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Objective: This study aimed to investigate risk factors predictive of local recurrence and/or lymph node metastasis after transoral resection of early hypopharyngeal cancer., Methods: Forty-nine consecutive patients who underwent transoral videolaryngoscopic surgery (TOVS) as an initial treatment for hypopharyngeal cancer were evaluated. On univariate and multivariate analysis, local recurrence rates were assessed respectively using log-rank test and cox regression analysis according to the following parameters: subsite, pT, mucosal margin, lymphatic invasion, vessel invasion, tumor thickness (> 4 mm vs ≤4 mm), history of esophageal cancer, and multiple Lugol-voiding lesions (LVLs) in the esophagus. Categorical variables were evaluated for their associations with lymph node metastasis using chi-squared test or Fisher's exact test., Result: The subsites of primary lesions were piriform sinus in 24 patients, posterior wall in 15 patients, and postcricoid in 10 patients. Thirty patients had esophageal cancer. Local recurrence occurred in 14 patients. Three patients had lymph node metastasis at the time of diagnosis and four patients developed lymph node metastasis after the initial treatment, resulting a total of seven patients having lymph node metastasis. While mucosal margin and LVLs showed significant associations with local recurrence on univariate analysis, only LVLs remained as a significant risk factor on multivariate analysis ( P  = .0395; hazard ratio = 8.897; 95% confidence interval, 1.113-71.15). Most cases of local recurrence were satisfactorily controlled by repeated TOVS. While multivariate analysis could not be performed due to the small number of the patients with lymph node metastases, venous invasion ( P  = .0166) and tumor thickness ( P  = .0092) were significantly associated with lymph node metastasis on univariate analysis., Conclusions: Local recurrence was more frequent in patients with LVLs, but most of them were salvaged by repeated TOVS. Patients with venous invasion and/or tumor thickness greater than 4 mm should be followed up with special attention to lymph node metastasis.Level of Evidence: 3., Competing Interests: The authors declare no conflicts of interest., (© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC. on behalf of The Triological Society.)

Background: We previously reported that a high tumor burden is a prognostic factor based on an analysis of 26 patients with radioactive iodine-refractory differentiated thyroid cancer (RR-DTC) who were treated with lenvatinib. However, the optimal tumor burden for starting lenvatinib still remains to be defined. The aim of this retrospective study was to further explore in the same patient cohort the optimal timing for the start of lenvatinib by focusing on the pre- and post-treatment tumor burden., Methods: The 26 patients were treated with lenvatinib from 2012 to 2017. We explored the optimal timing for the start of lenvatinib by comparing the characteristics of long-term responders who were defined as patients with progression-free survival ≥ 30 months and non-long-term responders., Results: Long-term responders had a smaller post-treatment tumor burden at maximum shrinkage than non-long-term responders. Further, post-treatment tumor burden had a strong linear correlation with baseline tumor burden. We created an estimation formula for baseline tumor burden related to prognosis, using these regression lines. Patients with a sum of diameters of target lesions < 60 mm or maximum tumor diameter < 34 mm at baseline were estimated to have significantly better survival outcomes., Conclusions: We found a strong linear correlation between pre- and post-treatment tumor burden. Our results suggested a cut-off value for baseline tumor burden for long-term prognosis among patients treated with lenvatinib., Competing Interests: NK has received grant support from Eisai, Inc.; research funding from Ono Pharmaceutical and Pfizer; and honoraria from Ono Pharmaceutical, Bristol-Meyers Squibb, Astra Zeneca, Eisai, Bayer and Merck Serono. K-iN has received honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Sanofi, Taiho, Nippon Shinyaku, MSD, Sanofi, Kyorin Tanabe-Mitsubishi, Rakuten Medical, Medtronic, Eisai, Astra Zeneca. HM has received research funding from Astellas, Bristol-Myers Squibb, Chugai, Dainippon Sumitomo Pharma, Eisai, Kyowa Hakko Kirin, Lilly Japan, Novartis, Ono Pharmaceutical, Sanofi, Taiho, Nippon Shinyaku, MSD, Boehringer Ingelheim, Daiichi Sankyo, Merck Serono, Takeda, Teijin Pharma, Yakult, Asahi Kasei and CSL Behring; and honoraria from Bayer, Bristol-Myers Squibb, Celgene, Chugai, Daiichi-Sankyo, Dainippon Sumitomo, Eisai, Janssen, Kowa, Kyowa Hakko Kirin, Lilly Japan, Merck Serono, Novartis, Ono Pharmaceutical, Otsuka, Pfizer, Sanofi, Shire, Taiho, Takeda and MSD; and filled a consulting/advisory role with Ono Pharmaceutical and Merck Serono. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Suzuki, Kiyota, Imamura, Goto, Suto, Chayahara, Toyoda, Ito, Miya, Miyauchi, Teshima, Otsuki, Nibu and Minami.)

Ror2 (receptor tyrosine kinase like orphan receptor 2) is highly expressed in various types of cancers; in the majority of these cancers, Ror2 expression is associated with more aggressive disease states. Recently, it has been reported that Ror2 is highly expressed in human papilloma virus (HPV)‑positive head and neck squamous cell cancer (HNSCC) cell lines, presumably indicating that Ror2 plays a critical role in HPV‑related cancers. However, the function of Ror2 in HPV‑positive HNSCC is currently unknown. Here, we first examined the expression levels of Ror2 in clinical specimens from patients with HPV‑negative and HPV‑positive oropharyngeal squamous cell cancer (OPSCC) via immunohistochemical analysis. We found that Ror2 was expressed in both HPV‑negative and HPV‑positive OPSCC tissues. We then confirmed that HPV‑positive HNSCC cell line, UPCI:SCC152 cells, express Ror2 higher than HPV‑negative cell lines as previously reported. Suppressed expression of HPV E6/7 resulted in reduced expression levels of Ror2. We also revealed that Ror2 downregulation significantly inhibited the proliferation of UPCI:SCC152 cells without inducing apoptosis. Moreover, Ror2 knockdown decelerated G 1 /S phase progression and abrogated invasive migration of UPCI:SCC152 cells. These results provide strong evidence that E6 and/or E7 oncoproteins regulate the progression of HPV‑positive HNSCC by upregulating Ror2 expression, suggesting that Ror2 could potentially be a novel target in HPV‑related cancers.

Objectives: The aim of this multicenter retrospective cohort study was to compare efficacy and subsequent postoperative treatment between transoral robotic surgery (TORS) and any non-robotic transoral surgery in Japanese patients with early oropharyngeal squamous cell carcinoma (OPSCC), hypopharyngeal SCC (HPSCC), or supraglottic SCC (SGSCC)., Materials and Methods: Clinical information and surgical outcomes were compared between patients with early-stage OPSCC, HPSCC, and SGSCC who underwent TORS (TORS cohort) and those who underwent non-robotic transoral surgery, including transoral videolaryngoscopic surgery (TOVS), endoscopic laryngopharyngeal surgery (ELPS), and transoral laser microsurgery (TLM) (non-robotic cohort). The data of the Head and Neck Cancer Registry of Japan (registry cohort) were used to validate the comparison. The main outcomes were the presence of positive margins under pathology and the requirement for postoperative therapy, including radiotherapy or chemoradiotherapy., Results: Sixty-eight patients in the TORS cohort, 236 patients in the non-robotic cohort, and 1,228 patients in the registry cohort were eligible for this study. Patients in the TORS cohort were more likely to have oropharyngeal tumor disease and T2/3 disease than those in the other cohorts (P<0.001 and P=0.052, respectively). The TORS cohort had significantly fewer patients with positive surgical margins than the non-robotic cohort (P=0.018), as well as fewer patients who underwent postoperative treatment, although the difference was not significant (P=0.069). In the subgroup analysis of patients with OPSCC, a total of 57 patients in the TORS cohort, 73 in the non-robotic cohort, and 171 in the registry cohort were eligible for the present study. Patients with OPSCC who underwent TORS were more likely to have lateral wall lesions than those in the other cohorts (P=0.003). The TORS cohort also had significantly fewer patients with positive surgical margins than the non-robotic cohort (P=0.026), and no patients in the TORS cohort underwent any postoperative treatment for OPSCC, although the difference was not significant (P=0.177)., Conclusions: Our results suggest that TORS leads to fewer positive surgical margins than non-robotic transoral surgeries. The clinical significance of TORS may be further validated through the results of all-case surveillance for patients who underwent TORS running in Japan in the future., (Copyright © 2021. Published by Elsevier B.V.)

Non-recurrent inferior laryngeal nerve (NRILN) is rare but one of the important anatomical variations in thyroid and parathyroid surgery. Almost all cases were observed on the right side with aberrant right subclavian artery and left NRILN have been reported in only five cases so far. Here, we reported a 38 year-old Japanese male with left NRILN accompanying adenomatous goiter. He was referred to our hospital for the surgical treatment of left thyroid goiter. Preoperative computed tomography revealed right-sided aortic arch and aberrant left subclavian artery with no signs of complete situs inversus viscerum, suggesting possible left NRLN. Left hemithyroidectomy was performed using nerve monitoring system. Intraoperatively, left recurrent laryngeal nerve was not identified along tracheoesophageal groove, but directly originated from vagal nerve and was running horizontally to larynx. Mobility of vocal cords were not impaired and postoperative course was uneventful. During thyroid surgery for the patients with right-sided aortic arch, meticulous care should be taken using nerve monitoring system to avoid nerve injury., Competing Interests: Declaration of Competing Interest All authors have no conflict of interests to be disclosed on this work., (Copyright © 2020. Published by Elsevier B.V.)

Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the "solid tumor component" has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease-free, and distant metastasis-free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease-free or distant metastasis-free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objectives: This study aimed to evaluate the efficacy of chemoradiotherapy (CRT) for patients with advanced cancer of the external auditory canal (EAC) by analyzing the outcome of the patients., Methods: This is a multi-institutional retrospective survey, and we reviewed the medical records of the subjects. A total of 181 patients with tumor (T)3 or T4 tumor in 17 institutions were enrolled. Further analysis was performed for 74 patients who underwent CRT under curative intent., Results: Overall 5-year survival rates of the patients who underwent CRT (n = 74) were 54.6%. Those of the patients who underwent CRT with modified TPF (docetaxel, cisplatin [CDDP], and 5-fluorouracil) regimen (n = 50) and CRT with CDDP regimens (n = 24) were 64.4% and 36.7%, respectively. Significant differences were observed between these two groups., Conclusion: Given the tendency that head and neck surgeons prefer CRT for advanced larger cancer of the EAC, CRT for advanced EAC cancer using the modified TPF regimen showed good clinical outcomes., Level of Evidence: 4 Laryngoscope, 131:E870-E874, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: This prospective study investigated the change of swallowing ability using the Swallowing Ability Scale System (SASS) and swallowing-related quality of life (QOL) by Performance Status Scale for Head and Neck Cancer patients (PSS-H&N). This study also investigated the risk factors for postoperative dysphagia in patients who received reconstructive surgery for oral cancer., Subjects and Methods: This study included 64 patients (33 men and 31 women) who underwent radical surgery with neck dissection and reconstructive surgery for oral cancers between July 2014 and February 2018. We evaluated risk factors for poor swallowing ability after treatment, including demographic factors, preoperative factors and perioperative factors, with univariate and multivariate analyses. The change of swallowing ability by the SASS and swallowing-related QOL by PSS-H&N were evaluated prospectively prior to the initiation of surgery within 1 week and at 1 and 3 months after treatment., Results: Advanced T stage (T3, 4) (odds ratio (OR) = 79.71), bilateral neck dissection (OR = 20.66) and the resection of unilateral or bilateral suprahyoid muscles (OR = 17.00) were associated with poor swallowing ability after treatment. The scores for time for food intake and Eating in Public were associated with decrease of QOL in the poor group., Conclusions: We propose that clinicians consider the risk factors identified in this study and pay close attention to the management of oral cancer patients with reconstructive surgery.

Background: To evaluate factors associated with osteoradionecrosis of the jaw (ORNJ) in patients with head and neck squamous cell carcinoma (HNSCC), focusing on jaw-related dose-volume histogram (DVH) parameters., Methods: We retrospectively reviewed the medical records of 616 patients with HNSCC treated with curative-intent or postoperative radiation therapy (RT) during 2008-2018. Patient-related (age, sex, history of smoking or alcohol use, diabetes mellitus, performance status, pre-RT dental evaluation, pre- or post-RT tooth extraction), tumor-related (primary tumor site, T-stage, nodal status), and treatment-related (pre-RT surgery, pre-RT mandible surgery, induction or concurrent chemotherapy, RT technique) variables and DVH parameters (relative volumes of the jaw exposed to doses of 10 Gy-70 Gy [V10-70]) were investigated and compared between patients with and without ORNJ. The Mann-Whitney U test was used to compare RT dose parameters. Univariate and multivariate Cox regression analyses were used to assess factors associated with ORNJ development. Kaplan-Meier analyses were performed for cumulative ORNJ incidence estimation., Results: Forty-six patients (7.5%) developed ORNJ. The median follow-up duration was 40 (range 3-145) months. The median time to ORNJ development was 27 (range 2-127) months. DVH analysis revealed that V30-V70 values were significantly higher in patients with than in those without ORNJ. In univariate analyses, primary tumor site, pre-RT mandible surgery, post-RT tooth extraction, and V60 > 14% were identified as important factors. In multivariate analyses, V60 > 14% (p = 0.0065) and primary tumor site (p = 0.0059) remained significant. The 3-year cumulative ORNJ incidence rates were 2.5% and 8.6% in patients with V60 ≤ 14% and > 14%, respectively (p < 0.0001), and 9.3% and 1.4% in patients with oropharyngeal or oral cancer and other cancers, respectively (p < 0.0001)., Conclusions: V60 > 14% and oropharyngeal or oral cancer were found to be independent risk factors for ORNJ. These findings might be useful to minimize ORNJ incidence in HNSCC treated with curative RT.

Orbital decompression (OD) for Graves' orbitopathy usually includes removal of orbital medial wall. While OD occasionally cause or worsen chronic sinusitis because of the obstructed sinus drainage by prolapsed orbital fat, to date few reports have been published on the management or prevention of sinusitis associated with OD. Here, we present two patients (three sides) with newly developed and one patient (one side) with worsening obstructive frontal sinusitis following OD. These three patients had OD including the removal of the superior attachment of uncinated process to lamina papyracea. Endoscopic modified Lothrop procedure (EMLP) was useful to relieve symptoms and keep an enough access to frontal sinuses for all cases. We also performed EMLP for another two patients (four sides) with pre-existing sinusitis before OD. Worsening of sinusitis could be avoided by EMLP before OD. EMLP was useful approach for both treatment and prevention of sinusitis related to OD. The superior attachment site of uncinated process and the pattern of frontal sinus drainage might predict the occurrence of obstructive frontal sinusitis following OD., Competing Interests: Declaration of Competing Interest All authors have no conflict of interest related with this paper., (Copyright © 2020. Published by Elsevier B.V.)

We hypothesized that, in discrimination between benign and malignant parotid gland tumors, high diagnostic accuracy could be obtained with a small amount of imbalanced data when anomaly detection (AD) was combined with deep leaning (DL) model and the L 2 -constrained softmax loss. The purpose of this study was to evaluate whether the proposed method was more accurate than other commonly used DL or AD methods. Magnetic resonance (MR) images of 245 parotid tumors (22.5% malignant) were retrospectively collected. We evaluated the diagnostic accuracy of the proposed method (VGG16-based DL and AD) and that of classification models using conventional DL and AD methods. A radiologist also evaluated the MR images. ROC and precision-recall (PR) analyses were performed, and the area under the curve (AUC) was calculated. In terms of diagnostic performance, the VGG16-based model with the L 2 -constrained softmax loss and AD (local outlier factor) outperformed conventional DL and AD methods and a radiologist (ROC-AUC = 0.86 and PR-ROC = 0.77). The proposed method could discriminate between benign and malignant parotid tumors in MR images even when only a small amount of data with imbalanced distribution is available.

Mucoepidermoid carcinoma (MEC) is rare, but the most common primary malignancy of the salivary gland and not infrequent in young individuals. CRTC1/3-MAML2 fusions are frequently detected in MEC and are useful as a diagnostic biomarker. However, there has been debate as to whether the fusions have prognostic significance. In this study, we retrospectively collected 153 salivary gland MEC cases from 11 tertiary hospitals in Japan. As inclusion criteria, the MEC patients in this study had curative surgery as the initial treatment, received no preoperative treatment, and had no distant metastasis at the time of the initial surgery. The MEC diagnosis was validated by a central pathology review by five expert salivary gland pathologists. The CRTC1/3-MAML2 fusions were detected using FISH and RT-PCR. In 153 MEC cases, 90 (58.8%) were positive for CRTC1/3-MAML2 fusions. During the follow-up period, 28 (18.3%) patients showed tumor recurrence and 12 (7.8%) patients died. The presence of the fusions was associated with favorable tumor features. Of note, none of the fusion-positive patients died during the follow-up period. Statistical analysis showed that the presence of the fusions was a prognostic indicator of a better overall survival in the total and advanced-stage MEC cohorts, but not in the early-stage MEC cohort. In conclusion, CRTC1/3-MAML2 fusions are an excellent biomarker for favorable overall survival of patients with salivary gland MEC., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Owing to the low incidence of adenoid cystic carcinoma (AdCC), reliable survival estimates and prognostic factors remained unclarified., Methods: In this multi-institutional retrospective analysis, we collected 192 AdCC cases, and investigated the impact of clinicopathological factors on clinical outcomes of the patients. All AdCC cases were of salivary gland origin and were surgically treated with curative intent. Diagnoses of AdCC were validated by a central pathology review by expert pathologists., Results: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 92.5 and 50.0%, respectively. Treatment failure occurred in 89 patients (46%) with the distant failures in 65 (34%). Multivariate analysis indicated that pN2 and a pathologically positive surgical margin were independent prognostic factors for both OS and DFS. Histological grade III was an independent prognostic factor for OS. A primary site in the submandibular gland, pT3/4, pN1, and histological grade II were independent prognostic factors for DFS. Postoperative radiation therapy (PORT) improved the locoregional control (LRC) rate. Prophylactic neck dissection was not associated with a better OS or better LRC among patients with cN0. Facial nerve dissection did not improve clinical outcomes in parotid AdCC cases without facial nerve palsy., Conclusions: A higher TN classification, a pathologically positive surgical margin, and a higher histological grade were associated with a lower OS. PORT improved LRC rates but neck dissection failed to improve clinical outcomes in patients with cN0. As the distant metastasis was frequent, effective systemic therapy is imperative to improve the survival of AdCC patients.

Objective: We conducted a 3-year prospective study on olfaction of patients with Parkinson's disease (PD) in order to examine the severity and frequency of smell disorder in PD using odor identification test, Open Essence (OE) and to verify the validity of olfactory tests as a predictor of cognitive symptom onset of PD., Patients and Methods: We conducted a prospective study by performing an annual examination over a 3-year period. For 56 cases diagnosed with PD by the Department of Neurology at our hospital, OE and Jet Stream Olfactometry (JSO) were performed to assess the olfactory function, and Mini-Mental-State Examination (MMSE) was conducted to measure cognitive impairment., Results: At the beginning, 56 cases were examined, of which 42 remained to be followed up for 3 years. Based on the results of baseline, we found a correlation between OE and the average cognitive thresholds of JSO, but did not find any correlation between OE and MMSE. OE (median 4.0→4.0) and the average cognitive thresholds of JSO (median 2.2→1.6)　decreased after 3 years, and MMSE (median 29→29) also declined, but not significantly. At the 3rd year, 6 cases with MMSE score of 23 or less were identified as suspected dementia and 36 cases with more than 24 points were defined as an invariant group. In order to distinguish these two groups, OE scores of baselines were evaluated with a combination of 12 odors. Sensitivity 1.0 and specificity 0.722 were obtained and the sensitivity+specificity value (1.722) was the highest when the number of correct answers was 4 or less using an odor combination of lumber, menthol, Japanese orange, gas for household use, Hinoki cypress and condensed milk., Conclusion: When the number of correct answers of 6 odors (lumber, menthol, Japanese orange, gas for household use, Hinoki cypress and condensed milk) is 4 or less in patients with PD, there is a possibility that MMSE declines in 3 years., (Copyright © 2020 Elsevier B.V. All rights reserved.)

To clarify the patterns of the recurrence and to assess the oncological and functional outcomes after salvage surgery for the patients with structural local recurrence of papillary thyroid cancer (PTC), twenty-five patients who underwent salvage surgery for structural local recurrence of PTC were retrospectively reviewed. Structural recurrences were observed in the tracheal lumen in 5 patients, intraluminal or intramuscular esophagus in 5 patients, trachea, and cricoid cartilage in 9 patients, cricoid and thyroid cartilage in 2 patients, intra-lumen of the larynx in 1 patient and soft tissue around thyroid in 3 patients, respectively. Although all local disease was resected with macroscopically negative margin, 10 patients diagnosed as microscopically positive margin. Major surgical complications occurred in 6 patients, including common carotid artery injury (n = 1), unintentional pharyngeal or esophageal injury (n = 2), recurrent laryngeal nerve paralysis (n = 2), and pharyngeal fistula resulting in common carotid artery rupture (n = 1), and were successfully managed. During the follow-up periods, 6 patients were alive without disease, 15 patients survived with distant metastases and/or locoregional recurrence, and 4 patients died of the disease. While tracheocutaneous fistula remained in 7 patients, the vocal function was preserved in all patients but one who underwent total laryngectomy. Normal oral intake was retained in all patients. In conclusion, although salvage surgery for structural recurrence of PTC has a high risk of complications, it may be worthwhile when macroscopic curative resection is available. The decision should be made considering various factors including curability, risk of surgical procedure, functional outcome, and life expectancy.

Temporal bone cancer is extremely rare; thus, the optimal surgical strategy for advanced tumors, en bloc vs piecemeal resection, remain controversial. Some authors have favored piecemeal resection and reported comparable outcomes.1 Other authors recommend the use of en bloc subtotal temporal bone resection (STBR) for advanced tumors and reported better outcomes, although long-term cancer control remains uncertain.2 Because of the technical difficulty and the lack of demonstrative surgical videos, STBR has not been sufficiently distributed. This video demonstrates en bloc STBR in a stepwise manner with particular focus on the neurosurgeon's role and aims to improve its safety, feasibility, and distribution. This video conforms to the description of Osawa et al3 in the designations for each segment of the petrous ICA. A 67-yr-old man suffered from consistent otorrhea and underwent tympanoplasty at an outside hospital 1 yr earlier. Following a histopathological diagnosis of squamous cell carcinoma in the specimen, he underwent chemoradiotherapy (cisplatin + 70 Gy). However, a current imaging revealed a recurrent tumor and he was admitted to our hospital for radical resection. Computed tomography revealed a disrupted external auditory canal and magnetic resonance imaging indicated a carcinoma equivalent to Pittsburg stage T3. The patient underwent radical STBR without complications. His postoperative course was uneventful. At 2 yr postoperative, his modified Rankin scale score was 1, no recurrence was noted, and his facial nerve function was restored to House-Brackmann Grade IV. This video was reproduced with informed consent from the patient., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: Although the American Joint Committee on Cancer TNM classification has been amended to include human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) as an independent entity, to the authors' knowledge the optimized de-escalating treatment modality has not been established to date., Methods: The authors conducted a retrospective, nationwide, observational study in patients with HPV-related OPSCC who were treated from 2011 to 2014 in Japan to determine the best treatment modality., Results: A total of 688 patients who were newly diagnosed with HPV-related OPSCC who were treated with curative intent at 35 institutions and had coherent clinical information and follow-up data available were included in the current study. In patients with T1-T2N0 disease (79 patients), both the 3-year recurrence-free survival and overall survival (OS) rates were 100% in the group treated with radiotherapy (RT) as well as the group receiving concurrent chemoradiotherapy (CCRT). The 3-year OS rates were 94.4% (for patients with T1N0 disease) and 92.9% (for patients with T2N0 disease) among the patients treated with upfront surgery. In patients with stage I to stage II HPV-related OPSCC, the 5-year recurrence-free survival and OS rates were 91.4% and 92%, respectively, in the patients treated with CCRT with relatively high-dose cisplatin (≥160 mg/m 2 ; 114 patients) and 74.3% and 69.5%, respectively, in the patients treated with low-dose cisplatin (<160 mg/m 2 ; 17 patients)., Conclusions: Despite it being a retrospective observational trial with a lack of information regarding toxicity and morbidity, the results of the current study demonstrated that patients with T1-T2N0 HPV-related OPSCC could be treated with RT alone because of the equivalent outcomes of RT and CCRT, and patients with stage I to stage II HPV-related OPSCC other than those with T1-T2N0 disease could be treated with CCRT with cisplatin at a dose of ≥160 mg/m 2 ., (© 2020 American Cancer Society.)

Background: To assess the role of a central pathology review in the diagnosis of salivary gland adenoid cystic carcinoma (AdCC)., Methods: Surgically resected salivary gland tumors diagnosed as AdCC (n = 219) in 15 reference hospitals in Japan were subjected to a retrospective pathological re-evaluation., Results: After the review, the AdCC diagnosis was revised in 21/219 cases (9.6%). The six benign tumors (2.7%) comprised five basal cell adenomas and one pleomorphic adenoma, and among these six patients, three received postoperative radiotherapy. The remaining 15 malignant tumors (6.8%) comprised nine basal cell adenocarcinomas and six other carcinomas. All revised basal cell adenoma/adenocarcinoma cases were of rare cribriform variants., Conclusions: A significant proportion of AdCC pathology reports were revised after the central pathology review. It should be emphasized that the greatest attention should be paid in differentiating AdCC from cribriform variant basal cell adenoma/adenocarcinoma, which is very rare in salivary gland tumors., (© 2020 Wiley Periodicals, Inc.)

The symptoms of Meniere's disease (MD) are generally considered to be related to endolymphatic hydrops (EH). There are many recent reports supporting the possibility that vasopressin (VP) is closely linked to the formation of EH in Meniere's disease. Based on this, we developed a clinically relevant animal model of Meniere's disease in which a VP type 2 receptor agonist was administered after electrocauterization of the endolymphatic sac. We report live imaging of the internal structure, and functional changes of the inner ear after electrocauterization of the endolymphatic sac and administration of a VP type 2 receptor agonist. In this model, the development of EH was visualized in vivo using optical coherence tomography, there was no rupture of Reissner's membrane, and low-tone hearing loss and vertiginous attacks were observed. This study suggested that acute attacks are caused by the abrupt development of EH. This is the first report of live imaging of the development of EH induced by the administration of a VP type 2 receptor agonist.

Background: No clear consensus has been reached on the indication of supraomohyoid neck dissection (SOHND) for clinically positive lymph-node metastasis., Patients: Consecutive 100 patients with previously untreated oral cancer treated at Kobe University Hospital were included in this study. All patients were clinically staged as anyTN1M0 and underwent radical dissection of the primary site and level I-V neck dissection as the initial treatment., Results: None of the 100 patients had pathological lymph-node metastasis (pLN) to level V. pLN to level IV was observed in two patients with tongue cancer in whom clinical lymph-node metastasis was preoperatively observed at level II., Conclusions: Level V may be excluded in the neck dissection for patients with N1 oral cancers. Level IV dissection should be considered in the patient with tongue cancer and clinical lymph-node metastasis at level II.

Background: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinomas (HNSCCs). Midkine expression is restricted in adult tissues but is increased in several malignant tumors, including HNSCCs., Aim: Here, we evaluated the antitumor effect of Midkine promoter-based conditionally replicative adenovirus expressing siRNA against EGFR for targeting HNSCCs expressing Midkine., Methods and Results: A conditionally replicative adenovirus vector controlled by the Midkine promoter, Ad-MK-siEGFR, was generated by integrating gene-expressing siRNA against EGFR. Antitumor effect of Ad-MK-siEGFR was tested in vitro using established HNSCC cell line, T891 with strong Midkine expression. Expression of EGFR in T891 infected with Ad-MK-siEGFR was significantly lower than that of T891 infected with control. Cytotoxicity assays showed significant growth suppression of Ad-MK-siEGFR in T891 cells., Conclusions: This study demonstrated the possibility of oncolytic therapy using the Midkine promoter-based conditional replication-selective adenovirus containing siRNA against EGFR in HNSCC cell line T891. Further validation of the findings in more cell lines and in vivo should be performed to clarify the potential clinical application., (© 2020 The Authors. Cancer Reports published by Wiley Periodicals, Inc.)

Aims: Mucoepidermoid carcinoma (MEC) is one of the most common salivary gland carcinomas. Epidermal growth factor receptor (EGFR) signalling pathway gene mutations are important in predicting a patient's prognosis, selecting molecularly targeted drugs and estimating the efficacy of a molecular therapy. However, their significance in MEC have been poorly clarified. CRTC1/3-MAML2 fusions are specific to MEC and may be associated with favourable characteristics in these patients., Methods and Results: We looked for CRTC1/3-MAML2 fusions and gene alterations in the EGFR, RAS family (KRAS, HRAS and NRAS), PIK3CA, BRAF and AKT1 in 101 MEC cases. We also examined mutations in TP53. CRTC1/3-MAML2 fusions were found in 62.4% of the cases. KRAS, HRAS and PIK3CA mutations were detected in 6.9%, 2.0% and 6.9%, respectively, but other EGFR pathway genes were not mutated. In total, gene mutations (RAS/PIK3CA) in the EGFR pathway were detected in 14.9% of the cases. TP53 mutations were found in 20.8%. CRTC1/3-MAML2 fusions were associated with a better prognosis and RAS/PIK3CA mutations a worse prognosis of the patients, respectively, and both were selected as independent prognostic factors for the overall survival of the patients. TP53 mutations had no prognostic impact. CRTC1/3-MAML2 fusion-positive rates were inversely associated with the patients' age and the fusions were found in 82% of patients aged < 30 years., Conclusions: RAS/PIK3CA mutations were frequently detected, and may be a biomarker for a poorer prognosis in MEC patients. CTRC1/3-MAML2 fusions were positive in most of the young MEC patients., (© 2020 John Wiley & Sons Ltd.)

Background: Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chemoradiotherapy (CRT). This study examined the safety and efficacy of ibuprofen gargle in healthy volunteers and patients with chemotherapy- and concomitant CRT-induced oral mucositis., Methods: We enrolled healthy volunteers and patients with chemotherapy- and CRT-induced oral mucositis. In cohort I, single and multiple doses of ibuprofen gargle (0.6% or 1.0%) were administered to healthy volunteers on day 1 and days 4-10. In cohort II, multiple doses of ibuprofen gargle (0.6%) were administered to patients with complicated grade 2-3 oral mucositis based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary endpoint of cohort I was the treatment-related adverse events (TRAEs) as defined by CTCAE version 4.0. The primary endpoint of cohort II was the change in the visual analogue scale (VAS) pain score from before to 15 min after gargle use on day 3. The incidence and severity of TRAEs were assessed based on the CTCAE version 4.0 and a subjective rating scale completed by healthy volunteers and patients., Results: In cohort I, 9 of 10 healthy volunteers were evaluable for safety. All 9 healthy volunteers reported the TRAE of oral irritation with single or multiple use of the gargle. In cohort II, 10 patients were enrolled and evaluable for safety and 7 of 10 patients were evaluable for efficacy. The mean change in the VAS pain score from before to 15 min after using the gargle on day 3 was - 1.28 (95% confidence interval: - 2.06, - 0.51), and all patients experienced some degree of pain relief (range: - 0.2 to - 2.5). All 10 patients reported the TRAE of oral irritation. No other TRAEs of ibuprofen gargle were observed in the healthy volunteers and patients., Conclusion: Despite oral irritation, the ibuprofen gargle appeared to be safe and effective for the pain related to chemo- or CRT-induced oral mucositis. However, ibuprofen-related oral irritation warrants further formulation improvement., Trial Registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000014433)., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

An 18-year-old man had a painless, elastic, firm mass in his left parotid area that gradually increased in size over a period of 6 months. At the time of examination, the parotid mass was poorly mobile and 46 mm in size. Although fine needle aspiration cytology revealed no malignant findings, we suspected a malignancy because the movement of his left mouth angle was slightly impaired; facial nerve paralysis as a result of tumor invasion was suspected. A superficial parotidectomy was performed. The tumor had a strong adhesion to the subcutaneous tissue and facial nerve. Histologically, multiple, randomly distributed cystic structures containing keratinized lamellae were present. The cystic spaces were lined with stratified squamous epithelium lacking a granular layer, and no skin appendage was observed. We diagnosed this case as a keratocystoma. Keratocystoma of the parotid gland is a rare benign tumor with only 6 cases reported worldwide. This case is the first to describe facial nerve palsy in association with a keratocystoma., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To investigate the oncological and functional outcomes of the patients treated with transoral CO2 laser cordectomy for early glottic cancer., Patients and Methods: Fifty-five consecutive patients who underwent CO2 laser cordectomy for early glottic cancer were retrospectively reviewed., Results: Overall survival, larynx preservation, and relapse free local control rates were 96%, 100%, and 91%, respectively. Five patients with local recurrences were salvaged with re-cordectomy and/or radiotherapy. In type I cordectomy, VHI-10 consistently improved during postoperative course and VHI-10 at postoperative 12months was significantly better than preoperative value (2.3 vs. 9.4, p=0.02). Perceptual grading, MPT, MFR and AC/DC also improved and were better than preoperative values. In type III cordectomy, shimmer at 12months after cordectomy was significantly better than preoperative value (14.7 vs. 9.3, p=0.007)., Conclusions: These results further support the rationale of CO2 cordectomy as initial and salvage surgery for early glottic cancer., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Free flap reconstruction in elderly patients is one of the most challenging surgeries in the treatment of head and neck cancers. The aim of this study was to examine the oncological and functional outcomes of free flap reconstruction for elderly patients with head and neck cancer., Methods: We retrospectively reviewed elderly patients who underwent free flap reconstruction for the treatment of head and neck cancers. All patients were 80 years or older. Clinicopathologic features, surgical procedures, oncological and functional outcomes were obtained from medical records., Results: Free flap reconstructions were performed in 13 patients (3 female, 10 male). The mean age was 82.6 ± 3.4 years (range: 80-91). The mean follow-up period was 23.3 months (range 4-41 months). The mean disease-free survival was 49 ± 6 months (range 4-60 months). All patients had been alive more than one year after surgery. Reconstruction was performed using free jejunum in 10 patients and radial forearm flap in 3 patients. Graft necrosis occurred in 2 patients. Other two patients experienced major postoperative medical complications., Conclusion: Free flap reconstruction in well-selected older adults is safe and effective. Advanced age should not preclude consideration of free flap reconstruction in those patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cardiac metastasis from head and neck cancers are very rare. Metastases to heart are mostly diagnosed at autopsy, and seldom found while patients are alive. Patients with cardiac metastasis do not present with specific symptoms in the early stages, and diagnosis is often delayed until the disease has advanced significantly. Here, we report a 66-year-old lady who was diagnosed with cardiac metastasis 10 months after surgical resection of oral cancer. She died one month following the discovery of cardiac metastasis. Cardiac metastasis should be considered when unexplained and progressive decline of general health is observed, even in the absence of abnormalities on the electrocardiogram. Early diagnosis may be made by analyzing the chronological changes in the cardiac accumulation of fluorodeoxyglucose during positron emission tomography-computed tomography scan., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Papillary thyroid carcinoma (PTC) occasionally invades tracheal cartilages. We adapted a reconstructive procedure "modified spiral tracheoplasty" to extensive tracheal defect after resection of locally advanced thyroid cancer. Extensive window resection of tracheal wall was performed in a 72-year-old woman and a 48-year-old man with PTC invading intraluminal trachea. Remaining stumps of trachea were separated from the esophageal wall and were rotated by 90 degrees in opposite directions. Posterior and lateral walls were anastomosed and tracheocutaneous fistula was created to prevent postoperative airway obstruction. Postoperative course was uneventful in both cases. Tracheocutaneous fistula was successfully closed 3 to 4 months after the initial surgery. Modified spiral tracheoplasty is a safe and useful method to recreate a framework of trachea after extensive window resection for advanced thyroid cancer., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Prostate cancer is one of the most common cancers in men. The overactivation of IL-6/JAK/STAT3 signaling and silencing of SOCS3 are frequently observed in prostate cancer. In the present study we undertook to develop Ad-SOCS3 gene therapy for the treatment of prostate cancer and also investigated whether Ad-SOCS3 increased sensitivity to NK cells. We demonstrated that Ad-SOCS3 could significantly inhibit growth of castration-resistant prostate cancer (CRPC) cell lines expressing pSTAT3, DU-145 (at 10, 20, and 40 MOI), and TRAMP-C2 (at 40 MOI), but not the PC-3 CRPC cell line with the STAT3 gene deleted. Ad-SOCS3 (40 MOI) could suppress IL-6 production in DU-145 cells and PD-L1 expression induced by IFN-γ in TRAMP-C2 cells, and increased the NK cell sensitivity of both TRAMP-C2 and DU-145 cells. In the DU-145 mouse xenograft tumor model, intratumoral injections (twice/week for 3 weeks) of 1 × 10 8 pfu of Ad-SOCS3 significantly inhibited tumor growth and combining the Ad-SOCS3 treatment with intratumoral injections (once/week for 2 weeks) of 1 × 10 7 human NK cells showed the highest tumor growth inhibitory effect. These results suggested that a combination of Ad-SOCS3 gene therapy and NK cell immunotherapy could be a powerful treatment option for advanced CRPC overexpressing pSTAT3.

Objective The endocytosis of cationized feritin (CF) via a clathrin-mediated pathway is regulated by a signaling network. Marginal cells showed the active endocytosis of CF via a clathrin-mediated pathway. The internalization of receptors through this clathrin-mediated pathway is an important regulatory event in signal transduction. Numerous kinases are involved in endocytosis, and each endocytic route is subjected to high-order regulation by cellular signaling mechanisms. In this study, we investigated whether ROCK and MLCK signaling cascades and G-proteins regulate the endocytosis of CF in marginal cells of the stria vascularis. Methods CF was infused into the cochlear duct with pertussis toxin (PTX),Clostridium botulinum C3 toxin (BTX), guanosine(g-thio)-triphosphate (GTP-γS), ML-7, Y-27632. Endocytic activity was measured at 30 min after the start of infusion under an electron microscope. Results In marginal cells, CF was internalized via a clathrin-mediated pathway that depends on F-actin and microtubules (MT). Its processes were controlled by myosin light chain kinase (MLCK) and Rho-associated kinase (ROCK), but not affected by G-protein-coupled receptor (GPCR) or the RhoA signaling cascade. Conclusion Our previous study showed that the main endocytotic pathway of microperoxidase (MPO) did not depend on the Rho/ROCK molecular switch or actin/myosin motor system, but was mainly regulated by the RhoA signaling cascade. The present study results indicate that these signaling cascades regulating CF internalization completely differ from the cascades for MPO internalization., (Copyright © 2019. Published by Elsevier B.V.)

Objective: The purpose of this study was to clarify the impact of superficial parotidectomy and postoperative radiotherapy (PORT) for the surgical treatment of early stage squamous cell carcinoma (SCC) in external auditory canal (EAC)., Materials and Methods: Thirty-seven patients with T1 (n = 14) or T2 (n = 19) SCC in EAC treated between 2000 and 2016 at Kobe University Hospital were enrolled in this study. Thirty-three patients were operated with sleeve resection or lateral temporal bone resection., Results: The 5-year overall survival and disease-specific survival rates were 95% and 100%, respectively. Surgical margin was positive in 4 patients, who were treated by PORT and have been alive without disease. Prophylactic superficial parotidectomy was simultaneously performed at the time of initial surgery in 15 patients, in whom no lymph node (LN) metastasis was observed. Among the other 22 patients, regional recurrence in parotid LN was observed in one patient, who was successfully salvaged by total parotidectomy. Potential parotid lymph node metastasis rates of T1 and T2 SCC in EAC was 0% (0/14) and 5% (1/19) respectively., Conclusions: Complete resection without positive surgical margins is essential for the treatment of the patients with T1 and T2 ear cancers. Prophylactic superficial parotidectomy or neck dissection is not mandatory for T1 and T2 diseases, as long as precisely extent of disease is assessed preoperatively. PORT should be performed for the patients with positive surgical margins., Levels of Evidence: 4., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The purpose of this study was to investigate the effectiveness of dental intervention before and after radiation therapy (RT) for head and neck malignancy on prevention of osteoradionecrosis (ORN) of the jaws., Methods: This is a single-arm prospective study according to intervention protocol of prophylactic dental extraction before RT and routine follow-up after RT. The primary endpoint was the occurrence of jawbone exposure during the first 2 years after RT., Results: Sixty-seven patients were assessed. Before RT, 144 teeth among 39 patients (58%) were prophylactically extracted. The occurrence of transient jawbone exposure during the first 2 years after RT was 7%. Because those jawbone exposures healed with intervention after RT, no jawbone exposure was found at 2 years after RT., Conclusions: Dental intervention both before and after RT seemed to be important to prevent ORN development. Further studies in larger cohorts are necessary.

Background: Multitarget kinase inhibitors (m-TKI), including lenvatinib, are now available as treatment options for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, the optimal timing of treatment initiation with m-TKI in these patients remains to be defined., Methods: We retrospectively reviewed the clinical records of 30 consecutive patients with RR-DTC. The relationship between clinical characteristics was evaluated, including tumor growth parameters at pretreatment/post-treatment and efficacy of lenvatinib., Results: A total of 26 patients with RR-DTC treated with lenvatinib were evaluable for response and eligible for analysis. From the results of multivariate analysis, baseline tumor size and tumor-related symptoms were independent negative prognostic factors for overall survival (OS) and progression-free survival (PFS). Pretreatment tumor growth parameters were not prognostic for either PFS or OS., Conclusions: Patients with RR-DTC with a high tumor burden and tumor-related symptoms had significantly worse prognosis. Greater tumor reduction after starting lenvatinib may lead to better prognosis, irrespective of pretreatment high tumor growth rate., (© 2019 Wiley Periodicals, Inc.)

Background: Papillary thyroid carcinoma frequently metastasizes to central and lateral neck lymph nodes, but metastasis to retropharyngeal lymph nodes (RPLN) is rare., Patients and Methods: We retrospectively reviewed 16 patients with RPLN metastasis of PTC who underwent therapeutic dissection of RPLN metastases., Results: Among 16 patients, 7 patients underwent RPLN dissection with initial surgery and remaining 9 patients as salvage surgery. RPLN metastasis arose unilaterally in 15 patients and bilaterally in 1 patient. Eleven patients showed temporal dysphagia and four patients showed temporal vocal cord paralysis, but both symptoms eventually recovered in all cases. Two patients with salvage RPLN dissection died of distant metastasis and six patients survived with distant metastasis and/or persistent loco-regional disease. Other eight patients have been alive without disease., Conclusions: Although transcervical approach for RPLN metastases of PTC provided acceptable functional and oncological outcomes, half of the patients with RPLN metastasis have had distant metastasis and/or persistent locoregional disease. Indications of surgery for patients with RPLN metastasis need to be performed carefully in consideration of patients' prognosis and quality of life.

Objectives: To evaluate the impact of retropharyngeal lymph node (RPLN) dissection in the surgical treatment of hypopharyngeal cancer., Methods: Between 2007 and 2016, 98 previously untreated patients with pathological diagnosed hypopharyngeal squamous cell carcinoma underwent total pharyngolaryngectomy and bilateral neck dissection at Kobe University Hospital. Bilateral dissection of RPLN was simultaneously performed in all patients. Pharynx was reconstructed with free jejunal transfer in 94 patients and primarily closed in 4 patients. Postoperative chemoradiotherapy was performed in patients with high risk factors including metastasis to RPLN, multiple lymph node metastasis, extranodal invasion, and/or positive/close surgical margins., Results: The median follow-up period was 25 months ranging from 1 to 105 months. RPLN adenopathy was preoperatively identified in 9 patients in FDG-positron emission tomography. All of them had pathologically diagnosed RPLN metastases, which had been controlled in all patients during the observation periods. Among the other 89 patients, 7 patients had RPLN metastasis. The 2-year overall survival rates of the patients with and without RPLN metastasis were 65.7% and 69.8% (P = .61), respectively., Conclusions: In the present study, patients with RPLN metastasis showed equally favorable oncological outcome compared with patients without RPLN metastasis. At least, ipsilateral RPLN dissection should be considered in the surgical treatment of advanced hypopharyngeal cancer and multiple neck lymph node metastasis regardless of primary subsite., (© 2019 Wiley Periodicals, Inc.)

Objectives: Parkinson disease (PD) is frequently associated with olfactory disorder at early stage, which is caused by deposition of Lewy bodies emerging from the olfactory bulb to higher olfactory centers. Early detection of olfactory disorder in the patients with PD may lead to the early diagnosis and treatment for this refractory disease., Methods: Visual analog scale (VAS), Jet Stream Olfactometry, and Japanese smell identification test, Open Essence (OE), were carried out on 39 patients with PD. Thirty-one patients with postviral olfactory disorder (PVOD), which was caused by the olfactory mucosal dysfunction, were also enrolled in this study as control., Results: There were no significant differences in detection thresholds (2.2 vs. 1.4, P=0.13), recognition thresholds (3.9 vs. 3.5, P=0.39) and OE (4.8 vs. 4.2, P=0.47) between PVOD and PD, while VAS scores of PVOD and PD were significantly different (2.0 and 6.2, P<0.01). In OE, significant differences were observed in the accuracy rates of menthol (68% vs. 44%, P=0.04) and Indian ink (42% vs. 15%, P=0.01) between PVOD and PD. Of particular interest, patients with PVOD tended to select "no detectable," while patients with PD tended to select wrong alternative other than "no smell detected.", Conclusion: Discrepancy between VAS and OE, and high selected rates of wrong alternative other than "undetectable" in OE might be significant signs of olfactory dysfunction associated with PD.

Background: Fine-needle aspiration (FNA) is the most reliable method for diagnosing thyroid nodules; however, some features such as atypia of undetermined significance or follicular lesion of undetermined significance can confound efforts to identify malignancies. Similar to BRAF, cyclin D1 may be a strong marker of cell proliferation., Methods: One hundred two patients with thyroidal nodule were enrolled in this prospective study. Expression of cyclin D1 in thyroid nodules was determined by immunohistochemistry using both surgical specimens and their cytological specimens. The identification of the optimal cut off points for the diagnosis of malignancy were evaluated using the receiver operating characteristic (ROC) curves and the assessment of the area under the ROC curve (AUC). The specificity, sensitivity, positive predictive value (PPV) of markers were evaluated from crosstabs based on cut off points and significance were calculated. We also analyzed genetic variants by target NGS for thyroid nodule samples., Results: The positive predictive value (PPV) and median stain ratio (MSR) of cyclin D1 nuclear staining was determined in papillary thyroid carcinoma (PPV = 91.5%, MSR = 48.5%), follicular adenoma (PPV = 66.7%, MSR = 13.1%), and adenomatous goiter and inflammation controls (MSR = 3.4%). In FNA samples, a threshold of 46% of immunolabelled cells allows to discriminate malignant lesions from benign ones (P < 0.0001), with 81% sensitivity and 100% specificity. A 46% cutoff value for positive cyclin D1 immunostaining in thyroid cells demonstrated 81% sensitivity and 100% specificity. In surgical specimens, ROC curve analysis showed a 5.8% cyclin D1 immunostaining score predicted thyroid neoplasms at 94.4% sensitivity and 92.3% specificity (P = 0.003), while a 15.7% score predicted malignancy at 86.4% sensitivity and 80.5% specificity (P < 0.0001). Finally, three tested clinico-pathological variables (extra thyroidal extension, intraglandular metastasis, and lymph node metastasis) were significant predictors of cyclin D1 immunostaining (P < 0.001)., Conclusion: Our cytological cyclin D1 screening system provides a simple, accurate, and convenient diagnostic method in precision medicine enabling ready determination of personalized treatment strategies for patients by next generation sequencing using cytological sample.

Background: In 2008, Kano developed a new laryngeal closure technique (Kano's method) for the treatment of severe aspiration. The aim of this study was to evaluate the safety and efficacy of this technique in patients with head and neck cancer., Methods: Since June 2014 until March 2018, six patients underwent Kano's method for management of severe aspiration after the treatment of head and neck cancers. The anterior parts of the thyroid and the cricoid cartilages were excised widely. The glottis was closed by suturing bilateral vocal folds and reinforced by the sternohyoid muscle. A tracheostoma was created with skin flaps, subglottic mucosal flaps, and stumps of cricoid and trachea cartilages., Results: No severe complications were observed after the surgery. Oral intake improved without developing aspiration., Conclusions: Kano's method can provide satisfactory functional results with minimal invasion for treating severe aspiration after advanced surgery, chemotherapy, and/or chemoradiotherapy, in patients with head and neck cancer., Level of Evidence: 4.

Sorafenib and lenvatinib showed efficacy for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) in pivotal phase 3 clinical trials. Although the efficacy of lenvatinib in patients who received previous treatment with multi-target kinase inhibitors (m-TKIs), including sorafenib, was reported, the efficacy of sorafenib in patients who previously received lenvatinib remains unknown. A 75-year-old woman diagnosed as RAI-refractory poorly differentiated carcinoma with multiple lung metastases and started treatment with lenvatinib. She continued to receive lenvatinib but with repeated dose interruptions and reductions due to continuous proteinuria. Because of severe and persistent proteinuria as well as newly developed renal impairment, lenvatinib was suspended after two years of treatment. After the 7-month suspension, her proteinuria and renal impairment were partially improved, but her lung metastases progressed. Because she was unable to tolerate previous treatment with lenvatinib, sorafenib was started. At 7 months of treatment with sorafenib, her lung metastases shrank and she could continue sorafenib without exacerbation of proteinuria or renal impairment. This case may suggest that sorafenib does not exacerbate the proteinuria or renal impairment induced by lenvatinib, and may be an effective treatment option for RAI-refractory DTC patients who are unable to tolerate lenvatinib., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The National Comprehensive Cancer Network (NCCN) guidelines recommend considering postoperative radiotherapy (PORT) for completely resected T1/2N0M0 salivary mucoepidermoid carcinomas when they show tumor spillage, perineural invasion, or intermediate/high-grade histology. CRTC1/3-MAML2 fusions have been associated with a favorable clinical outcome., Methods: Forty-seven T1/2N0M0 mucoepidermoid carcinoma cases positive for CRTC1/3-MAML2 fusions were completely resected and were not treated with PORT., Results: Pathologically, none of the cases showed tumor spillage or perineural invasion. Cases with intermediate/high-grade histology numbered 9 (19%) to 26 (55%) with the currently used 3 different grading systems. During the follow-up (median 60 months), locoregional tumor recurrence occurred in 4 cases, which were treated with surgery alone. At the last follow-up (median 60 months; 7-160), all patients were alive with no evidence of disease., Conclusion: An excellent prognosis may be achieved without PORT in T1/2N0M0 mucoepidermoid carcinoma patients positive for CRTC1/3-MAML2 fusions when the tumors are completely resected without tumor spillage., (© 2018 Wiley Periodicals, Inc.)

Objectives: Postoperative hypoparathyroidism (HPT) is one of the most common complications in total thyroidectomy for thyroid carcinoma. Parathyroid glands (PTGs) are at risk of being damaged during total thyroidectomy and central neck dissection mainly due to inadvertent removal, interruption of the blood supply or hematoma formation. The purpose of this study was to evaluate the efficacy of our surgical procedure to preserve for parathyroid function retrospectively and to clarify the risk factors of HPT after total thyroidectomy for thyroid cancer., Patients and Methods: Sixty-five patients undergoing total thyroidectomy with central neck dissection for thyroid cancer were enrolled in this retrospective study. Cancers were diagnosed as stage I in 15 patients, stage II in 24 patients, stage III in 19 patients, and stage IV in 7 patients. Lateral neck dissection and upper mediastinal dissection were simultaneously performed in 47 patients and one patient, respectively. Parathyroid glands (PTGs) were preserved in situ in 34 patients. Among 31 patients in whom PTG could not be preserved in situ, two or more PTGs were autotransplanted in 9 patients and one PTG was autotransplanted in 18 patients. PTG was not autotransplanted in 4 patients, since it could not be identified during the surgery., Results: Postoperative transient HPT and permanent HPT were observed in 44 (68%) patients and in 12 (18%) patients, respectively. Among 34 patients in whom PTGs were preserved in situ, transient HPT and permanent HPT were observed in 17 (50%) patients and in 6 (2%) patients, respectively. Among 31 patients in whom PTG were not preserved in situ, postoperative permanent HPT was observed in all 4 patients without PTG autotransplantation, and 6 (33%) out of the 18 patients who had one PTG autotransplantation. On the other hand, none of the 9 patients who had two or more PTG autotransplantation at the time of thyroidectomy developed permanent HPT (P=0.04). The patients with large tumor (≥40mm) and/or gross extra glandular invasion had a significantly higher risk of permanent postoperative HPT compared with the patients without these pathological features (P<0.01)., Conclusions: Two or more PTG should be autotransplanted in case where PTG is not preserved in situ to prevent postoperative HPT after total thyroidectomy with central neck dissection, especially in cases of large tumor and/or gross extrathyroidal extension., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Concomitant chemoradiotherapy (CCRT) produces severe mucositis and swallowing dysfunction, often resulting in malnutrition. Intensive nutrition support (INS) in addition to percutaneous endoscopic gastrostomy (PEG) is reported to decrease adverse effects during CCRT., Patients and Methods: Fifty-eight patients with oropharyngeal cancer treated by CDDP-based CCRT were retrospectively analyzed. Twenty-nine patients treated with INS in addition to PEG were classified as INS group, and other 29 patients treated with PEG but without INS were classified as control group., Results: INS in addition to PEG significantly increased calorie intake in the second half of CCRT and reduced adverse events including mucositis (p = 0.0019), leukopenia (p = 0.04), and renal function (p = 0.006). Moreover, 21 out of 29 patients had successfully administration of 200 mg/m2 or more of CDDP, while only 10 out of 29 patients had enough amount of CDDP in control group., Conclusions: These results suggest that INS in addition to prophylactic PEG not only decreases adverse effects but also may potentially improve oncological outcome of the patients with oropharyngeal cancer treated by CCRT.

In the mammalian olfactory epithelium (OE), neurogenesis continues throughout the lifetime, by replacing olfactory receptor neurons (ORNs) lost by normal turnover in the postnatal period. However, this ability decreases with age and/or because of various toxic factors. To date, no effective treatment for olfactory dysfunction' especially because of aging, is available in clinical practice. Here, we examined the effects of intranasal administration of fibroblast growth factor-2 and insulin-like growth factor-1 in gelatin hydrogel on the degenerated OE of aging mice induced by methimazole administration. These topical treatments led to increases in the number of olfactory marker protein-positive cells, which identified mature ORNs, resulting in the increased thickness of OE. These results indicate that both fibroblast growth factor-2 and insulin-like growth factor-1 promote the proliferation of basal cells and differentiation of immature ORNs into mature ORNs in the degenerated OE of aging mice. These agents might be promising candidates for the treatment of degenerated OE of aging humans.

Carcinoma arising in lingual thyroid is an extremely rare entity accounting for only 1% of all reported ectopic thyroids. Here, we report a case of carcinoma arising in lingual thyroid, which has been successfully managed by transoral resection and bilateral neck dissections. A lingual mass 4-cm in diameter with calcification was incidentally detected by computed tomography at medical check-up. No thyroid tissue was observed in normal position. Ultrasound examination showed bilateral multiple lymphadenopathies. Fine needle aspiration biopsy from lymph node in his right neck was diagnosed as Class III and thyroglobulin level of the specimen was 459ng/ml. Due to the difficulty in performing FNA of the lingual masses, right neck dissection was performed in advance for diagnostic purpose. Pathological examination showed existence of large and small follicular thyroid tissues in several lymph nodes, suggesting lymph node metastasis from thyroid carcinoma. Two months after the initial surgery, video-assisted transoral resection of lingual thyroid with simultaneous left neck dissection was performed. Postoperative course was uneventful. Papillary carcinoma was found in the lingual thyroid and thyroid tissues were also found in left cervical lymph nodes. Video-assisted transoral resection was useful for the treatment of thyroid cancer arising in lingual thyroid., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Human papillomavirus (HPV) infection has been identified as an etiologic factor of head and neck cancers (HNCs). We explored the potential use of antisense HPV RNA transcripts for gene therapy and its effect in combination with cisplatin (CDDP) for HPV-positive HNCs. We introduced the antisense RNA transcripts of the E6 and E7 genes of HPV type 16 into UM-SCC-47 cells harboring HPV 16 and YCU-T892 cells that were HPV-negative using a recombinant adenoviral vector, Ad-E6/E7-AS. We then analyzed the effects of the introduction of Ad-E7-AS on cell and tumor growth and the synergistic effect with CDDP in vitro and in vivo. After infection of Ad-E6/E7-AS, the cellular growth of UM-SCC-47 cells were suppressed, but not that of YCU-T892 cells. E7 protein expression was suppressed, and p53 and pRb protein expression increased after infection of Ad-E7-AS. Cell growth and tumorigenicity were greatly suppressed in combination with CDDP compared with Ad-E7-AS or CDDP treatment alone in vitro. Ad-E7-AS combined with CDDP treatment significantly reduced the volumes of established subcutaneous tumors. Transfection with HPV 16 E7 antisense RNA combined with CDDP treatment might be a potentially useful approach to the therapy of HPV 16-positive HNC.

Objective  Nasal and paranasal malignant tumors invading the skull base are rare and poorly studied. We evaluated postoperative complications in patients undergoing salvage surgery for such tumors. Design  Retrospective study. Setting  Kobe University Hospital. Participants  Among 48 patients who underwent surgery for tumors involving the skull base between 1993 and 2015, 21 patients had squamous cell carcinoma, 13 had olfactory neuroblastoma, 5 had adenocarcinoma, 2 had sarcoma, 2 had adenoid cystic carcinoma, and 1 each had malignant melanoma, poorly differentiated carcinoma, undifferentiated carcinoma, myoepithelial carcinoma, and malignant peripheral nerve sheath tumor. Prior to skull base surgery, radiotherapy, chemoradiotherapy (CRT), particle radiotherapy, chemotherapy, or surgery were applied in 3, 15, 4, 5, and 3 patients, respectively. Main Outcome Measures  Main outcome measures were postoperative complications in patients who underwent skull base surgery after concomitant CRT and/or particle therapy. Results  Major postoperative complications were observed in 14 surgical procedures (29%; 2 patients with cerebral herniation, 3 with cerebrospinal fluid leakages, 3 with meningitis, 1 with hydrocephalus, 6 with epidural abscesses, 2 with local infections, and 2 with partial flap necrosis). Four patients developed ≥2 complications. One patient died of postoperative lung infarction. Three (16.7%) of 18 patients without prior treatment and 9 (50%) of 18 patients who underwent preoperative radiotherapy/CRT had severe postoperative complications. Two (50%) of four patients treated with particle radiotherapy had postoperative complications. Conclusions  CRT or particle radiotherapy were significantly associated with a high risk of severe postoperative complications after skull base surgery. Meticulous care should be taken in patients treated with radiotherapy/particle therapy prior to skull base surgery.

Background: Aggressive fibromatoses are histologically benign fibrous neoplasms originating from musculoaponeurotic structures throughout the body. They are locally invasive and erode adjacent vital structures. The head and neck region constitutes 7-25% of all extra-abdominal cases., Case Report: Here, we report the case of a patient with aggressive fibromatosis in the left side of the neck. While the tumor deeply invaded the scalene muscles, the lesion was successfully treated by surgery followed by radiotherapy. The patient has been disease free for the last 7 years following treatment., Conclusion: Due to its unusual location in the head and neck region, aggressive fibromatosis should be considered in the differential diagnosis of invading lesions of the neck.

Objective: TALK score has been developed as an index for predicting the possibility of larynx preservation and prognosis of the patients with advanced laryngeal and hypopharyngeal cancers treated by concurrent chemoradiotherapy (CCRT). In this study, we validated the original TALK score in our clinical setting and modified the score for Japanese population., Methods: The subjects were 21 patients with laryngeal cancer and 50 patients with hypopharyngeal cancer who underwent CCRT at Kobe University Hospital between April 2007 and August 2012. Data regarding T stage, serum albumin level just before treatment, maximum alcohol use, Karnofsky Performance Status (KPS), 3-year overall survival rate and 3-year larynx-preservation rate were collected from medical records. In the revised TALK score (JTALK), the following scoring criteria were modified to adjust Japanese population: T stage of the primary tumor (≥T3), serum albumin level (<3.5 g/dl), maximum alcohol use (≥one 350-ml can of beer/day or an equivalent amount), and KPS (<80%)., Results: The original TALK score was not significantly associated with the larynx preservation rates or survival rates for laryngeal cancer or hypopharyngeal cancer. Instead, JTALK score was significantly associated with the 3-year larynx preservation rates and 3-year survival rates of the patients with hypopharyngeal and laryngeal cancer., Conclusion: These results indicate that JTALK score could be a useful index for predicting the possibility of larynx preservation and prognosis of Japanese patients with advanced laryngeal and hypopharyngeal cancer treated by CCRT.

In the mouse olfactory bulb (OB), interneurons such as granule cells and periglomerular cells are continuously replaced by adult-born neurons, which are generated in the subventricular zone (SVZ) of the brain. We have now investigated the role of commensal bacteria in regulation of such neuronal cell turnover in the adult mouse brain. Administration of mixture of antibiotics to specific pathogen-free (SPF) mice markedly attenuated the incorporation of bromodeoxyuridine (BrdU) into the SVZ cells. The treatment with antibiotics also reduced newly generated BrdU-positive neurons in the mouse OB. In addition, the incorporation of BrdU into the SVZ cells of germ-free (GF) mice was markedly reduced compared to that apparent for SPF mice. In contrast, the reduced incorporation of BrdU into the SVZ cells of GF mice was recovered by their co-housing with SPF mice, suggesting that commensal bacteria promote the incorporation of BrdU into the SVZ cells. Finally, we found that administration of ampicillin markedly attenuated the incorporation of BrdU into the SVZ cells of SPF mice. Our results thus suggest that ampicillin-sensitive commensal bacteria regulate the neurogenesis in the SVZ of adult mouse brain., (Copyright © 2018 Elsevier Inc. All rights reserved.)