記述言語：英語   掲載種別：研究論文（学術雑誌）  

Middle-ear salivary gland choristoma (SGCh) is a rare, benign tumor that causes conductive hearing loss owing to middle-ear morphological abnormalities. Early diagnosis is challenging, and surgical resection is indispensable for a definitive diagnosis. We report the case of a 3-year-old boy diagnosed with middle-ear SGCh during the follow-up period for left-sided hearing loss discovered at newborn hearing screening (NHS). Long-term follow-up after the NHS result, subsequent computed tomography/magnetic resonance imaging, and surgical resection led to its relatively early diagnosis and treatment.

DOI： 10.18926/AMO/67554

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Here, we describe the unique case of a pneumocephalus originating from an inverted papilloma (IP) in the frontoethmoidal sinus. A 71-year-old man with diabetes presented with headaches and altered consciousness. Imaging revealed the pneumocephalus together with bone destruction in the left frontal sinus. He underwent simultaneous endoscopic endonasal and transcranial surgery using an ORBEYE exoscope. Pathological diagnosis of the tumor confirmed IP. Post-surgery, the pneumocephalus was significantly resolved and the squamous cell carcinoma antigen level, which had been elevated, decreased. This case underscores the importance of a multidisciplinary approach and innovative surgical methods in treating complex sinonasal pathologies.

DOI： 10.18926/AMO/67550

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: There is no consensus on the optimal surgical technique for allergic rhinitis (AR). Furthermore, the appropriateness of surgical intervention in children and older individuals remains debatable. This study aimed to analyze trends and patterns in the surgical management of AR in Japan, focusing on parasympathetic neurectomy. METHODS: Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), we conducted a comprehensive review of procedures performed between April 2014 and March 2022. In addition, a cross-sectional survey targeting otolaryngologists across Japan was conducted to gather insights into surgical preferences and practices. RESULTS: The NDB data showed an increasing trend in neurectomies, with the most frequent age group being 25-29 years; the procedure was also performed in pediatric and older patients. The survey among otolaryngologists indicated that 58.2 % of surgeons preferred peripheral branch neurectomy of the posterior nasal nerve. The findings of this study also indicated a cautious approach toward conducting these procedures in children, with 51.2 % of surgeons considering patients less than 18 years of age unsuitable for the procedure. CONCLUSION: This study highlighted a shift toward simple and minimally invasive surgical methods, such as peripheral branch neurectomy, in Japan. However, further research is needed to understand the long-term outcomes and refine the surgical techniques. The findings of this study also emphasized the need for age-specific considerations when treating pediatric and older patients with AR.

DOI： 10.1016/j.anl.2024.07.005

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記述言語：英語  

DOI： 10.1016/j.alit.2024.01.005

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記述言語：英語  

This report describes a case of an electric toothbrush head being retained between the floor of the mouth and the submandibular gland following a fall. Computed tomography imaging is recommended in cases of oral cavity damage to assess tissue damage and ascertain the position of the foreign body concerning blood vessels.

DOI： 10.1002/ccr3.8987

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Otitis media (OM) is a prevalent respiratory disease in children and poses significant public health challenges due to its impact on child health and economic burdens. However, there have no nationwide epidemiological studies conducted in Japan. This study investigates the epidemiological trends of OM in Japan, taking into account the impact of the 7-valent pneumococcal conjugate vaccine (PCV7) introduction. METHOD: This study was retrospective cohort study using secondary data on the nationwide longitudinal birth cohort. This survey followed two cohorts born in 2001 (pre-PCV era) and 2010 (post-PCV era) until the age of 9. Every year, parents were surveyed about their children's health status, including occurrences of OM. The annual period prevalence and cumulative incidence of OM were assessed in this study, and the two cohorts were compared using a modified Poisson regression model adjusted environmental factors with the 2001 cohort as reference. RESULT: The study included 47,015 children from the 2001 cohort and 38,554 from the 2010 cohort. Peak annual period prevalence of OM varied by era. Cumulative incidence was 13.8 % for the 2001 cohort and 18.5 % for the 2010 cohort by 1.5 years of age and 28.9 % and 33.3 %, respectively, by 3.5 years of age. In particular, from the fourth survey onward, covering ages 2.5-3.5 years, a shift was observed from an increased risk to a decreased risk of OM. CONCLUSION: This nationwide longitudinal study emphasizes variations in OM epidemiology across Japan over time, with changes potentially influenced by the introduction of PCV7. In this study, due to the absence of individual PCV7 vaccination data, the effect of PCV7 was estimated based on the vaccination rate at the population level. The results suggest a notable decrease in the incidence of OM in later years, aligning with the increased uptake of PCV7.

DOI： 10.1016/j.vaccine.2024.05.020

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cga.12571

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Comprehensive information on genetic alterations in salivary gland cancer (SGC) is limited. This study aimed to elucidate the genetic and clinical characteristics of patients with SGC using the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, a Japanese national genomic database. We analyzed data of 776 patients with SGC registered in the C-CAT database between June 1, 2019, and June 30, 2023. Adenoid cystic carcinoma was the most common histologic type, followed by salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified. Genetic data of 681 patients receiving FoundationOne® CDx were analyzed. We identified specific features of the combination of TP53 and CDKN2A alterations among the histological types. Specific LYN amplification was mainly detected in carcinoma ex pleomorphic adenoma and myoepithelial carcinoma. For SDC, the frequency of ERBB2 and BRAF alterations were higher in cases with metastatic lesions than in those with primary lesions. Although 28.6% patients were offered recommended treatment options, only 6.8% received the recommended treatments. This study highlights the differences in genetic alterations among the histological types of SGC, with comprehensive genomic profiling tests revealing lower drug accessibility. These findings could contribute to the development of personalized treatment for patients with SGC.

DOI： 10.1002/ijc.34972

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

T cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T cell exhaustion, such as PD-1, can reinvigorate tumor-specific T cells and activate anti-tumor immunity in various types of cancer. Here, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA-sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed anti-tumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to PD-1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy.

DOI： 10.1158/0008-5472.CAN-23-0453

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Advanced surgical interventions are required to treat malignancies in the anterior skull base (ASB). This study investigates the utility of endoscopic endonasal and transcranial surgery (EETS) using a high-definition three-dimensional exoscope as an alternative to traditional microscopy. METHODS: Six patients with carcinomas of varying histopathologies underwent surgery employing the EETS maneuver, which synchronized three distinct surgical modalities: harvesting of the anterolateral thigh flap, initiation of the transnasal technique, and initiation of the transcranial procedure. RESULTS: The innovative strategy enabled successful tumor resection and skull base reconstruction without postoperative local neoplastic recurrence, cerebrospinal fluid leakage, or neurological deficits. CONCLUSION: The integration of the exoscope and EETS is a novel therapeutic approach for ASB malignancies. This strategy demonstrates the potential of the exoscope in augmenting surgical visualization, enhancing ergonomics, and achieving seamless alignment of multiple surgical interventions. This technique represents a progressive shift in the management of these complex oncological challenges.

DOI： 10.1002/hed.27724

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The pharyngeal flap (PF) is useful for reconstruction of soft palate defects, but effective arrangements of PF for various types of soft palate defects are controversial. Here, we classify three types of soft palate defects and discuss the arrangements of PF and their functional prognosis. METHODS: Reconstruction was performed based on the classification of the defects. Clinical details were collected, and postoperative function was analyzed. RESULTS: Eight patients were included in the study. The defect sizes ranged from 25 (width) × 40 (depth) to 40 × 60 mm. Six patients underwent pharyngeal flap reconstruction with free-flap reconstruction, and two underwent pharyngeal flap reconstruction. The pharyngeal flap was harvested at the maximum width of the posterior pharyngeal wall, ranging from 25 to 40 mm in length. Eating and speaking functions were maintained in all patients. CONCLUSIONS: Good postoperative function can be maintained by narrowing the velopharyngeal space with a pharyngeal flap.

DOI： 10.1002/hed.27712

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掲載種別：研究論文（学術雑誌）  

Malignant external otitis (MEO) is an intractable disease with a high mortality rate, despite advances in the development of antimicrobial agents. MEO mainly requires administration of antibiotics, local treatment, and strict management of diabetes mellitus, which takes a long time. We present 2 cases of MEO in elderly patients that were successfully treated by multidisciplinary collaboration. The two patients were referred to our department after conservative treatment failed to improve their condition. In both cases, remission was achieved with hospitalization and multidisciplinary treatment for diabetes mellitus, impaired renal function, activities of daily living (ADL), and cognitive function. As one of the factors contributing to the poor prognosis of MEO, treatment can often not be completed in the elderly, who are more likely to show deterioration of ADL and cognitive functions. In addition, MEO is often not well known, not only to patients, but also to physicians. Awareness of this disease and multidisciplinary treatment are essential to improve the outcomes of MEO.

DOI： 10.5631/jibirin.117.219

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The purpose of this study is to investigate the lung function in Chronic Rhinosinusitis (CRS) patients with Chronic Cough (CC). METHODS: A total of 1413 CC patients were retrospectively screened and 109 CRS patients with CC were enrolled. Lung function, Lund-Mackay Computed Tomography (CT) score, smoking status, peripheral blood eosinophil count, and immunoglobulin E concentration in serum samples, and Sino-Nasal Outcome Test were examined. Normal control subjects are also recruited. RESULTS: The Forced Expiratory Volume in 1 second (FEV1.0), Percent Predicted FEV1.0, and FEV1.0/Forced Vital Capacity (FVC) ratio in the patients were significantly low as compared with the control subjects. The FEV1.0/FVC ratio was negatively correlated with the Lund-Mackay CT scores of the patients with a high CT score. CONCLUSIONS: The CRS patients with CC should be investigated with lung function. In addition, the multidisciplinary evaluation including a pulmonologist is needed to manage the CRS patients with CC. LEVEL OF EVIDENCE: Level 4.

DOI： 10.1016/j.bjorl.2024.101424

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Catalase, a heme-containing antioxidant enzyme, was once considered essential for human survival. It is widely distributed in the human body and is particularly abundant in red blood cells. The term "acatalasemia" first appeared in the Proceedings of the Japan Academy in 1951, drawing global attention to families genetically deficient in catalase. This deficiency not only altered the significance of catalase but also played a pioneering role in human genetics during an era of limited genetic methodology. In this article, we examine the discovery of acatalasemia by an otolaryngologist during surgery on an 11-year-old girl. This remarkable journey led to epoch-making research spanning biochemistry, hematology, and human genetics.

DOI： 10.2183/pjab.100.024

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study investigated the association between housing type and clinical remission of infantile-onset allergic rhinitis (AR) in 53,575 children born in 2001 in Japan. Infantile-onset AR was defined as the presence of AR symptoms reported between ages 1.5 and 4.5 years, and remission was assessed between ages 10 and 12. The type of housing was categorized into detached houses and multi-unit residential buildings with 1-2, 3-5, or ≥6 floors. Among the 4,352 infantile-onset AR, 42.9% experienced remission. Notably, living in multi-unit residential buildings, particularly those with 1-2 and ≥6 floors, was positively associated with AR remission.

DOI： 10.1016/j.pedhc.2023.11.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aims: Among primary thyroid lymphomas (PTLs), diffuse large B-cell lymphoma (DLBCL) has a poorer prognosis than other indolent lymphomas such as mucosa-associated lymphoid tissue (MALT) or follicular lymphoma (FL). However, the clinical differences between DLBCL and indolent lymphoma remain unclear. Therefore, this retrospective study on PTL was aimed at investigating the clinical differences between DLBCL and indolent lymphomas and identifying the factors differentiating DLBCL from indolent lymphomas. Materials and Methods: Medical records of 28 patients diagnosed with PTL and treated at our institution between 2005 and 2022 were retrospectively analyzed. Data on the following clinical variables were extracted: sex, age, symptoms (pain and dysphagia), ultrasonographic appearance patterns, the presence of airway stenosis on computed tomography and laryngeal endoscopy, blood test results, disease stage, and pathological diagnosis. Results: In all, 13 patients were histologically diagnosed with DLBCL, 12 with MALT lymphoma, and 3 with FL. Significant differences in disease-specific survival rates were evident between the DLBCL and indolent lymphoma groups (68.2 vs 100%, P = .043). High lactate dehydrogenase levels (>230 U/mL) and airway stenosis were observed only in patients with DLBCL. Multivariate analysis identified that the presence of a linear echoic strand pattern and the absence of an echoic nodular pattern on ultrasound were independently associated with DLBCL (P = .0497 and .012, respectively). Conclusion: DLBCL can cause airway stenosis. The linear echogenic strand pattern and the absence of a nodular pattern should be recognized as predictive factors of DLBCL.

DOI： 10.1177/01455613231218130

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Biomarkers that predict response to immune checkpoint inhibitor (ICI) in recurrent metastatic squamous cell carcinoma of the head and neck (RMHNSCC) are not well known. METHODS: We prospectively measured the combined positive score (CPS) and administered ICI to patients with RMHNSCC. RESULTS: Of 51 patients, 23 patients had a CPS <20 and 12 patients (23.5%) had a CPS ≥90. CPS showed a negative correlation with serum albumin. Survival analysis showed a 2-year survival rate of 24.1%. In multivariate analysis, CPS ≥90 (HR 0.3026, p = 0.02614) and albumin >3.5 (HR 0.3463, p = 0.01354) were the significant factors and plus chemotherapy (HR 0.4648, p = 0.07632) was not significant. Seven patients (14%) with CPS ≥90 and albumin >3.5 showed a 2-year survival rate of 66. 7%. CONCLUSIONS: CPS ≥90 and albumin >3.5 cases are a subgroup of RMHNSCC that respond extremely well to ICI.

DOI： 10.1002/hed.27576

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Choosing the optimal side for cochlear implantation (CI) remains a major challenge because of the lack of evidence. We investigated the choice of the surgery side for CI (i.e., the better- or poorer-hearing ear) in patients with asymmetric hearing. Audiological records of 74 adults with a unilateral hearing aid who had undergone surgery at Okayama University Hospital were reviewed. The definition of 'better-hearing ear' was the aided ear, and the unaided ear was considered the poorer-hearing ear. We performed a multiple regression analysis to identify potential predictors of speech recognition performance after unilateral CI in the patients. Fifty-two patients underwent CI in the poorer-hearing ear. The post-Ci bimodal hearing rate was far higher in the poorer-ear group (77.8% vs. 22.2%). A multivariate analysis revealed that prelingual hearing loss and the patient's age at CI significantly affected the speech recognition outcome (beta coefficients: 24.6 and -0.33, 95% confidence intervals [11.75-37.45] and [-0.58 to -0.09], respectively), but the CI surgery side did not (-6.76, [-14.92-1.39]). Unilateral CI in the poorer-hearing ear may therefore be a reasonable choice for adult patients with postlingual severe hearing loss, providing a greater opportunity for postoperative bimodal hearing.

DOI： 10.18926/AMO/66150

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The status of human papilloma virus (HPV) and p16 overexpression for nasal vestibule squamous cell carcinoma (NVSCC) is unclear. The purpose of this retrospective study was to analyze the presence of HPV and the role of p16 overexpression as a surrogate marker in cases of NVSCC. METHODS: Retrospective analysis was performed on patients who were diagnosed and treated for NVSCC at the University of Tokyo Hospital, Japan. p16 immunohistochemistry was considered positive with at least moderate staining intensity and diffuse staining (≥75% of tumor cells), according to the 8th edition of the American Joint Commission on Cancer. HPV-DNA testing was performed using multiplex polymerase chain reaction. RESULTS: Five patients were included in the study. Ages ranged from 55 to 78 years; there were two men and three women; two had T2N0, and three had T4aN0. Surgery was performed in one case, surgery plus radiation therapy (RT) in one case, and chemoradiation therapy (CRT) in three cases. Four of the five tumors showed p16 overexpression. One of five cases had an HPV-16 genotype. The mean follow-up period was 73 months, and all the patients survived. One patient with p16-negative carcinoma had local recurrence and underwent salvage surgery. Of the four patients with p16-positive carcinoma, one with CRT and one with surgery plus RT, each had delayed cervical lymph node metastasis, which was salvaged with neck dissection subsequent RT. CONCLUSIONS: In NVSCC, four of the five cases were p16-positive, and one was high-risk HPV infection.

DOI： 10.1016/j.anl.2023.03.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Objectives This retrospective study aimed to investigate the relationships between the Keros classification, the Gera classification, the vertical height of the posterior ethmoid roof (ER), and anterior ethmoidal artery (AEA) types in Japanese patients. Methods We investigated the computed tomography (CT) slices of paranasal sinuses (120 sides) of 60 patients; measured the cribriform plate (CP) depth, lateral lamella CP angle (LLCPA), and vertical height of the lateral ER from the hard palate (LERHP) at the coronal plane of the posterior ethmoidal artery (PEA); and reviewed the AEA types, whether floating or non-floating. Results CP depth was positively correlated with LLCPA (r=0.63; p<0.01) and the height of LERHP (r=0.19; p<0.05). The height of the LERHP in females was significantly lower than that in males. With increased CP depth, floating AEAs became prevalent (p<0.001). Conclusion In females, low height of the posterior ethmoid sinus roof, where cerebrospinal fluid (CSF) leaks occurred while penetrating the basal lamella, often existed; the heights positively correlated with the Keros classification in Japanese patients. The Keros and Gera classifications, AEA type, and posterior ER height do not individually constitute a complete risk assessment but may correlate, preventing major complications, such as CSF leak and orbital hemorrhage.

DOI： 10.7759/cureus.49273

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cochlear implant (CI) surgery is a safe surgical technique, although some patients require revision CI surgery. AIMS/OBJECTIVES: This study investigated the cause and underlying reason of revision CI surgery as well as hearing outcomes in a single institution. PATIENTS AND METHODS: This retrospective study evaluated patients who underwent CI surgery between April 2006 to March 2022 (n = 351). Sex, aetiology of hearing loss (HL), age and period from initial CI surgery to reimplantation, cause of revision, and related factors were examined. RESULTS: Twelve patients (8 males, 4 females) received CI reimplantation. The revision surgery rate was 2.59% (3.15% children, 1.69% adults); the period from initial surgery to reoperation was 8.60 ± 6.56 years for 9 children with congenital HL and 15.27 ± 5.72 years for 3 adults with progressive HL. Device failure was the most common cause (n = 8), followed by infections (n = 2), advanced facial irritation symptoms (n = 1), and electrode slip-out (n = 1). Mean preoperative and postoperative CI thresholds were 44.0 ± 9.46 dBnHL and 39.19 ± 8.89 dBnHL (p < .068), respectively. CONCLUSION AND SIGNIFICANCE: Caregiver education, surgical technique advances, flap design, and extensive antibiotic use may decrease the revision surgery rate. The lack of post-revision deterioration of the hearing threshold contributed to well-being in patients with CI.

DOI： 10.1080/00016489.2023.2270701

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記述言語：英語  

Low-grade papillary Schneiderian carcinoma (LGPSC) is a rare and newly described type of cancer arising from the Schneiderian epithelium. Owing to cellular atypia, it is difficult to differentiate this type from other papillomas and malignancies. Although this condition remains unclear, it is associated with mortality and recurrence. Therefore, treating physicians should be aware of the possibility of LGPSC for prompt diagnosis and treatment. In this article, we present an additional case of nasopharyngeal LGPSC with cervical lymph node metastasis and reviewed the 14 cases reported thus far in the literature. A 76-year-old female was referred to our department for detailed examination of nasopharyngeal and cervical lymph node tumors detected by positron emission tomography-computed tomography. Based on the biopsy of the nasopharyngeal tumor, we suspected LGPSC. Considering the clinical course and pathological findings, the patient was diagnosed with cervical lymph node metastasis through neck dissection. We performed radiotherapy for the primary lesion of the nasopharynx, which led to the disappearance of the tumor. After 13 months following the radiotherapy, the patient died from a recurrence of retroperitoneal liposarcoma without the recurrence of LGPSC.

DOI： 10.1016/j.anl.2022.12.010

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記述言語：英語  

In Japan, near-infrared photoimmunotherapy (NIR-PIT) was introduced in 2021 as a treatment option for unresectable recurrent head and neck cancer. The treatment targets the epidermal growth factor receptor (EGFR), which is overexpressed in 80-90 % of head and neck squamous cell carcinoma (HNSCC). NIR-PIT should theoretically show therapeutic efficacy if EGFR is expressed, even in nonsquamous cell carcinomas (non-SCC). To the best of our knowledge, there are no case reports of NIR-PIT for non-SCC. We performed NIR-PIT in a patient with non-SCC of the head and neck region. After performing two NIR-PIT treatments, small free clusters of residual tumor cells were observed. Immunostaining in this specimen revealed EGFR expression in residual tumor cells. The residual tumor cells had been irradiated sufficiently to achieve necrosis. It is suggested that not only laser irradiation and expression of EGFR but also other factors are involved in the efficacy of this treatment. Further investigation for these other factors is warranted.

DOI： 10.1016/j.anl.2023.09.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aim of the "Japanese Clinical Practice Guidelines for Head and Neck Cancer - 2022 Update" is to review the latest evidence regarding head and neck cancer and to present the current standard approaches for diagnosis and treatment. These evidence-based recommendations were created with the consensus of the Guideline Committee, which is composed of otorhinolaryngologists and head and neck surgeons, together with radiologists, radiation oncologists, medical oncologists, plastic surgeons, dentists, palliative care physicians, and rehabilitation physicians. These guidelines were created by the Clinical Practice Guideline Committee of the Japan Society for Head and Neck Cancer based on the "Head and Neck Cancer Treatment Guidelines 2018 Edition," and the revised draft was compiled after evaluation by the Assessment Committee and public comments. The 'Clinical questions and recommendations' section consists of 13 categories, and 59 clinical questions are described in total. Here we describe 6 clinical questions specific to other sets of guidelines with recommendations and comments.

DOI： 10.1016/j.anl.2023.07.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hyalinizing clear cell carcinoma (HCCC) is a rare indolent malignant tumor of minor salivary gland origin with EWSR1::ATF1 rearrangement. Pathologically, the tumor cells possess a clear cytoplasm in a background of hyalinized stroma. Generally, the tumor cells are positive for p63 and p40 and negative for s100 and α-smooth muscle actin, suggesting that they differentiate into squamous epithelium and not into myoepithelium. In this study, we performed a detailed histopathological and genomic analysis of 6 cases of HCCC, including 2 atypical subtypes-a case of "high-grade transformation" and 1 "possessing a novel partner gene for EWSR1." We performed a sequential analysis of the primary and recurrent tumor by whole-exome sequencing, RNA sequencing, Sanger sequencing, and fluorescence in situ hybridization to investigate the effect of genomic changes on histopathology and clinical prognosis. A fusion gene involving the EWSR1 gene was detected in all cases. Five cases, including the "high-grade transformation," harbored a known EWSR1::ATF1 fusion gene; however, 1 case harbored a novel EWSR1::LARP4 fusion gene. This novel EWSR1::LARP4-fused HCCC has a SOX10-positive staining, which is different from the EWSR1::ATF1-fused HCCC. According to whole-exome sequencing and fluorescence in situ hybridization analysis, the "whole-genome doubling" and focal deletion involving CDKN2A, CDKN2B, and PTEN were detected in HCCC with "high-grade transformation." Conclusively, we identified a novel partner gene for EWSR1, LARP4, in indolent HCCC. Importantly, "high-grade transformation" and poor prognosis were caused by whole-genome doubling and subsequent genomic aberrations.

DOI： 10.1016/j.labinv.2023.100213

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

PURPOSE: A longitudinal study was conducted to examine the effects of handwashing and gargling education for children on the prevention of respiratory tract infections (RTIs) in children in Japan. METHODS: The study included 38,554 children born in 2010 who were enrolled in a longitudinal study. Information on children's hygiene education regarding handwashing and gargling was collected in a survey at the age of 3.5 years. Based on parents' reports of doctors' diagnoses, airway infections and influenza events in the 12-month duration before the survey were evaluated for RTIs at the ages of 4.5 and 9 years. Poisson regression with robust variance was performed to examine the effects of hygiene education on RTIs prevention. The supplementary analysis was stratified by household income. RESULTS: Children were categorized into different groups: 38% in the handwashing and gargling group, 29% in the handwashing group, 0.1% in the gargling group, and 9.7% in the no-education group. Exclusions were made for non-respondent children (23%) and those in the gargling group. Hygiene education was associated with decreased influenza at the age of 4.5 years in the handwashing (adjusted RR [aRR] = 0.8; 95% CI, 0.8-0.9) and handwashing and gargling groups (aRR = 0.8; 95% CI, 0.8-0.9) compared with no education. However, no preventive effects on airway infections at the age of 4.5 and 9, influenza at the age of 9, or hospitalization between the ages of 3.5 and 9 years were detected. Handwashing and gargling could significantly prevent influenza in low-income households (aRR = 0.7; 95% CI, 0.6-0.8).     Conclusions: Gargling education was widespread and mostly combined with handwashing education in Japan. Hygiene education significantly affected prevention of influenza infections at the age of 4.5 years, especially in low-income households. WHAT IS KNOWN: • Previous intervention studies showed handwashing and gargling are effective in preventing respiratory tract infections. WHAT IS NEW: • We conducted a longitudinal study on handwashing and gargling education in Japanese children and found that handwashing and gargling were widely practiced together. • Handwashing and gargling education were related to a reduction in influenza, particularly in low-income households.

DOI： 10.1007/s00431-023-05062-5

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その他リンク： https://link.springer.com/article/10.1007/s00431-023-05062-5/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To clarify whether age impacts the development of endolymphatic hydrops (ELH) in neurotologic patients. Documentation of ELH in living patients on magnetic resonance imaging (MRI) allows analysis of patient age and formation of ELH, which is impossible by means of postmortem temporal bone pathology. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Fifty patients (100 ears) with top 3 diagnoses of definite Menière's disease, delayed ELH, or probable Menière's disease. INTERVENTIONS: Endolymph MRI after intravenous gadolinium injection and pure-tone audiometry. MAIN OUTCOME MEASURES: Cochlear and vestibular ELH confirmed by MRI. RESULTS: The prevalences of ears showing both cochlear and vestibular ELH were similar among age groups <30 years (30%), 30-59 years (25.9%), and ≥60 years (34.4%; p > 0.05; χ2 test). Using logistic regression modeling, mean hearing level at the six frequencies was positively associated with a higher risk of cochlear ELH (odds ratio, 1.3; 95% confidence interval, 1.1-1.5 per 10-dB increment). In the same regression model, age did not impact the outcome of cochlear ELH (odds ratio, 1.0; 95%confidence interval, 0.7-1.4 per 10-year increment). Age did not differ among ears with no ELH (mean ± standard deviation age, 48.6 ± 14.4 yr), ears with only cochlear ELH (59.3 ± 10.7 yr), ears with only vestibular ELH (50.4 ± 16.9 yr), or ears with both cochlear and vestibular ELH (51.5 ± 18.4 yr; p > 0.05, analysis of variance). CONCLUSION: Chronological age was not associated with the formation of ELH. Aging per se may not be associated with the development of ELH in neurotologic patients.

DOI： 10.1097/MAO.0000000000003945

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Immune checkpoint inhibitors (ICI) have become widely used becuse of their effectiveness and relatively low rate of severe adverse events. However, active treatment should be continued after discontinuation of ICI as response rates are lower than that of conventional cytotoxic chemotherapy. The purpose of the present study was to determine the efficacy of treatment after ICI discontinuation. METHODS: This was a retrospective study from hospital charts of 99 consecutive cases treated with ICI at our facility since 2017. Of these, 79 cases of squamous cell carcinoma which had already discontinued ICI were enrolled in the present study. RESULTS: After discontinuation of ICI, 40 cases received active treatment with salvage chemotherapy (SCTx; 33 cases) or surgery or radiotherapy (seven patients) and 39 cases received nonactive treatment. SCTx comprising paclitaxel and cetuximab (PTX-Cmab) was administered to 15 cases and other SCTx regimens to 18 cases. A significant increase in overall survival (OS) was observed with active treatment compared with nonactive treatment. No significant differences in OS or progression-free survival (PFS) were observed between SCTx regimens; however, there was a trend toward increased survival with PTX-Cmab. Univariate analysis of overall response rate (ORR) demonstrated significant differences in the site of disease at ICI and SCTx regimens. A significant difference in disease control rate was observed between SCTx regimens. Multivariate analysis of ORR demonstrated a significant correlation with PTX-Cmab treatment. CONCLUSION: Active treatment after ICI discontinuation and the use of PTX-Cmab as SCTx may increase OS in head and neck squamous cell carcinoma. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 2023.

DOI： 10.1002/lary.30851

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

BACKGROUND: Chronic rhinosinusitis (CRS) can be divided into endotypes by functional or pathophysiologic findings. OBJECTIVE: The aim of this study was to analyze the expression of cytokines, prostaglandin (PG) synthases, and their receptors related to the pathogenesis of CRS, especially those contributing to nasal polyp (NP) formation. METHODS: NPs and uncinate tissue (UT) samples were collected from 90 patients who underwent endoscopic sinus surgery. They included 75 patients with CRS (including 45 with eosinophilic CRS [eCRS] and 30 with non-eCRS) and 15 patients without CRS. A total of 30 genes were selected for our original DNA array plate to analyze the levels of expression of 10 cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-13, IL-17A, IL-22, IL-25, IL-33, and TSLP), 4 prostaglandin synthases (prostaglandin D2 [PGD2] synthase, prostaglandin E2 synthase, COX-1, and COX-2), and their 16 receptors. Clustering analysis was performed according to the expression results, and clinical findings of patients from each cluster were investigated. RESULTS: The samples could be divided into 3 clusters. Cluster 1 showed elevated levels of expression of IL4, IL5, IL13, TSLP, IL1RL1 (ST2 [an IL-33 receptor]), HPGDS, and GPR44 (CRTH2, a PGD2 receptor); cluster 2 showed elevated levels of expression of IL17A and PTGES; and cluster 3 showed an elevated level of expression of IL25. Regarding clinical features, the main characteristics of each cluster were as follows: NPs from patients with eCRS for cluster 1, NPs and/or UT samples from patients with non-eCRS for cluster 2, and UTs from patients with non-CRS for cluster 3. CONCLUSION: The results suggest that there are associations between type 2 inflammation/PGD2 and eCRS and also between type 3 inflammation/prostaglandin E2 and non-eCRS.

DOI： 10.1016/j.jacig.2023.100123

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Advances in endoscopic imaging technology have led to an increase in detection of superficial pharyngeal squamous carcinoma. Endoscopic submucosal dissection (ESD) has been reported to be effective for the treatment of these lesions, however there is still insufficient evidence on the long-term results of pharyngeal ESD. METHODS: This is a single-center retrospective study of all cases of superficial pharyngeal cancer that underwent ESD as primary treatment between January 2010 and May 2022. A total of 83 lesions in 63 patients were analyzed. RESULTS: The en bloc resection rate was 100%, and R0 resection rate was 59.0%, with an adverse event rate of 6.0%. During a mean observation period of 1134 days, there were 0 cases of disease-specific metastasis or death. However, the 5-year cumulative incidence of metachronous head and neck cancer after resection was 27.1% and the 5-year overall survival and 10-year overall survival after pharyngeal ESD were 87.0% and 69.6%, respectively. Of the 34 cases with non-R0 resection, local recurrence occurred in 8.8%. Location of lesion (p = 0.011), disparity between demarcation of the lesion with NBI and iodine staining (p = 0.026), and non-effective laryngeal elevation (p = 0.080) were risk factors for non-R0 resection. CONCLUSION: Pharyngeal ESD is effective and safe. Further studies are needed to improve and standardize indications and strategies for pharyngeal ESD.

DOI： 10.1007/s00464-022-09820-8

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記述言語：英語  

A 35-year-old female presented with headache, photophobia and developed sudden loss of vision after having undergone right-side ophthalmectomy and radiochemotherapy for retinoblastoma in infancy. A neoplastic lesion was found in the left middle cranial fossa and was surgically removed. The diagnosis was radiation-induced osteosarcoma with RB1 gene alteration. Although she received chemotherapy for the residual tumor, it progressed 17 months later. Maximal surgical resection with craniofacial reconstruction was required. We utilized two three-dimensional models for surgical planning. She was discharged without neurological deficits other than loss of light perception subsequent to left ophthalmectomy. In cases where retinoblastoma is treated with radiotherapy, long-term follow-up is necessary to monitor for radiation-induced tumor development.

DOI： 10.18926/AMO/64367

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掲載種別：研究論文（学術雑誌）  

We present the case of a 63-year-old woman with cerebrospinal fluid (CSF) rhinorrhea of the clivus. She presented with a 6-week history of left-sided watery nasal discharge. RI cisternography showed evidence of a CSF leak in the sphenoid sinus at the previous institution, so the patient was referred to our hospital for further examination. CT and MR imaging revealed fluid collection in the left-sided sphenoid sinus and a clival bone defect. Transnasal endoscopic repair was performed using autologous grafts of her abdominal fat and fascia, and a mucosal flap from the nasal septum. Histological examination showed no evidence of tumor. We made the final diagnosis of idiopathic CSF rhinorrhea. There were no signs of a CFS leak or any new lesion at the clivus at the 2-year follow-up. Reconstruction with a mucosal flap from the nasal septum is considered as being useful for CSF rhinorrhea in the clivus.

DOI： 10.5631/jibirin.116.881

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掲載種別：研究論文（学術雑誌）  

We present the case of a 77-year-old male patient with relapsing polychondritis localized to the nasal septum, who presented with a history of recurrent epistaxis and nasal pain. After definitive confirmation of the diagnosis of relapsing polychondritis by biopsy, the patient was kept under observation and the lesion healed spontaneously, without steroid administration; the patient was followed up for 5 years, with no signs of recurrence. Careful follow-up might be an option for patients with localized relapsing polychondritis without systemic symptoms.

DOI： 10.5631/jibirin.116.573

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: cT1/2 oral tongue squamous cell carcinoma (OTSCC) often metastasizes to cervical lymph nodes. However, predicting neck lymph-node metastasis (NLM) remains challenging. Pathomorphological evaluation of tumor budding grade (TBG) and tumor-stroma ratio (TSR) reportedly can predict lymph-node metastases. Hence, this study aimed to evaluate TBG and TSR in OTSCC and investigate their relationship to occult NLM and cancer relapse. METHODS: Clinicopathological data of patients with cT1/2N0 OTSCC treated at the University of Tokyo Hospital between 2007 and 2017 were collected. TBG and TSR were evaluated using hematoxylin-eosin staining and cytokeratin AE1/AE3 immunostaining. RESULTS: Out of 70 patients, 16 underwent elective neck dissection in addition to primary-tumor resection, whereas 54 did not. During follow-up, NLM was found in 35 patients. NLM correlated with the pathological depth of invasion (pDOI) (p < 0.001), TBG (p = 0.008), and TSR (p < 0.001) in univariate analysis and pDOI (p = 0.01) and TSR (p = 0.02) in multivariate analysis. The 5-year recurrence-free survival rate (RFS) was 78% for patients with a pDOI ≤ 5 mm and stroma-poor tumors and 33% for patients with a pDOI > 5 mm and stroma-rich tumors. CONCLUSION: Patients with a pDOI > 5 mm and stroma-rich tumors have a high risk for cancer relapse. TSR and pDOI may be promising NLM predictors in cT1/2N0 OTSCC.

DOI： 10.1007/s10147-022-02249-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Molecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73-13.1, p = 7.8 × 10-6). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies.

DOI： 10.1038/s41698-022-00324-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.18926/AMO/64033

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Epithelioid hemangioendothelioma (EHE) is a rare and slow-growing malignant vascular neoplasm composed of epithelioid endothelial cells within a distinctive myxohyaline stroma. It most commonly involves somatic soft tissue, lungs, liver and bone. Herein, we describe a case of EHE arising in the axillary region. CASE PRESENTATION: A 61-year-old man was under observation for multiple hepatic hemangiomas. Fluorodeoxyglucose-positron emission tomography/computed tomography showed specific uptake in a right axillary tumor. The patient was referred to our department for further investigation of the axillary tumor. An elastic-soft and poorly mobile tumor was palpable in the right axilla. Contrast-enhanced computed tomography showed a right axillary tumor and enlarged hepatic hemangiomas. In addition, multiple nodules in both lungs, a left renal angiomyolipoma, and left adrenal adenoma were revealed. Ultrasonography showed masses in both lobes of the thyroid gland, and a 30-mm lobulated hypoechoic mass in the axilla with well-defined and rough borders, showing internal heterogeneity. Fine-needle aspiration cytology was performed on the thyroid and axillary tumors: the thyroid tumor was class V, raising suspicion of papillary thyroid cancer (PTC); the left superior internal jugular node was class V, raising suspicion of metastasis of PTC; and the axillary tumor was class III, raising suspicion of a mesenchymal tumor with few epithelioid cells. The multiple lung nodules were diagnosed as metastatic tumors derived from thyroid cancer. We diagnosed these diseases as PTC of T1b(m)N1bM1(lung) Stage IVB and a right axillary tumor of unclear origin. However, it was assumed to be a primary mesenchymal tumor or a lymph node metastasis from lung cancer or occult breast cancer. We performed total thyroidectomy, left cervical lymph node dissection, and right axillary tumor excision. Histopathologic examination revealed the thyroid tumor as a PTC and the axillary tumor as an EHE. The EHE showed nuclear atypia, necrosis and high mitotic figures. Hence, it was considered to be a high-risk EHE. CONCLUSIONS: We experienced a rare primary subcutaneous axillary EHE with metastatic thyroid cancer in the lung. Since our case was classified as a high-risk EHE, a close follow-up would be appropriate.

DOI： 10.1186/s40792-022-01521-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Candidemia is a bloodstream infection (BSI) by Candida spp. and is associated with high mortality. However, there have been few reports about BSI in head and neck cancer (HNC). We aimed to evaluate the impact of candidemia in patients with HNC and compared it with bacteremia. STUDY DESIGN: A multicenter retrospective study. METHODS: We retrospectively analyzed 83 BSI episodes in HNC (2011 to 2020) and divided them into the candidemia and bacteremia groups. We then compared the survival rate and risk factors for candidemia between the groups. RESULTS: The overall cumulative incidence (risk) of candidemia in BSI was 12 out of 83 episodes (14.5%). The 1-year mortality for the bacteremia and candidemia groups was 33.3% and 58.3%, respectively (log-rank p = 0.041). Broad-spectrum antibiotics (odds ratio [OR]: 29.5; 95% confidence interval [CI], 2.49-350), mucositis (OR 11.0; 95% CI, 1.52-80.1), and malignant wounds (OR 79.5; 95% CI 1.33-4737) were significant risk factors for candidemia in HNC. CONCLUSIONS: Candidemia causes high mortality in patients with HNC. To our knowledge, malignant wounds have not been previously reported as a risk factor for candidemia. For early diagnosis and treatment of candidemia, risk factors should be considered, and antifungal therapy started earlier.

DOI： 10.1007/s00520-022-07010-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Combination intranasal drugs with a corticosteroid and antihistamine are available in several countries with better effect than treatments with single agents. However, it remains unclear whether this effect is also seen in Japanese cedar pollinosis (JCP), the most prevalent seasonal allergic rhinitis in Japan. We investigated the effect of an add-on intranasal antihistamine with an intranasal corticosteroid in JCP during the pollen dispersal period. (UMIN000025508) METHODS: We performed a double-blinded, randomized, placebo-controlled trial from March 1 to 14, 2017. Patients (n = 20 per group) received either a mometasone furoate nasal spray (MFNS) plus a levocabastine nasal spray (levocabastine group) or MFNS plus a placebo nasal spray (placebo group). The primary endpoint was the difference in the total nasal symptom score (TNSS) after treatment between the two groups. Differences in the total ocular symptom score, total symptom score, total medication score, total symptom-medication score, and five individual symptoms as well as safety were the secondary endpoints. RESULTS: The change in the TNSS from baseline was significantly greater in the levocabastine group than in the placebo group. A significant reduction in the TNSS was observed more than 6 days earlier in the levocabastine group than in the placebo group. Such add-on effects were also seen in the secondary endpoints. Both treatments were well-tolerated. CONCLUSION: The intranasal antihistamine provided better control of not only nasal symptoms, but also of ocular symptoms, and decreased the need for rescue medications when added to intranasal corticosteroid treatment in JCP patients.

DOI： 10.1016/j.anl.2022.05.007

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記述言語：英語  

Labyrinthitis occurs because of the inflammation of the inner ear. We present a rare case of labyrinthitis ossificans following an acute otitis media. The T2-weighted magnetic resonance imaging showed decreased signal intensity in the right inner ear due to labyrinthitis ossificans, consistent with the clinical presentation.

DOI： 10.1002/ccr3.5898

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The vestibulo-ocular reflex (VOR) in neurotologic patients can be evaluated most quickly by spontaneous nystagmus examinations, and the video Head Impulse Test (vHIT) quantitatively evaluates the VOR of the semicircular canals. We aimed to clarify the concordance and discrepancies between spontaneous nystagmus and vHIT findings, to provide guidance on screening vestibular functions by initial spontaneous nystagmus examination then vHIT. We evaluated 169 outpatients by spontaneous nystagmus examination in the dark using a charge-coupled device camera, then by horizontal vHIT the same day. Vestibular loss on vHIT was defined if both reduced VOR gain (<0.8) and corrective saccade were observed. Adjusted logistic regression modelling revealed that differences in right and left VOR gain positively impacted the presence of nystagmus, which suggests lateralised vestibular dysfunction (P<0.05; odds ratio 1.39 [95% confidence interval, 1.1-1.8] per 0.1 increment). When vHIT is regarded as the standard clinical test, the positive predictive value of nystagmus for vestibular loss on vHIT was 44.4%, and the negative predictive value was 93.5%. The adjusted odds ratio of adults ≥65 years old compared to younger patients associated with a discrepancy of nystagmus and vHIT was significant (2.4 [1.1-5.3]). In conclusion, if spontaneous nystagmus is initially observed in patients, further assessment by vHIT could confirm vestibular dysfunction in 40-50% of cases. If no nystagmus is observed, vHIT might also result in a negative finding in >90% of cases. Older adults appear more likely to show discrepancies between nystagmus and vHIT.

DOI： 10.1016/j.jocn.2022.03.018

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記述言語：英語  

DOI： 10.1016/j.alit.2022.03.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Histological evaluation of lymph node is crucial for the definitive diagnosis of Kikuchi-Fujimoto disease (KFD). However, lymph node biopsy under local anesthesia is often difficult in pediatric patients. OBJECTIVES: We evaluated cytological findings for pediatric patients with prolonged cervical lymphadenitis clinically suggestive of KFD and investigated the clinical characteristics of patients diagnosed with KFD by fine-needle aspiration cytology (FNAC). METHODS: This retrospective clinical study included 58 Japanese pediatric patients with cervical lymphadenitis who underwent FNAC. RESULTS: Cytological diagnosis was KFD for 22 and suspicion of KFD for 11 patients. The remaining 25 patients were diagnosed with non-specific lymphadenitis (NSL). Tenderness was independently associated with a higher frequency of both KFD in narrow and broad senses, compared with NSL (p = .009; p = .038). The percentage of patients who underwent FNAC within 28 days from symptom onset tended to be higher among patients with KFD in a narrow sense than those with NSL (p = .052). CONCLUSION: This study indicated that the period from symptom onset to FNAC (<28 days) and the symptom of tenderness were associated with the cytological diagnosis of KFD.

DOI： 10.1080/00016489.2022.2040744

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Protothecosis is a rare infection in humans and animals caused by the achlorophyllic algae Prototheca species. More than half of the protothecosis cases are cutaneous infections, and most cases are observed in immunocompromised individuals. CASE PRESENTATION: We report a case of Prototheca wickerhamii infection in the mucosa of the pharynx in a 53-year-old immunocompetent woman with an incidentally found mass lesion at the left tongue base. Histopathological findings of the mass lesion suggested cryptococcosis, but P. wickerhamii was identified from the oropharynx scrape culture based on DNA sequencing. After surgical resection, fosfluconazole treatment was initiated, and subsequently, treatment was switched to topical amphotericin B. The residual mass lesion did not deteriorate during the 4-month antifungal treatment and 1-year observational period. CONCLUSIONS: Prototheca species can be easily misdiagnosed as yeasts because of their morphological and pathological similarities. Prototheca, in addition to Cryptococcus should be considered if slow-growing, large Gram-positive organisms are encountered. Lactophenol cotton blue staining of the colony helps distinguish these organisms. Further study is needed to determine the appropriate treatment according to the infection focus.

DOI： 10.1186/s12941-022-00495-6

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Sinonasal inverted papilloma (SNIP) can recur; however, the factors related to tumor recurrence remain unclear. This study aimed to analyze risk factors, including human papillomavirus (HPV) infection, as well as other factors associated with SNIP recurrence. Thirty-two patients who were diagnosed with SNIP and underwent surgery between 2010 and 2019 were enrolled: 24 men and 8 women, with a mean age of 59.2 years. The mean follow-up was 57.3 months. Demographics and information about history of smoking, diabetes mellitus (DM), hypertension, allergic rhinitis, alcohol consumption, tumor stage, surgical approach, and recurrence were reviewed retrospectively. Specimens were investigated using polymerase chain reaction to detect HPV DNA (high-risk subtypes: 16, 18, 31, 33, 35, 52b, and 58; low-risk subtypes: 6 and 11). Seven patients (21.9%) experienced recurrence. HPV DNA was detected in five (15.6%) patients (high-risk subtypes, n = 2; low-risk subtypes, n = 3). Patients with recurrence of SNIP had a higher proportion of young adults and displayed higher rates of HPV infection, DM, and advanced tumor stage than those without recurrence. HPV infection, young adulthood, DM, and advanced tumor stage could be associated with a high recurrence rate, which suggests that patients with these risk factors could require close follow-up after surgery.

DOI： 10.3390/diagnostics12020454

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

<sec><title>Objective</title>Salivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only <italic>de novo</italic> but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy.

</sec><sec><title>Materials and Methods</title>The EZH2 and H3K27me3 immunohistochemical expression and <italic>EZH2</italic> Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases).

</sec><sec><title>Results</title>EZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. <italic>EZH2</italic> Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups.

</sec><sec><title>Conclusions</title>A high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.

</sec>

DOI： 10.3389/fonc.2021.779882

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1001/jamaoto.2021.3392

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In head and neck cancer, early detection of recurrence after treatment is important. The contemporary development of therapeutic agents have improved the prognosis after recurrence; however, no biomarker has been established for evaluating therapeutic effects or detecting recurrence. Recently, circulating tumor DNA (ctDNA), which comprises DNA derived from tumor cells and exists in the form of cell-free DNA in the blood, has attracted attention as a minimally invasive and repeatable biomarker for detecting cancer. We validated the usefulness of ctDNA of human papilloma virus (HPV)-derived sequences as a biomarker in HPV-related p16-positive oropharyngeal cancer by assessing 25 patients with p16-positive oropharyngeal cancer. Blood samples were collected from each patient at multiple time points during the treatment, and the plasma was preserved. The ctDNA was extracted from the plasma and analyzed using digital polymerase chain reaction. HPV-derived ctDNA was detected in 14 (56%) of the 25 patients. In all the patients, the samples were found to be ctDNA-negative after initial treatment. Cancer recurrence was observed in 2 of the 14 patients; HPV-derived ctDNA was detected at the time of recurrence. Our results indicate that HPV-derived ctDNA can be a prospective biomarker for predicting the recurrence of p16-positive oropharyngeal cancer.

DOI： 10.1038/s41598-021-04307-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Although patients with oral squamous cell carcinoma who develop contralateral neck metastasis (CLNM) have worse survival outcomes than those without CLNM, accurate prediction of occult CLNM in clinically negative contralateral neck (contralateral cN0) remains difficult. This study aimed to identify clinicopathological factors that could reliably predict CLNM in patients with locally advanced (clinical T3 and T4a) tongue squamous cell carcinoma (TSCC). PATIENTS AND METHODS: The medical data of 32 patients with cT3-4a TSCC who underwent curative surgery between 2010 and 2017 were retrospectively analyzed. The correlation of clinicopathological variables with CLNM was examined using logistic regression analysis. The diagnostic performance of significant variables was evaluated using the area under the receiver operating characteristic curves (AUC). Overall survival (OS) and disease-free survival (DFS) were assessed using a Cox proportional hazards model. RESULTS: CLNM was eventually confirmed in 11 patients (34.4%). Multivariate logistic regression showed that midline involvement [odds ratio (OR) = 23.10, P = 0.017] and perineural invasion (PNI, OR = 14.96, P = 0.014) were independent predictors of CLNM. Notably, the prediction model comprising a combination of midline involvement and PNI exhibited superior diagnostic performance with an even higher OR of 80.00 (P < 0.001), accuracy of 90.3%, and AUC of 0.876. The multivariate Cox hazards model revealed independent significance of CLNM as an unfavorable prognostic factor for both OS [hazard ratio (HR) = 5.154, P = 0.031] and DFS (HR = 3.359, P = 0.038), as well as that of PNI for OS (HR = 5.623, P = 0.033). CONCLUSION: Our findings suggest that coexisting midline involvement and PNI of the primary tumor is highly predictive of CLNM development, which independently affects both OS and DFS in patients with locally advanced TSCC. Such reliable prediction enables efficient control of CLNM by optimizing management of the contralateral cN0 neck, which will likely contribute to improved prognosis of those patients without unnecessarily compromising their quality of life.

DOI： 10.3389/fonc.2022.1010252

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The efficacy and safety of human epidermal growth factor receptor 2 (HER2)-targeted therapy and androgen deprivation therapy (ADT) for locally advanced or recurrent or metastatic (LA/RM) salivary duct carcinoma (SDC) have been reported in prospective studies. However, the survival benefit of these therapies to conventional therapy remains controversial, and whether HER2-targeted therapy or ADT should be chosen in HER2- and androgen receptor (AR)-positive SDC patients remains unknown. METHODS: Overall, 323 LA/RM SDC patients treated at seven institutions between August 1992 and June 2020 were retrospectively enrolled. The primary aim was to analyze the effect of HER2-targeted therapy and ADT on overall survival from the diagnosis of LA/RM disease to death from any cause (OS1). The secondary indicators included the overall response rate (ORR), clinical benefit rate (CBR), overall survival from therapy initiation for LA/RM disease (OS2), progression-free survival (PFS), time to second progression (PFS2), duration of response (DoR), and duration of clinical benefit (DoCB) of HER2-targeted therapy or ADT as first-line therapy for HER2-positive/AR-positive SDC. RESULTS: Patients treated with HER2-targeted therapy or ADT had longer OS1 than those treated without these therapies (Median OS1: historical control, 21.6 months; HER2-targeted therapy, 50.6 months; ADT, 32.8 months; HER2-targeted therapy followed by ADT, 42.4 months; and ADT followed by HER2-targeted therapy, 45.2 months, p < 0.001). Among HER2-positive/AR-positive SDC patients, although HER2-targeted therapy had better ORR, CBR, and PFS than those of ADT as first-line therapy, we found no significant differences between HER2-targeted therapy and ADT regarding OS2, PFS2, DoR, and DoCB. CONCLUSION: Patients treated with HER2-targeted therapy and ADT showed longer survival in LA/RM SDC. HER2-targeted therapy can be recommended prior to ADT for HER2-positive/AR-positive SDC. It is warranted to establish a biomarker that could predict the efficacy of clinical benefit or better response in ADT.

DOI： 10.1177/17588359221119538

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Understanding how sensorineural hearing loss (SNHL) impacts postural balance in patients is important, as postural balance predicts the risk of falls. AIMS/OBJECTIVES: We aimed to clarify the relationship between characteristics in the configuration of audiograms and static postural balance as measured by posturography. MATERIALS AND METHODS: We evaluated 385 outpatients (mean [± standard deviation] age, 58.4 ± 18.4 years) with SNHL by audiometry and posturography. Data were analysed by multiple regression models with the outcome of postural sway area with eyes closed (PSA) and predictive variables of audiometric data, adjusted for sex, age and the presence of nystagmus. RESULTS: The increased hearing threshold in the better hearing ear was associated with poorer or higher PSA (beta coefficient [β] = 0.39, 95% confidence interval [CI] = 0.03-0.75, per 10-dB increment). No difference in PSA was detected between patients with asymmetric or symmetric SNHL. None of the frequent diagnoses (presbyacusis, Meniere's disease, and idiopathic sudden SNHL) were associated with poorer PSA. Hearing thresholds at middle (β = 0.39, 95%CI = 0.10-0.67) and high frequencies (β = 0.31, 95%CI = 0.07-0.55) were associated with poorer PSA, whereas those at low frequencies was not. CONCLUSIONS AND SIGNIFICANCE: Postural balance in neurotologic patients may be associated with middle-high-frequency hearing levels during ageing.

DOI： 10.1080/00016489.2022.2047222

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although transcriptome alteration is an essential driver of carcinogenesis, the effects of chromosomal structural alterations on the cancer transcriptome are not yet fully understood. Short-read transcript sequencing has prevented researchers from directly exploring full-length transcripts, forcing them to focus on individual splice sites. Here, we develop a pipeline for Multi-Sample long-read Transcriptome Assembly (MuSTA), which enables construction of a transcriptome from long-read sequence data. Using the constructed transcriptome as a reference, we analyze RNA extracted from 22 clinical breast cancer specimens. We identify a comprehensive set of subtype-specific and differentially used isoforms, which extended our knowledge of isoform regulation to unannotated isoforms including a short form TNS3. We also find that the exon-intron structure of fusion transcripts depends on their genomic context, and we identify double-hop fusion transcripts that are transcribed from complex structural rearrangements. For example, a double-hop fusion results in aberrant expression of an endogenous retroviral gene, ERVFRD-1, which is normally expressed exclusively in placenta and is thought to protect fetus from maternal rejection; expression is elevated in several TCGA samples with ERVFRD-1 fusions. Our analyses provide direct evidence that full-length transcript sequencing of clinical samples can add to our understanding of cancer biology and genomics in general.

DOI： 10.1038/s42003-021-02833-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy. METHODS: In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs). RESULTS: Overall, 256 patients received a median of 6.0 doses (range: 1-52) of nivolumab over a median duration of 72.5 days (range: 1-736). Median OS was 9.5 months [95% confidence interval (CI) 8.2-12.0] and median PFS was 2.1 months (95% CI 1.8-2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9-11.9) and 3.5 months (95% CI 2.3-5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis. CONCLUSIONS: Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.

DOI： 10.1007/s10147-021-02047-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Several surgical procedures for posterior nasal neurectomy have been reported, but no conclusion has been reached about which procedure is best. OBJECTIVES: The aim is to evaluate the improvement in symptom medication scores for resection of the posterior nasal nerve trunk in an underwater environment, with submucous inferior turbinectomy, without injuring the sphenopalatine artery (SPA) in severe allergic rhinitis. MATERIAL AND METHODS: Improvements in symptom medication scores were retrospectively compared between 27 consecutive cases who underwent resection of the posterior nasal nerve trunk with turbinoplasty in an underwater environment without injuring the SPA (Underwater group) and, as a historical control, 16 consecutive cases who underwent resection of peripheral branches of the posterior nasal nerve with turbinoplasty (Control group). RESULTS: The improvements in symptom medication scores in the Underwater group were significantly better than in the Control group (3.07 vs. 1.96, p = 0.02). CONCLUSIONS AND SIGNIFICANCE: By using underwater posterior nasal neurectomy, we can easily and safely resect the posterior nasal nerve trunk under a clear surgical view without injuring the SPA. This technique with submucous inferior turbinectomy may, more than resection of peripheral branches of the posterior nasal nerve, be able to reduce the medication score and symptom medication score.

DOI： 10.1080/00016489.2021.1925151

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MAO.0000000000003220

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.

DOI： 10.1002/cam4.3927

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

External auditory canal carcinoma (EACC) is a rare disease. The current study aimed to evaluate the clinical outcomes of patients treated with external beam radiotherapy (EBRT) for EACC. The present study retrospectively reviewed 34 consecutive patients treated for EACC with EBRT between February 2001 and January 2019 at the University of Tokyo Hospital. Clinical staging was performed according to the modified Pittsburgh classification. Of all the included patients, seven patients were in the early stages (I or II) and 27 in the advanced stages (III or IV) of EACC. A total of 16 patients underwent EBRT and surgery (S+RT) pre- and/or postoperatively, while 18 patients underwent definitive radiotherapy (dRT). The median prescribed doses for the S+RT and dRT groups were 66 and 70 Gy, respectively. The median follow-up period for all patients was 22.4 months (range, 2-205 months). The 5-year overall survival rates of the S+RT and dRT groups were 66.7 and 45.1%, respectively. The progression-free survival rate at 5-year was 55.6% (95% confidence interval: 36.5-71.1%) for the entire cohort. A total of 14 patients experienced disease relapse after treatment, consisting of 11 locoregional recurrences and three distant metastases. The current study revealed the clinical outcomes of EBRT for EACC.

DOI： 10.3892/mco.2021.2207

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Several comprehensive studies have demonstrated that the NOTCH pathway is altered in a bimodal manner in head and neck squamous cell carcinoma (HNSCC). In a previous study, it was found that the NOTCH4/HEY1 pathway was specifically upregulated in HNSCC and promoted epithelial‑mesenchymal transition (EMT), and that HEY1 activation supported SOX2 expression. However, the interactions in this pathway have not yet been fully elucidated. The present study investigated the NOTCH4/HEY1/SOX2 axis in HNSCC using in vitro models and the Cancer Genome Atlas (TCGA) database. To explore the association, reporter and ChIP RT‑qPCR assays using SOX2‑overexpressing (SOX2‑OE) cells were performed. The association between NOTCH4 and HEY1 was examined in the same manner using HEY1‑overexpressing (HEY1‑OE) cells. The results of the in vitro experiments indicated that HEY1 promoted EMT in the HNSCC cells. Furthermore, the overexpression of HEY1 also promoted sphere formation and increased murine xenograft tumorigenicity. Reporter assays and ChIP RT‑qPCR experiments indicated that SOX2 regulated HEY1 expression via direct binding of the HEY1 promoter. HEY1 expression significantly correlated with SOX2 expression in primary lung SCC and other SCCs using the TCGA database. HEY1 also regulated NOTCH4 expression to create a positive reciprocal feedback loop. On the whole, the present study demonstrates that HEY1 expression in HNSCC is regulated via the promotion of SOX2 and promotes EMT. The NOTCH4/HEY1 pathway is specifically upregulated via a positive reciprocal feedback loop mediated by the HEY1‑medaited regulation of NOTCH4 transcription, and SOX2 correlates with HEY1 expression in SCC from other primary sites.

DOI： 10.3892/ijo.2020.5156

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: This study aims to evaluate whether the accumulation of TP53 mutations is associated with clinical outcome by comparing full-coverage TP53 deep sequencing of the initial and recurrent head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Medical records and surgical specimens of 400 patients with HNSCC surgically treated with curative intent, of which 95 patients developed local or locoregional recurrence, were reviewed. Of these patients, 63 were eligible for genomic analysis. Full-coverage TP53 deep sequencing of 126 paired initial and recurrent tumor samples was examined using next-generation sequencing (NGS). Temporal changes in the mutation status, molecular characterization, and clinical outcome were compared. Fisher's exact test, Kaplan-Meier method, log-rank test, and Cox regression models were used for statistical analysis. RESULTS: Of the recurrent tumors, 22% harbored accumulation of TP53 mutations, and 16% lost the original mutation. The accumulation of TP53 mutations was significantly more frequent in oral cancer than in pharyngeal or laryngeal cancer (33% vs. 7%, p = 0.016). Two-year post-recurrence survival (PRS) was associated with TP53 status for recurrent tumors, but not for initial tumors. The TP53 status for recurrent tumors was an independent risk factor in multivariate analysis (hazard ratio, 5.76; 95% confidence interval, 1.86-17.8; p = 0.0023). CONCLUSION: Approximately one-third of the recurrent HNSCC cases showed a different TP53 status from the initial tumor. Temporal changes in the mutation status differed by primary site. Full-coverage TP53 deep sequencing of recurrent tumors was useful in predicting post-recurrence prognosis.

DOI： 10.1016/j.oraloncology.2020.105091

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epidemiological data suggest that inflammation and innate immunity play significant roles in the pathogenesis of age-related hearing loss (ARHL) in humans. In this mouse study, real-time RT-PCR array targeting 84 immune-related genes revealed that the expressions of 40 genes (47.6%) were differentially regulated with greater than a twofold change in 12-month-old cochleae with ARHL relative to young control mice, 33 (39.3%) of which were upregulated. These differentially regulated genes (DEGs) were involved in functional pathways for cytokine-cytokine receptor interaction, chemokine signaling, TNF signaling, and Toll-like receptor signaling. An NF-κB subunit, Nfkb1, was upregulated in aged cochleae, and bioinformatic analyses predicted that NF-κB would interact with the genomic regulatory regions of eight upregulated DEGs, including Tnf and Ptgs2. In aging cochleae, major proinflammatory molecules, IL1B and IL18rap, were upregulated by 6 months of age and thereafter. Remarkable upregulations of seven immune-related genes (Casp1, IL18r1, IL1B, Card9, Clec4e, Ifit1, and Tlr9) occurred at an advanced stage (between 9 and 12 months of age) of ARHL. Immunohistochemistry analysis of cochlear sections from the 12-month-old mice indicated that IL-18r1 and IL-1B were localized to the spiral ligament, spiral limbus, and organ of Corti. The two NF-κB-interacting inflammatory molecules, TNFα and PTGS2, immunolocalized ubiquitously in cochlear structures, including the lateral wall (the stria vascularis and spiral ligament), in the histological sections of aged cochleae. IBA1-positive macrophages were observed in the stria vascularis and spiral ligament in aged mice. Therefore, inflammatory and immune reactions are modulated in aged cochlear tissues with ARHL.

DOI： 10.1371/journal.pone.0258977

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.

DOI： 10.1038/s41388-020-01431-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Salivary duct carcinoma (SDC) is an aggressive, uncommon tumor histologically comparable to high-grade mammary ductal carcinoma. SDCs are usually androgen receptor (AR)-positive and often HER2-positive. Recently, therapies targeting these molecules for SDC have attracted attention. Lipid metabolism changes have been described in association with biological behavior in various cancers, although no such relationship has yet been reported for SDC. We therefore analyzed the clinicopathological relevance of the immunohistochemical expression of adipophilin (ADP) and fatty acid synthase (FASN), representative lipid metabolism-related proteins, in 147 SDCs. ADP and FASN were variably immunoreactive in most SDCs (both 99.3%), and the ADP and FASN expression was negatively correlated (P = 0.014). ADP-positive (≥ 5%) SDCs more frequently exhibited a prominent nuclear pleomorphism and high-Ki-67 labeling index than those ADP-negative (P = 0.013 and 0.011, respectively). In contrast, a high FASN score, calculated by the staining proportion and intensity, (≥ 120) was correlated with the high expression of AR and FOXA1 (P < 0.001 and = 0.003, respectively). The ADP and FASN expression differed significantly among the subtypes based on biomarker immunoprofiling, as assessed by the AR, HER2, and Ki-67 status (P = 0.017 and 0.003, respectively). A multivariate analysis showed that ADP-positive expression was associated with a shorter overall and progression-free survival (P = 0.018 and 0.003, respectively). ADP was associated with an aggressive histopathology and unfavorable prognosis, and FASN may biologically interact with the AR signaling pathway in SDC. ADP may, therefore, be a new prognostic indicator and therapeutic target in SDC.

DOI： 10.1007/s00428-020-02777-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers worldwide. LOXL2 demonstrates alternative splicing events in patients with human papillomavirus (HPV)-negative HNSCC. The current study explored the role of a dominant LOXL2 variant in HPV-negative HNSCC. METHODS: Expression of the LOXL2 variant was analyzed using The Cancer Genome Atlas cohorts and validated using quantitative reverse transcriptase-polymerase chain reaction in a separate primary tumor set. The authors defined the effect of LOXL2 splice variants in assays for cell proliferation using a cell viability assay and colony formation assay. Cell migration and invasion were examined using a cell scratch assay and transwell cell migration and invasion assay in LOXL2 splice variant gain and loss of expression cells. Western blot analysis and gene set enrichment analysis were used to explore the potential mechanism of the LOXL2 splice variant in HPV-negative HNSCC. RESULTS: Expression of a novel LOXL2 variant was found to be upregulated in The Cancer Genome Atlas HPV-negative HNSCC, and confirmed in the separate primary tumor validation set. Analyses of loss and gain of function demonstrated that this LOXL2 variant enhanced proliferation, migration, and invasion in HPV-negative HNSCC cells and activated the FAK/AKT pathway. A total of 837 upregulated and 820 downregulated genes and 526 upregulated and 124 downregulated pathways associated with LOXL2 variant expression were identified using gene set enrichment analysis, which helped in developing a better understanding of the networks activated by this LOXL2 variant in patients with HPV-negative HNSCC. CONCLUSIONS: The novel LOXL2 variant can promote the progression of HPV-negative HNSCC, in part through FAK/AKT pathway activation, which may provide a new potential therapeutic target among patients with HPV-negative HNSCC.

DOI： 10.1002/cncr.32610

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Human papilloma virus (HPV) related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV positive HNSCC. EXPERIMENTAL DESIGN: The expression of cannabinoid receptors CNR1 and CNR2 was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs or shRNA based models to explore the roles of CNR1 and CNR2 in HPV positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS). RESULTS: In TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV positive HNSCC compared with HPV negative HNSCC, and knockdown of CNR1/CNR2 expression inhibited proliferation in HPV positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as non-selective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration, and induced apoptosis. Using whole genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure. CONCLUSION: Cannabinoids can promote progression of HPV positive HNSCC through p38 MAPK pathway activation.

DOI： 10.1158/1078-0432.CCR-18-3301

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype. We identified 319 spliceosome genes and employed a discovery pipeline to identify 13 candidate spliceosome genes altered in HNSCC using The Cancer Genome Atlas (TCGA) HNSCC data. Phenotypic screens identified amplified and overexpressed CPSF1 as a target gene alteration that was validated in proliferation, colony formation, and apoptosis assays in cell line and xenograft systems as well as in primary HNSCC. We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models. Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.

DOI： 10.1371/journal.pone.0233380

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A solitary fibrous tumor (SFT) is a rare neoplasm with recurrent NAB2-STAT6 gene fusion. An SFT may develop almost anywhere throughout the body, including the head and neck region, and is characterized by a broad spectrum of malignancy. Here we present a case involving a 57-year-old male with a dumbbell-shaped SFT in the cervical spine that mimicked schwannoma. Repeated fine-needle aspiration cytology failed to establish a definitive diagnosis. Given that the tumor size increased significantly over a 10-month period, open biopsy was then performed. Though the biopsy result was inconclusive, a nonepithelial tumor, including sclerosing epithelioid fibrosarcoma or ossifying fibromyxoid tumor, was suspected. The tumor was then completely removed together with adjacent parts of C2 and C3 vertebrae and left vertebral artery via combined anterior and posterior approaches. Histologically, the tumor consisted of round cells with prominent stromal hyalinization and was immunohistochemically positive for STAT6, CD34, and cytokeratin. Finally, Todai OncoPanel, a next-generation sequencing-based molecular profiling system using formalin-fixed paraffin-embedded samples, demonstrated fusion transcript in which NAB2 exon 6 was fused to STAT6 exon 16 supporting the diagnosis of SFT, while whole-exome sequencing analysis detected no somatic mutations which were known to be oncogenic.

DOI： 10.1016/j.anl.2019.12.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We aimed to use genomic data for optimizing polymerase chain reaction (PCR) primer/probe sets for detection of human papillomavirus (HPV)-16 in body fluids of patients with HPV-related head and neck squamous cell carcinoma (HPV-HNSCC). METHODS: We used genomic HPV-HNSCC sequencing data from a single institutional and a TCGA cohort. Optimized primer/probe sets were designed and tested for analytical performance in CaSki HPV-16 genome and confirmed in salivary rinse samples from patients with HPV-HNSCC. RESULTS: The highest read density was observed between E5 and L2 regions. The E1 region contained a region that was universally present. Among candidate PCR primer/probe sets created, six reliably detected 30 HPV-16 copy number. In a CLIA certified laboratory setting, the combination of two novel primer/probe with E7 sets improved performance in salivary rinse samples with a sensitivity of 96% and specificity of 100%. CONCLUSIONS: PCR-based detection of HPV-16 DNA in HPV-HNSCC can be improved using rational genomic design.

DOI： 10.1002/hed.26041

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Salivary duct carcinoma (SDC) is a rare, aggressive malignancy that histologically resembles high-grade mammary duct carcinoma. Because of the rarity of this entity, data verifying the association between histologic features and patient survival are limited. We conducted a comprehensive histologic review of 151 SDC cases and performed an analysis of the association between various histomorphologic parameters and the clinical outcome with the aim of developing a histologic risk stratification model that predicts the prognosis of SDC patients. A multivariate analysis revealed that prominent nuclear pleomorphism (overall survival [OS]: P=0.013; progression-free survival [PFS]: P=0.019), ≥30 mitoses/10 HPF (PFS: P=0.013), high tumor budding (OS: P=0.011; PFS: P<0.001), and high poorly differentiated clusters (OS: P<0.001; PFS: P<0.001) were independent prognostic factors. Patients with vascular invasion demonstrated a marginally significant association with shorter PFS (P=0.064) in a multivariate analysis. We proposed a 3-tier histologic risk stratification model based on the total number of positive factors among 4 prognostically relevant parameters (prominent nuclear pleomorphism, ≥30 mitoses/10 HPF, vascular invasion, and high poorly differentiated clusters). The OS and PFS of patients with low-risk (0 to 1 point) (23% of cases), intermediate-risk (2 to 3 points) (54% of cases), and high-risk (4 points) (23% of cases) tumors progressively deteriorated in this order (hazard ratio, 2.13 and 2.28, and 4.99 and 4.50, respectively; Ptrend<0.001). Our histologic risk stratification model could effectively predict patient survival and may be a useful aid to guide clinical decision-making in relation to the management of patients with SDC.

DOI： 10.1097/PAS.0000000000001413

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: A diagnostic indicator for differentiating squamous cell carcinomas (SCCs) from inverted papillomas (IPs) has not been established. Objectives: This study aimed to evaluate whether CT attenuation values relative to those of the brainstem (relative CT number) could be useful in differentiating IPs from SCCs. Material and Methods: Consecutive patients who were pathologically diagnosed with IP or SCC between 2007 and 2017 were retrospectively identified. Relative CT numbers were compared between the two patient groups. The factors with predictive power for differentiating IPs from SCCs were identified by univariate and multivariate logistic regression analyses. Results: Fifty-four sinonasal tumour cases were finally analysed (IP, 25 cases; SCC, 29 cases). Relative CT numbers were significantly higher in SCC than in IP (p < .001). The univariate logistic regression analysis showed BMI, relative CT number, and disease duration to have predictive value for differentiating IPs from SCCs. In the multivariate logistic regression analysis, only the relative CT number had predictive value for distinguishing IP from SCC (odds ratio, 1.97), with a relative CT number of ≥1.4 being significantly associated with SCC. Conclusions: High relative CT numbers could potentially be used to identify SCCs, and their measurement could provide a basis for differentiating IPs from SCCs.

DOI： 10.1080/00016489.2019.1659515

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer is a disease clinically and biologically distinct from smoking-related head and neck squamous cell carcinoma (HNSCC). Despite its rapidly increasing incidence, the mutational landscape of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) remains understudied. METHODS: This article presents the first mutational analysis of the 46 HPV+ OPSCC tumors within the newly expanded cohort of 530 HNSCC tumors from The Cancer Genome Atlas. A separate exome sequencing analysis was also performed for 46 HPV+ OPSCCs matched to their normal lymphocyte controls from the Johns Hopkins University cohort. RESULTS: There was a strikingly high 33% frequency of mutations within genes associated with chromatin regulation, including mutations in lysine methyltransferase 2C (KMT2C), lysine methyltransferase 2D (KMT2D), nuclear receptor binding SET domain protein 1 (NSD1), CREB binding protein (CREBBP), E1A-associated protein p300 (EP300), and CCCTC-binding factor (CTCF). In addition, the commonly altered genes phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and fibroblast growth factor receptor 3 (FGFR3) showed distinct domain-specific hotspot mutations in comparison with their HPV- counterparts. PIK3CA showed a uniquely high rate of mutations within the helicase domain, and FGFR3 contained a predominance of hotspot S249C alterations that were not found in HPV- HNSCC. CONCLUSIONS: This analysis represents one of the largest studies to date of HPV+ OPSCC and lends novel insight into the genetic landscape of this biologically distinct disease, including a high rate of mutations in histone- and chromatin-modifying genes, which may offer novel therapeutic targets.

DOI： 10.1002/cncr.32068

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Intensity-modulated radiation therapy (IMRT) yields better outcomes and fewer toxicities for radiation therapy (RT) of head and neck cancers (HNCs), including nasopharyngeal cancer (NPC). IMRT is the standard RT treatment and has been widely adopted in Western countries to treat HNCs. However, its uptake in clinical practice among NPC patients has never been studied. METHODS: We investigated the use of IMRT for NPC using data from a nationwide cancer registry to describe the use of IMRT among NPC patients in Japan. We analyzed the data of patients with HNC, including NPC, who underwent IMRT between 2012 and 2014, as recorded in the hospital-based cancer registries linked with insurance claims. We calculated the proportion of patients with NPC who underwent IMRT at each hospital. To evaluate the use of IMRT for NPC, the IMRT use for NPC was compared with the proportion of patients with prostate cancer who underwent IMRT. RESULTS: Among 508 patients with NPC who underwent RT at one of 87 hospitals, 348 (69%) underwent IMRT. This proportion gradually increased between 2012 and 2014 (62%, 64% and 77%). Meanwhile, 4790 patients with prostate cancer (90%) underwent IMRT. Although some hospitals where IMRT was performed treated many patients with NPC, the proportion of patients with NPC who were treated with IMRT was low. CONCLUSIONS: IMRT has not been widely adopted in Japan for treating NPC. Barriers for adopting its use should be identified to close the gap between the standard and actual medical practice in Japan.

DOI： 10.1093/jjco/hyz042

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00441-019-03047-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although promoter-associated CpG islands have been established as targets of DNA methylation changes in cancer, previous studies suggest that epigenetic dysregulation outside the promoter region may be more closely associated with transcriptional changes. Here we examine DNA methylation, chromatin marks, and transcriptional alterations to define the relationship between transcriptional modulation and spatial changes in chromatin structure. Using human papillomavirus-related oropharyngeal carcinoma as a model, we show aberrant enrichment of repressive H3K9me3 at the transcriptional start site (TSS) with methylation-associated, tumor-specific gene silencing. Further analysis identifies a hypermethylated subtype which shows a functional convergence on MYC targets and association with CREBBP/EP300 mutation. The tumor-specific shift to transcriptional repression associated with DNA methylation at TSSs was confirmed in multiple tumor types. Our data may show a common underlying epigenetic dysregulation in cancer associated with broad enrichment of repressive chromatin marks and aberrant DNA hypermethylation at TSSs in combination with MYC network activation.

DOI： 10.1038/s41467-019-09937-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/0008-5472.CAN-18-1220

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tumor molecular profiling is becoming a standard of care for patients with cancer, but the optimal platform for cancer sequencing remains undetermined. We established a comprehensive assay, the Todai OncoPanel (TOP), which consists of DNA and RNA hybridization capture-based next-generation sequencing panels. A novel method for target enrichment, named the junction capture method, was developed for the RNA panel to accurately and cost-effectively detect 365 fusion genes as well as aberrantly spliced transcripts. The TOP RNA panel can also measure the expression profiles of an additional 109 genes. The TOP DNA panel was developed to detect single nucleotide variants and insertions/deletions for 464 genes, to calculate tumor mutation burden and microsatellite instability status, and to infer chromosomal copy number. Clinically relevant somatic mutations were identified in 32.2% (59/183) of patients by prospective TOP testing, signifying the clinical utility of TOP for providing personalized medicine to cancer patients.

DOI： 10.1111/cas.13968

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-019-07287-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) exhibits a different composition of epigenetic alterations. In this study, we identified differentially methylated regions (DMRs) with potential utility in screening for HPV-positive OPSCC. Genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV-positive OPSCC tissues and 25 normal tissues. Fifty-one DMRs were defined with maximal methylation specificity to cancer samples. The Cancer Genome Atlas (TCGA) methylation array data was used to evaluate the performance of the proposed candidates. Supervised hierarchical clustering of 51 DMRs found that HPV-positive OPSCC had significantly higher DNA methylation levels compared to normal samples, and non-HPV-related head and neck squamous cell carcinoma (HNSCC). The methylation levels of all top 20 DNA methylation biomarkers in HPV-positive OPSCC were significantly higher than those in normal samples. Further confirmation using quantitative methylation specific PCR (QMSP) in an independent set of 24 HPV-related OPSCCs and 22 controls showed that 16 of the 20 candidates had significant higher methylation levels in HPV-positive OPSCC samples compared with controls. One candidate, OR6S1, had a sensitivity of 100%, while 17 candidates (KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, ELMO1, SFMBT2, C1QL3, MIR129-2, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P and ZNF773) had specificities of 100%. The prediction accuracy of the 20 candidates rang from 56.2% to 99.8% by receiver operating characteristic analysis. We have defined 20 highly specific DMRs in HPV-related OPSCC, which can potentially be applied to molecular-based detection tests and improve disease management.

DOI： 10.1002/ijc.31778

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide, and alternative splicing is considered to play important roles in tumor progression. Our study is designed to identify alternative splicing events (ASEs) in human papillomavirus (HPV)-negative HNSCC.Experimental Design: RNA sequencing data of 407 HPV-negative HNSCC and 38 normal samples were obtained from The Cancer Genome Atlas (TCGA), and splice junctions were discovered using MapSplice. Outlier analysis was used to identify significant splicing junctions between HPV-negative HNSCC and normal samples. To explore the functional role of the identified DOCK5 variant, we checked its expression with qRT-PCR in a separate primary tumor validation set and performed proliferation, migration, and invasion assays.Results: A total of 580 significant splicing events were identified in HPV-negative HNSCC, and the most common type of splicing events was an alternative start site (33.3%). The prevalence of a given individual ASE among the tumor cohort ranged from 9.8% and 64.4%. Within the 407 HPV-negative HNSCC samples in TCGA, the number of significant ASEs differentially expressed in each tumor ranged from 17 to 290. We identified a novel candidate oncogenic DOCK5 variant confirmed using qRT-PCR in a separate primary tumor validation set. Loss- and gain-of-function experiments indicated that DOCK5 variant promoted proliferation, migration, and invasion of HPV-negative HNSCC cells, and patients with higher expression of DOCK5 variant showed decreased overall survival.Conclusions: Analysis of ASEs in HPV-negative HNSCC identifies multiple alterations likely related to carcinogenesis, including an oncogenic DOCK5 variant. Clin Cancer Res; 24(20); 5123-32. ©2018 AACR.

DOI： 10.1158/1078-0432.CCR-18-0752

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Data have been limited on donor-site mechanical bowel obstruction after pharyngolaryngectomy with free jejunum graft reconstruction. METHODS: Using a nationwide Japanese inpatient database, we extracted data on patients who underwent pharyngolaryngectomy for hypopharyngeal cancer between July 2007 and March 2014. A Cox proportional hazard model was used to determine the association between background characteristics and the occurrence of mechanical bowel obstruction. RESULTS: Among the 3320 eligible patients from 332 hospitals, 108 patients (3.3%) developed mechanical bowel obstruction after a median 88 (interquartile range 26-217) postoperative days. Multivariable Cox regression analysis revealed that older age (≥60 years old) was independently associated with an increased risk of mechanical bowel obstruction, whereas sex, body mass index [BMI], smoking status, comorbidity at admission, blood transfusion, history of surgery, and hospital type were not. CONCLUSION: In pharyngolaryngectomy, careful attention should be paid to the risk of abdominal complications and, thus, to the graft choice, especially in elderly patients.

DOI： 10.1002/hed.25139

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掲載種別：研究論文（学術雑誌）  

Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. We sought to evaluate clinical outcomes and toxicities of radiation therapy (RT) alone compared to RT with concurrent chemotherapy (CCT) for nasopharyngeal carcinoma (NPC) treatment. We conducted a retrospective review of consecutive patients with biopsy-proven nonmetastatic NPC who underwent RT at our institution. From May 2001 to April 2015; 62 newly diagnosed NPC patients were treated with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) with or without CCT. The patients were classified as follows: 8% stage I, 15% stage II, 32% stage III, and 45% stage IVA/IVB. A total of 76% of tumors were World Health Organization types II or III. Acute and late toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0. Overall survival (OS), progression-free survival (PFS), locoregional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS) were analyzed. The median follow-up period for living patients was 53 months. The median actual delivered dose was 70 Gy with a range of 28 to 70 Gy in fraction sizes of 2 Gy. The estimated 5-year OS, PFS, LRPFS, and DMFS rates were 72.7%, 59.8%, 77.9%, and 84.2%, respectively. The use of CCT was a predictive factor of significantly better OS and PFS, whereas stage IV was a significant predictor of poor OS and PFS. The most severe acute toxicities included Grade 3 mucositis in 56% and Grade 3 dermatitis in 8%. Subset analysis revealed that Grade 2 xerostomia was significantly lower in the IMRT (23%) group than in the 3D-CRT (52%) group (P = .02). RT yielded favorable outcomes. CCT was associated with longer PFS and OS than RT alone.

DOI： 10.1097/MD.0000000000010502

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases. Similar to other types of cancers, these studies also indicate that the NOTCH pathway is closely related to HNSCC progression. However, the role of NOTCH4 in HNSCC is less well understood.Experimental Design: We analyzed NOTCH4 pathway and downstream gene expression in the TCGA data set. To explore the functional role of NOTCH4, we performed in vitro proliferation, cisplatin viability, apoptosis, and cell-cycle assays. We also compared the relationships among NOTCH4, HEY1, and epithelial-mesenchymal transition (EMT)-related genes using the TCGA data set and in vitro assays.Results:HEY1 is specifically upregulated in HNSCC compared with normal tissues in the TCGA data set. NOTCH4 is more significantly related to HEY1 activation in HNSCC in comparison with other NOTCH receptors. NOTCH4 promotes cell proliferation, cisplatin resistance, inhibition of apoptosis, and cell-cycle dysregulation. Furthermore, NOTCH4 and HEY1 upregulation resulted in decreased E-cadherin expression and increased Vimentin, Fibronectin, TWIST1, and SOX2 expression. NOTCH4 and HEY1 expression was associated with an EMT phenotype as well as increased invasion and cell migration.Conclusions: In HNSCC, the NOTCH4-HEY1 pathway is specifically upregulated, induces proliferation and cisplatin resistance, and promotes EMT. Clin Cancer Res; 24(3); 619-33. ©2017 AACR.

DOI： 10.1158/1078-0432.CCR-17-1366

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53, 68%; PIK3CA, 18%; H-RAS, 16%; BRAF, 4%; and AKT1, 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.

DOI： 10.18632/oncotarget.22927

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd.  

Background: TP53 is the most frequently mutated gene in human cancers. Previous studies reported that TP53 mutations correlated with poor prognoses in patients with head and neck squamous cell carcinoma (HNSCC). However, the relationship between TP53 mutations and hypopharyngeal squamous cell carcinoma (HPSCC) is not known. The current study aimed to evaluate TP53 mutation status as a predictive biomarker in patients with HPSCC. Methods: We retrospectively reviewed the clinical charts of 57 HPSCC patients treated with initial surgery between 2008 and 2014. TP53 mutation status was determined by Sanger sequencing, and patients were classified into wild-type, missense mutation, and truncating mutation groups. Additionally, p53 expression was determined using immunohistochemistry in surgical specimens. Results: TP53 mutations were identified in 39 (68%) patients. The 3-year disease-specific survival (DSS) rate of wild-type, missense mutation, and truncating mutation group were 94%, 61%, and 43%, respectively. The TP53 mutation group displayed significantly worse DSS and overall survival rates than the wild-type group (P = 0.01 and P = 0.007, respectively). Multivariate analyses revealed that the presence of TP53 mutations and ≥4 metastatic lymph nodes were independent adverse prognostic factors for HPSCC. p53 immunopositivity was detected in 22 patients, including 5 (28%) and 17 (71%) patients in the wild-type and missense mutation groups, whereas none of the patients with truncating mutation exhibited p53 immunopositivity (P = 0.0001). Conclusion: The TP53 mutation status correlated with poor prognosis in surgically treated HPSCC patients. Specifically, truncating mutations which were not detected by p53 immunohistochemistry were predictive of worst survival.

DOI： 10.1186/s12885-017-3913-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background
Half of Japanese possess a polymorphism of aldehyde dehydrogenase 2(ALDH2), while few white individuals possess this mutation. The purpose of this study was to investigate the possibility of ALDH2 polymorphism as a prognostic factor for oropharyngeal cancer (OPC) among Japanese population.
Methods
We analyzed 82 Japanese patients with OPC treated between 2006 and 2011. The median observation period was 50 months. P16-staining and ALDH2 polymorphisms were investigated. To examine the frequencies of second primary pharyngeal and esophageal cancers (SPPEC), 37 Japanese patients with OPC treated at Tokyo University Hospital were included for statistical analysis.
Results
Statistically significant differences were noted in OS among sex, age, N classification, and p16 (p = 0.045, 0.024, 0.020, 0.007, respectively). In addition, OS and DSS rates of the patients with heterozygous ALDH2 tended to be worse than those of the patients with homozygous ALDH2 (p = 0.21, 0.086, respectively). Of note, OS and DSS of the patients with p16-negative OPC and heterozygous ALDH2 was significant poorer than those of the patients with p16-positive OPC (p = 0.002, 0.006, respectively), while there was no significant difference in OS and DSS between patients with p16-positive OPC and patients with p16-negative OPC and homozygous ALDH2.
Conclusions
ALDH2 polymorphism might be a promising prognostic factor for Japanese patients with p16-negative OPC.

DOI： 10.1371/journal.pone.0187992

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

The purpose of this study was to investigate an association between the prognosis for oro-hypopharynx squamous cell carcinoma treated with radiation therapy and the pre-therapeutic level of C-reactive protein (CRP). Patient with oro-hypopharyngeal squamous cell carcinoma who underwent definitive radiotherapy in our institution from January 2002 to August 2016 were enrolled. The patient were divided into elevated CRP (over 0.3 mg/dl) group and normal CRP groups, according to pre-treatment serum levels. There were 276 evaluable patients, and the median follow up was 41 months, ranging from 2 to 171 months. The 3-year OS and CSS for all enrolled patients were 67.0% and 72.8%, respectively. The OS and CSS rates were significantly worse in the elevated CRP group than in the normal CRP group, according to Kaplan-Meier survival curves analysed by a Log-rank test (p = 0.005 and p &lt; 0.001, respectively). Multivariate analyses indicated that serum CRP levels remained independent predictors for both OS (HR: 1.588, p = 0.022) and CSS (HR: 1.989, p = 0.005). The pre-treatment CRP level is an independent predictor of treatment prognosis in patients with oro-hypopharyngeal cancer who underwent definitive radiotherapy. Especially, it is curious that an elevated CRP serum level is a significant predictor of loco-regional recurrence.

DOI： 10.1038/s41598-017-18233-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

To investigate the status and treatment of superficial pharyngeal squamous cell carcinoma in Japan.
We analyzed all cases diagnosed between 2011 and 2013, as recorded in the national database of hospital-based cancer registries. We extracted data on patient sex, age, tumor locations, histology, presentation routes, initial treatments, and TNM stages. Additionally, we compared the characteristics of pharyngeal carcinoma to those of esophageal cancer.
A total of 16,521 oropharyngeal and hypopharyngeal cancers from 409 institutions were included. Diagnosis of Tis tumors was infrequent, and both cancers were likely to be diagnosed at an advanced stage (n = 866, 5.3%). Tis diseases were the most commonly detected during follow-up examinations for other diseases (n = 608, 70%). While more oropharyngeal Tis patients were men compared to T1-4 patients (88 vs 82%, respectively), hypopharyngeal cancer patients comprised an equally high proportion of men (94 vs 92%, respectively). The most common location of oropharyngeal Tis tumors was the posterior wall (32%), whereas T1-4 tumors were most commonly found on the lateral wall (36%). In hypopharyngeal cancer, both Tis and T1-4 were most commonly located in the pyriform sinus (62%). The proportion of Tis tumors diagnosed at individual institutions showed a positive correlation with the number of endoscopic treatments (r = 0.32, P &lt; 0.001) and the number of esophageal cancer cases (r = 0.37, P &lt; 0.001).
Our national database study elucidated the current characteristics of superficial pharyngeal squamous cell carcinoma patients in Japan. Further improvements in early diagnosis and standardized treatments are warranted.

DOI： 10.1007/s10147-017-1135-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background. We aimed to determinate the prognostic value of lymphovascular invasion in the specimens resected during total laryngopharyngectomy for hypopharyngeal carcinoma.
Methods. Patients who underwent total laryngopharyngectomy at our institution between 2004 and 2014 were included in this study and retrospectively analyzed. We then discriminated for vascular invasion and lymphatic invasion of the primary tumor in all cases.
Results. We reviewed 135 records (120 men and 15 women; age range, 36-84 years). Tumors with lymphatic invasion tended to be associated with more metastatic lymph nodes and extracapsular spread (ECS) of metastatic lymph nodes. Tumors with vascular invasion tended to be associated with nonpyriform sinus locations. In a multivariate analysis, nonpyriform sinus locations, &gt;3 metastatic lymph nodes, and vascular invasion remained significant prognostic factors for overall survival (OS); in recursive partitioning analysis, ECS and vascular invasion remained important categorical variables for OS.
Conclusion. Vascular invasion is a strong prognostic biomarker for advanced hypopharyngeal carcinoma. (C) 2017 Wiley Periodicals, Inc.

DOI： 10.1002/hed.24705

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background: The posterior nasal nerve is the dominant source of the parasympathetic, sympathetic, and sensory fibers that innervate the nasal respiratory mucosa. Therefore, a posterior nasal neurectomy (PNN) induces denervation of the nasal mucosa and relieves the nasal symptoms of intractable rhinitis. PNN depletes nerve fibers, choline acetyltransferase, and neuropeptides in nasal respiratory mucosa, and reduces nasal secretion. However, the histological and symptomatic changes over an extended period after PNN remain unknown.
Methods: Using a rat model of PNN via the transorbital approach, we investigated chronological changes of nasal morphology, innervation, and secretion over a 48-week postoperative period after PNN.
Results: The respiratory nasal mucosa exhibited squamous metaplasia, lymphocyte and plasma cell infiltration, basement membrane thickening, loss of cilia, and hyperplasia of the mucus gland in thickened epithelium with increased connective tissue from24 weeks after PNN. These changes resemble the characteristics of remodeling in chronic rhinosinusitis. DNA microarray and quantitative polymerase chain reaction analysis revealed that mucin 5ac, interleukin 13, and brain-derived neurotrophic factor messenger RNA ( mRNA) were upregulated in PNN-treatedmucosa compared to untreated mucosa. During this period, nerve fibers including sensory, sympathetic, and parasympathetic fibers gradually reinnervated the mucosa from 12 weeks after PNN. However, nasal secretion was decreased even at 48 weeks after PNN probably due to the prolonged absence of choline acetyltransferase.
Conclusion: Prolonged denervation induces remodeling of the nasal mucosa. Although the depleted nerves were partially reinnervated a few months after PNN, nasal secretion was still suppressed, partly due to a sustained deficiency of acetylcholine synthesis. (C) 2017 ARS-AAOA, LLC.

DOI： 10.1002/alr.21952

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

Objectives Temporal bone squamous cell carcinoma (TSCC) is a rare malignancy. Due to its low incidence rate, studies involving TSCC treatment are limited. The aim of this study is to define the prognostic factors of surgery for TSCC by evaluating our clinical experience.
Methods We reviewed the clinical charts of patients presenting at the University of Tokyo Hospital between 2001 and 2014 and identified 33 patients with TSCC who had been treated with surgery as initial curative treatment.
Results Lateral and subtotal temporal bone resections were performed in 17 and 16 patients, respectively. The 5-year disease-specific and overall survival rate were 71 and 62%, respectively. The significant poor prognostic factors were pathological T4 (P = 0.03), dural invasion (P = 0.008), temporomandibular joint invasion (P = 0.04), and a positive surgical margin (P = 0.009).
Conclusion We demonstrated that the outcome of curative surgery for TSCC as initial treatment was favorable. However, because of the difficulty to ensure an adequate or clear surgical margin due to anatomical complexity, the surgical indication for T4 TSCC with temporomandibular joint invasion should be reconsidered.

DOI： 10.1007/s10147-016-1076-8

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Society for Head and Neck Cancer  

Carcinoma of the external auditory canal (EAC) is a very rare disease. Although a relationship between frequent ear-picking and EAC carcinoma has been suspected, no statistical analysis has been reported. We retrospectively reviewed ear-picking habit in patients with carcinoma of EAC and in healthy Japanese people and statistically analyzed the data. As a result, in the“ younger ( under 50 years old)” group, both“ frequency” and“ materials” showed a significant difference between the patients and the healthy population( p=0.0021 and p=0.0012, respectively). Ear-picking more than once a day and with hard materials might be risk factors for carcinoma of EAC in the younger generation.

DOI： 10.5981/jjhnc.43.76

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

BackgroundFocal adhesion kinase (FAK) plays an important role in tumor metastasis. The purpose of this study was to evaluate the significance of FAK expression in surgically treated patients with hypopharyngeal cancer.
MethodsWe retrospectively reviewed the clinical charts of patients treated at our institution between 2004 and 2012 and identified 87 patients with hypopharyngeal cancer. FAK expression status was retrospectively evaluated using immunohistochemistry.
ResultsFAK-positive patients displayed significantly worse disease-specific survival than FAK-negative patients (p=.001). Multivariate analyses revealed that FAK positivity and extracapsular spread (ECS) were independent, significant adverse prognostic factors. Furthermore, FAK positivity significantly correlated with the number of metastatic lymph nodes (p=.048), and FAK-positive patients displayed a higher incidence of distant metastases (p=.009).
ConclusionThe current study demonstrated that upregulated FAK expression correlates with poor prognosis and tumor dissemination in surgically treated patients with hypopharyngeal cancer. (c) 2016 Wiley Periodicals, Inc. Head Neck 38:1164-1169, 2016

DOI： 10.1002/hed.24176

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/lio2.18

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

ELF4 (also known as MEF) is a member of the ETS family of transcription factors. An oncogenic role for ELF4 has been demonstrated in hematopoietic malignancies, but its function in epithelial tumors remains unclear. Here, we show that ELF4 can function as a tumor suppressor and is somatically inactivated in a wide range of human tumors. We identified a missense mutation affecting the transactivation potential of ELF4 in oral squamous cell carcinoma cells. Restoration of the transactivation activity through introduction of wild-type ELF4 significantly inhibited cell proliferation in vitro and tumor xenograft growth. Furthermore, we found that ELF1 and ELF2, closely related transcription factors to ELF4, also exerted anti-proliferative effects in multiple cancer cell lines. Mutations in ELF1 and ELF2, as in ELF4, were widespread across human cancers, but were almost all mutually exclusive. Moreover, chromatin immunoprecipitation coupled with high-throughput sequencing revealed ELF4-binding sites in genomic regions adjacent to genes related to cell-cycle regulation and apoptosis. Finally, we provide mechanistic evidence that the antiproliferative effects of ELF4 were mediated through the induction of HRK, an activator of apoptosis, and DLX3, an inhibitor of cell growth. Collectively, our findings reveal a novel subtype of human cancer characterized by inactivating mutations in the ELF subfamily of proteins, and warrant further investigation of the specific settings where ELF restoration may be therapeutically beneficial.

DOI： 10.1158/0008-5472.CAN-14-3816

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

BackgroundThe impact of comorbidities on patients with advanced head and neck cancer treated with major surgery has not been reported before.
MethodsWe retrospectively reviewed clinical charts between 2004 and 2011 at our institution and identified 185 patients with clinical stage III to IV head and neck cancer treated with major surgery. Comorbidities were scored using the Adult Comorbidity Evaluation-27 (ACE-27) index manual.
ResultsPatients with ACE-27 2 had significantly worse overall survival (OS) and disease-specific survival (DSS) than those with ACE-27 1 (p&lt;.0001 and p=.0047, respectively). Multivariate analyses revealed that ACE-27 2 and extracapsular spread (ECS) were independently significant adverse prognostic factors for OS and DSS. In addition, patients with ACE-27 2 had a higher incidence of distant metastases (p=.0057).
ConclusionThe current study suggests that comorbidities may predict poor prognosis and development of distant metastases for patients with advanced head and neck cancer treated with major surgery. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 364-369, 2016

DOI： 10.1002/hed.23897

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background: The clinical significance of the Epstein-Barr virus (EBV) status and p16 expression was unknown in nasopharyngeal carcinoma (NPC). Methods: We retrospectively studied our pathology database for 13 years to determine the prevalence of EBV and p16 expression and their association with prognosis in cases of NPC. We performed immunohistochemistry for the p16 protein and in situ hybridization (ISH) for EBV-encoded small RNAs and human papillomavirus (HPV) DNA. Results: Of the 43 patients with NPC, 27 (63%), 6 (14%), and 10 (23%) cases were EBV positive, EBV negative with keratinization, and EBV negative without keratinization, respectively. No cases were HPV positive by ISH. Among the 21 EBV-positive tumours that were tested for p16, only 2 tumours were p16 positive. The keratinization-positive group included only males, typically &gt; 60 years of age (5 of 6) and with T4 tumours (3 of 6). In contrast, the EBV-positive cohort tended to be younger (&lt; 60 years, 13 of 27) and have progressive N-stage tumours (N2-3, 14 of 27). The keratinization and EBV-negative cohort included predominantly males (9 of 10) who were likely p16 negative (4 of 10) and smokers (7 of 10). Multivariate analysis confirmed that keratinization was an independent prognostic factor for progression-free survival. Conclusion: In areas, such as Japan, that are nonendemic for both EBV and HPV, the causality of NPC appears to be more heterogeneous. (C) 2017 S. Karger AG, Basel

DOI： 10.1159/000455901

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background: In human papillomavirus (HPV)-induced carcinogenesis, the arginine (Arg) allele of the TP53 codon 72 polymorphism binds more efficiently to the HPV E6 oncoprotein than the proline (Pro) allele. We investigated the physical status of HPV-16 DNA and the TP53 codon 72 polymorphism in oropharyngeal squamous cell carcinoma (OPSCC). Methods: Tumor samples from 70 p16-positive OPSCC patients were tested for HPV-16 physical status by examining the E2 and E6 open reading frames. The TP53 codon 72 polymorphism was screened by direct sequencing. Results: Of 70 patients, 53 were E6 positive, 29 had integrated forms of HPV-16 DNA, and 24 had mixed or episomal forms. Furthermore, 44 carried the Arg/Arg or Arg/Pro genotype, 3 carried the Pro/Pro genotype, and in 6 patients we were unable to obtain sequencing data. Conclusions: HPV-16 physical status was heterogeneous in our OPSCC patients. Most OPSCC patients had the TP53 Arg/Arg or Arg/Pro genotype. (C) 2016 S. Karger AG, Basel

DOI： 10.1159/000442354

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background. Carcinosarcoma is a rare tumor with biphasic growth of the carcinomatous and sarcomatous components. Prognosis is generally poor and characterization of the molecular mechanisms may provide information for the development of novel antitumor agents and biomarkers.
Methods and Results. We present the case of 66-year-old man with a complaint of nasal obstruction. He was diagnosed with maxillary carcinosarcoma and coexisting papilloma. He underwent multimodal treatment but died of uncontrolled local disease 10 months after the initial presentation. Genetic testing using next-generation sequencing (NGS) revealed that both the carcinomatous and sarcomatous components carried a somatic mutation in the conserved domain of the mesenchymal-epithelial transition factor (MET) proto-oncogene.
Conclusion. Our observation highlighted the importance of the MET gene in the oncogenesis of maxillary carcinosarcoma and is indicative of the common clonal origin of both malignant components. This suggested a possibility of treating MET mutation-positive carcinosarcomas with c-MET inhibitors. (C) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/hed.24043

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oto-Rhino-Laryngological Society of Japan Inc.  

We have performed transoral surgical resection for patients with T1/T2 hypopharyngeal cancer and induction chemotherapy with docetaxel for patients with T2/T3 disease. The patients were analyzed in order to determine the current situation of larynx preservation in patients with hypopharyngeal cancer. The data of a total of 83 patients with hypopharyngeal cancer were analyzed retrospectively. The primary subsites were: pyriform sinus (PS) in 61 patients, posterior wall (PW) in 13 patients, and postcricoid (PC) in 9 patients. The number of patients classified as having T1, T2, T3 and T4 disease were 14, 29, 23 and 17, respectively. The main therapies employed in the patients were as follows: transoral surgical resection plus radiation therapy for Tl disease, radiation therapy, induction chemotherapy, and partial resection for T2 disease, induction chemotherapy, radiation therapy, and pharyngo-laryngoesophagectomy for T3 disease, and pharyngo-laryngoesophagectomy plus induction chemotherapy for T4 disease. The 5-year larynx preservation rates in the patients with T1, T2, T3 and T4 disease were 100%, 73%, 39% and 35%, respectively. Our method was able to improve the larynx preservation rate without having any adverse effect on the survival rate. However, the strength of treatment for T 3 disease needs to be improved, because a large number of recurrences and deaths due to the primary disease were encountered in this patient group.

DOI： 10.3950/jibiinkoka.118.1118

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

In a previous study, we reported the value of p16 expression and alcohol consumption in oropharyngeal carcinoma in Japan. We now report the clinical significance of human papillomavirus status and p16 expression in oropharyngeal carcinoma in Japan.
Over a 9-year period, a retrospective case comparison study of the pathology database was conducted at the University of Tokyo to identify tumor samples of oropharyngeal carcinoma. We performed immunohistochemistry for the p16 protein, in situ hybridization for human papillomavirus-deoxyribonucleic acid and polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 in oropharyngeal carcinoma in Japanese patients. We evaluated the human papillomavirus status in patients with oropharyngeal carcinoma to determine its prevalence and association with prognosis. We defined human papillomavirus(+) and human papillomavirus(-) oropharyngeal carcinoma cohorts as those with and without polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 or in situ hybridization-human papillomavirus.
In oropharyngeal carcinoma, the prevalences of p16(+)human papillomavirus(+), p16(+)human papillomavirus(-), p16(-)human papillomavirus(+) and p16(-)human papillomavirus(-) were 32% (48/150), 7% (10/150), 2% (3/150) and 59% (89/150), respectively. Low tobacco and alcohol consumption, tonsil or base of tongue localization, but not age, were associated with p16(+)human papillomavirus(+). Low alcohol consumption was associated with p16(+)human papillomavirus(-). There was a significant difference in overall survival between p16(+)human papillomavirus(-) and p16(-)human papillomavirus(-) (P = 0.03). In multivariate Cox regression models, p16 was the independent prognostic factor, regardless of human papillomavirus status.
p16 expression was a reliable prognostic biomarker regardless of human papillomavirus status.

DOI： 10.1093/jjco/hyv085

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE PUBLICATIONS LTD  

Objective The molecular mechanisms underlying perineural invasion (PNI)a characteristic pathological feature of adenoid cystic carcinoma (ACC)remain largely unclear. Recently, nerve growth factor (NGF) has been implicated in perineural invasion in certain malignancies. Overexpression of Myb related to the MYB-NFIB fusion gene in ACC has also been correlated with perineural invasion and survival. However, this concept is controversial. The aim of this study was to examine the expression of NGF together with its receptors, tropomyosin receptor kinase A (TrkA) and p75NRT, and Myb in ACC and assess their relationship with perineural invasion and survival.
Study Design Case series with chart review.
Setting The University of Tokyo Hospital.
Subjects and Methods We retrospectively analyzed 37 patients with ACC surgically treated from 1991 to 2011. We examined expression levels of NGF, TrkA, p75NRT, and Myb in the ACC specimens and their correlations with PNI and prognosis.
Results NGF, TrkA, p75NRT, and Myb overexpression rates were 65%, 65%, 30%, and 62%, respectively. Pearson product-moment correlation coefficient revealed a strong correlation between NGF/TrkA immunostaining and PNI (NGF: r = 0.68, P &lt; .0001; TrkA: r = 0.53, P = .0007). Moreover, NGF overexpression was significantly associated with worse 8-year local control rate (27% vs 80%, P = .005). However, p75NRT and Myb expression was related to neither perineural invasion nor survival.
Conclusion Our findings demonstrated that NGF and TrkA overexpression, but not Myb and p75NRT overexpression, may contribute to PNI and thus cause local recurrence in patients with ACC.

DOI： 10.1177/0194599815584762

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

Total pharyngolaryngectomy (TPL) is a conventional and standard surgical method for locoregional control of advanced hypopharyngeal cancer (HPC). This study aimed to define the clinicopathological prognostic factors of TPL by evaluating our surgical experience of TPL in the treatment of HPCs.
We retrospectively reviewed the clinical charts of patients with HPC who were treated between 1995 and 2011 at the University of Tokyo Hospital and enrolled 119 patients who underwent TPL as an initial curative treatment.
The mean follow-up period was 46 months (range, 2-164 months). The 5-year overall survival (OS), disease-specific survival (DSS), locoregional control rates, and relapse-free survival for all patients were 44, 53, 76, and 50 %, respectively. In multivariate analysis, the number of a parts per thousand yen4 metastatic lymph nodes (LNs) was a significant poor prognostic factor for both OS and DSS (p = 0.03 and p = 0.01). Patients with moderate to severe comorbidities had poor prognoses for OS (p = 0.002). In addition, patients with the number of a parts per thousand yen4 metastatic LNs had a higher incidence of distant metastases (p &lt; 0.0001).
The locoregional control rate following TPL was acceptable and the number of metastatic LNs was associated with the incidence of distant metastases.

DOI： 10.1007/s10147-014-0709-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Objectives/Hypothesis: Local residual or recurrent pharyngeal cancer after definitive radiotherapy (RT) or chemoradiotherapy (CRT) is correlated to poor prognosis. We analyzed the efficacy of salvage surgery for patients with local residual or recurrent pharyngeal cancer after RT or CRT.
Study Design: Retrospective clinical study with chart review.
Methods: Between 2001 and 2011, we treated 207 patients with resectable pharyngeal cancer, including 98 patients with oropharyngeal cancer (OPC) and 109 patients with hypopharyngeal cancer (HPC) who received definitive RT or CRT. Local residual or recurrence developed in 59 patients (23 with OPC; 36 with HPC), of whom 42 (18 with OPC; 24 with HPC) underwent salvage surgery. These 42 patients were investigated in this study.
Results: The initial treatments were RT; RT with induction chemotherapy (IC); and concurrent CRT in 12, 9, and 21 patients, respectively. The median radiation dose was 70 Gy. The 3-year disease-specific survival rate after salvage surgery was 40% (median, 26 months). The significant prognostic factors were stage IV prior to initial therapy (P=.049), development of concurrent local and regional relapse (P=.02), and OPC (P=.04).
Conclusions: The efficacy of salvage surgery for local residual or recurrent pharyngeal cancer was limited. Oropharynx origin, stage IV prior to initial therapy, and concurrent regional relapses were significantly poor prognostic factors. Salvage surgery for HPC is worth challenging aggressively. Conversely, the indication of salvage surgery for OPCs should be carefully considered because of its low cure rate.

DOI： 10.1002/lary.24695

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

To determine the clinical significance of human papillomavirus subclinical infection in patients with oropharyngeal squamous cell carcinoma in Japan.
Over a 9-year period, a retrospective case comparison study of the pathology database was conducted at the University of Tokyo to identify samples of oropharyngeal squamous cell carcinoma. We performed in situ hybridization for human papillomavirus-DNA to identify subclinical human papillomavirus infections among patients with oropharyngeal squamous cell carcinoma. Second primary malignancies were classified as synchronous, if identified within 6 months of the diagnosis of the first tumor, or metachronous, if identified after this 6-month period. Univariate and multivariate analyses using logistic stepwise regression models were performed to identify factors associated with synchronous and metachronous second primary malignancy.
Of the 150 patients with oropharyngeal squamous cell carcinoma, 14% (21/150) and 20.7% (31/150) developed synchronous and metachronous second primary malignancies, respectively. Esophageal carcinoma was the most frequent second primary malignancy (10/21 for synchronous and 10/31 for metachronous second primary malignancies). The prevalence of oropharyngeal squamous cell carcinoma positive for human papillomavirus was 31% (47/150). Multivariate analysis identified alcohol consumption as a significant unfavorable risk factor for the occurrence of synchronous second primary malignancy, and either a human papillomavirus-negative status or N0 classification was a significant unfavorable risk factor for the occurrence of metachronous second primary malignancy.
Evaluation of the human papillomavirus status may help identify patients at risk for metachronous second primary malignancy. Upper gastrointestinal endoscopy is very important in the diagnosis of oropharyngeal squamous cell carcinoma among heavy drinkers in Japan.

DOI： 10.1093/jjco/hyu042

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/leu.2013.278

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Purpose: Head and neck squamous cell carcinoma of an unknown primary site (HNSCCUP) is a heterogeneous group of tumors that includes the human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma. To investigate the relationship between HNSCCUP and HPV, we reviewed p16 overexpression and HPV DNA in lymph node metastases and examined their correlation with the primary site and clinical features. Materials and Methods: Thirty-three patients with HNSCCUP were retrospectively studied. Dissected neck metastases were analyzed for p16 overexpression by immunohistochemistry, and the presence of HPV DNA was investigated by in situ hybridization. Results: Of the 33 patients, 8 (24%) exhibited p16 overexpression. p16-positive lymph node metastases contained significantly more HPV DNA and were most frequently associated with occult primary lesions in the oropharynx and a favorable prognosis. Patients with a lower alcohol consumption, only level II/III metastasis, and cystic lymph node metastasis tended to have p16 overexpression. Conclusions: This is the first report on the relationship of HNSCCUP with p16 and HPV DNA status in Asian patients. In total, 24% of the HNSCCUP patients were p16 positive. p16 overexpression in neck metastasis was predictive of both an occult primary lesion in the oropharynx and an association with HPV infection. Alcohol consumption, location, and features of neck metastasis were correlated with p16 expression. (C) 2014 S. Karger AG, Basel

DOI： 10.1159/000363190

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：4  

Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma with a 5-year overall survival rate of &lt
30%. To identify carcinogenesis-related genes in PTCL, we conducted high-throughput resequencing of target-captured cDNA in a PTCL specimen, revealing a total of 19 missense mutations among 18 independent genes. One of such substitutions, c.2201G&gt
A in STK10 cDNA, replaces an arginine residue to a histidine (R634H) in the encoded protein. Of note, while wild-type STK10 suppresses NF-κ
B activity and potentiates dexamethasone-induced apoptosis, the R634H change significantly decreases such pro-apoptotic activity. This c.2201G&gt
A change of STK10 was also identified in another PTCL specimen, but now registered as a single nucleotide polymorphism in the latest dbSNP database. Furthermore, other somatic mutations of STK10 have been reported, and we now reveal that some of them (L85P and K277E) have more profound anti-apoptotic effects compared to R634H. These results suggest that STK10 functions as a tumor suppressor gene, and that dysfunction of STK10 activity either through polymorphism or somatic mutations may confer anti-apoptotic effects contributing to carcinogenesis.

DOI： 10.3892/or.2013.2605

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a 5-year survival rate of similar to 50%. With the use of a custom cDNA-capture system coupled with massively parallel sequencing, we have now investigated transforming mechanisms for this malignancy. The cDNAs of cancer-related genes (n = 906) were purified from a human HNSCC cell line (T3M-1 Cl-10) and subjected to high-throughput resequencing, and the clinical relevance of non-synonymous mutations thus identified was evaluated with luciferase-based reporter assays. A CASP8 (procaspase-8) cDNA with a novel G-to-C point mutation that results in the substitution of alanine for glycine at codon 325 was identified, and the mutant protein, CASP8 (G325A), was found to activate nuclear factor-kappa B (NF-kappa B) signaling to an extent far greater than that achieved with the wild-type protein. Moreover, forced expression of wild-type CASP8 suppressed the growth of T3M-1 Cl-10 cells without notable effects on apoptosis. We further found that most CASP8 mutations previously detected in various epithelial tumors also increase the ability of the protein to activate NF-kappa B signaling. Such NF-kappa B activation was shown to be mediated through the COOH-terminal region of the second death effector domain of CASP8. Although CASP8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regard to activation of NF-kappa B signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC.

DOI： 10.1111/cas.12191

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：8  

DOI： 10.1111/cas.12191

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATL ACAD SCIENCES  

Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities. Whereas HRAS, NRAS, and KRAS frequently acquire transforming missense mutations in human cancer, little is known of the oncogenic roles of other small GTPases, including Ras-related C3 botulinum toxin substrate (RAC) proteins. We show that the human sarcoma cell line HT1080 harbors both NRAS(Q61K) and RAC1(N92I) mutant proteins. Whereas both of these mutants were able to transform fibroblasts, knockdown experiments indicated that RAC1(N92I) may be the essential growth driver for this cell line. Screening for RAC1, RAC2, or RAC3 mutations in cell lines and public databases identified several missense mutations for RAC1 and RAC2, with some of the mutant proteins, including RAC1(P29S), RAC1(C157Y), RAC2(P29L), and RAC2(P29Q), being found to be activated and transforming. P29S, N92I, and C157Y mutants of RAC1 were shown to exist preferentially in the GTP-bound state as a result of a rapid transition from the GDP-bound state, rather than as a result of a reduced intrinsic GTPase activity. Activating mutations of RAC GTPases were thus found in a wide variety of human cancers at a low frequency; however, given their marked transforming ability, the mutant proteins are potential targets for the development of new therapeutic agents.

DOI： 10.1073/pnas.1216141110

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

2005年1月から2011年12月までの7年間に喉頭癌に対し一次治療として根治手術を行った53症例を検討対象とした。男性44例、女性9例、年齢は46歳～87歳(中央値70歳)、観察期間は4～80ヵ月(中央値24ヵ月)、声門上癌36例、声門癌15例、声門下癌2例であった。潜在リンパ節転移率は声門癌N0で6.7%、声門上癌N0で30%、声門上癌N1、N2bの対側頸部で20%であった。予防的頸部廓清術は声門癌N0には不要で声門上癌N0には適応があると考えられた。N1、N2bの対側頸部の頸部郭清術の適応は今後の検討課題と考えられた。郭清範囲は患側のLevel II～IIIで充分な可能性が示唆された。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J04210&link_issn=&doc_id=20130311410013&doc_link_id=10.5106%2Fjjshns.22.323&url=https%3A%2F%2Fdoi.org%2F10.5106%2Fjjshns.22.323&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本頭頸部癌学会  

(化学)放射線治療後の局所再発・残存に対し救済手術を施行した下咽頭癌症例について、その治療意義を明らかにする事を目的に検討した。2001年4月から2010年8月の間に当科で初回治療として根治的(化学)放射線治療を行った下咽頭癌101例中、局所再発・残存を35例(35%)に認めた。内、救済手術を行いえた24例を対象として後向きに検討した。初回照射線量は69～72Gy、化学療法は同時/導入/なし:8/7/9例であった。救済術式は咽喉食摘術/下咽頭部分切除術/内視鏡的咽喉頭手術(ELPS):20/3/1例、術後観察期間は1～115ヵ月(平均30ヵ月)、術後3年生存率は60%であった。一方、術後合併症は11例(46%)で起きていた。一般に救済手術の予後は不良とされるが、比較的切除安全域を取りやすい下咽頭癌での救済手術は生命予後の改善に意義があると考えられた。(著者抄録)

DOI： 10.5981/jjhnc.39.55

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J04195&link_issn=&doc_id=20130507330010&doc_link_id=10.5981%2Fjjhnc.39.55&url=https%3A%2F%2Fdoi.org%2F10.5981%2Fjjhnc.39.55&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

The scirrhous subtype of gastric cancer is a highly infiltrative tumor with a poor outcome. To identify a transforming gene in this intractable disorder, we constructed a retroviral complementary DNA (cDNA) expression library from a cell line (OCUM-1) of scirrhous gastric cancer. A focus formation assay with the library and mouse 3T3 fibroblasts led to the discovery of a transforming cDNA, encoding for MAP2K1 with a glutamine-to-proline substitution at amino acid position 56. Interestingly, treatment with a MAP2K1-specific inhibitor clearly induced cell death of OCUM-1 but not of other two cells lines of scirrhous gastric cancer that do not carry MAP2K1 mutations, revealing the essential role of MAP2K1(Q56P) in the transformation mechanism of OCUM-1 cells. By using a next-generation sequencer, we further conducted deep sequencing of the MAP2K1 cDNA among 171 human cancer specimens or cell lines, resulting in the identification of one known (D67N) and four novel (R47Q, R49L, I204T and P306H) mutations within MAP2K1. The latter four changes were further shown to confer transforming potential to MAP2K1. In our experiments, a total of six (3.5%) activating mutations in MAP2K1 were thus identified among 172 of specimens or cell lines for human epithelial tumors. Given the addiction of cancer cells to the elevated MAP2K1 activity for proliferation, human cancers with such MAP2K1 mutations are suitable targets for the treatment with MAP2K1 inhibitors.

DOI： 10.1093/carcin/bgs099

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

The recent advent of whole exon (exome)-capture technology, coupled with second-generation sequencers, has made it possible to readily detect genomic alterations that affect encoded proteins in cancer cells. Such target resequencing of the cancer genome, however, fails to detect most clinically-relevant gene fusions, given that such oncogenic fusion genes are often generated through intron-to-intron ligation. To develop a resequencing platform that simultaneously captures point mutations, insertions-deletions (indels), and gene fusions in the cancer genome, we chose cDNA as the input for target capture and extensive resequencing, and we describe the versatility of such a cDNA-capture system. As a test case, we constructed a custom target-capture system for 913 cancer-related genes, and we purified cDNA fragments for the target gene set from five cell lines of CML. Our target gene set included Abelson murine leukemia viral oncogene homolog 1 (ABL1), but it did not include breakpoint cluster region (BCR); however, the sequence output faithfully detected reads spanning the fusion points of these two genes in all cell lines, confirming the ability of cDNA capture to detect gene fusions. Furthermore, computational analysis of the sequence dataset successfully identified non-synonymous mutations and indels, including those of tumor protein p53 (TP53). Our data might thus support the feasibility of a cDNA-capture system coupled with massively parallel sequencing as a simple platform for the detection of a variety of anomalies in protein-coding genes among hundreds of cancer specimens. (Cancer Sci 2012; 103: 131-135)

DOI： 10.1111/j.1349-7006.2011.02105.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：1  

The recent advent of whole exon (exome)-capture technology, coupled with second-generation sequencers, has made it possible to readily detect genomic alterations that affect encoded proteins in cancer cells. Such target resequencing of the cancer genome, however, fails to detect most clinically-relevant gene fusions, given that such oncogenic fusion genes are often generated through intron-to-intron ligation. To develop a resequencing platform that simultaneously captures point mutations, insertions-deletions (indels), and gene fusions in the cancer genome, we chose cDNA as the input for target capture and extensive resequencing, and we describe the versatility of such a cDNA-capture system. As a test case, we constructed a custom target-capture system for 913 cancer-related genes, and we purified cDNA fragments for the target gene set from five cell lines of CML. Our target gene set included Abelson murine leukemia viral oncogene homolog 1 (ABL1), but it did not include breakpoint cluster region (BCR)
however, the sequence output faithfully detected reads spanning the fusion points of these two genes in all cell lines, confirming the ability of cDNA capture to detect gene fusions. Furthermore, computational analysis of the sequence dataset successfully identified non-synonymous mutations and indels, including those of tumor protein p53 (TP53). Our data might thus support the feasibility of a cDNA-capture system coupled with massively parallel sequencing as a simple platform for the detection of a variety of anomalies in protein-coding genes among hundreds of cancer specimens. © 2011 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2011.02105.x

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

To identify useful molecular markers for the treatment of head and neck cancers (HNCs), mutations of the TP53 and EGFR genes were analyzed in 56 HNCs, including 39 head and neck squamous cell carcinomas (HNSCCs). No EGFR mutation was observed in the fragments of exons 18-21. By contrast, 17 of 39 (44%) HNSCCs, as well as 3 of 6 cases (50%) with salivary gland carcinoma showed TP53 mutation in the fragments of exons 5-9. The incidence of nonsense mutation was 47%, which was higher than that in previous reports in other countries, suggesting the presence of etiological factors characteristic to Japanese patients. Further clinical assessment, including drug response and prognosis, is required in HNSCCs carrying the null-type mutation of TP53.

DOI： 10.5981/jjhnc.37.1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI LTD  

Some classical textbooks of anatomy provided a detailed description of the lingual nodes, which are small inconstant lymph nodes in the floor-of-mouth and the upper neck. The clinical importance of these lymph nodes in cancer therapy. however, has been underestimated so far. We previously reported an extremely poor prognosis of oral tongue cancer patients who had lesions at the root of the lingual artery and assumed that metastases in occult lingual nodes might be responsible for such lesions. This case report clearly demonstrates the distinctive draining course of the lateral lingual nodes, which may potentially be left untreated by a neck dissection. A 63-year-old Japanese male with T2 squamous cell carcinoma of the oral tongue showed multiple metastatic involvements of the lateral lingual nodes; three nodes in close contact with the sublingual gland, and one node at the root of the lingual artery. A systematic inspection of lymph nodes along the draining course of the lateral lingual nodes should be included, because a neck dissection in continuity with the primary tumor (a pull-through approach) is still inadequate for the removal of the lymph nodes at the root of the lingual artery. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.anl.2009.10.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A clinical study was made of 179 patients with previously untreated glottic carcinoma registered in our department between 1998 and 2004. In our facility, T1 glottic cancer was treated by radiotherapy, T2 glottic cancer by radiotherapy or chemoradiotherapy using low-dose CDDP, and T3 and T4 glottic cancer by laryngectomy. The five-year cause-specific survival rate for glottic carcinoma was 95.1%, 96.5% for stage I, 96.6% for stage II, 92.9% for stage III, and 68.6% for stage IV. The five-year local control rate for early glottic carcinoma treated by radiotherapy was 83.1% for T1a, 60.7% for T1b, and 62.5% for T2. In T2 cases, the local control rate was 49.2% for treatment by radiotherapy, and 83.6% for low-dose CDDP with radiotherapy. Low-dose CDDP with radiotherapy contributes to high local control rate in T2 cases. © 2010, Japan Society for Head and Neck Cancer. All rights reserved.

DOI： 10.5981/jjhnc.36.322

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

We evaluated patients with small oral tongue cancer suffering from recurrence, which develops in the intervening area between the primary site and the neck. Lesions in the area around the cornu of the hyoid bone (&apos;para-hyoid&apos; area) often involve the hypoglossal nerve and the root of the lingual artery, resulting in treatment failure and death.
A 10-year retrospective chart review was conducted of 248 oral tongue cancer patients with small primary tumors (T1/2). No patients who underwent postoperative radiotherapy (PORT) were included.
After excluding those who had local failure or developed new primary lesions, 6.3% of the patients were noted to have a para-hyoid lesion. A similar incidence was observed between the patients with and without previous neck dissection, 6.9% and 5.7%, respectively. All but one patient died due to uncontrolled neck disease.
Recurrent para-hyoid lesions could occur, irrespective of a previous neck dissection. In other words, the para-hyoid area is beyond the limits of a neck dissection. Once a para-hyoid lesion becomes clinically evident, it seems difficult to salvage. Therefore, a careful inspection of the area should be included intraoperatively in any type of neck dissection (i.e. elective or therapeutic) for patients with oral tongue cancer. This may be the key to improving the regional control rate of patients with small oral tongue cancer. We believe that some patients will benefit from more aggressive treatment of the neck, although PORT seems unnecessary for the majority of the patients with limited neck disease.

DOI： 10.1093/jjco/hyp001

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Purpose: Many articles have discussed the clinical features of previously untreated parotid cancer, but the clinical characteristics and treatment of recurrent parotid cancer have not yet been fully described. Materials: We retrospectively reviewed 20 patients with recurrent parotid cancer and analyzed the therapeutic strategies and the prognostic factors. Results: Twelve patients (60%) underwent definitive surgery, including 3 who underwent skull base surgery. The 5-year overall survival (OS) and 5-year disease-free survival (DFS) in the surgery group were 66.7 and 64.1%. In the definitive surgery group, the presence of lymph node metastasis and high-grade malignant histopathology were associated with a poor prognosis (p &lt; 0.01). On the other hand, the presence of facial palsy at presentation, the surgical margin, the time of relapse and the T stage did not affect the DFS in our series. Conclusions: The results suggest that aggressive definitive surgery may be justified for the treatment of recurrent parotid cancer. The presence of lymph node metastasis and the histopathological malignancy grade are poor prognostic factors for OS and DFS. Copyright (C) 2009 S. Karger AG, Basel

DOI： 10.1159/000236013

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Mucoepidermoid carcinoma of the thyroid gland is a rare tumor first described by Rhatigan et al. in 1977. Its pathogenesis is still controversial. With regard to its most likely origin, some authors have suggested that it arises directly from follicular epithelium whereas others have proposed that it arises from ultimobranchial body (diverticulum from the fourth pharyngeal pouch) remnants, also known as solid cell nests (SCN). Herein is reported a unique case of thyroid mucoepidermoid carcinoma. The patient, a 67-year-old man, presented with a non-tender thyroid mass and vocal cord fixation. The tumor was poorly defined, necessitating subtotal thyroidectomy with composite resection of the adjacent structures. Pathologically, the tumor cells had characteristics of mucoepidermoid carcinoma, along with layers of columnar cells showing marked ciliation resembling respiratory-type epithelium, suggesting that this rare tumor had originated from SCN. p63 immunopositivity in the tumor provided additional evidence for the pathogenesis.

DOI： 10.1111/j.1440-1827.2008.02303.x

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掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We analyzed 32 cases of lateral wall oropharyngeal carcinoma treated at our institution retrospectively. Five-year overall and disease-specific survival rates were 50% and 62%, respectively. The 5-year locoregional control rate was 57%, and including salvage therapy it was improved up to 62%. It was difficult to control locoregional tumor with surgery in far-advanced cases where the tumor had invaded the nasopharynx or larynx. There is a possibility of salvage if the recurrence is solitary, but a case with multiple recurrence is difficult to salvage. © 2008, Japan Society for Head and Neck Cancer. All rights reserved.

DOI： 10.5981/jjhnc.34.526

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpainsymman.2007.08.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO  

Mucosa-associated lymphoid tissue (MALT) lymphoma is a distinct subtype of lymphoma. Parotid MALT lymphoma is a rare tumor that is hard to diagnose by fine-needle aspiration cytology. Therefore, partial parotidectomy is often required for a pathological diagnosis. We report a case of MALT lymphoma presented as unilateral diffuse swelling of the parotid gland, who was diagnosed by partial parotidectomy and underwent radiotherapy. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.amjoto.2005.01.011

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掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：耳鼻咽喉科臨床学会  

症例は77歳男性で、2週間前頃から喉頭違和感を自覚しており、当科初診日深夜に呼吸困難が出現したため当院に救急搬送された。精査によりたこつぼ型心筋症と狭心症が明らかとなり、さらにCTで気管狭窄を伴う甲状腺腫瘍が認められた。急速に増大する甲状腺腫瘍であったため、未分化癌や悪性リンパ腫を疑い穿刺吸引細胞診を施行したが、検体不良との結果で診断を得られなかった。早期の確定診断に加え、気道管理の面から経皮的な気道確保への移行が必要と判断し、入院4日目に輪状軟骨開窓術と開放生検を同時に行う方針とした。術後2週目にび漫性大細胞性リンパ腫の確定診断に至り、たこつぼ型心筋症と狭心症は呼吸・循環管理により改善していたため、血液内科に転科のうえ術後21日目から化学療法が開始され、6コース完遂後に腫瘍は完全奏効となった。

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記述言語：日本語   出版者・発行元：耳鼻咽喉科臨床学会  

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記述言語：日本語   出版者・発行元：(一社)日本耳鼻咽喉科頭頸部外科学会  

p16陽性中咽頭癌の初回手術治療例において,予後に影響を与える因子を明らかにすることを目的に検討を行った.東京大学耳鼻咽喉科・頭頸部外科で2004〜2019年に初回治療に根治手術を行ったp16陽性中咽頭癌55例を対象とし,後向きに検討した.検討項目は新旧病期分類,切除断端,転移リンパ節の個数,節外浸潤および術後照射の有無とし,単変量解析による比較を行った.年齢は46〜82歳(中央値67歳),性別は男性/女性=47/8例.旧分類ではStage I/II/III/IV=3/10/13/29例,新Stage分類はI/II/III=47/6/2例であった.経口法/外切開を40/15例,うち断端陽性が15例(経口法11例/外切開4例)であった.55例の内,5個以上のリンパ節転移が6例,節外浸潤ありを7例に認めた.単変量解析ではpN0が予後良好因子であり,術後に放射線治療を追加した症例で予後良好な傾向にあったが有意差は得られなかった.全症例の5年粗生存率,5年無再発生存率はそれぞれ86.2%,75.2%であり,5年粗生存率,5年無再発生存に影響したのは第8版によるStage分類,病理学的リンパ節の個数(pN分類)であった.単一施設の後ろ向き研究であるが,初回手術治療例で病理学的リンパ節の個数がp16陽性中咽頭癌の予後を正しく定義し,pNによる予後層別化の可能性を示唆した.(著者抄録)

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記述言語：日本語   出版者・発行元：(株)医学書院  

78歳男性。発熱、呼吸苦を主訴に、近医のPCR検査にてCOVID-19陽性と診断された。診断後は4日間の自宅療法ののち、診断5日後に前医の入院加療を開始したが、動脈血酸素飽和度が徐々に増悪し、診断7日後に当院搬送となった。当院でHFNC管理を継続し、レムデシベル、トシリズマブ、バリシチニブによる加療を開始したが、酸素状態は改善せず、診断29日後に肺炎、呼吸不全の改善目的でシングルユース軟性鼻咽喉鏡(Ambu内視鏡)を用いて気管切開術を施行した。術後は引き続き人工呼吸器管理、加療を継続中である。単回使用製品であるAmbu内視鏡はスタッフの感染防御に有用であった。

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記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞POINT ◆標準治療が終了(もしくは終了見込み)した固形がん患者が対象となる.◆出検に先立ち,患者の生命予後や薬剤投与の見込みを評価することが必要である.◆得られた結果に対応する治療は日進月歩であり,知識が固定化できないことを認識する.

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記述言語：日本語   出版者・発行元：(一社)日本耳鼻咽喉科頭頸部外科学会  

Cowden症候群は種々の臓器に過誤腫性病変を生じるまれな遺伝性疾患で,悪性腫瘍を高率に合併する.今回われわれは縦隔内に進展する甲状腺腫瘍を契機にCowden症候群と診断した症例を経験したが,耳鼻咽喉科からの報告例が少なかったためここに報告する.症例は46歳女性.縦隔内甲状腺腫瘍にて紹介初診となった.特徴的皮膚所見と脂肪腫,消化管ポリポーシスの合併からCowden症候群を疑い,甲状腺全摘術を施行した.病理学的に甲状腺癌が明らかとなり,家族歴も併せて診断した.本症例のように甲状腺病変を有する症例は多く,悪性腫瘍早期発見のため包括的に診断し,診断後は長期間経過観察すべきである.(著者抄録)

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

COVID-19の流行下における当院での鼻科手術実施にあたっての対策と現状について報告した。2020年4月から5月にかけて緊急症例や悪性腫瘍関連の症例以外は新規手術の予約の停止、予定の手術の延期等を行った。2020年6月以降は術前にPCR検査を施行することが可能となり、経鼻手術は術前に原則としてPCR施行の上で再開した。手術再開後、2020年8月から11月にかけて経鼻手術はほぼ例年同様の手術症例数となったが、流行の第3波の影響を受け2020年12月から2021年2月にかけて大きく手術数が減少した。手術を含めたすべての診療に関連して、新型コロナウイルスの感染リスクに関する問題が生じた場合は院内の感染制御部と連携し、助言を受けることが可能な体制となっている。

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

【はじめに】シスプラチン感受性再発・遠隔転移頭頸部癌に対してEXTREMEレジメンは有意な生存期間の延長をもたらす。【方法】2015年〜2019年の間に当院で同レジメンを施行したシスプラチン抵抗性を除いた再発・転移頭頸部癌28症例について後方視的に予後因子解析を行った。【結果】1年全生存期間(OS)は60%,1年無増悪生存期間(PFS)は16%であった。原病診断からのシスプラチン総蓄積量が300mg/m2を超えた症例の1年OSは79%で,300mg/m2未満の症例に比して有意に良好であった。【考察】シスプラチンが十分投与できた症例が結果的に長期生存につながっていた。(著者抄録)

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

胆道感染症は,胆石や胆泥により胆汁が鬱滞することで十二指腸乳頭より上行性に細菌感染が生じ発症する。長期間の絶食や経口摂取量不足が続くと胆汁がよどみ,胆石や胆泥発生の好条件となる。また,オピオイド鎮痛薬によるオッジ括約筋機能不全に陥る場合もあり,化学放射線療法中の腹部症状には注意を要する。今回われわれは外耳道癌に対するセツキシマブ併用放射線療法中に発症した胆道感染症を経験した。胆道感染症は診断と治療が遅れれば,開腹手術を要することがある。化学放射線療法を行う機会のある耳鼻咽喉科医は留意すべき治療中合併症のひとつであろう。(著者抄録)

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

巨大な鼻腔血管腫の手術では良好な視野の確保が困難となることが多く,また術中に大量出血をきたすことがあるため,術式の選択が重要とされる。本症例は,78歳女性,左鼻腔を充満する血管腫症例である。術前塞栓術を試みたが施行できなかったため,手術の最初に栄養血管である蝶口蓋動脈の処理が必要であった。TACMI法とEndoscopic Denker's Approachを併用することで,蝶口蓋動脈凝固切断後の腫瘍の一塊切除が,内視鏡下に可能となった。これらの術式の併用は,巨大な鼻腔腫瘍,特に蝶口蓋動脈の処理も必要な場面において有用であると考えられた。(著者抄録)

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記述言語：日本語   出版者・発行元：耳鼻咽喉科臨床学会  

当科で化学療法を施行した小児、思春期・若年(CAYA)世代がん患者20例を対象に、妊孕性温存に関する説明の実態調査を行った。その結果、妊孕性低下・消失について説明していた患者は2例のみであり、それぞれ17歳と23歳の未婚若年女性であった。一方、その他の女性5例(30歳台)や男性(13〜38歳)には説明が行われていなかった。また、妊孕性温存ガイドラインが出版された2017年の前後で妊孕性低下・消失について説明を実施した割合には著しい変化はみられず、妊孕性に対する配慮は担当医レベル、診療科レベルでも改善できる余地が十分にあると考えられた。

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

1日2回の生理食塩水洗浄と抗菌薬の保存的加療により、人工内耳植え込み術後の局所感染を制御できた小児の1例(1歳11ヵ月男児)について報告した。本症例で術後創部感染の保存的加療が可能であった要因として、「起炎菌がMRSAなどではなく、MSSAであったこと」「鼓膜所見や起炎菌から、中耳からの感染ではなく、皮膚からの感染であったため」「当院では、人工内耳植え込み術の際、minimum invasive surgeryを行っていること」が考えられた。

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記述言語：日本語   出版者・発行元：(一社)日本鼻科学会  

若年性血管線維腫は思春期男性に好発する易出血性の血管性腫瘍で,局所浸潤性が高く,鼻腔内から翼口蓋窩を中心に周囲組織を破壊進展する。手術療法は,様々な外切開が適応とされることが多かったが,近年では手術器具,技術,ナビゲーションシステムなどの進歩により経鼻内視鏡下に摘出される報告が増えている。Endoscopic tri-port approach法とは,Omuraらの提唱したTransseptal access with crossing multiple incisions(TACMI法),Direct approach to the anterior and lateral part of the maxillary sinus with an endoscope(DALMA法)と,Weberらの提唱した鼻涙管切断を伴う下鼻甲介処置を組み合わせることで,両外鼻孔からの経鼻中隔,経鼻腔,経上顎洞前壁の3つのポートを使用して,0度の内視鏡で翼口蓋窩や眼窩などへアプローチする方法である。今回我々は17歳の男性で,鼻腔,上咽頭から翼口蓋窩に一部進展の認める若年性血管線維腫,Radkowski分類Stage IIA期に対して,術前日に選択的血管塞栓術を施行した後に,Endoscopic tri-port approach法にて一塊切除した。Endoscopic tri-port approach法は顔面の外切開や歯齦部切開を施行することなく,可能な限り鼻中隔や下鼻甲介を温存しながら,広い術野で病変部への到達が可能であり,翼口蓋窩進展を認める若年性血管線維腫に対して有用なアプローチ法と考えられた。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

【背景】頭頸部癌患者には重複癌が生じやすく頭頸部領域と上部消化管の重点的検索が必要であるが,口腔癌に限った重複癌部位と年齢等のリスク因子に関する報告は少ない。【方法】当院で加療した口腔癌患者155人を対象とした後ろ向き観察研究。【結果】同時性重複癌11例,異時性重複癌39例,同時性かつ異時性重複癌3例を認めた。重複癌のリスク因子は,同時性ではPack-year 25以上,異時性では67歳以上とPack-year 37以上であった。若年または非喫煙者の上部消化管に生じた異時性重複癌は3例と少なかった。【結語】60歳未満または非喫煙者においては,上部消化管内視鏡による食道癌,胃癌の指摘率は少なかった。(著者抄録)

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

2013年4月から2017年12月に当科でシスプラチン(CDDP)併用根治的化学放射線療法を施行した頭頸部癌症例計49例において,胃瘻栄養の必要性と治療効果について後方視的に検討した。経管栄養を使用した症例は計30例であった。喉頭癌では咽頭癌と比較して経管栄養使用率が低く,また経管栄養使用の有無と治療成績およびCDDP積算量との間に有意な相関は認められなかった。頸部リンパ節転移がなく予防的頸部照射のみの症例においても経管栄養使用率は低かった。治療前体重が64kg未満の症例で経管栄養使用例が多く,治療前体重64kg未満の症例において経管栄養の使用が治療中の体重低下を予防する傾向が見られた。(著者抄録)

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記述言語：日本語   出版者・発行元：岡山医学会  

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記述言語：日本語   出版者・発行元：岡山医学会  

頭頸部扁平上皮癌の発癌メカニズム解明と標的治療を目指したゲノム解析は着実に進んでいるものの、画期的な発見がなされているとは言い難い。本稿では、ヒトパピローマウイルス(HPV)関連中咽頭癌を含む頭頸部扁平上皮癌のゲノム解析研究やがんゲノム医療の現状について、以下の項目で概説した。1)網羅的ゲノム解析の黎明期、2)HPV関連中咽頭癌と子宮頸癌、3)HPV関連中咽頭癌のエピゲノム、4)がんゲノム医療時代の頭頸部扁平上皮癌。2020年に発表されたESMO(European Society for Medical Oncology)ではESCAT(ESMO Scale for Clinical Actionability of Molecular Targets)に従った遺伝子異常と対応薬剤のエビデンス分類を発表しており、頭頸部扁平上皮癌のマーカーとして、HRAS活性型変異、Microsatellite instability-high(MSI-H)、TMB≧10/Mb(TMB-high)、NTRK融合遺伝子が挙げられている。

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

日本頭頸部外科学会では2009年より頭頸部がん専門医制度を定めている。今回,院内がん登録を用いて指定/非指定研修施設での頭頸部癌治療の現状を比較検討した。2012-2015年の頭頸部癌94,006症例(705施設)を検討したところ,63.6%が指定研修施設にて治療されており,より標準治療に沿った治療が行われていることが示唆された。部位や地域による差も明らかとなった。また,2009-2013年症例の予後を検討した結果,指定研修施設の全生存率が有意に高かった。治療難易度が高い症例,治療選択の多様性がある症例が指定研修施設に集まっていることが示唆され,専門医制度の目的に沿った現状が構築されつつあると考える。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞POINT ▼舌癌の深部浸潤の見極めと筋層切離には熟練を要する。切離中によく触診し,確実な深部安全域を確保する。▼pull-through法の意義は口腔底と舌根方向の良好な視野を得ることであり,pullだけでなくrotateを意識する。▼口腔底のリンパ節群は頸部郭清術で取り残す可能性があるため,注意を要する。

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記述言語：日本語   出版者・発行元：日本唾液腺学会  

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

今回、われわれは第一鰓裂性瘻孔症例を経験したので報告する。症例は7歳女児で、主訴は右顎下部の発赤・腫脹である。下顎角前上方に発赤を伴う皮膚瘻孔を認め、MRIでは瘻管は外耳道軟骨部から耳下腺内浅葉浅層を下方に進展し、下顎部で皮膚瘻孔に連続していた。耳下腺手術に準じて瘻管摘出術を施行した。瘻管は下顎角部から軟骨部外耳道に存在し、顔面神経外側を走行し、外耳道で盲端となっていた。術後顔面神経麻痺などの合併症は認めなかった。病理組織学的には重層扁平上皮とともに毛髪を含む皮膚付属器を認めた。第一鰓裂性瘻孔の治療では瘻管および瘻孔と顔面神経との位置関係が多岐にわたることを認識しておく必要がある。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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記述言語：日本語   出版者・発行元：(一社)日本頭頸部癌学会  

外耳道癌は稀かつ予後不良な疾患である。その危険因子として過剰な耳かきが臨床上推測されているが、統計学的に検討した報告は少ない。今回、我々は当科で加療を行った外耳道癌患者14例を対象とし年齢、性別、耳かき頻度、耳かきに使用する道具の材質、罹患側、病理組織について検討した。また、本研究に同意を得た健常人69名を対象とし、年齢、性別、耳かき頻度、耳かきに使用する道具の材質について調査し患者群と比較検討した。その結果、50歳未満の若年群における患者群と健常人群間において、有意に耳かき頻度、および硬質素材を用いる率が高かった。今回の結果から、過剰な刺激の耳かきが外耳道癌発生を誘発する可能性が示唆された。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J04195&link_issn=&doc_id=20170511480014&doc_link_id=10.5981%2Fjjhnc.43.76&url=https%3A%2F%2Fdoi.org%2F10.5981%2Fjjhnc.43.76&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

喉頭原発の全悪性腫瘍の中で軟骨肉腫は比較的稀であるが、扁平上皮癌、腺癌についで多く、過去にも症例報告が散見される。その治療法は外科的切除であり、有効な化学療法や放射線療法は確立されていない。今回われわれは輪状軟骨原発軟骨肉腫に対し喉頭を温存して切除し得た1例を経験したため報告する。症例は77歳男性、CTで輪状軟骨左側に28mm大の腫瘤性病変が指摘され当科受診した。外切開による腫瘍生検にてGrade Iの軟骨肉腫と診断し、後日喉頭側方からのアプローチで喉頭を温存しての腫瘍摘出術を施行した。術後経過は良好で音声・嚥下機能は温存された。術後1年経過現在、外来にて経過観察中である。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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記述言語：日本語   出版者・発行元：(NPO)日本頭頸部外科学会  

2001年1月から2012年12月までの12年間に一次根治治療を行った喉頭癌240例を検討した。年齢は37〜89歳(中央値69歳)、男性/女性は219例/21例、T1/T2/T3/T4=88/81/49/22であった。T1-2症例169例には喉頭摘出術/喉頭温存手術/放射線(化学)療法をそれぞれ7/5/157例に行い、T3-4症例71例には喉頭摘出術/喉頭温存手術/放射線(化学)療法をそれぞれ55/3/13例に行った。原病死を39例、他因死を36例に認め、他因死のうち肺癌が14例(39%)であった。粗生存率/疾患特異的生存率は69.5%、79.8%であった。疾患特異的生存に対して併存症、N分類、T分類、高齢、重度飲酒者が、粗生存に対して併存症、T分類、N分類と重度喫煙者が有意な予後不良因子であった。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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記述言語：日本語   出版者・発行元：(株)東京医学社  

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記述言語：日本語   出版者・発行元：日本頭頸部癌学会  

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記述言語：日本語   出版者・発行元：日本頭頸部癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本頭頸部癌学会  

下咽頭・頸部食道癌は上部消化管の悪性腫瘍を合併することが多く、通常の咽頭喉頭頸部食道全摘では対応できず、全食道を合併切除する必要がある症例も存在する。一方で、根治性を損なわない範囲内で可及的に機能温存を図る手術の広がりに伴い、下咽頭部分切除が施行される症例も増えてきている。今回、われわれはこうした種々の下咽頭癌・頸部食道癌切除法に対応した再建法について検討した。対象は下咽頭・頸部食道癌の切除・再建術のうち、TPLEに加え食道全切除も必要であった拡大切除5例と、下咽頭部切などの縮小切除5例である。再建方法は拡大手術では、延長胃管、遊離空腸+胃管等で、縮小手術では遊離空腸パッチ、遊離前腕皮弁であった。各種の再建方法にはそれぞれ長所、短所があるが、再建法を決める際には耳鼻科や食道外科と切除・郭清範囲、温存される血管、侵襲の程度などについて事前に十分に打ち合わせ、総合的に検討する必要があると考えられた。(著者抄録)

DOI： 10.5981/jjhnc.37.121

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その他リンク： http://search.jamas.or.jp/link/ui/2011212858

記述言語：日本語   出版者・発行元：(株)東京医学社  

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記述言語：英語   出版者・発行元：Japan Society for Head and Neck Cancer  

われわれは，舌癌において制御困難な再発をきたし得る部位として「舌骨傍領域」に注目している。同領域は舌癌における原発巣と頸部の継ぎ目に位置し，口腔からのアプローチは困難で，かつ通常の頸部郭清術の郭清範囲外である。病巣は舌下神経の深部で舌動脈を巻き込むように出現し，やがて副咽頭間隙に広く進展して根治困難となりうる。このような再発は，舌動脈に沿って出現する小リンパ節への転移によるものであろうと考えている。臨床的に明らかな再発病巣として発見される時点では既に周囲へ浸潤していることが多く，治癒切除を施行するためには遊離皮弁が必要となる場合がある。病巣は可能な限り早期に発見されるべきだが，舌骨傍領域の画像診断には限界があるため，頸部郭清術を施行する際には必ず同領域の組織を摘出するようにしている。治療後の機能温存が強く求められる部位であるので，合併症のより少ない治療を選択すべきである。

DOI： 10.5981/jjhnc.36.303

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記述言語：日本語   掲載種別：書評論文，書評，文献紹介等   出版者・発行元：Oto-Rhino-Laryngological Society of Japan Inc.  

Single-stage reconstruction of the pharyngoesophagus with a free jejunal graft is considered standard surgical treatment for hypopharyngeal cancer. We reviewed postoperative cervical CTs in 72 of 136 consecutive patients (1982-2002) undergoing this therapy in our department. Of these, 29 (40%) showed mesenteric lymph node swelling (&gt
10mm) in grafts. Most swelling is considered reactive, but 1 patient showed pathological metastasis in fine-needle aspiration cytology (FNA). When metastasis is clinically suspected in imaging study and other examinations, FNA should be done carefully with guided ultrasound echo-imaging, to avoid damaging vascular grafts and necrosis of the jejunal graft.

DOI： 10.3950/jibiinkoka.109.19

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記述言語：日本語  

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