-based multiplex analyte profiling method), in combination with the polymerase chain reaction-reverse sequence-specific oligonucleotide method. Here we evaluated the basic performance of our system and confirmed its high specificity and reproducibility in detecting KRAS mutations at codons 12 and 13 in both plasmid DNAs carrying mutant KRAS genes and formalin-fixed paraffin-embedded tissues from mCRC patients. We demonstrated the KRAS mutation status in paraffin-embedded tissues of mCRC and confirmed that the results were comparable to those of the direct sequencing method. Our high-throughput method has an advantage in simultaneous analysis of multiple mutations in one well of 96-well PCR plates, and will advance the KRAS mutation test in clinical laboratories.

Is chemoimmunotherapy a game changer in the treatment of locally advanced head and neck squamous cell carcinoma?

Pembrolizumab and chemotherapy (chemoimmunotherapy) were administered to 2 head and neck squamous cell carcinoma (HNSCC) patients with extremely advanced local tumors and distant metastases with palliative intent. However, they demonstrated strikingly good responses and achieved remission. Expanded application of induction chemoimmunotherapy may be useful for locally advanced HNSCC.

A summary of the Clinical Practice Guideline for the Diagnosis and Management of Voice Disorders, 2018 in Japan.

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.

Nasal septal abscess caused by anaerobic bacteria of oral flora.

Although nasal septal abscess (NSA) was formerly common, it has become rare since the development of antibiotics. NSA, if left untreated, can lead to intracranial complications such as meningitis and eventually result in saddle-nose deformity. NSA often occurs after injury, and indigenous skin bacteria such as Staphylococcus aureus are frequently detected. We treated a patient who had injured the upper alveolus in a fall on the stairs and developed NSA two weeks later. Anaerobic bacteria, including Veillonella parvula and Peptostreptococcus sp., were detected. Symptoms were relieved by needle and incisional drainage. Our patient represents a very rare case of NSA in terms of the cause of onset and the detected bacteria. Early drainage can result in good outcomes.

Protective effect of an astaxanthin nanoemulsion against neomycin-induced hair-cell damage in zebrafish.

Objective: The cause of those hair cells disorder is oxidative stress due to free radicals. In particular, hair cells are very susceptible to aminoglycosides. Antioxidant is known to reduce the generation of oxygen-derived free radicals. Various antioxidant is marketed, and different dosage form is developed with the same drug. Using a zebra fish lateral line, we report hair cell protection effect of astaxanthin from neomycin-induced trauma. Methods: Zebrafish larvae were exposed to the astaxanthin nanoemulsion or to the suspension for 1 h, or were left unexposed. Subsequently, the larvae were exposed to neomycin for 1 h by adding the neomycin solution. Results were calculated as the mean hair-cell survival as a percentage of the control. Results: Hair cells were not protected in the group treated with astaxanthin suspension and neomycin. On the other hand, there was dose-dependent protection against neomycin-induced hair-cell death in the zebrafish lateral-line hair cells in the group treated with nano astaxanthin. Conclusion: The results of the current study performed using a zebra fish lateral-line, nano astaxanthin protected sensory hair cells against neomycin-induced death. This suggests that nano-astaxanthin is more efficiently absorbed in the body than astaxanthin, and may be useful as a protective drug for the inner ear.

Bilateral glomus tympanicum tumors: Human temporalbone study.

To describe human temporal bones with bilateral glomus tympanicum tumors. Patient is 83-year-old black female who no pulsatile tinnitus. The histopathologic characteristics of human temporal bones after death were setting Department of Otolaryngology of University of Minnesota in USA. Histopathologic observation of temporal bones showed bilateral small glomus tympanicum tumors limited to the promontory. Although there was bilateral tinnitus, there was no pulsatile tinnitus, no conductive hearing loss and both of the tympanic membranes were intact. Histopathologic observation of temporal bones after death showed bilateral glomus tympanicum tumors. To our knowledge, this is the first reported case of bilateral glomus tympanicum tumors.

Validation of a new snoring detection device based on a hysteresis extraction algorithm.

OBJECTIVE: This paper aims to introduce and validate our newly developed snoring detection device to automatically identify the incidence and amplitude of snores using the hysteresis extraction method. METHODS: Thirty patients (16 males and 14 females) with a history of snoring were included in this study. Each patient underwent a conventional polysomnography (PSG). Natural overnight snoring was recorded from each subject using our original snore detection device and an integrated circuit (IC) recorder while the patient slept during PSG. A new algorithm based on hysteresis extraction was used to detect snores and qualify the level of each event at 30-s intervals (one epoch). The automated and subjective assessment concordance was evaluated by comparing a total of 27,295 epochs, and sensitivity, specificity, and accuracy were calculated. RESULTS: Study population analysis revealed a mean rate of snore time against the total sleep time of 14.1±7.9%. Further, validation of the automatic snore detection revealed the following: sensitivity, 71.2%; specificity, 93.1%; positive predictive value, 77.7%; negative predictive value, 94.6%; and accuracy, 90.7%. CONCLUSIONS: This study revealed the efficacy of our newly developed snoring detection device and indicated that it may serve as a useful method in further snoring analysis via objective medical assessment. However, the sample size of 30 subjects was relatively small; therefore, further research is needed to evaluate this device.

Acoustic analysis of snoring sounds by a multidimensional voice program.

OBJECTIVES: This prospective study aimed to determine whether the acoustic characteristics of snoring sounds differed between simple snorers and patients with obstructive sleep apnea syndrome (OSAS) by using a multidimensional voice program (MDVP) that analyzes various aspects of voice. METHODS: Fifty-eight patients (48 men, 10 women) with a history of snoring were included in the study. All patients underwent conventional polysomnography (PSG). Twelve subjects were diagnosed as simple snorers and 46 subjects were diagnosed with OSAS. The mean body mass index (BMI) of simple snorers was 24.7 kg/m and that of patients with OSAS was 25.8 kg/m. Natural overnight snoring was recorded from each subject while they slept during PSG. Using the multiple token protocols of MDVP, 30 snores from each subject were analyzed automatically. For data analysis, four markers were used: peak frequency, soft phonation index (SPI), noise to harmonics ratio (NHR), and power ratio. RESULTS: The Mann-Whitney U test revealed significant differences between the SPI, NHR, and power ratio of simple snorers and patients with OSAS. Simple snorers had a high SPI value. OSAS-related snorers demonstrated a high NHR and low power ratio. CONCLUSIONS: MDVP can be used for snoring sound analysis as a noninvasive examination of sleep-related breathing disorders for differential diagnosis. However, a suitable option that is rapid and has an easy-to-use interface would be more advantageous for analyzing snoring sounds.

Thyroid gland rupture caused by blunt trauma to the neck.

BACKGROUND: Thyroid rupture following blunt trauma is extremely rare, and neck pain without swelling may be the only presenting symptom. However, hemorrhage and hematoma subsequently causes severe tracheal compression and respiratory distress. CASE PRESENTATION: A 71-year-old Japanese woman visited our emergency room with a complaint of increasing right-sided neck pain at the thyroid cartilage level after she tripped and accidentally hit her neck against a pole 3 h back. On admission, her vital signs were stable. There was no swelling or subcutaneous emphysema. Laryngeal endoscopy revealed mild laryngeal edema, although there was no impairment in vocal fold mobility on either side. Contrast-enhanced computed tomography (CT) revealed rupture of the right lobe of the thyroid gland accompanied by a large hematoma extending from the neck to the mediastinum. Under general anesthesia, the right lobe was resected and the hematoma was evacuated. CONCLUSION: Only a few isolated cases of thyroid rupture caused by blunt neck trauma have been reported in patients with normal thyroid glands and neck pain without swelling may be the only presenting symptom. When suspected, CT should be performed to confirm the diagnosis determine the optimal treatment.

[Combination therapy for severe sleep apnea syndrome].

We assessed the treatment of severe SAS (sleep apnea syndrome) patients who had an AHI (apnea hypopnea index) over 100. Eleven (3.3%) of the 374 patients who came to our hospital between May 2002 and December 2003 had an AHI over 100. They received CPAP (continuous positive airway pressure) therapy as initial therapy, and the AHI recovered within normal limit in the five patients who did not have tonsillar hypertrophy. The other six patients had tonsillar hypertrophy, and the effect of CPAP was poor. Two of the six patients with tonsillar hypertrophy, underwent UPPP (uvuropalatopharyngoplasty), and CPAP become effective postoperatively. These results indicate that combined treatment by CPAP and surgery is an effective means of treating severe SAS with tonsillar hypertrophy.

Evaluation of body growth in prepubertal Japanese children with obstructive sleep apnea after adenotonsillectomy over a long postoperative period.

OBJECTIVE: The aim of this study was to identify changes in body growth patterns in prepubertal Japanese children with obstructive sleep apnea (OSA) after adenotonsillectomy (AT) over a long postoperative period. METHODS: We retrospectively analyzed the hospital records of 69 children, aged 3-10 years with OSA, who were followed-up for a median period of 38 months (range, 24-92 months) after AT. Height and weight were measured during the preoperative period and 12, and 24 months postoperatively, data were converted to standard deviation scores (SDS) using current gender- and age-specific values for the growth parameters adopted by the National growth chart of Japan. Comparisons between the pre and postoperative SDS values for height and weight were performed. The numerical data were examined statistically. RESULTS: The SDS for height and weight of Japanese OSA children significantly increased 24 months post AT and continued over the entire 24-month follow-up period. Height growth acceleration after AT ended earlier in children of 6.0 ± 1.5 years at the time of AT than in children of 4.7 ± 1.3 years who could not catch-up. CONCLUSION: In prepubertal Japanese children with OSA, AT was effective for the growth of those children over a long postoperative period.

Aminopeptidase N isoforms from the midgut of Bombyx mori and Plutella xylostella -- their classification and the factors that determine their binding specificity to Bacillus thuringiensis Cry1A toxin.

Novel aminopeptidase N (APN) isoform cDNAs, BmAPN3 and PxAPN3, from the midguts of Bombyx mori and Plutella xylostella, respectively, were cloned, and a total of eight APN isoforms cloned from B. mori and P. xylostella were classified into four classes. Bacillus thuringiensis Cry1Aa and Cry1Ab toxins were found to bind to specific APN isoforms from the midguts of B. mori and P. xylostella, and binding occurred with fragments that corresponded to the BmAPN1 Cry1Aa toxin-binding region of each APN isoform. The results suggest that APN isoforms have a common toxin-binding region, and that the apparent specificity of Cry1Aa toxin binding to each intact APN isoform seen in SDS-PAGE is determined by factors such as expression level in conjunction with differences in binding affinity.