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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Coenzyme Q10 protects hair cells against aminoglycoside.

It is well known that the production of free radicals is associated with sensory cell death induced by an aminoglycoside. Many researchers have reported that antioxidant reagents protect sensory cells in the inner ear, and coenzyme Q10 (CoQ10) is an antioxidant that is consumed as a health food in many countries. The purpose of this study was to investigate the role of CoQ10 in mammalian vestibular hair cell death induced by aminoglycoside. Cultured utricles of CBA/CaN mice were divided into three groups (control group, neomycin group, and neomycin + CoQ10 group). In the neomycin group, utricles were cultured with neomycin (1 mM) to induce hair cell death. In the neomycin + CoQ10 group, utricles were cultured with neomycin and water-soluble CoQ10 (30-0.3 µM). Twenty-four hours after exposure to neomycin, the cultured tissues were fixed, and vestibular hair cells were labeled using an anti-calmodulin antibody. Significantly more hair cells survived in the neomycin + CoQ10 group than in the neomycin group. These data indicate that CoQ10 protects sensory hair cells against neomycin-induced death in the mammalian vestibular epithelium; therefore, CoQ10 may be useful as a protective drug in the inner ear.

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.

Evaluation of adenotonsillectomy and tonsillectomy for pediatric obstructive sleep apnea by rhinomanometry and the OSA-18 questionnaire.

CONCLUSION: Nasal resistance and the OSA-18 score were useful for evaluating surgical treatments. The sleep disturbance score may also be useful for predicting the severity of obstructive sleep apnea (OSA) in children. OBJECTIVE: We evaluated the effect of surgery on children with OSA using polysomnography (PSG) parameters, nasal resistance, and the OSA-18 questionnaire, and also investigated the cut-off OSA-18 score to screen for pediatric OSA. METHODS: This was a retrospective study in which PSG parameters and nasal resistance were measured using a rhinomanometer and the OSA-18 score was obtained from the OSA-18 questionnaire before and after surgery in 45 children with OSA. RESULTS: The mean age of the 45 patients was 5.7 ± 2.0 years. The mean value of the obstructive apnea hypopnea index (O-AHI) improved from 16.2 ± 14.3/h before surgery to 1.1 ± 1.7/h after surgery, the mean nasal resistance improved from 0.44 ± 0.19 to 0.32 ± 0.10 Pa/cm(3)/s, and the mean OSA-18 score improved from 61.1 ± 13.7 to 30.4 ± 5.8, and all these improvements were significant. The O-AHI value was lower than 1/h after surgery in 64.4% of patients (29/45). The O-AHI value was significantly correlated with the sleep disturbance score (r = 0.352, p = 0.018). When the cut-off OSA-18 score for screening was set at 40, sensitivity was 100%.

Analytical performance of newly developed multiplex human papillomavirus genotyping assay using Luminex xMAP™ technology (Mebgen™ HPV Kit).

Regional differences in human papillomavirus (HPV) genotypes and the presence of mixed HPV infections may affect adversely the efficacy of the HPV vaccine. Therefore, a simple and high-throughput HPV genotyping system is required. Recently, a novel HPV genotyping kit (the Mebgen™ HPV kit) was developed. This kit uses multiplex PCR and Luminex xMAP™ technology to detect 13 types of high-risk HPVs and an internal control in a 96-well format. In the present study, the analytical performance of the kit was examined using HPV plasmid DNA. All 13 types of HPVs were detected with a minimum detection sensitivity of 250 copies/test, and highly specific signals were observed. HPV 16 plasmid was detected in samples containing mixtures with other HPV-type plasmids in ratios ranging from 1:1 to 1:1000. No cross reactivity was observed with DNA from 27 types of other infectious microbes. A clinical evaluation was carried out using cervical samples from 356 patients with persistent abnormal smears diagnosed at mass public health screenings for cervical cancer. The samples were preserved in Tacas™ medium until analysis. HPV was detected in 162 (45.5%) samples including 110 (67.9%) with single infections and 52 (32.1%) with multiple infections. The type distribution of the 13 high-risk HPVs was as follows: 28.4% HPV 16, 11.7% HPV 18, 6.8% HPV 31, 3.1% HPV 33, 3.7% HPV 35, 9.3% HPV 39, 1.9% HPV 45, 8.6% HPV 51, 37.0% HPV 52, 9.3% HPV 56, 16.7% HPV 58, 3.7% HPV 59, and 1.9% HPV 68. To evaluate sample stability over time, changes in the detection of HPV DNA derived from HeLa and SiHa cells were measured in 3 types of liquid-based cytology media. HPV DNA was detected in Tacas and Thinprep™ samples after storage at 4°C or 30°C for 4 weeks and within 1 week of collection in Surepath™ samples. These results suggest that this newly developed HPV genotyping kit is suitable for use in both clinical applications and large-scale epidemiological studies.

Effectiveness of laryngotracheal separation in neurologically impaired pediatric patients.

CONCLUSION: Laryngotracheal separation (LTS) can prevent aspiration pneumonia, improve the respiratory condition, and offer the possibility of home care for neurologically impaired children. OBJECTIVES: This study aimed to evaluate the effectiveness of LTS in neurologically impaired pediatric patients from the viewpoint of postoperative success of pneumonia prevention, improvement in the respiratory condition, and postoperative success rate of home-based care. METHODS: The medical records of 21 children who underwent LTS at an academic medical center from September 2004 to March 2013 were retrospectively investigated. Pre- and postoperative data, including the frequency of pneumonia treatment, the frequency of sputum suctioning, the respiratory condition, the nutrition method, and the outcome after LTS were assessed. We also used the scoring system for patients with severe motor and intellectual disabilities, medical care dependent group (SMID-MCDG) in Japan for evaluating the usefulness of LTS. RESULTS: The frequency of pneumonia treatment and that of suctioning decreased considerably after LTS. Furthermore, the respiratory condition improved at a rate of 63.19%. The SMID-MCDG score significantly reduced after LTS. No significant complications were observed and two-thirds of the patients were successfully discharged for home care after the procedure.

Surgical planning of Isshiki type I thyroplasty using an open-source Digital Imaging and Communication in Medicine viewer OsiriX.

CONCLUSION: Preoperative surgical planning of Isshiki type I thyroplasty with the Digital Imaging and Communication in Medicine (DICOM) viewer OsiriX can be used for strategic and predictable type I thyroplasty. OBJECTIVES: The aim of this study was to determine the efficacy of the preoperative planning of type I thyroplasty using the DICOM viewer OsiriX. METHODS: Five patients with unilateral vocal cord paralysis and severe breathy dysphonia were included in this study. Multidetector computed tomography (CT) DICOM data were obtained and breath holding was performed during image acquisition. Using three-dimensional multiplanar reconstruction, we outlined the optimal location for a window. Type I thyroplasty was performed using Isshiki's original method, and only the placement of the window was decided according to the preoperative simulation point. To verify the advantages of this method, we compared our data with the previous data for total operation time and voice quality at 3 months after the operation without the DICOM viewer planning. RESULTS: All patients are free from dysphonia and their glottic closures have resolved satisfactorily. Postoperative CT revealed that appropriate implant positioning resulted in successful surgical intervention. The comparison of total operation time showed that with the new method, operation duration was shortened by 12 min.