記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Predictive biomarkers for nivolumab in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC) have not yet been established. METHODS: The tumor proportion score (TPS), combined positive score (CPS), and soluble forms of programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2) were retrospectively analyzed in patients with RMHNSCC treated with nivolumab. RESULTS: The positivity rates for TPS (PD-L1), CPS (PD-L1), TPS (PD-L2), and CPS (PD-L2) were 73.8%, 78.2%, 56.4%, and 78.2%, respectively. Patients with high TPS (PD-L1), CPS (PD-L1), or CPS (PD-L1 and PD-L2) showed significantly prolonged progression-free survival. Favorable overall survival was associated with high CPS (PD-L1 and PD-L2) and low soluble PD-L1 and PD-L2 levels. The expressions of tissue and soluble PD-L1/2 were not correlated. CONCLUSIONS: Our study revealed that compared to PD-L1 expression alone, dual expression of PD-L1 and PD-L2 in tissue or soluble form could be feasible biomarkers in patients with RMHNSCC who received nivolumab.

DOI： 10.1002/hed.27787

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Intratumoral hypoxia is associated with tumor progression, aggressiveness, and therapeutic resistance in several cancers. Hypoxia causes cancer cells to experience replication stress, thereby activating DNA damage and repair pathways. MutT homologue-1 (MTH1, also known as NUDT1), a member of the Nudix family, maintains the genomic integrity and viability of tumor cells in the hypoxic tumor microenvironment. Although hypoxia is associated with poor prognosis and can cause therapeutic resistance by regulating the microenvironment, it has not been considered a treatable target in cancer. This study aimed to investigate whether hypoxia-induced MTH1 is a useful target for immunotherapy and whether hypoxic conditions influence the antitumor activity of immune cells. Our results showed that MTH1 expression was elevated under hypoxic conditions in head and neck cancer cell lines. Furthermore, we identified a novel MTH1-targeting epitope peptide that can activate peptide-specific CD4+ helper T cells with cytotoxic activity. The proliferation and cytotoxic activity of T cells were maintained under hypoxic conditions, and PD-1 blockade further augmented the cytotoxicity. These results indicate that MTH1-targeted immunotherapy combined with checkpoint blockade can be an effective strategy for the treatment of hypoxic tumors.

DOI： 10.3390/cancers16173013

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The identification of epitope peptides from tumor-associated antigens (TAAs) is informative for developing tumor-specific immunotherapy. However, only a few epitopes have been detected in mouse TAAs of head and neck cancer (HNSCC). METHODS: Novel mouse c-Met-derived T-cell epitopes were predicted by computer-based algorithms. Mouse HNSCC cell line-bearing mice were treated with a c-Met peptide vaccine. The effects of CD8 and/or CD4 T-cell depletion, and vaccine combination with immune checkpoint inhibitors (ICIs) were evaluated. Tumor re-inoculation was performed to assess T-cell memory. RESULTS: We identified c-Met-derived short and long epitopes that elicited c-Met-reactive antitumor CD8 and/or CD4 T-cell responses. Vaccination using these peptides showed remarkable antitumor responses via T cells in which ICIs were not required. The c-Met peptide-vaccinated mice rejected the re-inoculated tumors. CONCLUSIONS: We demonstrated that novel c-Met peptide vaccines can induce antitumor T-cell response, and could be a potent immunotherapy in a syngeneic mouse HNSCC model.

DOI： 10.1002/hed.27703

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担当区分：筆頭著者   出版者・発行元：Cold Spring Harbor Laboratory  

ABSTRACT

Effective T cell immunotherapy requires understanding antigen-specific T cell development during tumorigenesis and immune surveillance. Here, we aimed to examine the dynamics of antigen-specific T cells from tumor initiation through progression in a tobacco carcinogen mimetic, 4-nitroquinoline-1-oxide (4NQO)-induced head and neck carcinogenesis model utilizing genetically engineered K5^CreERT/+/ROSA^OVA-GFP/p53^fl/fl(KOG) mice. Our findings showed that early ovalbumin (OVA) expression via direct lingual tamoxifen (T) did not impact cancer development and survival, by comparing mice with tongue epithelium expressing OVA (KOG/T/OVA⁺) to those without OVA (KOG/T/OVA^-) controlled by doxycycline. This equivalent tumor growth cannot be attributed to the loss of OVA expression. Intriguingly, although OVA-specific T cells were initially generated in tumor-draining lymph nodes (TDLN), they became undetectable 3 weeks after tamoxifen injection. Moreover, therapeutic anti-PD-1 was unable to restore OVA-specific T cells in TDLN and did not yield anti-tumor activity. Remarkably, OVA synthetic long peptide (SLP) vaccine induced OVA-specific T cells in KOG/T/OVA+ mice, and the combination of SLP vaccine and anti-PD-1 significantly reduced tongue tumor burden and prolonged survival. This study highlights the role of impaired endogenous antigen-specific T cell responses in immune resistance in head and neck cancer and the potential of cancer vaccines to improve outcomes.

DOI： 10.1101/2024.06.26.600828

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been observed, but further insights into the mechanisms underlying resistance and approaches to improve responses are needed. EXPERIMENTAL DESIGN: We integrated data from syngeneic mouse oral carcinoma (MOC) models and neoadjuvant pembrolizumab HNSCC patient tumor RNA-sequencing data to explore the mechanism of aPD1 resistance. Tumors and tumor-draining lymph nodes (DLN) from MOC models were analyzed for antigen-specific priming. CCL5 expression was enforced in an aPD1-resistant model. RESULTS: An aPD1-resistant mouse model showed poor priming in the tumor DLN due to type 1 conventional dendritic cell (cDC1) dysfunction, which correlated with exhausted and poorly responsive antigen-specific T cells. Tumor microenvironment analysis also showed decreased cDC1 in aPD1-resistant tumors compared with sensitive tumors. Following neoadjuvant aPD1 therapy, pathologic responses in patients also positively correlated with baseline transcriptomic cDC1 signatures. In an aPD1-resistant model, intratumoral cDC1 vaccine was sufficient to restore aPD1 response by enhancing T-cell infiltration and increasing antigen-specific responses with improved tumor control. Mechanistically, CCL5 expression significantly correlated with neoadjuvant aPD1 response and enforced expression of CCL5 in an aPD1-resistant model, enhanced cDC1 tumor infiltration, restored antigen-specific responses, and recovered sensitivity to aPD1 treatment. CONCLUSIONS: These data highlight the contribution of tumor-infiltrating cDC1 in HNSCC aPD1 response and approaches to enhance cDC1 infiltration and function that may circumvent aPD1 resistance in patients with HNSCC.

DOI： 10.1158/1078-0432.CCR-23-3477

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Understanding head and neck tissue specific immune responses is important for elucidating immunotherapy resistance mechanisms to head and neck squamous cell carcinoma (HNSCC). In this study, we aimed to investigate HNSCC-specific immune response differences between oral and subcutaneous flank tumor transplantation in preclinical models. MATERIALS AND METHODS: The MOC1 syngeneic mouse oral carcinoma cell line or versions expressing either the H2Kb-restricted SIINFEKL peptide from ovalbumin (MOC1OVA) or ZsGreen (MOC1ZsGreen) were inoculated into mouse oral mucosa (buccal space) or subcutaneous flank and compared for immune cell kinetics in tumors and tumor-draining lymph nodes (TDLNs) and for anti-PD1 response. RESULTS: Compared to subcutaneous flank tumors, orthotopic oral MOC1OVA induced a higher number of OVA-specific T cells, PD1 + or CD69 + activated OVA-specific T cells in both primary tumors and TDLNs. Tumors were also larger in the flank site and CD8 depletion eliminated the difference in tumor weight between the two sites. Oral versus flank SIINFEKL peptide vaccination showed enhanced TDLN lymphocyte response in the former site. Notably, cDC1 from oral TDLN showed enhanced antigen uptake and co-stimulatory marker expression, resulting in elicitation of an increased antigen specific T cell response and increased activated T cells. Parental MOC1 in the oral site showed increased endogenous antigen-reactive T cells in TDLNs and anti-PD1 blockade rejected oral MOC1 tumors but not subcutaneous flank MOC1. CONCLUSION: Collectively, we find distinct immune responses between orthotopic oral and heterotopic subcutaneous models, including priming by cDC1 in TDLN, revealing important implications for head and neck cancer preclinical studies.

DOI： 10.1016/j.oraloncology.2024.106795

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In CD70-expressing tumors, the interaction of CD70 on tumor cells with its lymphocyte receptor, CD27, is thought to play a role in immunosuppression in the tumor microenvironment and elevated serum levels of soluble CD27 (sCD27). Previous studies showed that CD70 is expressed in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related malignancy. However, the association between intratumoral CD70/CD27 expression and serum levels of sCD27 in NPC remains unclear. In the present study, we show that CD70 is primarily expressed by tumor cells in NPC and that CD27-positive lymphocytes infiltrate around tumor cells. NPC patients with CD27-positive lymphocytes had significantly better prognosis than patients lacking these cells. In addition, high CD70 expression by tumor cells tended to be correlated with shorter survival in NPC patients with CD27-positive lymphocytes. Serum sCD27 levels were significantly increased in patients with NPC and provided good diagnostic accuracy for discriminating patients from healthy individuals. The concentration of serum sCD27 in patients with CD70-positive NPC with CD27-positive lymphocytes was significantly higher than in patients with tumors negative for CD70 and/or CD27, indicating that the intratumoral CD70/CD27 interaction boosts the release of sCD27. Furthermore, positive expression of CD70 by NPC cells was significantly correlated with EBV infection. Our results suggest that CD70/CD27-targeted immunotherapies may be promising treatment options and that sCD27 may become an essential tool for evaluating the applicability of these therapies by predicting the intratumoral CD70/CD27 interaction in NPC.

DOI： 10.1111/cas.16079

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy for patients with SGC. Our study described promising results of epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel in patients with SGC. METHODS: The medical records of patients with recurrent SGC treated with weekly cetuximab combined with paclitaxel (Cmab-PTX) between December 2017 and December 2022 at our institutions were retrospectively analyzed. RESULTS: Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months (range of 2-36 months). The overall responses were three with complete response, two with partial response, one with stable disease (>24 weeks), and one with progressive disease. The objective response and disease control rates were 71.4% and 85.7%, respectively. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. CONCLUSION: Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC. Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy in patients with SGC. Our study described promising results of cetuximab (Cmab), epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel (PTX) in patients with SGC. Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months. The overall responses were three with complete response, two with partial response, one with stable disease (>24 weeks), and one with progressive disease. The objective response rate was 71.4%. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. Our study revealed a preferable objective response rate of Cmab-PTX for patients with high-grade SGC. Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC.

DOI： 10.1159/000534516

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The incidence of thyroid cancer (TC) has increased over the past 30 years. Although differentiated thyroid cancer (DTC) has a good prognosis in most patients undergoing total thyroidectomy followed by radioiodine therapy (RAI), 5-10% of patients develop metastasis. Anaplastic thyroid cancer (ATC) has a low survival rate and few effective treatments have been available to date. Recently, tyrosine kinase inhibitors (TKIs) have been successfully applied to RAI-resistant or non-responsive TC to suppress the disease. However, TC eventually develops resistance to TKIs. Immunotherapy is a promising treatment for TC, the majority of which is considered an immune-hot malignancy. Immune suppression by TC cells and immune-suppressing cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, is complex and dynamic. Negative immune checkpoints, cytokines, vascular endothelial growth factors (VEGF), and indoleamine 2,3-dioxygenase 1 (IDO1) suppress antitumor T cells. Basic and translational advances in immune checkpoint inhibitors (ICIs), molecule-targeted therapy, tumor-specific immunotherapy, and their combinations have enabled us to overcome immune suppression and activate antitumor immune cells. This review summarizes current findings regarding the immune microenvironment, immunosuppression, immunological targets, and immunotherapy for TC and highlights the potential efficacy of immunotherapy.

DOI： 10.3390/vaccines12010045

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記述言語：英語  

A 15-year-old girl presented with a 3-year-history of continuous outflow of saliva from a pharyngocutaneous fistula, located at 5 mm superior to her tracheal stoma. She was diagnosed with Miller-Dieker syndrome at birth. At 2 years of age, pediatric surgeons at our institution carried out laryngotracheal separation to prevent aspiration pneumonia. At the age of 12 years, she developed continuous saliva discharge from the fistula. We performed central-part laryngectomy and resection of the pharyngocutaneous fistula, which relieved her from the continuous saliva discharge. Central-part laryngectomy is less invasive and easier to perform than total laryngectomy. We hereby present a case and retrospective analysis of 12 patients, who underwent central-part laryngectomy.

DOI： 10.1016/j.anl.2022.04.011

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Brachyury is a transcription factor belonging to the T-box gene family and is involved in the posterior formation of the mesoderm and differentiation of chordates. As the overexpression of Brachyury is a poor prognostic factor in a variety of cancers, the establishment of Brachyury-targeted therapy would be beneficial for the treatment of aggressive tumors. Because transcription factors are difficult to treat with a therapeutic antibody, peptide vaccines are a feasible approach for targeting Brachyury. In this study, we identified Brachyury-derived epitopes that elicit antigen-specific and tumor-reactive CD4+ T cells that directly kill tumors. T cells recognizing Brachyury epitopes were present in patients with head and neck squamous cell carcinoma. Next, we focused on gemcitabine (GEM) as an immunoadjuvant to augment the efficacy of antitumor responses by T cells. Interestingly, GEM upregulated HLA class I and HLA-DR expression in tumor, followed by the upregulation of anti-tumor T cell responses. As tumoral PD-L1 expression was also augmented by GEM, PD-1/PD-L1 blockade and GEM synergistically enhanced the tumor-reactivity of Brachyury-reactive T cells. The synergy between the PD-1/PD-L1 blockade and GEM was also confirmed in a mouse model of head and neck squamous cell carcinoma. These results suggest that the combined treatment of Brachyury peptide with GEM and immune checkpoint blockade could be a promising immunotherapy against head and neck cancer.

DOI： 10.1007/s00262-023-03460-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The engagement of CD27 on lymphocytes with its ligand, CD70, on tumors is believed to mediate tumor immune evasion and the elevation of serum soluble CD27 (sCD27) levels in patients with CD70-positive malignancies. We previously showed that CD70 is expressed in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), an Epstein-Barr virus (EBV)-related malignancy. However, little is known about serum sCD27 expression and its association with the clinical characteristics of, and the CD27/CD70 interaction in, ENKL. In the present study, we show that serum sCD27 is significantly elevated in the sera of patients with ENKL. The levels of serum sCD27 provided excellent diagnostic accuracy for discriminating patients with ENKL from healthy subjects, correlated positively with the levels of other diagnostic markers (lactate dehydrogenase, soluble interleukin-2 receptor, and EBV-DNA), and decreased significantly following treatment. Elevated serum sCD27 levels also correlated significantly with advanced clinical stage and tended to correspond with shorter survival, in patients with ENKL. Immunohistochemistry indicated that CD27-positive tumor-infiltrating immune cells exist adjacent to CD70-positive lymphoma cells. In addition, serum sCD27 levels in patients with CD70-positive ENKL were significantly higher than those in patients with CD70-negative ENKL, suggesting that the intra-tumoral CD27/CD70 interaction boosts the release of sCD27 in serum. Furthermore, the EBV-encoded oncoprotein latent membrane protein 1 upregulated CD70 expression in ENKL cells. Our results suggest that sCD27 may serve as a novel diagnostic biomarker and also may serve as a tool for evaluating the applicability of CD27/CD70-targeted therapies by predicting intra-tumoral CD70 expression and CD27/CD70 interaction in ENKL.

DOI： 10.1007/s00262-023-03394-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Homeobox B7 (HOXB7) is a master regulatory gene that regulates cell proliferation and activates oncogenic pathways. Overexpression of HOXB7 correlates with aggressive behavior and poor prognosis in patients with cancer. However, the expression and role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we observed that most samples from patients with oropharyngeal cancer and HNSCC expressed HOXB7. As no direct inhibitor has been reported, we identified a potent peptide epitope to target HOXB7-expressing tumors through immune cells. A novel HOXB7-derived peptide epitope (HOXB78-25 ) elicited antigen-specific and tumor-reactive promiscuous CD4+ T cell responses. These CD4+ T cells produced γ-interferon (IFN-γ) and had the direct ability to kill tumors through granzyme B. Notably, downregulation of HOXB7 using siRNA enhanced human leukocyte antigen class II expression on tumor cells by decreasing the phosphorylation of MAPK. Mitogen-activated protein kinase inhibition augmented IFN-γ production by HOXB7-reactive CD4+ T cell responses without decreasing the expression of HOXB7. These results suggest that combining HOXB7 peptide-based vaccine with MAPK inhibitors could be an effective immunological strategy for cancer treatment.

DOI： 10.1111/cas.15619

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

DOI： 10.1158/1557-3265.AACRAHNS23-PO-078

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Preclinical models of cancer have long been paramount to understanding tumor development and advancing the treatment of cancer. Creating preclinical models that mimic the complexity and heterogeneity of human tumors is a key challenge in the advancement of cancer therapy. About ten years ago, we created the mouse oral carcinoma (MOC) cell line models that were derived from 7, 12-dimethylbenz(a) anthracene (DMBA)-induced mouse oral squamous cell cancers. This model has been used in numerous investigations, including studies on tumor biology and therapeutics. We have seen remarkable progress in cancer immunology in recent years, and these cell lines, which are syngeneic to C57BL/6 background, have also been used to study the anti-tumor immune response. Herein, we aim to review the MOC model from its development and characterization to its use in non-immunological and immunological preclinical head and neck squamous cell carcinoma (HNSCC) studies. Integrating and refining these MOC model studies and extending findings to other systems will provide crucial insights for translational approaches aimed at improving head and neck cancer treatment.

DOI： 10.1016/j.oraloncology.2022.106012

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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 present study was to analyze the clinical characteristics, surgical treatments and clinical outcome of patients with parotid gland tumors and to compare the results with those cited in the literature. A retrospective study was conducted in 140 patients (male, n=77; female, n=63) with parotid gland tumors who underwent parotidectomy at Hokuto Hospital Department of Otolaryngology-Head and Neck Surgery (Obihiro, Japan) between April 2007 and December 2021. Of the 140 patients enrolled, 118 (84.3%) patients had benign tumors, including 63 (45%) patients with pleomorphic adenomas and 43 (30.7%) patients with Warthin tumors, and 22 patients (15.7%) had parotid carcinoma. Comparison of the three groups of patients with parotid gland tumors indicated that pack years as an indicator of smoking status were significantly higher in patients with Warthin tumors than in those with parotid carcinomas (P=0.011) or pleomorphic adenoma (P<0.001). Fine-needle aspiration cytology (FNAC) was non-diagnostic for only 6 (4.3%) of 140 patients. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of FNAC by both conventional smear and liquid-based cytology (LBC) for parotid carcinomas were 70, 99, 93.3, 94.4 and 82.9%, respectively. Among the 22 patients with parotid carcinoma, extended total/total and superficial parotidectomy were performed in 10 (45%) and 11 (50%) cases, respectively. Total and selective neck dissection of the area from level II to I, II and III were performed in 6 (24%) and 7 (32%) patients, respectively. Postoperative radiotherapy (50 Gy) was performed in 15 (68%) patients. The overall survival (OS) and disease-free survival (DFS) rates at 5 years were 51.5 and 76.4%, respectively. Univariate analysis revealed that age >65 years was significantly associated with poorer 5-year OS (P<0.001) and DFS (P<0.001). Multivariate analysis revealed that an age of more than 65 years combined with high-grade histologic malignancy was associated with worse DFS (P=0.02; hazard ratio, 3.628; 95% confidence interval, 1.283-9.514). In conclusion, the clinical characteristics and treatment outcomes of parotid gland tumors were consistent with the results of previous reports. Smoking may be closely related to the pathogenesis of Warthin tumors. LBC potentially provides improved accuracy in FNAC.

DOI： 10.3892/ol.2022.13328

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A combination therapy with immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy has become the first-line treatment for recurrent or metastatic head and neck squamous carcinoma (HNSCC). Although steroids are often used as anti-emetic medications during chemotherapy, their adverse effects on immune-combined chemotherapy are unclear in HNSCC. METHODS: The effects of dexamethasone on tumor growth and immune cell population were evaluated in a mouse HNSCC model treated with PD-1 blockade combined with cisplatin. The effect of various doses of dexamethasone on cell proliferation, survival, surface markers, IFN-γ production, and antitumor effects in antigen-specific T cells was examined in vitro. The recovery of T cell dysfunction by IL-2 was assessed in vitro and in vivo. RESULTS: In a mouse HNSCC model, dexamethasone showed limited antitumor effects on immunochemotherapy. Dexamethasone decreased the number of T cells and inhibited T cell differentiation into effector and central memory T cells. In the in vitro assessment, dexamethasone induced cell death, limited proliferation, and reduced the reactivity against HNSCC cell lines of antigen-specific T cells in a dose-dependent manner. The expression of inhibitory receptors on T cells was not affected by steroids. This inhibition was recovered by IL-2 and IL-2/anti-IL-2 complexes (IL-2 Cx) in vitro and in vivo, respectively. CONCLUSION: Our preclinical data indicate that dexamethasone diminishes the antitumor effects of immunochemotherapy in patients with HNSCC. IL-2 Cx recovered the inhibition of antitumor immunity by steroids and might be a potent immune adjuvant for patients who require steroids during PD-1 blockade and chemotherapy.

DOI： 10.1016/j.tranon.2022.101358

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The success of the immune checkpoint blockade has provided a proof of concept that immune cells are capable of attacking tumors in the clinic. However, clinical benefit is only observed in less than 20% of the patients due to the non-specific activation of immune cells by the immune checkpoint blockade. Developing tumor-specific immune responses is a challenging task that can be achieved by targeting tumor antigens to generate tumor-specific T-cell responses. The recent advancements in peptide-based immunotherapy have encouraged clinicians and patients who are struggling with cancer that is otherwise non-treatable with current therapeutics. By selecting appropriate epitopes from tumor antigens with suitable adjuvants, peptides can elicit robust antitumor responses in both mice and humans. Although recent experimental data and clinical trials suggest the potency of tumor reduction by peptide-based vaccines, earlier clinical trials based on the inadequate hypothesis have misled that peptide vaccines are not efficient in eliminating tumor cells. In this review, we highlighted the recent evidence that supports the rationale of peptide-based antitumor vaccines. We also discussed the strategies to select the optimal epitope for vaccines and the mechanism of how adjuvants increase the efficacy of this promising approach to treat cancer.

DOI： 10.3390/vaccines10010070

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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/coa.13876

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掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Fibroblast growth factor receptor 1 (FGFR1) is overexpressed in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Being associated with poor prognosis, FGFR1 is a potential therapeutic target for aggressive tumors. T cell-based cancer immunotherapy has played a central role in novel cancer treatments. However, the potential of antitumor immunotherapy targeting FGFR1 has not been investigated. Here, we showed that FGFR-tyrosine kinase inhibitors (TKIs) augmented antitumor effects of immune checkpoint inhibitors in an HNSCC mouse model and upregulated tumoral MHC class I and MHC class II expression in vivo and in vitro. This upregulation was associated with the mitogen-activated protein kinase signaling pathway, which is a crucial pathway for cancer development through FGFR signaling. Moreover, we identified an FGFR1-derived peptide epitope (FGFR1305-319) that could elicit antigen-reactive and multiple HLA-restricted CD4+ T cell responses. These T cells showed direct cytotoxicity against tumor cells that expressed FGFR1. Notably, FGFR-TKIs augmented antitumor effects of FGFR1-reactive T cells against human HNSCC cells. These results indicate that the combination of FGFR-TKIs with immunotherapy, such as an FGFR1-targeting peptide vaccine or immune checkpoint inhibitor, could be a novel and robust immunologic approach for treating patients with FGFR1-expressing cancer cells.

DOI： 10.1080/2162402X.2021.2021619

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Identification of immunogenic tumor antigens, their corresponding T cell epitopes and the selection of effective adjuvants are prerequisites for developing effective cancer immunotherapies such as therapeutic vaccines. Murine double minute 2 (MDM2) is an E3 ubiquitin-protein ligase that negatively regulates tumor suppressor p53. Because MDM2 overexpression serves as a poor prognosis factor in various types of tumors, it would be beneficial to develop MDM2-targeted cancer vaccines. In this report, we identified an MDM2-derived peptide epitope (MDM232-46) that elicited antigen-specific and tumor-reactive CD4+ T cell responses. These CD4+ T cells directly killed tumor cells via granzyme B. MDM2 is expressed in head and neck cancer patients with poor prognosis, and the T cells that recognize this MDM2 peptide were present in these patients. Notably, Nutlin-3 (MDM2-p53 blocker), inhibited tumor cell proliferation, was shown to augment antitumor T cell responses by increasing MDM2 expression, HLA-class I and HLA-DR through class II transactivator (CIITA). These results suggest that the use of this MDM2 peptide as a therapeutic vaccine combined with MDM2 inhibitors could represent an effective immunologic strategy to treat cancer.

DOI： 10.1007/s00262-021-02940-5

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掲載種別：研究論文（学術雑誌）  

<h4>Abstract</h4>A 13-year-old Japanese boy with a 6-month history of bilateral nasal obstruction and a 3-week history of recurrent epistaxis from the right nose was admitted to our department. Nasal endoscopy revealed a reddish, smooth-walled tumor occupying the right nasal cavity. Computed tomography scan revealed a 3.5 × 4.5 × 7.0-cm heterogeneously enhancing mass involving the right nasal cavity and extending posteriorly to the nasopharynx, and laterally to the pterygopalatine fossa and the medial part of the infratemporal fossa. We diagnosed as juvenile nasopharyngeal angiofibroma with Radkowski classification stage IIC. The internal maxillary and ascending pharyngeal arteries were embolized with polyvinyl alcohol followed by Embosphere using a conventional Seldinger technique. En bloc resection was performed with an endoscopic ipsilateral endonasal and sublabial Caldwell-Luc transmaxillary approach under general anesthesia. As of 3 years postoperatively, no recurrence has been found. We report a child case of juvenile nasopharyngeal angiofibroma successfully treated with less invasive surgery with preoperative embolization.

DOI： 10.1097/scs.0000000000007495

DOI： 10.1097/SCS.0000000000007495

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We analyzed the effects of early nutritional intervention by a nutritional support team (NST) in patients with head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy or radiotherapy. METHODS: This study investigated whether early nutritional interventions by a multidisciplinary NST improve body weight loss, mucositis, serum albumin level, and hospital length of stay. RESULTS: Sixty-one patients with HNSCC were treated during the study, and 32 patients received NST intervention since admission. The median weight loss rates were 3.3% and 7.3% and grade 3 mucositis was observed in 25.0% and 70.0% of patients in the intervention and nonintervention groups, respectively. In the intervention group, serum albumin level through treatment increased and the hospital length of stay from the end of treatment was shortened. CONCLUSION: Early nutritional intervention by a multidisciplinary NST improved body weight loss rate, mucositis, albumin level, and hospital length of stay, which might lead to better clinical outcomes.

DOI： 10.1002/hed.26502

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Georg Thieme Verlag KG  

Abstract

We conducted a retrospective analysis of the data of 107 cases of peritonsillar abscess treated at our hospital between January 2014 and December 2018. Data on age, sex, affected site, duration of hospitalization, method of drainage, presence/absence of laryngeal edema, antibacterial drugs used, and isolated bacteria were analyzed. Of the 107 patients, 71 were males and 36 were females; the median age was 44 years (range: 18–88 years).The left side was affected in 55 patients, the right side in 50 patients, and both sides in two patients. The abscess was localized in the superior pole in 71 patients, and in the inferior pole in 36 patients. Thirty-five patients had laryngeal edema, of which three underwent tracheotomy. Recurrence of the abscess was observed in 15 cases, with the recurrence developing within 3 months in 7 cases, and over a period of 3 years in 4 cases. As for the sensitivity of the causative bacteria to antibacterial drugs, 17% of the causative bacteria showed resistance to clindamycin, while none showed resistance to ampicillin/sulbactam (ABPC/SBT). We concluded that ABPC/SBT might be suitable for the initial treatment of peritonsillar abscess, and that we need to bear in mind the possibility of long-term recurrence.

DOI： 10.1055/s-0041-1722857

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Georg Thieme Verlag KG  

Abstract

Purpose The use of peripherally inserted central venous catheters (PICCs) has increased recently; several reports have revealed that they can be easily and safely used in patients with various diseases. However, there are few reports on the use of PICCs in patients with head and neck cancer. This study was aimed at evaluating the safety and feasibility of use of PICCs in patients with head and neck cancer.

Materials and Methods We retrospectively analyzed the date of 118 PICC insertions in 85 patients with head and neck cancer from January 2014 to December 2017. The PICCs have been placed under ultrasound guidance in all cases.

Results The PICC puncture success rate was 95.2%. Catheter-related bloodstream infection occurred in four cases. The most common complication necessitating PICC removal was suspected catheter-related bloodstream infection (24 cases). All cases with confirmed and suspected catheter-related bloodstream infection improved with administration of antimicrobial agents. Phlebitis occurred in five cases, in all of whom the PICC placement had been made via an antecubital vein; the condition improved without treatment in all five cases. Deep vein thrombosis occurred in two cases, both of which improved with oral anticoagulant therapy.

Conclusion This study demonstrated that the complications associated with ultrasound-guided PICC insertion are manageable, and improve with conservative treatment in the majority of cases. Therefore, use of PICCs may be considered for easy and safe central venous access in patients with head and neck cancer, because the insertion success rate was acceptable.

DOI： 10.1055/s-0041-1728747

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Placenta-specific 1 (PLAC1) is expressed primarily in placental trophoblasts but not in normal tissues and is a targetable candidate for cancer immunotherapy because it is a cancer testis antigen known to be up-regulated in various tumors. Although peptide epitopes capable of stimulating CD8 T cells have been previously described, there have been no reports of PLAC1 CD4 helper T lymphocyte (HTL) epitopes and the expression of this antigen in head and neck squamous cell carcinoma (HNSCC). Here, we show that PLAC1 is highly expressed in 74.5% of oropharyngeal and 51.9% of oral cavity tumors from HNSCC patients and in several HNSCC established cell lines. We also identified an HTL peptide epitope (PLAC131-50) capable of eliciting effective antigen-specific and tumor-reactive T cell responses. Notably, this peptide behaves as a promiscuous epitope capable of stimulating T cells in the context of more than one human leukocyte antigen (HLA)-DR allele and induces PLAC1-specific CD4 T cells that kill PLAC1-positive HNSCC cell lines in an HLA-DR-restricted manner. Furthermore, T-cells reactive to PLAC131-50 peptide were detected in the peripheral blood of HNSCC patients. These findings suggest that PLAC1 represents a potential target antigen for HTL based immunotherapy in HNSCC.

DOI： 10.1080/2162402X.2020.1856545

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glomangiopericytoma (GPC) is a rare mesenchymal tumor arising from the nasal cavity or paranasal sinuses. GPC was categorized as a borderline and low-malignant-potential tumor by the World Health Organization in 2005 and accounts for less than 0.5% of all sinonasal tumors. We report a case of GPC in a 74-year-old woman with a history of recurrent epistaxis and nasal obstruction. A reddish tumor was seen in the right nasal cavity. Enhanced computed tomography showed a mass lesion occupying the right nasal cavity. The tumor, which originated from the nasal septum in the olfactory fissure area, was resected with 5-mm mucosal margins by endoscopic sinus surgery. Histologic examination revealed a uniform proliferation of oval-to-short spindle-shaped cells beneath the epithelium. Immunohistologic analysis demonstrated the tumor cells were positive for α-smooth muscle actin, β-catenin and Vimentin, and negative for AE1/AE3, Bcl-2, CD34, CD117, Factor VIIIR Ag, S-100 protein, or STAT6. The percentage of Ki-67-positive cells was approximately 5%. Genetic analysis using next-generation sequencing revealed a missense mutation in the CTNNB1 gene (c.110C > G, p.S37C). While other CTNNB1 mutations have been described in GPC; this is the first report of this specific mutation. The mutation was confirmed using Sanger sequencing.

DOI： 10.1007/s12105-018-0961-z

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記述言語：英語  

Metastasis from lung carcinoma to the sphenoid bone is rare. Patients with symptoms related to sphenoid bone metastasis as the initial presentation of carcinoma are thus also rare. Herein, we report the case of a patient presenting with only cheek dysesthesia as the first sign of lung adenocarcinoma. The 74-year-old woman presented with a 2-month history of left cheek dysesthesia. CT showed a tumor around 2.5 cm in diameter with heterogeneous enhancement of the central focus at the left foramen rotundum in the sphenoid bone. We endoscopically biopsied the tumor through the left sphenoid sinus. Results of histologic examination were consistent with lung adenocarcinoma. FDG-PET/CT analysis demonstrated lung carcinoma that had already metastasized to mediastinal lymph nodes and multiple bones, such as the ribs and lumbar vertebras, in addition to the sphenoid bone. As EGFR gene mutation (p.L858R) was identified, the patient was treated with oral gefinitib. This treatment proved quite effective, and the patient remains alive without tumor growth as of 18 months.

DOI： 10.1159/000502053

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Thyroid carcinoma (TC) has characteristic genetic alterations, including point mutations in proto-oncogenes and chromosomal rearrangements that vary by histologic subtype. Recent developments in next-generation sequencing (NGS) technology enable simultaneous analysis of cancer-associated genes of interest, thus improving diagnostic accuracy and allowing precise personalized treatment for human cancer. A total of 50 patients who underwent thyroidectomy between 2014 and 2016 at Hokuto Hospital were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 24 cancer-associated genes were amplified by PCR, barcoded and sequenced using an Illumina MiSeq platform. Subjects included 30 patients with papillary carcinoma (PC), two with PC tall cell variant (TVPC), two with PC follicular variant (FVPC), eight with follicular carcinoma, seven with poorly differentiated carcinoma (PDC), and one with anaplastic carcinoma (AC). The BRAF V600E mutation was present in 25 of 30 (83%) patients with PC, 2 of 2 (100%) patients with TVPC, 6 of 7 (86%) patients of PDC, and one patient with AC. PIK3CA mutations were present in 3 of 30 (delPV104P, A1046T and C420R; 10%) patients with PC and 1 of 7 (H1047R; 14%) patients with PDC. The TP53 mutation was present in 1 of 30 (R306*; 3.3%) patients with PC and 1 of 7 (Q152*; 14%) patients with PDC. The NRAS mutation was present in 1 of 2 (Q61K, 50%) patients with FVPC. Statistical analysis showed that patients without the BRAF V600E mutation had advanced pathologic T and N stages compared with those with the mutation (P=0.047 and P=0.019, respectively). The BRAF V600E mutation was not correlated with overall and disease-free survival in patients with PC. A patient with PC with a mutation in EGFR (K852Q) and the PIK3CA mutation had an aggressive course with multiple bone and lung metastases. Detection of mutations in cancer-associated genes using NGS could enhance the understanding of the clinical behavior of TC.

DOI： 10.3892/ol.2018.9538

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担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：Georg Thieme Verlag KG  

Abstract

Acute epiglottitis is an acute inflammation of the upper respiratory airway that rarely causes airway obstruction. A retrospective study was conducted on 115 patients with acute epiglottitis from April 2007 to December 2017 (65 males and 50 females; aged 12–85 years old, median age of 45 years). When counting the number of patients according to the month, from April to September more than 10 patients were treated. Median duration from symptom onset to first visit was 3 days (1–14 days). Eight (7%) of 115 patients had diabetes, and 16 (13.9%) had epiglottic cyst. We divided all the patients into six groups by laryngeal findings according to the classification of Katori and Tsukuda. Number of patients classified as IA, IB, IIA, IIB, IIIA, and IIIB was 41 (35.7%), 21 (18.3%), 22 (19.1%), 15 (13%), 8 (7%), and 8 (7%), respectively. Median duration of hospitalization was 5 days (2–26 days). In the blood test on the first day of hospitalization, the number of white blood cells (WBC) ranged from 3,400 to 25,350/μL (median 10,350/μL) and the C-reactive protein (CRP) ranged from 0.01 to 23.3 mg/dL (median, 2.5 mg/dL). The number of WBC and CRP at the fourth day after the hospitalization was significantly lower than those at the first day. Eight (7%) patients required the airway management such as tracheotomy or cricothyroidotomy. Age, laryngeal finding (severe epiglottis swelling and arytenoid edema; Katori and Tsukuda's classification IIIB), and high inflammatory reaction in blood test (WBC ≥ 20,000/μL and CRP ≥ 20 mg/dL) were the factors that significantly correlated with the airway management.

DOI： 10.1055/s-0038-1660522

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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  

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：(NPO)日本気管食道科学会  

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記述言語：英語  

We report a rare case of granulomatosis with polyangiitis (GPA) presenting with hypertrophic cranial pachymeningitis (HCP), abducens nerve palsy, and stenosis of the internal carotid artery (ICA). A 59-year-old Japanese man presented with a year history of nasal obstruction and a 2-month history of slight headache. Histopathological examination of the granulomatous mucosa in the ethmoid sinuses resected by endoscopic sinus surgery revealed necrotizing vasculitis with multinucleated giant cells. The patient was diagnosed with the limited form of GPA as a result of the systemic examination. He declined immunosuppressive treatment. Eighteen months after the diagnosis of GPA, he presented with diplopia and severe headache. Though nasal findings indicating GPA were not observed in the nasal cavity, CT scan revealed a lesion of the right sphenoid sinus eroding the bone of the clivus. Gadolinium-enhanced MRI of the brain showed thickening of the dura mater around the right cavernous sinus and clivus. Magnetic resonance angiography and cerebral angiography revealed narrowing at the C5 portion of the ICA. Intravenous methylprednisolone pulse therapy followed by oral prednisolone and cyclophosphamide resolved headache and dramatically improved HCP and stenosis of the ICA.

DOI： 10.1155/2017/9687383

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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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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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00580&link_issn=&doc_id=20220610470009&doc_link_id=10.5631%2Fjibirin.115.503&url=https%3A%2F%2Fdoi.org%2F10.5631%2Fjibirin.115.503&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

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  

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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  

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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  

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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  

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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  

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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  

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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  

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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  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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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  

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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  

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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  

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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  

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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  

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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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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J00580&link_issn=&doc_id=20201203290006&doc_link_id=10.5631%2Fjibirin.113.787&url=https%3A%2F%2Fdoi.org%2F10.5631%2Fjibirin.113.787&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

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)日本鼻科学会  

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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)日本頭頸部癌学会  

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記述言語：日本語   出版者・発行元：耳鼻咽喉科展望会  

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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：耳鼻咽喉科臨床学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2019&ichushi_jid=J00580&link_issn=&doc_id=20190111260007&doc_link_id=10.5631%2Fjibirin.112.37&url=https%3A%2F%2Fdoi.org%2F10.5631%2Fjibirin.112.37&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

記述言語：日本語   出版者・発行元：(一社)日本鼻科学会  

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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  

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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  

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記述言語：日本語   出版者・発行元：日本職業・環境アレルギー学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2018&ichushi_jid=J03989&link_issn=&doc_id=20180628030014&doc_link_id=%2Fco9oceal%2F2018%2F002502%2F014%2F0101-0107%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fco9oceal%2F2018%2F002502%2F014%2F0101-0107%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：日本内分泌外科学会・日本甲状腺外科学会  

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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  

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記述言語：日本語   出版者・発行元：(NPO)日本気管食道科学会  

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記述言語：日本語   出版者・発行元：(NPO)日本気管食道科学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2018&ichushi_jid=J01054&link_issn=&doc_id=20180215400008&doc_link_id=%2Fea4broes%2F2018%2F006901%2F008%2F0038-0044%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fea4broes%2F2018%2F006901%2F008%2F0038-0044%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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学会  

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記述言語：日本語   出版者・発行元：日本職業・環境アレルギー学会  

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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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