Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Background/Objectives: The OTOF gene is reported to be the causative gene for non-syndromic recessive sensorineural hearing loss and auditory neuropathy spectrum disorder. About 300 variants have been reported, but there have been no reports to date on copy gain variants. Methods: We identified a copy gain variant in the OTOF gene through short-read next-generation sequencing analysis from one patient with auditory neuropathy. We also performed long-read next-generation sequencing analysis using the Oxford Nanopore Technologies adaptive sampling procedure. Results: The four-year-old male carried a duplication of chr2: 26,477,852 to 26,483,106 (a 5254-base duplication including exon 14 to exon 18 of the OTOF gene NM_001287489) and a c.5385C>A single nucleotide variant. We also confirmed that these two variants were located in the trans configuration based on haplotype phasing results using the long-read next-generation sequencing data. Conclusions: This is the first report of an auditory neuropathy patient with a large duplication variant in the OTOF gene. The identified variants were novel, but based on the clinical phenotype of the patient, these variants seem to be the genetic cause of this patient’s phenotype. Oxford Nanopore Technologies adaptive sampling is a powerful tool for the analysis of structural variants (particularly for determining the breakpoint and direction) and haplotype phasing.

DOI： 10.3390/genes16020116

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.7759/cureus.76342

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The MYO7A gene is known to be responsible for both syndromic hearing loss (Usher syndrome type1B:USH1B) and non-syndromic hearing loss including autosomal dominant and autosomal recessive inheritance (DFNA11, DFNB2). However, the prevalence and detailed clinical features of MYO7A-associated hearing loss across a large population remain unclear. In this study, we conducted next-generation sequencing analysis for a large cohort of 10,042 Japanese hearing loss patients. As a result, 137 patients were identified with MYO7A-associated hearing loss so that the prevalence among Japanese hearing loss patients was 1.36%. We identified 70 disease-causing candidate variants in this study, with 36 of them being novel variants. All variants identified in autosomal dominant cases were missense or in-frame deletion variants. Among the autosomal recessive cases, all patients had at least one missense variant. On the other hand, in patients with Usher syndrome, almost half of the patients carried biallelic null variants (nonsense, splicing, and frameshift variants). Most of the autosomal dominant cases showed late-onset progressive hearing loss. On the other hand, cases with autosomal recessive inheritance or Usher syndrome showed congenital or early-onset hearing loss. The visual symptoms in the Usher syndrome cases developed between age 5–15, and the condition was diagnosed at about 6–15 years of age.

DOI： 10.1038/s41598-024-57415-1

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research (AACR)  

Abstract

Adoptive cell therapy (ACT) using retrovirally transduced T cells represents a promising strategy for enhancing antitumor responses. When used with TriVax, a peptide vaccination strategy, this approach synergistically expands antigen-specific cell populations. STAT5 plays a vital role as a transcription factor in regulating T-cell proliferation and their differentiation into effector and memory T cells. We aimed to explore the combination therapy using CD8 T cells engineered to express constitutively active STAT5 (CA-STAT5) with vaccines. CD8 T cells were transduced with a retrovirus (RV) encoding the mouse gp100 T-cell receptor (TCR). In certain treatment groups, cells were also co-transduced with RV encoding CA-STAT5. We assessed transduction efficiency and functional activity through flow cytometry and various functional assays. B16F10 tumor-bearing mice were treated with ACT using RV-transduced CD8 T cells and subsequently vaccinated with TriVax. We demonstrate that TriVax selectively enhanced the expansion of ACT cell populations bearing gp100-specific TCRs. T cells engineered to express CA-STAT5 showed not only increased expansion and polyfunctionality but also reduced PD-1 expression, leading to decreased cellular exhaustion. In a B16F10 melanoma mouse model, our approach yielded a potent antitumor effect, with CA-STAT5 further amplifying this response. We found that CA-STAT5 improved antitumor activities, in part, by attenuating the PD-1/PD-L1 inhibitory pathway. These findings indicate that TCR-transduced CD8 T cells can undergo antigen-dependent expansion when exposed to TriVax. Additionally, the expression of CA-STAT5 enhances T-cell proliferation and persistence, partly by promoting resistance to PD-1/PD-L1–mediated inhibition in antitumor T cells.

DOI： 10.1158/1535-7163.mct-24-0505

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Other Link： https://aacrjournals.org/mct/article-pdf/doi/10.1158/1535-7163.MCT-24-0505/3525091/mct-24-0505.pdf

Language：Japanese   Publisher：(一社)日本耳科学会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Oto-Rhino-Laryngological Society of Japan, Inc.  

DOI： 10.3950/jibiinkotokeibu.127.9_971

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.24805/jiaio.4.3_123

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.7759/cureus.66665

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：日本口腔・咽頭科学会  

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Language：Japanese   Publisher：日本口腔・咽頭科学会  

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Language：Japanese   Publisher：Japanese Society of Cancer Nursing  

DOI： 10.18906/jjscn.38_95_nonaka

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Fluorine 18-fluoro-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is commonly used for the staging of head and neck cancer. This study aimed to evaluate the correlation between 18F-FDG PET/CT, haematological parameters and prognosis in patients with advanced head and neck cancer. METHODS: This was a single-institutional retrospective study of 83 patients with advanced head and neck squamous cell carcinoma (HNSCC) who underwent 18F-FDG PET/CT imaging before initial treatment between 2014 and 2018. 18F-FDG PET/CT after treatment was performed in 57 patients. The prognostic parameters of the pre- and post-treatment maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV), total lesion glycolysis (TLG) of primary tumours and haematological parameters were analysed to evaluate the association between overall survival (OS) and progression-free survival (PFS). RESULTS: Pre-MTV, pre-TLG and post-SUVmax were significantly associated with poor OS and PFS (p < 0.05). Haematological parameters, including pretreatment neutrophil/lymphocyte ratio and C-reactive protein/albumin ratio, were associated with 18F-FDG PET/CT parameters. In multivariate analysis, post-SUVmax was an independent prognostic factor for OS and PFS. CONCLUSION: A correlation between PET/CT metabolic and haematological parameters was observed. The volume and intensity of 18F-FDG uptake region, in addition to haematological parameters, are feasible markers for predicting the progression of HNSCC in daily practice. Further, post-SUVmax could be an independent parameter for predicting poor survival.

DOI： 10.1111/coa.14195

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BACKGROUND: Tonsillectomy with steroid pulse therapy (TSP) and tonsillectomy monotherapy (T) have improved the prognosis of patients with immunoglobulin A nephropathy (IgAN). However, a consensus has not been reached on the best treatment for these patients. This study aimed to compare the efficacies of TSP and T. METHODS: Data of patients with IgAN who received TSP or T were retrospectively analyzed. The exclusion criterion was a serum creatinine level > 1.5 mg/dL. The clinical remission and renal survival rates were compared. RESULTS: Patients were divided into groups based on the treatment method: the TSP (n = 82) and T groups (n = 41). No significant differences were observed in patient characteristics, except for the observation period (TSP: 60 months, T: 113 months). The log-rank test revealed that the clinical remission rate was significantly higher in the TSP group than in the T group (p < 0.05). The superiority of TSP was also observed in the urinary protein excretion (> / = or < 1 g/day) of the two subgroups. According to the Cox proportional-hazards model, the treatment method and daily urinary protein extraction were independent factors affecting clinical remission. The 10-year renal survival rates in the TSP and T groups were 100% and 92.5%, respectively. The log-rank test revealed a tendency for a higher renal survival rate in the TSP group than in the T group (p = 0.09). CONCLUSION: The clinical remission rate was significantly higher with TSP than with T, regardless of urinary protein levels. TSP tended to have a better renal survival rate than T.

DOI： 10.1007/s10157-024-02527-1

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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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis. Each year, approximately 880,000 patients are newly diagnosed with HNSCC worldwide, and 450,000 patients with HNSCC die. Risk factors for developing HNSCC have been identified, with cigarette smoking, alcohol consumption, and viral infections being the major factors. Owing to the prevalence of human papillomavirus infection, the number of HNSCC cases is increasing considerably. Surgery and chemoradiotherapy are the primary treatments for HNSCC. With advancements in tumor biology, patients are eligible for novel treatment modalities, namely targeted therapies, immunotherapy, and photoimmunotherapy. Because this area of research has rapidly progressed, clinicians should understand the basic biology of HNSCC to choose an appropriate therapy in the upcoming era of personalized medicine. This review summarized recent developments in tumor biology, focusing on epidemiology, genetic/epigenetic factors, the tumor microenvironment, microbiota, immunity, and photoimmunotherapy in HNSCC, as well as how these findings can be translated into clinical settings.

DOI： 10.1016/j.anl.2023.08.006

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating, yet their efficacy remains controversial. Understanding the tumor microenvironment (TME), including the expression of immune checkpoint molecules in SGC, is crucial to optimizing immunotherapy. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma generally exhibit immune-hot TME with high immune cell infiltration, frequent genetic mutations, and robust immune checkpoint molecule expression. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies showed promising clinical efficacy of ICIs, with an objective response rate ranging from 20.0-33.3%, indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies including anti-human epidermal growth factor receptor 2 and anti-androgen receptor therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies including chimeric antigen receptor-T therapy and cancer vaccines. This review discusses the current understanding and future directions of immunotherapies for SGCs, including ongoing clinical trials.

DOI： 10.3390/cancers16061205

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Authorship：Corresponding author   Language：English  

Lipomas are among the most common soft tissue tumors. Surgical removal of lipoma is considered if the patient has symptoms or cosmetic challenges. Lipomas that develop from any fat tissue in the body and involve the eustachian tube are extremely rare. Herein, we report the case of a patient with a lipoma arising in the eustachian tube. We also summarized the literature on tumors originating from the eustachian tubes. A 62-year-old female presented to our department with a five-year history of left nasal congestion. Nasal endoscopy revealed a tumor in the left eustachian tube. The tumor was considered a lipoma on computed tomography (CT) and magnetic resonance imaging (MRI) and was removed using a transnasal endoscopic approach. Nasal endoscopy and radiologic imaging can be used to detect tumors in the nasopharynx, including the eustachian tubes. Magnetic resonance imaging is particularly useful for the diagnosis of lipomas. A lipoma in the eustachian tube can cause nasal congestion and aural fullness, and the transnasal endoscopic approach is useful for tumor removal.

DOI： 10.7759/cureus.56597

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Chronic rhinosinusitis (CRS) is a persistent inflammatory disease of the nasal cavity and paranasal sinuses. Traditional classification is denoted by the presence (CRSwNP) or absence of nasal polyps (CRSsNP). Particularly, CRSwNP is distinguished by the presence of infiltrating cells and inflammatory markers in the nasal mucosa. Patients with CRSwNP in Western countries predominantly display a type 2 endotype, whereas those in Asian regions display a mixed type 2 endotype. Nevertheless, recent transcriptome analyses have revealed two types of nasal polyps - type 2 and non-type 2 polyps, suggesting that geographical differences in endotypes likely resulted from the different proportions of each endotype. Moreover, various endotypes of CRSsNP have been identified, making phenotype a crucial factor for predicting treatment efficacy. Type 2 endotypes, designated as eosinophilic CRS (ECRS) in Japan, are characterized by severe eosinophilic infiltration into the paranasal sinus tissue and are particularly refractory. In this review, we discuss the latest developments in ECRS. We also provide recent findings on the involvement of nasal epithelial cells in pathogenesis.

DOI： 10.1016/j.anl.2023.08.002

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by elevated serum IgG4, tissue infiltration of IgG4-positive cells, and fibrosis. Although a number of IgG4-RD patients show sinonasal involvement, there is little known about sinonasal inflammation associated with IgG4-RD. This study aimed to describe the clinicopathological features of sinonasal inflammation associated with IgG4-RD and to compare with other inflammatory diseases, such as eosinophilic chronic rhinosinusitis (ECRS) and granulomatosis with polyangiitis (GPA). METHODS: A retrospective analysis of clinicopathological features of patients with sinonasal lesions and high serum IgG4 was performed. Patient data were reviewed to determine whether they fulfilled the diagnostic criteria for other inflammatory diseases. RESULTS: Six of 7 patients were diagnosed with IgG4-RD, while 1 patient was diagnosed with GPA. In the 6 patients with IgG4-RD, intranasal findings showed nasal polyps in 3 patients (50%) and nasal crusting in the 3 patients (50%). Computed tomography showed ethmoid sinus involvement in 5 patients (83%). Five of the 6 patients (83%) were diagnosed with IgG4-RD based on nasal biopsy, whereas 1 patient (17%) was diagnosed based on lacrimal gland biopsy. Four patients fulfilled the Japanese epidemiological survey of refractory ECRS (JESREC) criteria. However, none of the patients showed eosinophil infiltration. Although the patient with GPA showed high levels of serum IgG4 and tissue infiltration of IgG4-positive cells in the nasal biopsy, the patient showed common clinical features of GPA. CONCLUSION: Patients with sinonasal inflammation associated with IgG4-RD had similar clinical characteristics with ECRS and GPA. Histopathological findings of the nasal biopsy from clinically diagnosed GPA was consistent with that of IgG4-RD. Sinonasal inflammation associated with IgG4-RD should be diagnosed based not only on tissue infiltration of IgG4-positive cells but in conjunction with clinical findings such as local nasal characteristics, involvement of other organs, and serum antineutrophil cytoplasmic antibody levels. IgG4-RD should be ruled out in patients with eosinophilia without histopathological eosinophil infiltration.

DOI： 10.1159/000538365

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Language：Japanese   Publisher：JAPAN SOCIETY FOR HEAD AND NECK SURGERY  

Marine-Lenhart syndrome consists of coexisting Basedow’s and Plummer’s diseases. Here, we report a case of Marine-Lenhart syndrome, in which hyperthyroidism was detected during the follow-up of a thyroid tumor, and the diagnosis was made based on scintigraphy findings.
<br>A 69-year-old woman had been diagnosed with a left thyroid tumor more than 20 years ago. Because cytological examination suggested a benign tumor, surgical removal was not performed. She was diagnosed with hyperthyroidism by a local family doctor, and was referred to our department for further examination. TRAb was positive, and CT and echography showed a substantial mass with a maximum diameter of 32 mm in the left lobe of the thyroid gland. I¹²³ scintigraphy showed an accumulation in the left lobe tumor, and weak but diffuse accumulation in other lesions of the thyroid glands. Based on these findings, she was diagnosed with Marine-Lenhart syndrome. The patient was treated with total thyroidectomy, and no malignant findings were observed.

DOI： 10.5106/jjshns.34.99

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

In the treatment of salivary gland cancer, radical resection with negative surgical margins is paramount in determining the patient’s prognosis, and therefore, the indication for concomitant resection of the facial nerve should be carefully considered, based on not only the findings on preoperative examination, but also on the intraoperative findings. We report a case of high-grade parotid carcinoma with positive surgical margins that resulted from discrepancies between the findings during preoperative treatment planning and the intraoperative findings, which led to a poor prognosis. In addition, histopathology revealed a rare tumor, namely, dedifferentiated epithelial myoepithelial carcinoma (EMC). Therefore, in this case report, we also review this rare disease entity. The patient was a 58-year-old man who presented with a swelling below the left ear that he had first noticed about 5 months prior to his first visit to our department, and he was referred to us with a suspected left parotid tumor. Physical examination revealed a hard mass with poor mobility below the left ear and multiple enlarged lymph nodes at levels II and III in the left cervical region. CT and MRI showed two irregular masses with poor enhancement within the left parotid gland, one 3.4 cm in diameter and the other 3.2 cm in diameter, and enlarged lymph nodes at levels I-III of the left neck. FDG-PET/CT showed accumulation in the same masses and in the left cervical enlarged lymph nodes. Core needle biopsy of the left parotid tumor revealed poorly differentiated carcinoma, and a total left parotidectomy was performed with left cervical dissection. Histopathology showed a bilayer of cuboidal cells with eosinophilic spherocytes inside and bright cells outside, and a focal and dense infiltrative growth of atypical cells containing enlarged nuclei with prominent nucleoli; based on the findings, we made the diagnosis of dedifferentiated EMC. Since the tumor resection margins were partially positive, and multiple metastases to the dissected lymph nodes and some extranodal invasion were also observed, radiation therapy (60 Gy) was added as adjuvant therapy. One year after the completion of radiotherapy, there was no apparent disease recurrence. Herein, we described a case of dedifferentiated EMC presenting as a high-grade parotid carcinoma. In the treatment of salivary gland carcinoma, radical resection with negative surgical margins is crucial in determining the patient’s prognosis. Therefore, the indication for resection of the facial nerve should be considered based on the distance between the facial nerve and the tumor, the tumor histology, and the malignancy grade of the salivary gland cancer, and sometimes it is considered necessary not to hesitate to perform resection of the facial nerve in order to achieve a complete resection. While some reports of cases of dedifferentiated EMC, which are considered to be very rare, have been published previously, a larger number of cases should be accumulated to further elucidate the characteristics of dedifferentiated EMC.

DOI： 10.5631/jibirin.117.233

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I033365984

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Myxoinflammatory fibroblastic sarcoma (MIFS) is a low-grade malignant soft tissue tumor that typically arises in the distal aspects of the extremities. Although a few cases of the tumors occurring in the nose and eyeball have been reported, MIFS is uncommon in the head and neck region. Herein, we describe a rare case of MIFS arising in the anterior neck. The patient was a 69-year-old woman who presented to our department with a tumor in the anterinr neck measuring 4.4 cm in diameter. Ultrasound-guided fine needle aspiration cytology revealed a poorly differentiated malignant tumor. The tumor was surgically removed, and postoperative histopathology revealed the diagnosis of MIFS. The patient remains recurrence-free one year after adjuvant radiation therapy. The histologic and clinical features of MIFS have been discussed. Because local recurrence is known to occurr in approximately 20% of all reported cases, careful postoperative follow-up is necessary.

DOI： 10.5631/jibirin.117.647

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I033616512

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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 (&gt;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 (&gt;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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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BACKGROUND Malignant lymphomas can occur at various sites. Hypopharyngeal tumors are at risk for airway obstruction and require rapid diagnosis and treatment. Most hypopharyngeal malignancies are squamous cell carcinomas; other tumors are rare. To date, only a few cases of malignant hypopharyngeal lymphoma have been reported, and its specific characteristics are unknown. Herein, we report a case of right hypopharyngeal diffuse large B-cell lymphoma (DLBCL) in a 74-year-old man with dysphagia. CASE REPORT A 74-year-old man presented to our hospital with dysphagia. He had no relevant medical history. Endoscopic examination revealed a right hypopharyngeal tumor. The surface of the tumor was smooth, with no evidence of hemorrhage. Computed tomography revealed a 40-mm mass located in the hypopharynx. We performed a tracheotomy and biopsy of the tumor. Histopathological examination revealed a diffuse proliferation of large atypical B cells with negative staining for Epstein-Barr virus by in situ hybridization. Immunohistochemical staining was positive for CD20 but negative for CD3 and CD10. The patient was administered chemotherapy. The tumor reduced in size, and the patient recovered completely. During the two-year follow up, no recurrence of cancer was observed. CONCLUSIONS Although most hypopharyngeal tumors are squamous cell carcinomas (SCCs), the possibility of other types of tumors should also be considered. Malignant lymphoma of the hypopharynx is rare, and more cases need to be studied and reported in the future.

DOI： 10.12659/AJCR.942070

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/emp2.13082

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DOI： 10.1007/s13760-023-02181-6

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A 69-year-old man with impaired consciousness, right hemiplegia, and aphasia was admitted to our emergency room for thorough examination. Magnetic resonance imaging (MRI) and 3-dimensional computed tomography (3D CT) scan of the head revealed a cerebral infarction due to dissection of the left internal carotid artery. Contrast-enhanced CT prior to internal carotid artery stenting showed that the left elongated styloid process ran in close proximity to the left internal carotid artery, with a minimum distance of 2 mm. The patient underwent stenting at the internal carotid artery 16 days after disease onset. The patient was referred to our department for left elongated styloid process resection to reduce the risk of further internal carotid artery injury. Resection of the left styloid process through a cervical incision was performed. Six months after surgery, there was no recurrence of the internal carotid artery dissection.

DOI： 10.1016/j.anl.2023.01.011

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DOI： 10.1002/emp2.13087

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Immune checkpoint inhibitors (ICIs) are a novel treatment option for treating head and neck squamous cell carcinoma (HNSCC). Among the immune-related adverse effects, cerebral infarction (CI) is a rare but fatal complication, and it has been reported in various cancers, except HNSCC. Herein, we describe three cases of patients diagnosed with HNSCC who experienced CI following ICI treatment. In addition, we conducted a comprehensive literature review on ICI-related thrombosis. Three patients with recurrent HNSCC were treated with nivolumab. Two patients had a history of CI, or heart disease, and were concurrently prescribed antithrombotic medications during nivolumab treatment. The number of nivolumab administrations varied from 1-25 before the onset of CI. All patients experienced worsening of neurological symptoms due to CI, irrespective of antithrombotic treatment, and they ultimately succumbed to the disease within 16-222 days following their initial ICI administration. ICIs may cause thromboembolisms, leading to CI. Based on our review of the literature, a history of thromboembolism or heart disease could be a risk factor for ICI-related thrombosis.

DOI： 10.7759/cureus.47406

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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Upper airway infections caused by anaerobic bacteria, including pharyngitis and tonsillitis, are a common cause of septic thrombosis (Lemierre's syndrome). Although otitis media rarely progresses to systemic infection, an abscess surrounding the middle ear can affect the central nervous system. Trueperella bernardiae was originally considered a non-pathogenic aerobic bacterium but has subsequently been reported to cause bacteremia and brain abscesses. Here, we report a case of otitis media caused by T. bernardiae complicated by meningitis, subdural empyema, and septic pulmonary emboli in an immunocompetent patient.

DOI： 10.7759/cureus.42977

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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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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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Language：Japanese   Publisher：日本口腔・咽頭科学会  

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Language：Japanese   Publisher：日本口腔・咽頭科学会  

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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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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Authorship：Lead author   Language：Japanese   Publisher：一般社団法人 日本耳鼻咽喉科頭頸部外科学会  

免疫療法は癌治療において手術, 抗癌剤, 放射線療法に次ぐ第4の柱として確立された. 現状で用いられている免疫療法は, 腫瘍や腫瘍微小環境において抗腫瘍免疫を抑制する負の免疫チェックポイント分子への阻害抗体であり, PD-1 / PD-L1 や CTLA-4 がその代表的な分子として挙げられる. これらの分子に対する中和抗体は抗原性が高い悪性腫瘍として知られる悪性黒色腫で臨床応用が開始され, 一定の臨床効果を示した. 頭頸部癌も比較的抗原性が高い腫瘍として知られており, 2017年に Nivolumab, 2019年には Pembrolizumab の臨床応用が開始された. 臨床応用から数年が経過し, 免疫療法はリアルワールドで2割前後の奏効率を示している. 免疫チェックポイント阻害薬の使用に対するハードルは下がり, 全国で多くの耳鼻咽喉科・頭頸部外科医が免疫療法に携わっている. そのため, 臨床医にとっても頭頸部癌における腫瘍免疫の詳細な理解が求められるようになってきた. 本稿では, 頭頸部癌を中心とした増殖・転移に関するメカニズムおよび腫瘍免疫を応用した治療法の現状と未来について概説する.

DOI： 10.3950/jibiinkotokeibu.126.2_81

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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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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Myoepithelioma is a relatively rare salivary gland tumor. Herein, we report a case of myoepithelioma of the soft palate. The patient was 48-year-old man who was found, during dental examination, to have a swelling on the left side of the soft palate, and was referred to a local clinic. Fine-needle aspiration cytology revealed ductal epithelial cells and myoepithelial cells, so that the initial diagnosis was pleomorphic adenoma. The patient was referred to our department, and we performed resection of the soft palate tumor. On histopathological examination, the tumor was found to be composed of plasmacytoid myoepithelial cells, and immunohistochemistry showed positive staining of the cells for AE1/AE3, S-100 protein, vimentin, and GEAP. The MIB-1 index, an indicator of malignant cell proliferation, was low (4%). The final diagnosis of the tumor was myoepithelioma, plasmacytoid cell type. Until the last follow-up, one year after the surgery, the patient showed no evidence of recurrence. Because several reports have suggested that myoepitheliomas could show malignant transformation, we propose to carefully follow-up our patient reported herein, with oral myoepithelioma.

DOI： 10.5631/jibirin.116.45

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Language：Japanese   Publisher：Japan Society of Stomato-pharyngology  

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis （PFAPA） syndrome is an autoinflammatory disease and is generally seen in children under 5 years of age. Because the etiology and pathogenesis of PFAPA syndrome are unknown, the syndrome is often misdiagnosed as recurrent tonsillitis. Medication is normally chosen for the first treatment, but tonsillectomy is considered when the medication is ineffective. Herein, we report five cases of PFAPA syndrome who underwent tonsillectomy in our department. The age of onset ranged from 0 to 5 years （median 3 years）, and the age at tonsillectomy ranged from 2 to 7 years （median 5 years）. Symptoms included periodic fever in 5 cases, aphthous stomatitis in 1 case, cervical lymphadenitis in 2 cases, and pharyngitis in 5 cases. After tonsillectomy, the periodic fever disappeared in four cases, and the fever onset became less frequent in the remaining case. Therefore, tonsillectomy was effective in the treatment of PFAPA syndrome. When patients are introduced by a pediatrician who suggests that tonsillectomy is indicated because of failure of the initial treatment, we should recommend the operation for the patients.

DOI： 10.14821/stomatopharyngology.36.102

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DOI： 10.7248/jjrhi.62.269

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There have been very few reports of thyroid metastasis from cervical carcinoma. This article reports a case of metastasis from cervical carcinoma. A 69-year-old woman with a history of cervical cancer presented to our department with right cervical swelling. She had suffered from paralysis of the left recurrent laryngeal nerve after undergoing left hemithyroidectomy 16 years ago. Computed Tomography (CT) and magnetic resonance imaging scans revealed a right thyroid tumor with bilateral enlargement of the cervical lymph nodes. Fluorodeoxyglucose positron emission tomography/CT imaging revealed high uptake in the right thyroid tumor, cervical lymph nodes, and right iliac bone. Fine-needle aspiration cytology revealed atypical epithelial cells with a high nuclear/cell ratio and hyperchromatic nuclei, which resembled cervical cancer cells. Given the risk of airway obstruction and dysphagia, the patient underwent tracheostomy, right hemithyroidectomy, and neck dissection for preserving the quality of life. Pathological examination revealed normal thyroid tissue with p16-positive atypical epithelial cells, which suggested thyroid metastasis from the cervical cancer. The patient has remained alive without any symptoms for 5 postoperative months.

DOI： 10.1016/j.bjorl.2023.03.005

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Peripheral facial nerve palsy is more frequent in Bell’s palsy and Ramsay Hunt syndrome. We performed a retrospective review of the data of 67 patients with Bell’palsy (29 males, 38 females; median age, 63 years) and 18 patients with Ramsay Hunt syndrome (6 males, 12 females; median age, 53.5 years) diagnosed between April 2015 and March 2020. In the patient group with Bell’s palsy, the initial paralysis score was ≤ 8 in 21 patients (31.3%), 10–18 in 28 patients (41.8%), and ≥ 20 in 18 patients (26.9%), and the final paralysis score was 40 in 45 patients (65.7%), 36 to 38 in 11 patients (16.4%), 32 to 34 in 2 patients (3.0%), 20 to 30 in 7 patients (10.4%), and 10–18 in 2 patients (3.0%). Bell’s palsy was cured in 56 of 67 the patients, corresponding to a cure rate of 83.6%. In the patient group with Ramsay Hunt syndrome, the initial paralysis score was ≤ 8 in 9 patients (50.0%), 10–18 in 6 patients (33.3%), and ≥ 20 in 3 patients (16.7%) and the final paralysis score was 40 in 8 patients (44.4%), 36–38 in 3 patients (16.7%), 32–34 in 2 patients (11.1%), 20–30 in 2 patients (11.1%), and 10–18 in 2 patients (11.1%). Ramsay Hunt syndrome was cured in 11 of the 18 patients, corresponding to a cure rate of 61.1%. The findings of electroneurography were found to be associated with cure/non-cure in patients with Bell’s palsy, whereas the initial paralysis score was significantly associated with the prognosis in patients with Ramsay Hunt syndrome.

DOI： 10.5631/jibirin.116.25

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Pleomorphic adenoma is the most common type of salivary gland tumors. The most frequently affected sites are the parotid for major and the palatal region for minor salivary glands. Pleomorphic adenoma arising in the buccal region is rare, and is difficult to resect because of cosmetic reasons. Herein, we report a case of giant pleomorphic adenoma arising in the buccal region. The patient was an 89-year-old woman who presented with a swelling in the right buccal region. She had undergone resection by an external approach for a diagnosis of buccal pleomorphic adenoma 15 years ago. The tumor, which was located anterior to the masseter muscle, was resected via an intraoral approach, and the pathological diagnosis was pleomorphic adenoma without malignant transformation. Until the present, three years after the surgery, there has been no evidence of recurrence. In summary, transoral removal is a cosmetically feasible approach for minor salivary gland tumors. It is important to determine the surgical approach, including transoral or external incision, in individual cases by considering the histological type, anatomical location, and cosmetic aspects.

DOI： 10.5631/jibirin.116.161

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OBJECTIVE: To evaluate the efficacy and safety of Alternating Chemoradiotherapy (ACRT) using cisplatin and 5-Fluorouracil (5-FU) in patients with nasopharyngeal carcinoma. METHODS: This was a retrospective study in which patients' clinical records were reviewed to identify patients with a new diagnosis of nasopharyngeal carcinoma at our institution between January 2005 and January 2019. Thirty-seven eligible patients were identified; of these, the clinical details of 27 patients treated with ACRT were evaluated. Patient outcomes, including overall survival and progression-free survival, and adverse events were assessed. RESULTS: Of these initial 37 patients, 1, 10, 13, 10, and 3 were staged as I, II, III, IVA, and IVB, respectively, as defined by the 8th edition of the TNM classification system. Twenty-seven patients received ACRT comprising sequential administration of chemotherapy, radiotherapy (wide field), chemotherapy, radiotherapy (shrinking field), and chemotherapy. The 5-year overall survival and progression-free survival rates were 83.7% and 88.9%, respectively. Treatment compliance was 93%, which is comparable to that of previous reports. CONCLUSION: ACRT using cisplating and 5-fluorouracil was well tolerated with acceptable efficacy. LEVEL OF EVIDENCE: IVa.

DOI： 10.1016/j.bjorl.2022.12.004

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OBJECTIVE: Immune checkpoint inhibitors (ICIs) have been considered as novel therapeutic approaches for various cancers. ICIs were reportedly efficacious against rare cancers, including salivary gland carcinoma (SGC). We aimed to analyze the efficacy and safety of ICIs in patients with SGC. METHODS: We retrospectively analyzed the oncologic outcomes and immune-related adverse events (irAEs) in patients with SGC treated with at least one cycle of nivolumab or pembrolizumab. RESULTS: Among 12 patients, there were two with a complete response (CR), two with a partial response, five with stable diseases, and three with progressive diseases. The overall response rate was 33.3%. A CR was achieved in patients with poorly differentiated carcinoma (carcinoma ex pleomorphic adenoma) and salivary duct carcinoma. The progression-free survival ranged between 1 and 18 months (median, 4 months), while the overall survival ranged between 2 and 25 months (median, 13.5 months). An irAE was observed in only one patient who developed grade 3 erythema multiforme, and this patient's condition improved with withdrawal of pembrolizumab alone. CONCLUSION: Programmed death-1 blockade was an effective therapy for patients with SGC, including aggressive histologic types.

DOI： 10.1002/lio2.863

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Language：English   Publisher：(一社)日本癌学会  

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Although neoantigens are one of the most favorable targets in cancer immunotherapy, it is less versatile and costly to apply neoantigen-derived cancer vaccines to patients due to individual variation. It is, therefore, important to find highly immunogenic antigens between tumor-specific or associated antigens that are shared among patients. Considering the cancer immunoediting theory, immunogenic tumor cells cannot survive in the early phase of tumor progression including two processes: elimination and equilibrium. We hypothesized that highly immunogenic molecules are allowed to be expressed in tumor cells after an immune suppressive tumor microenvironment was established, if these molecules contribute to tumor survival. In the current study, we focused on TWIST1 as a candidate for highly immunogenic antigens because it is upregulated in tumor cells under hypoxia and promotes tumor metastasis, which is observed in the late phase of tumor progression. We demonstrated that TWIST1 had an immunogenic peptide sequence TWIST1140-162 , which effectively activated TWIST1-specific CD4+ T-cells. In a short-term culture system, we detected more TWIST1-specific responses in breast cancer patients compared with in healthy donors. Vaccination with the TWIST1 peptide also showed efficient expansion of TWIST1-reactive HTLs in humanized mice. These findings indicate that TWIST1 is a highly immunogenic shared antigen and a favorable target for cancer immunotherapy.

DOI： 10.1111/cas.15429

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Novel insights into Epstein-Barr virus (EBV) pathogenicity were presented at the "19th International Symposium on Epstein-Barr Virus and Associated Diseases" in Asahikawa, Japan. In addition, basic and translational findings on EBV-associated tumors, including natural killer (NK)/T-cell lymphoma, gastric cancer, and nasopharyngeal cancer, were presented by an international group of scientists and clinicians.

DOI： 10.3390/cancers14122924

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Language：English   Publisher：耳鼻咽喉科臨床学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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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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DOI： 10.1111/coa.13876

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A coin cell lithium battery is a common foreign body that can become lodged in the pediatric pharyngoesophageal junction. Because the voltage of such batteries is relatively high, their rapid removal is necessary to avoid mucosal necrosis. Despite being the initial choice for removal, flexible endoscopy cannot remove such foreign bodies from the esophagus. Various removal methods, including rigid esophagoscopy, should be considered for removing lithium coin cell batteries. The transcervical approach is feasible for removing esophageal foreign bodies, but it carries the risk of complications such as esophageal stenosis. Here we report a case of lithium coin battery ingestion that was successfully removed using a rigid esophagoscope. A 2-year-old girl was referred to a local doctor with cough and general fatigue. Chest X-ray and flexible endoscopy revealed a coin cell lithium battery stuck in the pharyngoesophageal junction, but it could not be removed. The foreign body was removed using Nishihata forceps through a rigid esophagoscope under general anesthesia.

DOI： 10.22037/aaem.v10i1.1430

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

S-1, an oral 5-FU prodrug, is an antineoplastic agent used for the treatment of various types of cancer, including cancer of the head and neck. In addition to inflammation, infection, trauma, and iatrogenic causes, nasolacrimal duct obstruction could also be caused by S-1. Herein, we report the case of a patient with nasolacrimal duct obstruction that was suspected to be caused by S-1, and was successfully treated by endoscopic dacryocystorhinostomy (DCR). The patient, a 69-year-old woman, was initiated on treatment with S-1 as adjuvant therapy after resection of breast cancer. Four months later, she developed epiphora, and the lacrimal ducts were intubated with silicone tubes. A year later, she presented with recurrence of epiphora, and was referred to our department. We performed right DCR for nasolacrimal duct obstruction, and the epiphora improved. Although the mechanism of nasolacrimal duct obstruction caused by S-1 has not yet been clarified, otorhinolaryngologists should be aware of this condition.

DOI： 10.5631/jibirin.115.503

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Isolated fracture of the malleus is a rare condition and is often caused by typical events, such as sudden withdrawal of a finger from the ear canal. Here, we report a case of isolated fracture of the malleus. The patient, a 36-year-old man, put his finger in the left ear canal and pulled it out suddenly, and immediately developed hearing loss on the same side. His left audiogram showed conductive hearing loss, and isolated fracture of the malleus was suspected based on the typical medical history. We performed transcanal endoscopic ear surgery (TEES) in order to obtain a good view of the tympanic cavity, and fixed the malleus fracture with calcium phosphate bone cement, which has appropriate osteoconductive characteristics. After the surgery, normal hearing was restored in the patient. Calcium phosphate bone cement is a useful material for restoring osteoconductive hearing.

DOI： 10.5631/jibirin.115.485

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Language：Japanese   Publisher：東京 : 眼科臨床紀要会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Lead author   Language：Japanese   Publisher：Japanese Society of Otorhinolaryngology-Head and Neck Surgery  

DOI： 10.3950/jibiinkotokeibu.124.12_1565

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I031892771

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Activation of STING signaling plays an important role in anti-tumor immunity, and we previously reported the anti-tumor effects of STING through accumulation of M1-like macrophages in tumor tissue treated with a STING agonist. However, myeloid cells express SIRPα, an inhibitory receptor for phagocytosis, and its receptor, CD47, is overexpressed in various cancer types. Based on our findings that breast cancer patients with highly expressed CD47 have poor survival, we evaluated the therapeutic efficacy and underlying mechanisms of combination therapy with the STING ligand cGAMP and an antagonistic anti-CD47 mAb using E0771 mouse breast cancer cells. Anti-CD47 mAb monotherapy did not suppress tumor growth in our setting, whereas cGAMP and anti-CD47 mAb combination therapy inhibited tumor growth. The combination therapy enhanced phagocytosis of tumor cells and induced systemic anti-tumor immune responses, which rely on STING and type I IFN signaling. Taken together, our findings indicate that coadministration of cGAMP and an antagonistic anti-CD47 mAb may be promising for effective cancer immunotherapy.

DOI： 10.1084/jem.20200792

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Language：Japanese   Publisher：(一社)日本鼻科学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jha2.233

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Stimulator of interferon genes (STING) contributes to anti-tumor immunity by activating antigen-presenting cells and inducing mobilization of tumor-specific T cells. A role for tumor-migrating neutrophils in the anti-tumor effect of STING-activating therapy has not been defined. We used mouse tumor transplantation models for assessing neutrophil migration into the tumor triggered by intratumoral treatment with STING agonist, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Intratumoral STING activation with cGAMP enhanced neutrophil migration into the tumor in an NF-κB/CXCL1/2-dependent manner. Blocking the neutrophil migration by anti-CXCR2 monoclonal antibody impaired T cell activation in tumor-draining lymph nodes (dLNs) and efficacy of intratumoral cGAMP treatment. Moreover, the intratumoral cGAMP treatment did not show any anti-tumor effect in type I interferon (IFN) signal-impaired mice in spite of enhanced neutrophil accumulation in the tumor. These results suggest that both neutrophil migration and type I interferon (IFN) induction by intratumoral cGAMP treatment were critical for T-cell activation of dLNs and the anti-tumor effect. In addition, we also performed in vitro analysis showing enhanced cytotoxicity of neutrophils by IFN-β1. Extrinsic STING activation triggers anti-tumor immune responses by recruiting and activating neutrophils in the tumor via two signaling pathways, CXCL1/2 and type I IFNs.

DOI： 10.1007/s00262-021-02864-0

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Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden "stealth" antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re-expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re-expression in xenografts in BALB/c-nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T-cells with a SPESP1-derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1-specific helper T-cells were obtained; these cells produced interferon-γ against HLA-matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.

DOI： 10.1111/cas.14973

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Extranodal NK/T-Cell Lymphoma, nasal type (ENKTL-NT) has some salient aspects. The lymphoma is commonly seen in Eastern Asia, has progressive necrotic lesions in the nasal cavity, makes midfacial destructive lesions, and shows poor prognosis. The lymphoma cell is originated from either NK- or γδ T-cells, which express CD56. Since the authors first demonstrated the existence of Epstein-Barr virus (EBV) DNA and EBV oncogenic proteins in lymphoma cells, ENKTL-NT has been recognized as an EBV-associated malignancy. Because the angiocentric and polymorphous lymphoma cells are mixed with inflammatory cells on a necrotic background, the diagnosis of ENKTL-NT requires CD56 immunostaining and EBER in situ hybridization. In addition, serum the EBV DNA level is useful for the diagnosis and monitoring of ENKTL-NT. Although ENKTL-NT is refractory lymphoma, the prognosis is improved by the development of therapies such as concomitant chemoradiotherapy. The basic research reveals that a wide variety of intracellular/cell surface molecules, cytokines, chemokines, and micro RNAs are involved in lymphomagenesis, and some of them are related to EBV. Understanding lymphoma behavior introduces new therapeutic strategies, such as the usage of immune checkpoint inhibitors, peptide vaccines, and molecular targeting therapy. This review addresses recent advances in basic and clinical aspects of ENKTL-NT, especially its relation to EBV features.

DOI： 10.3390/microorganisms9071381

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Language：Japanese   Publisher：THE JAPAN LARYNGOLOGICAL ASSOCIATION  

A 41-year-old woman, presented with sore throat and dyspnea of 1 week’s duration. Fiberoptic laryngoscopy showed a swollen edematous epiglottis. Because the patient developed stridor and shortness of breath, tracheostomy was performed to secure the airway. Contrast-enhanced computed tomography (CT) showed high-density areas in the epiglottis, base of the tongue, and aryepiglottic folds. The patient was positive for proteinase 3 (PR3)-antineutrophil cytoplasmic antibody (ANCA, 4.9 U/ml) and negative for myeloperoxidase (MPO)-ANCA. A histo-pathological examination of an epiglottis biopsy specimen showed geographic necrotizing granuloma with a few scattered multinucleated giant cells. Transmural inflammation, luminal occlusion, and vessel disruption were observed on elastic staining. Based on these findings, the patient was diagnosed with granulomatosis with polyangiitis (GPA). Two months after the patient started therapy with high-dose steroids and cyclophosphamide, the epiglottic swelling improved. The level of PR3-ANCA returned to the normal range two months after starting treatment. Subglottic stenosis is reportedly a common clinical feature of GPA. Although the involvement of supraglottic structures, including the epiglottis, is rare in GPA, clinicians should include GPA in the differential diagnosis of a life-threatening airway obstruction.

DOI： 10.5426/larynx.33.31

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Language：Japanese   Publisher：日本耳鼻咽喉科免疫アレルギー感染症学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Purpose: The use of peripherally inserted central venous catheters (PICCs) has increased recently; several reports have indicated 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 data 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： 10.5631/jibirin.114.801

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I031757885

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Lyme disease, a tick-borne disease, is a systemic infection caused by Borrelia burgdorferi. In Japan, this disease has mainly been reported in Hokkaido prefecture. Although eczema is the most common symptom, some patients suffer from neurological complications. Herein, we report the case of a patient with Lyme disease who developed peripheral facial nerve palsy. The patient, a 72-year-old woman, was bitten by a tick in the right auricle. Two weeks later, she developed erythema and swelling of the right auricle, which were treated with ampicillin. A month later, she developed peripheral facial nerve palsy without other cranial nerve involvements, and was referred to our department. Based on the positive test result for serum anti-Borrelia burgdorferi antibody, the patient was diagnosed as having Lyme disease. She was treated with ceftriaxone and prednisolone, and the facial nerve palsy improved. Among Lyme disease-related neurological symptoms, facial nerve palsy is among the most frequent. It is necessary to be aware of the possible occurrence of facial nerve palsy as a manifestation of neuroborreliosis.

DOI： 10.5631/jibirin.114.231

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Carcinoma of the external auditory canal is among the rarer forms of head and neck cancer. We retrospectively analyzed the data of 15 cases of carcinoma of the external auditory canal treated at our hospital between January 2009 and December 2018. The patients consisted of 7 male and 8 female patients, aged 38 to 85 years, with a median age of 66 years. The histopathological type was squamous cell carcinoma in all cases, and the mean follow-up period was 36.2 months (range, 3 to 102 months). The tumor stage was T1 in 5 cases, T2 in 1 case, T3 in 6 cases, and T4 in 3 cases. There were no cases with lymph node or distant metastasis. According to the Pittsburgh staging classification, 5 patients had Stage I disease, 1 patient had Stage II disease, 6 patients had Stage III disease, and 3 patients had Stage IV disease. Ten patients underwent surgery as the initial treatment, and 5 patients with positive margins received postoperative chemoradiotherapy. Three patients received super-selective intra-arterial rapid infusion chemotherapy as the initial treatment. Two patients received radiotherapy alone. The 5-year overall survival and 5-year disease-specific survival rates as evaluated by the Kaplan- Meier method were 57.7% and 72.5%, respectively. The 5-year disease-specific survival rate was 100% in patients with Stage I/II disease, 40.0% in those with Stage III disease, and 50.0% in those with Stage IV disease. Six patients with early-stage disease showed good outcomes with surgery or radiotherapy, but the outcomes became poorer as the disease became more advanced. It is necessary to accumulate a larger number of advanced cases and consider effective treatment methods to improve the treatment outcomes.

DOI： 10.5631/jibirin.114.373

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I031498545

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

We conducted a retrospective analysis of the data 107 cases of peritonsillar abscess treated at our hospital between January 2014 and December 2018. Data on the 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 to 88 years). The left side was affected in 55 patients, the right side in 50 patients, and both sides in 2 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 3 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 CLDM, while none showed resistance to 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： 10.5631/jibirin.114.553

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Authorship：Lead author   Language：Japanese   Publisher：Japan Society of Stomato-pharyngology  

DOI： 10.14821/stomatopharyngology.34.157

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I032533165

Language：Japanese   Publisher：Japan Rhinologic Society  

The Japanese Rhinologic Society has held a “Hands-on Seminar on Basic Research for Clinicians” led by the Society since 2014. The aims of the seminar are to raise the motivation and research skills for basic research among clinical otorhinolaryngologists, and to encourage interdisciplinary collaboration through research with universities. The attendees at the seminar are clinicians who are performing basic research in Japan. The seventh seminar was held at the 59th Annual Meeting of the Japanese Rhinologic Society (Tokyo), and focused on isolation of mononuclear cells from peripheral blood, nasal polyps, and tonsils. In contrast to past seminars, the seminar was held online and experimental procedures were shown by video because of the worldwide SARS-CoV-2 pandemic. A questionnaire completed by participants indicated a high level of satisfaction and a belief that the research seminar is needed. The seminar provides a great opportunity for rhinologists to obtain ideas for expansion of avenues for basic understanding of rhinologic disorders, and we believe that it should be continued for as long as possible.

DOI： 10.7248/jjrhi.60.566

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Language：Japanese   Publisher：JAPAN SOCIETY FOR HEAD AND NECK SURGERY  

We experienced two cases of tracheostomy for a new coronavirus positive patient （COVID-19）. Case 1 was a man in his 80s. Long-term tracheal intubation management was required, so a tracheostomy was performed with full PPE using an N95 mask. Case 2 was a man in his 60s. Given that it was difficult to secure a visual field in the first tracheostomy, a surgical tracheotomy was performed under a powered air-purifying respirator （PAPR）. By using the PAPR, we were able to solve the problem of securing the visual field when performing surgical tracheostomy with full PPE, and it was considered to be useful for surgical tracheostomy under safe infection control.

DOI： 10.5106/jjshns.21-006

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Language：Japanese   Publisher：Japan Society for Pediatric Otorhinolaryngology  

Burkitt lymphoma is a high-grade B-cell lymphoma. In children, the symptoms of this disease vary depending on the primary site and include a few systemic symptoms, including fever and weight loss. Malignant lymphoma of the nasal cavity and paranasal sinuses is very rare. Herein, we report two cases of Burkitt lymphoma in the paranasal sinuses in children with rapid onset of visual impairment.

Both cases developed visual impairment and were admitted to the pediatric department and then referred to our department. Computed tomography and magnetic resonance imaging revealed mass lesions in the paranasal sinuses. Biopsies led to diagnosis of Burkitt lymphoma. Chemotherapy was administered and complete remission has been maintained since the end of treatment. However, blindness developed as a complication in case 1. These cases emphasize the need to be aware of the rapid progression of symptoms of Burkitt lymphoma.

DOI： 10.11374/shonijibi.42.342

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I032540742

Language：Japanese   Publisher：Japan Rhinologic Society  

Thyroid-like low grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is a rare malignant tumor that originates in the nasopharynx. Pathologically, the tumor shows papillary thyroid cancer-like findings of a thyroid transcription factor-1 (TTF-1)-positive and thyroglobulin (TG)-negative status. We report a case of nasopharyngeal papillary adenocarcinoma at the posterior end of the nasal septum.

A 50-year-old woman presented with sore throat in our department. Nasal endoscopy revealed a pedunculated tumor at the posterior end of the nasal septum. CT and MRI showed a pedunculated tumor without cervical lymph node swelling. Biopsy revealed a TL-LGNPPA that was TTF-1-positive and TG-negative. The tumor was endoscopically resected under general anesthesia without any complications. The pathological margin was negative. No recurrence or metastasis has been observed in one year and 6 months after the operation.

DOI： 10.7248/jjrhi.60.495

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Other Link： https://search.jamas.or.jp/link/ui/2022105062

Authorship：Lead author   Language：Japanese   Publisher：Japan Society of Immunology, Allergology and Infection in Otorhinolaryngology  

Extranodal NK/T cell lymphoma, nasal type (nasal NK/T cell lymphoma) is a rare malignant disease, which mainly involves the head and neck. In the late 20^th century, monoclonal expression of Epstein–Barr virus (EBV) was detected in a clinical specimen. Subsequently, accumulating evidence has suggested that EBV and its related protein play an etiological role in the aggressive proliferation of this lymphoma. The viral load of EBV in serum has been used as a prognostic marker in clinical practice. EBV-derived micro-RNA is also a reliable marker for the progression of lymphoma. This lymphoma produces several cytokines and chemokines to proliferate under the EBV-LMP1-mediated pathway. In addition to its pathological role, EBV is an ideal target for immunotherapy. We have previously described that EBV-LMP1 contains an epitope that could activate antitumor CD4 helper T cells. Here, I briefly summarize the current knowledge regarding the etiological role of EBV in nasal NK/T cell lymphoma, the immune microenvironment surrounding this lymphoma, and the novel treatment strategy of targeting EBV with antitumor immune cells.

DOI： 10.24805/jiaio.1.3_147

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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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Language：Japanese   Publisher：THE JAPAN LARYNGOLOGICAL ASSOCIATION  

Varicella-zoster virus (VZV) reactivation is known to rarely cause inferior cranial nerve paralysis with symptoms such as pharyngeal pain, hoarseness, and dysphagia. We herein report 5 cases involving patients with laryngeal paralysis caused by VZV reactivation, in which the diagnosis was confirmed by a serological analysis. The symptoms of the five patients included pharyngeal pain (n=4), hoarseness (n=3), and dysphagia (n=3). The 5 patients were treated with acyclovir (750 mg/day) for 7 days and intravenous steroids; all patients were cured and achieved complete relief from their symptoms after various periods of time.

Among the 69 patients with laryngeal paralysis caused by VZV that were reported in the relevant Japanese literature (including our 5 patients), 53 of the 56 patients (95%) showed symptoms of sore throat, hoarseness, or dysphagia. Vagal (X), glossopharyngeal (Ⅸ), facial (Ⅶ) and hypoglossal (Ⅻ) nerve paralysis was reportedly observed in 69 (100%), 56 (81%), 30 (43%) and 6 (7%) of the 69 patients, respectively. Forty-nine (71%) of the 69 patients were treated with the combination of acyclovir and steroids, and 52 (75%) patients with laryngeal paralysis were cured.

In consideration of our 5 patients and the 64 patients reported in the relevant literature, in cases in which symptoms such as pharyngeal pain, hoarseness, and dysphagia, and findings of erythema and laryngeal paralysis are not found simultaneously, careful and frequent endoscopic observation could lead to an early diagnosis and appropriate treatment of laryngeal paralysis caused by VZV.

DOI： 10.5426/larynx.32.189

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

PD-1 blockade is a feasible approach in treating mucosal malignant melanomas of the middle ear.

DOI： 10.1002/ccr3.3424

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Language：Japanese   Publisher：(一社)日本鼻科学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jpeds.2020.06.010

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Language：Japanese   Publisher：日本がん免疫学会  

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Language：Japanese   Publisher：日本がん免疫学会  

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Language：Japanese   Publisher：The Japan Broncho-esophagological Society  

Parathyroid cysts are benign tumors that present with neck swelling. Among such cysts, 10% of cases are functional and 90% are non-functional. Aspiration of cystic fluid or surgical resection is recommended. For surgical resection, video-assisted neck surgery (VANS) has advantages in terms of aesthetic aspect and recognition of nerves, vessels and parathyroid with an expanded view. Although numerous thyroid tumors are operated by VANS, few such cases have been reported. Here, we report two cases of patients with parathyroid cyst operated by VANS.

DOI： 10.2468/jbes.71.325

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Language：Japanese   Publisher：(一社)日本頭頸部癌学会  

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Language：Japanese   Publisher：THE JAPAN LARYNGOLOGICAL ASSOCIATION  

We herein report the case of a patient with adult T-cell leukemia of the larynx.Adult T cell Leukemia was first described by Takatsuki in 1975. ATL is associated with human T cell lymphotropic virus typeⅠ(HTLV-1). Patients with this condition usually show lymphadenopathy and skin rash. The association of local laryngeal mass lesions is rare.

The patient, a 67-year-old woman, complained of throat pain that persisted for two weeks. She had a tumor of the epiglottis as well as cervical lymphadenopathy, and ulceration of a finger. To obtain a definite diagnosis, we obtained a biopsy specimen from the laryngeal tumor; however, the lesion was necrotic. Thus, we then obtained a biopsy specimen of the right cervical lymph node. The pathological findings suggested malignant lymphoma originating from the T cells. HTLV-1 was found in her serum, and a provirus was identified in ATL cells. The patient was treated with chemotherapy and the epiglottal mass gradually disappeared.

Otolaryngologists should consider ATL in the differential diagnosis of laryngeal carcinoma.

DOI： 10.5426/larynx.32.73

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Other Link： https://search.jamas.or.jp/link/ui/2021000989

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Colorectal cancer (CRC) patients with metastatic lesions have low 5-year survival rates. During metastasis, cancer cells often obtain unique characteristics such as epithelial-mesenchymal transition (EMT). Vimentin a biomarker contributes to EMT by changing cell shape and motility. Since abnormal phosphorylation is a hallmark of malignancy, targeting phosphorylated vimentin is a feasible approach for the treatment of metastatic tumors while sparing non-tumor cells. Recent evidence has revealed that both CD8 cytotoxic T lymphocytes (CTLs) and also CD4 helper T lymphocytes (HTLs) can distinguish post-translationally modified antigens from normal antigens. Here, we showed that the expression of phosphorylated vimentin was upregulated in metastatic sites of CRC. We also showed that a chemotherapeutic reagent augmented the expression of phosphorylated vimentin. The novel phosphorylated helper peptide epitopes from vimentin could elicit a sufficient T cell response. Notably, precursor lymphocytes that specifically reacted to these phosphorylated vimentin-derived peptides were detected in CRC patients. These results suggest that immunotherapy targeting phosphorylated vimentin could be promising for metastatic CRC patients.

DOI： 10.1007/s00262-020-02524-9

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Authorship：Lead author   Language：Japanese   Publisher：Japan Society for Infection and Aerosol in Otorhinolaryngology  

The clinical course of common cold is typically self-limiting, and specific treatments are not required to cure common cold. Meanwhile, the clinical symptoms of common cold, such as sore throat and headache, are frequently found in life-threatening diseases. Therefore, it is necessary to understand red flag signs and differentiate common cold from other diseases. For risk assessment and management, the early detection of vulnerable patients prevents the further development of fatal diseases that resemble common cold. In this review, we summarize the risk factors and details of “common cold”-like serious diseases.

DOI： 10.24805/jjsiao.8.2_129

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Although cisplatin (CDDP) has been used as a major chemotherapeutic drug for head and neck squamous cell carcinoma (HNSCC), its impact on T-cell functions is controversial. Therefore, we investigated the immunologic effects of CDDP and antitumor effects by combination therapy of CDDP with a ligand for stimulator of interferon genes, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Direct impacts of CDDP on T-cell functions were addressed by comparing T-cell functions between human subjects treated and untreated with CDDP. The immune responses and the efficacy of combination therapy using CDDP and cGAMP were assessed using BALB/c mice inoculated with mouse squamous cell carcinoma (SCC) cell lines. CDDP inhibited T-cell proliferation in a dose-dependent manner. T-cell functions of CDDP-treated HNSCC patients were comparable to those of healthy donors and CDDP-untreated HNSCC patients. In the mice bearing SCC cell lines, combination therapy using CDDP and cGAMP enhanced the gene expressions of CXCL9 and CXCL10 in the tumor tissues and inhibited tumor growth. The antitumor effect was cancelled by anti-CXCR3 monoclonal antibody. These findings suggest that the combination therapy using CDDP and an immunomodulating drug like cGAMP would be a rational cancer immunotherapy for patients with HNSCC.

DOI： 10.1016/j.bbrc.2019.11.107

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Language：Japanese   Publisher：日本耳鼻咽喉科感染症・エアロゾル学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The effect of PD-1 blockade as a first-line therapy in nonmetastatic head and neck squamous cell carcinoma (HNSCC) remains unknown. We report a case of an exceptional response to PD-1 blockade as a first-line therapy in a patient with HNSCC and lung cancer. A 59-year-old man presented with cheek swelling and chest pain. He was diagnosed with maxillary sinus carcinoma (squamous cell carcinoma) and lung cancer (non-small-cell lung cancer, not otherwise specified). The maxillary sinus carcinoma was completely resolved after 8 cycles of pembrolizumab. Immune checkpoint blockade warrants further evaluation in previously untreated patients with HNSCC.

DOI： 10.1159/000509485

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Language：Japanese   Publisher：Japan Society of Stomato-pharyngology  

We report a case of myoepithelioma in the hard palate. The patient was a 69-year-old woman with a mass in the hard palate. The hard elastic mass was covered with normal mucosa and located on the right side of the hard palate. We diagnosed myoepithelioma by biopsy and surgically removed the tumor. An epithelioid organization was the main histopathology finding, and multiple histology was mixed. Actin, αSMA, and S-100 protein, which is a marker of the myoepithelium system, and GFAP were positive by immunostaining. The MIB-1 index, which is an index of malignancy, was 5％, suggesting the mass was benign. A diagnosis of myoepithelioma（mixed type）was made. Postoperative observation revealed no recurrence as of 10 months after the operation, but there are reports of recurrence and malignant transformation, so careful follow-up is necessary.

DOI： 10.14821/stomatopharyngology.33.45

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I032538511

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Secretory carcinoma (SC) is a low-grade salivary gland carcinoma similar to secretory breast carcinoma harboring the ETV6-NTRK3 fusion gene, that was first proposed as a distinct disease entity in 2010 by Skálová et al. SC has heterogeneous histopathological manifestations, so that definitive diagnosis of the tumor by histopathological examination is difficult. Many fusion partners of ETV6 are known in other malignant tumors. In the case of SC also, previously unknown fusion partners of ETV6 (ETV6-X) have been reported recently. Herein, we report a case of SC of the submandibular gland harboring an ETV6-X fusion gene. A 32-year-old man presented to our department with a mass in his right submandibular region that he had first noticed one month earlier. We diagnosed the mass as a submandibular gland tumor and performed submandibular gland excision. The postoperative histopathological findings led to suspicion of the tumor as a SC. Subsequently, FISH analysis led to a confirmed the diagnosis of SC with an ETV6-X fusion gene. No evidence of recurrence was noted during postoperative follow-up of the patient for 20 months without any further therapy. Because of the difficulty in the histological diagnosis and absence of any availability of established treatments for tumors harboring the NTRK family genes, it is important to perform genetic examination for confirmatory diagnosis in patients with suspected SC.

DOI： 10.5631/JIBIRIN.113.787

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I030799723

Language：Japanese   Publisher：(一社)日本耳科学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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IgA nephropathy (IgAN) is a tonsil-related disease. We previously showed that oligodeoxynucleotides with CpG (CpG-ODN) and B-cell activation factor (BAFF) are involved in hyperproduction of IgA from tonsillar mononuclear cells of patients with IgAN (IgAN-TMCs). In this study, we focused on a proliferation-inducing ligand (APRIL), homologous to BAFF. IgAN-TMCs produced more APRIL than non IgAN-TMCs in the presence of both CpG-ODN and control-ODN. TLR9 expression was higher in B-cells of IgAN-TMCs, and treatment with CpG-ODN enhanced transmembrane activator and CAML interactor (TACI) expression. IgA production from IgAN-TMCs was inhibited by APRIL neutralization antibody or TACI blocking antibody, and enhanced by co-treatment of APRIL and CpG-ODN. Serum APRIL levels were higher in patients with IgAN, and decreased after tonsillectomy. These findings suggest that APRIL is involved in the hyperproduction of IgA from IgAN-TMCs, and that CpG-ODN enhanced APRIL-induced IgA production by increasing TACI expression on B-cells of IgAN-TMCs.

DOI： 10.1016/j.cellimm.2019.103925

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BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) originates from squamous epithelium of the upper aerodigestive tract and is the most common malignancy in the head and neck region. Among HNSCCs, oropharynx squamous cell carcinoma (OSCC) has a unique profile and is associated with human papillomavirus infection. Recently, anti-programmed cell death-1 monoclonal antibody has yielded good clinical responses in recurrent and/or metastatic HNSCC patients. Therefore, programmed death-ligand 1 (PD-L1) may be a favorable target molecule for cancer immunotherapy. Although PD-L1-expressing malignant cells could be targeted by PD-L1-specific CD8+ cytotoxic T lymphocytes, it remains unclear whether CD4+ helper T lymphocytes (HTLs) recognize and kill tumor cells in a PD-L1-specific manner. METHODS: The expression levels of PD-L1 and HLA-DR were evaluated using immunohistochemical analyses. MHC class II-binding peptides for PD-L1 were designed based on computer algorithm analyses and added into in vitro culture of HTLs with antigen-presenting cells to evaluate their stimulatory activity. RESULTS: We found that seven of 24 cases of OSCC showed positive for both PD-L1 and HLA-DR and that PD-L1241-265 peptide efficiently activates HTLs, which showed not only cytokine production but also cytotoxicity against tumor cells in a PD-L1-dependent manner. Also, an adoptive transfer of the PD-L1-specific HTLs significantly inhibited growth of PD-L1-expressing human tumor cell lines in an immunodeficient mouse model. Importantly, T cell responses specific for the PD-L1241-265 peptide were detected in the HNSCC patients. CONCLUSIONS: The cancer immunotherapy targeting PD-L1 as a helper T-cell antigen would be a rational strategy for HNSCC patients.

DOI： 10.1186/s12967-019-1957-5

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Authorship：Lead author   Language：Japanese   Publisher：耳鼻咽喉科展望会  

DOI： 10.11453/orltokyo.62.supplement1_s34

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Authorship：Lead author   Language：Japanese   Publisher：THE JAPAN LARYNGOLOGICAL ASSOCIATION  

We herein report a patient with late-onset laryngeal stenosis after burn and inhalation injury. The patient, an 18-year-old male, suffered a burn and smoke inhalation injury. Because of laryngeal edema, the patient was intubated for two days followed by tracheotomy. Fourteen days later, endoscopic laryngoscopy revealed normal laryngeal finding. However, 14 months after the injury, he started to complain of hoarseness and respiratory distress. Given findings of a severe reduction in oxygen saturation, the patient underwent tracheotomy. A laryngeal examination revealed posterior glottic adhesion that was released by laryngeal microsurgery with steroid injection. Over one year of follow-up, no recurrence of his laryngeal stenosis was observed. Although late-onset laryngeal stenosis after burn and inhalation injury is rare, clinicians should consider the risk of this potentially fatal condition in susceptible patients.

DOI： 10.5426/larynx.31.34

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Other Link： https://search.jamas.or.jp/link/ui/2019300654

Language：Japanese   Publisher：耳鼻咽喉科臨床学会  

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Nasal natural killer/T-cell lymphoma (NNKTL) is closely associated with Epstein-Barr virus (EBV) and is characterized by poor prognosis, resulting from rapid progression of lesions in the affected organs. Recent data have shown that NNKTL is associated with the aberrant expression of cyclin-dependent kinase 1 (CDK1) and its downstream target survivin, but little is known about the functional roles of CDK1 and survivin in NNKTL. In the current study, we show that knockdown of the EBV-encoded oncoprotein latent membrane protein 1 (LMP1) induces downregulation of CDK1 and survivin in NNKTL cells. Immunohistochemistry detected CDK1 and survivin expression in LMP1-positive cells of NNKTL biopsy specimens. Inhibition of CDK1 and survivin in NNKTL cells with several inhibitors led to a dose-dependent decrease in cell proliferation. In addition, the Sp1 inhibitor mithramycin, which can downregulate both CDK1 and survivin, significantly suppressed the growth of established NNKTL in a murine xenograft model. Our results suggest that LMP1 upregulation of CDK1 and survivin may be essential for NNKTL progression. Furthermore, targeting CDK1 and survivin with Sp1 inhibitors such as mithramycin may be an effective approach to treat NNKTL, which is considered to be a treatment-refractory lymphoma.

DOI： 10.1038/s41374-018-0182-9

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Language：Japanese   Publisher：(一社)日本アレルギー学会  

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Vaccines consisting of synthetic peptides representing cytotoxic T-lymphocyte (CTL) epitopes have long been considered as a simple and cost-effective approach to treat cancer. However, the efficacy of these vaccines in the clinic in patients with measurable disease remains questionable. We believe that the poor performance of peptide vaccines is due to their inability to generate sufficiently large CTL responses that are required to have a positive impact against established tumors. Peptide vaccines to elicit CTLs in the clinic have routinely been administered in the same manner as vaccines designed to induce antibody responses: injected subcutaneously and in many instances using Freund's adjuvant. We report here that peptide vaccines and poly-ICLC adjuvant administered via the unconventional intravenous route of immunization generate substantially higher CTL responses as compared to conventional subcutaneous injections, resulting in more successful antitumor effects in mice. Furthermore, amphiphilic antigen constructs such as palmitoylated peptides were shown to be better immunogens than long peptide constructs, which now are in vogue in the clinic. The present findings if translated into the clinical setting could help dissipate the wide-spread skepticism of whether peptide vaccines will ever work to treat cancer.

DOI： 10.1007/s00262-018-02294-5

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Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NNKTL) has very unique epidemiological, etiologic, histologic, and clinical characteristics. It is commonly observed in Eastern Asia, but quite rare in the United States and Europe. The progressive necrotic lesions mainly in the nasal cavity, poor prognosis caused by rapid local progression with distant metastases, and angiocentric and polymorphous lymphoreticular infiltrates are the main clinical and histologic features. Phenotypic and genotypic studies revealed that the lymphoma is originated from either NK- or γδ T-cell, both of which express CD56. In 1990, the authors first reported the presence of Epstein-Barr virus (EBV)-DNA and EBV-oncogenic proteins, and EBV has now been recognized to play an etiological role in NNKTL. in vitro studies revealed that a wide variety of cytokines, chemokines, and micro RNAs, which may be produced by EBV-oncogenic proteins in the lymphoma cells, play important roles for tumor progression in NNKTL, and could be therapeutic targets. In addition, it was revealed that the interaction between NNKTL cells and immune cells such as monocytes and macrophages in NNKTL tissues contribute to lymphoma progression. For diagnosis, monitoring the clinical course and predicting prognosis, the measurements of EBV-DNAs and EBV-micro RNAs in sera are very useful. For treatment with early stage, novel concomitant chemoradiotherapy such as DeVIC regimen with local radiotherapy and MPVIC-P regimen using intra-arterial infusion developed with concomitant radiotherapy and the prognosis became noticeably better. However, the prognosis of patients with advanced stage was still poor. Establishment of novel treatments such as the usage of immune checkpoint inhibitor or peptide vaccine with molecular targeting therapy will be necessary. This review addresses recent advances in the molecular understanding of NNKTL to establish novel treatments, in addition to the epidemiologic, clinical, pathological, and EBV features.

DOI： 10.3389/fped.2019.00141

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Authorship：Lead author   Language：Japanese   Publisher：Japan Rhinologic Society  

The Japanese Rhinologic Society has held “Hands-on Seminar on Basic Research for Clinicians” led by the Society since 2014. These seminars are planned with the aim of raising the motivation and research skills of clinical otorhinolaryngologists toward basic research, and in turn to encourage inter-disciplinary collaboration through research with universities. The fifth seminar was held at the 57^th Annual Meeting of the Japanese Rhinologic Society (Asahikawa) including four different topics, isolation of single cells from nasal samples, ELISA, Western blot, and CRISPER-Cas9. Based on the questionnaire, the participants had a high need and satisfaction of these research seminars. Because this seminar is a great opportunity for rhinologists to obtain an idea to expand the avenue of basic understanding of rhinologic disorders, this seminar should be continued as far as there is a demand.

DOI： 10.7248/jjrhi.58.152

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Other Link： https://search.jamas.or.jp/link/ui/2023114525

Language：Japanese   Publisher：Japan Rhinologic Society  

Primary malignant lymphoma rarely occurs in extranodal organs such as the paranasal sinus. However, the prognosis of the small number of patients with primary malignant lymphoma of the paranasal sinus is poor. Herein, we report five patients with this disease who were treated in our department. Three patients were male and two were female. The median age of the patients was 75 years, with an age range of 55 to 84 years. The maxillary sinus was involved in all cases. Histological examination revealed that three cases were diffuse large B-cell lymphoma, one was follicular lymphoma, and one was high-grade B-cell lymphoma, not otherwise specified. Based on the Ann Arbor system, two patients were classified as Stage IEA, two as Stage IIEA, and one as Stage IVEA. Three patients were treated with chemoradiotherapy, one with chemotherapy alone, and one with radiotherapy alone. All patients achieved complete response (CR) with initial treatment, but two relapsed. The overall CR rate was 80% with salvage treatment (chemotherapy or removal of skin metastasis). The high curability rate suggests that chemoradiation is effective for treatment of B-cell origin malignant lymphoma of the paranasal sinus.

DOI： 10.7248/jjrhi.58.698

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Authorship：Lead author   Language：Japanese   Publisher：日本鼻科学会  

DOI： 10.7248/jjrhi.58.107

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Other Link： https://search.jamas.or.jp/link/ui/2019308332

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Cytotoxic T lymphocytes (CTLs) are effective components of the immune system capable of destroying tumor cells. Generation of CTLs using peptide vaccines is a practical approach to treat cancer. We have previously described a peptide vaccination strategy that generates vast numbers of endogenous tumor-reactive CTLs after two sequential immunizations (prime-boost) using poly-ICLC adjuvant, which stimulates endosomal toll-like receptor 3 (TLR3) and cytoplasmic melanoma differentiation antigen 5 (MDA5). Dendritic cells (DCs) play an important role not only in antigen presentation but are critical in generating costimulatory cytokines that promote CTL expansion. Poly-ICLC was shown to be more effective than poly-IC in generating type-I interferon (IFN-I) in various DC subsets, through its enhanced ability to escape the endosomal compartment and stimulate MDA5. In our system, IFN-I did not directly function as a T cell costimulatory cytokine, but enhanced CTL expansion through the induction of IL15. With palmitoylated peptide vaccines, CD8α+ DCs were essential for peptide crosspresentation. For vaccine boosts, non-professional antigen-presenting cells were able to present minimal epitope peptides, but DCs were still required for CTL expansions through the production of IFN-I mediated by poly-ICLC. Overall, these results clarify the roles of DCs, TLR3, MDA5, IFN-I and IL15 in the generation of vast and effective antitumor CTL responses using peptide and poly-IC vaccines.

DOI： 10.1007/s00262-018-2164-6

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Language：Japanese   Publisher：耳鼻咽喉科臨床学会  

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Peptide vaccines can be a successful and cost-effective way of generating T-cell responses against defined tumor antigens, especially when combined with immune adjuvants such as poly-IC. However, strong immune adjuvants can induce a collateral increase in numbers of irrelevant, nonspecific T cells, which limits the effectiveness of the peptide vaccines. Here, we report that providing prolonged IL2 signaling in the form of either IL2/anti-IL2 complexes or pegylated IL2 overcomes the competitive suppressive effect of irrelevant T cells, allowing the preferential expansion of antigen-specific T cells. In addition to increasing the number of tumor-reactive T cells, sustained IL2 enhanced the ability of T cells to resist PD-1-induced negative signals, increasing the therapeutic effectiveness of the vaccines against established tumors. This vaccination strategy using peptides and sustained IL2 could be taken into the clinic for the treatment of cancer. Cancer Immunol Res; 6(5); 617-27. ©2018 AACR.

DOI： 10.1158/2326-6066.CIR-17-0549

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The human T cell receptor is capable of distinguishing between normal and post-translationally modified peptides. Because aberrant phosphorylation of cellular proteins is a hallmark of malignant transformation, the expression of the phosphorylated epitope could be an ideal antigen to combat cancer without damaging normal tissues. p53 activates transcription factors to suppress tumors by upregulating growth arrest and apoptosis-related genes. In response to DNA damage, p53 is phosphorylated at multiple sites including Ser33 and Ser37. Here, we identified phosphorylated peptide epitopes from p53 that could elicit effective T helper responses. These epitope peptides, p5322-41/Phospho-S33 and p5322-41/Phospho-S37, induced T helper responses against tumor cells expressing the phosphorylated p53 protein. Moreover, chemotherapeutic agents augmented the responses of such CD4 T cells via upregulation of phosphorylated p53. The upregulation of phosphorylated p53 expression by chemotherapy was confirmed in in vitro and xenograft models. We evaluated phosphorylated p53 expression in the clinical samples of oropharyngeal squamous cell carcinoma and revealed that 13/24 cases (54%) were positive for phosphorylated p53. Importantly, the lymphocytes specific for the phosphorylated p53 peptide epitopes were observed in the head and neck squamous cell cancer (HNSCC) patients. These results reveal that a combination of phosphorylated p53 peptides and chemotherapy could be a novel immunologic approach to treat HNSCC patients.

DOI： 10.1080/2162402X.2018.1466771

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOCIETY OF IMMUNOLOGY AND ALLERGOLOGY IN OTOLARYNGOLOGY  

Nasal NK/T-cell lymphoma (NNKTL) is characterized by progressive necrotic lesions in the nasal cavity and/or palate. NNKTL cells are derived from two lineages, NK- and γδT-cell. Our previous studies showed the presence of Epstein-Barr virus (EBV) DNA, EBV oncogenic proteins, and the clonotypic EBV genome in this lymphoma, indicating that NNKTL is an EBV-related malignancy. It has been established histologically that many inflammatory cells such as lymphocytes, monocytes, and macrophages infiltrate NNKTL tissue. This finding gives rise to the speculation that tumor-reactive T lymphocytes might also exist in NNKTL tissue to attack the lymphoma cells. EBV-encoded latent membrane protein 1 (LMP1) has oncogenic potential and is expressed in NNKTL. Thus, LMP1 is regarded as a potential tumor-associated antigen for immunotherapy. In this review, we present the identification of a peptide epitope derived from the EBV-LMP1 antigen that is capable of stimulating CD4 helper T-lymphocyte responses in the context of several human leukocyte antigen class II alleles. Furthermore, we discuss the therapeutic strategies of the peptide immunotherapy combined with immune adjuvants and anti-programmed death-1/programmed death-ligand 1 antibodies for NNKTL.

DOI： 10.5648/jjiao.36.15

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PD-1 is a co-repressive receptor that curbs T cell activation and thereby serves as a protection mechanism against autoimmunity under physiological conditions. Under pathological conditions, tumor cells express PD-L1 as an adaptive resistant mechanism to suppress PD-1+ T cells to evade host immunosurveillance. PD-1 therefore is a key target in cancer immunotherapy. Despite the extensive studies of PD-1 expression regulation, the pdcd1 transcription machinery and regulatory mechanisms are still not fully understood. We report here that the NF-κB p50 homodimer is a transcription regulator of PD-1 in activated T cells. A putative κB sequence exists at the pdcd1 promoter. All five NF-κB Rel subunits are activated in activated T cells. However, only the p50 homodimer directly binds to the κB sequence at the pccd1 promoter in CD4+ and CD8+ T cells. Deficiency in p50 results in reduced PD-1 expression in both CD4+ and CD8+ T cells in vitro. Using an in vivo mixed bone marrow chimera mouse model, we show that p50 regulates PD-1 expression in a cell-intrinsic way and p50 deficiency leads to decreased PD-1 expression in both antigen-specific CD4+ and CD8+ T cells in vivo. The expression levels of H3K4me3-specific histone methyltransferase increased significantly, resulting in a significant increase in H3K4me3 deposition at the pdcd1 promoter in activated CD4+ and CD8+ T cells. Inhibition of H3K4me3 significantly decreased p50 binding to the pdcd1 promoter and PD-1 expression in a T cell line. Our findings determine that the p50-H3K4me3 axis regulates pdcd1 transcription activation in activated T cells.

DOI： 10.1080/2162402X.2018.1483302

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Inhibition of specific Akt isoforms in CD8+ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating antitumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8+ T-cell differentiation and assessed the potential use of PI3K isoform-specific inhibitors to favorably condition CD8+ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen-specific CD8+ T cells was assessed in the presence of PI3K-α, -β, or -δ inhibitors. Inhibition of PI3K-δ, but not PI3K-α or PI3K-β, delayed terminal differentiation of CD8+ T cells and maintained the memory phenotype, thus enhancing their proliferative ability and survival while maintaining their cytokine and granzyme B production ability. This effect was preserved in vivo after ex vivo PI3K-δ inhibition in CD8+ T cells destined for adoptive transfer, enhancing their survival and also the antitumor therapeutic activity of a tumor-specific peptide vaccine. Our results outline a mechanism by which inhibitions of a single PI3K isoform can enhance the proliferative potential, function, and survival of CD8+ T cells, with potential clinical implications for adoptive cell transfer and vaccine-based immunotherapies. Cancer Res; 77(15); 4135-45. ©2017 AACR.

DOI： 10.1158/0008-5472.CAN-16-1925

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Recent advances in cancer immunology, such as the discovery of immune checkpoint inhibitors, have validated immune cells as potential key players for effective cancer treatment. The efficacy of these therapies seems to be codependent on a tumor-reactive T lymphocyte response. For many years, numerous attempts and strategies in developing vaccines to generate tumor-reactive T cells have yielded poor results in the clinic due to suboptimal immunogenicity and the inability to overcome an immunosuppressive tumor microenvironment. In this review, we summarize past and current advances in T cell vaccines and describe our experience in developing optimized methods for antigen/adjuvant selection and vaccine administration in order to induce powerful anti-tumor responses.

DOI： 10.1016/j.coi.2017.07.003

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Nasal natural killer/T-cell lymphoma (NNKTL) is an aggressive neoplasm with poor therapeutic responses and prognosis. The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway plays an important role in immune evasion of tumor cells through T-cell exhaustion. The aim of the present study was to examine the expression of PD-L1 and PD-1 molecules in NNKTL. We detected the expression of PD-L1 in biopsy samples from all of the NNKTL patients studied. PD-L1 was found on both malignant cells and tumor-infiltrating macrophages, while PD-1-positive mononuclear cells infiltrated the tumor tissues in 36% of patients. Most significantly, soluble PD-L1 (sPD-L1) was present in sera of NNKTL patients at higher levels as compared to healthy individuals and the levels of serum sPD-L1 in patients positively correlated with the expression of PD-L1 in lymphoma cells of tumor tissues. In addition, the high-sPD-L1 group of patients showed significantly worse prognosis than the low-sPD-L1 group. Furthermore, we confirmed that membrane and soluble PD-L1 was expressed on the surface and in the culture supernatant, respectively, of NNKTL cell lines. The expression of PD-L1 was observed in tumor tissues and sera from a murine xenograft model inoculated with an NNKTL cell line. Our results suggest that sPD-L1 could be a prognostic predictor for NNKTL and open up the possibility of immunotherapy of this lymphoma using PD-1/PD-L1 axis inhibitors.

DOI： 10.1007/s00262-017-1987-x

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Stimulator of IFN genes (STING) spontaneously contributes to anti-tumor immunity by inducing type I interferons (IFNs) following sensing of tumor-derived genomic DNAs in the tumor-bearing host. Although direct injection of STING ligands such as cyclic diguanylate monophosphate (c-di-GMP) and cyclic [G(2',5')pA(3',5')p] (cGAMP) into the tumor microenvironment exerts anti-tumor effects through strong induction of type I IFNs and activation of innate and adaptive immunity, the precise events caused by STING in the tumor microenvironment remain to be elucidated. We describe here our finding that a CD45+ CD11bmid Ly6C+ cell subset transiently accumulated in mouse tumor microenvironment of 4T1 breast cancer, squamous cell carcinomas, CT26 colon cancer, or B16F10 melanoma tissue after intratumoral injection of cGAMP. The accumulated cells displayed a macrophage (M ) phenotype since the cells were positive for F4/80 and MHC class II and negative for Ly6G. Intratumoral cGAMP treatment did not induce Mφ accumulation in STING-deficient mice. Depletion of CD8+ T cell using anti-CD8 mAb impaired the anti-tumor effects of cGAMP treatment. Depletion of the Mφ using clodronate liposomes impaired the anti-tumor effects of cGAMP treatment. Functional analysis indicated that the STING-triggered tumor-migrating Mφ exhibited phagocytic activity, production of tumor necrosis factor alpha TNFα), and high expression levels of T cell-recruiting chemokines, Cxcl10 and Cxcl11, IFN-induced molecules, MX dynamin-like GTPase 1 (Mx1) and 2'-5' oligoadenylate synthetase-like 1 (Oasl1), nitric oxide synthase 2 (Nos2), and interferon beta 1 (Ifnb1). These results indicate that the STING-triggered tumor-migrating Mφ participate in the anti-tumor effects of STING-activating compounds.

DOI： 10.1007/s00262-017-1975-1

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Language：English   Publisher：日本がん免疫学会  

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Synthetic peptide vaccines aim to elicit and expand tumor-specific T cells capable of controlling or eradicating the tumor. Despite the high expectations based on preclinical studies, the results of clinical trials using peptide vaccines have been disappointing. Thus, many researchers in the field have considered peptide vaccines as outdated and no longer viable for cancer therapy. However, recent progress in understanding the critical roles of immune adjuvants, modes of vaccine administration and T cell dynamics has lead to a rebirth of this approach and reconsidering the use of peptide vaccines for treating malignant disorders.

DOI： 10.1016/j.coi.2016.11.001

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The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory has been involved in the development of synthetic peptide-based anti-cancer therapeutic vaccines. We first dedicated our efforts in the identification and validation of peptide epitopes for both CD8 and CD4 T cells from tumor-associated antigens (TAAs). Because of suboptimal immune responses and lack of therapeutic benefit of peptide vaccines containing these epitopes, we have focused our recent efforts in optimizing peptide vaccinations in mouse tumor models using numerous TAA epitopes. In this focused research review, we describe how after taking lessons from the immune system's way of dealing with acute viral infections, we have designed peptide vaccination strategies capable of generating very high numbers of therapeutically effective CD8 T cells. We also discuss some of the remaining challenges to translate these findings into the clinical setting.

DOI： 10.1007/s00262-016-1834-5

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Substantial evidence indicates that immunotherapy is a feasible and effective approach for the treatment of numerous types of cancer. Among various immunotherapy options, peptide vaccines to generate antitumor T cells appear as promising candidates, because of their cost effectiveness and ease of implementation. Nevertheless, most peptide vaccines are notorious for being weekly immunogenic and, thus, optimization of the vaccination strategy is essential to achieve therapeutic effectiveness. In addition, effective peptide vaccines must stimulate both CD8 cytotoxic and CD4 helper T lymphocytes. Our group has been successful in designing effective peptide vaccination strategies for inducing CD8 T-cell responses in mouse tumor models. Here, we describe a somewhat similar, but distinct, peptide vaccination strategy capable of generating vast CD4 T-cell responses by combining synthetic peptides with toll-like receptor (TLR) agonists and OX40/CD40 costimulation. This vaccination strategy was efficient in overcoming immune tolerance to a self-tumor-associated antigen and generated significant antitumor effects in a mouse model of malignant melanoma. The optimized peptide vaccine also allowed the expansion of adoptively transferred CD4 T cells without the need for lymphodepletion and IL2 administration, generating effective antimelanoma responses through the enhancement of proliferative and antiapoptotic activities of CD4 T cells. These results have practical implications in the design of more effective T-cell-based immunotherapies. Cancer Immunol Res; 5(1); 72-83. ©2016 AACR.

DOI： 10.1158/2326-6066.CIR-16-0194

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DOI： 10.1189/jlb.3CE0216-091R

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Tumor immune escape has been a major problem for developing effective immunotherapy. The human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule whose primary function is to protect the fetus from the mother's immune system. While HLA-G is hardly found in normal adult tissues, various tumor cells are known to express it, aiding their escape from the immune system. Thus, HLA-G is an attractive immunotherapy target. CD4(+) helper T lymphocytes (HTLs) play an important role in the immune reaction against tumors by assisting in the generation and persistence of CD8(+) cytotoxic T lymphocytes (CTLs) or by displaying direct antitumor effects. We report here that HLA-G expression in breast cancer significantly correlates with a poor prognosis. Also, we describe that the MHC class II-binding peptide HLA-G26-40 was effective in eliciting tumor-reactive CD4(+) T cell responses. Furthermore, treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine increased HLA-G expression in tumors and subsequently enhanced recognition by HLA-G26-40-specific HTLs. These findings predict that a combination immunotherapy targeting HLA-G together with a DNA methyltransferase inhibitor could be useful against some cancers.

DOI： 10.1080/2162402X.2016.1169356

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Other Link： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=27471649

Language：English   Publishing type：Research paper (scientific journal)  

The success of adoptive T cell-based immunotherapy (ACT) in cancer is limited in part by the accumulation of myeloid-derived suppressor cells (MDSC), which block several T cell functions, including T cell proliferation and the expression of various cytotoxic mediators. Paradoxically, the inhibition of CD8+ T cell differentiation into cytotoxic populations increased their efficacy after ACT into tumor-bearing hosts. Therefore, we aimed to test the impact of conditioning CD8+ T cells with MDSC on their differentiation potential and ACT efficacy. Our results indicate that MDSC impaired the progression of CD8+ T cells into effector populations, without altering their activation status, production of IL-2, or signaling through the T cell receptor. In addition, culture of CD8+ T cells with MDSC resulted in an increased ACT anti-tumor efficacy, which correlated with a higher frequency of the transferred T cells and elevated IFNγ production. Interestingly, activated CD62L+ CD8+ T cells were responsible for the enhanced anti-tumor activity showed by MDSC-exposed T cells. Additional results showed a decreased protein synthesis rate and lower activity of the mammalian/mechanistic target of rapamycin (mTOR) in T cells conditioned with MDSC. Silencing of the negative mTOR regulator tuberous sclerosis complex-2 in T cells co-cultured with MDSC restored mTOR activity, but resulted in T cell apoptosis. These results indicate that conditioning of T cells with MDSC induces stress survival pathways mediated by a blunted mTOR signaling, which regulated T cell differentiation and ACT efficacy. Continuation of this research will enable the development of better strategies to increase ACT responses in cancer.

DOI： 10.18632/oncotarget.8197

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BACKGROUND: Epidermal growth factor receptor (EGFR)-targeted therapy has been widely accepted as a promising treatment for solid tumors. Steroid treatment is used to prevent adverse effect of anti-EGFR antibody; however, influence of steroids in the antitumor activity of targeted antibody remains poorly understood. Herein, we demonstrated the impact of steroids in induced antibody-dependent cellular cytotoxicity (ADCC) activity of natural killer (NK) cells by cetuximab. METHODS: Various numbers of NK cells from healthy donors were co-cultured with tumor and/or cetuximab with or without dexamethasone. After incubation, NK cells, ADCC activity, survival, and activation markers expression were determined. RESULTS: Clinical concentration of dexamethasone treatment clearly inhibited cetuximab-induced ADCC activity of NK cells against head and neck squamous cell carcinoma (HNSCC) and colon cancer. Dexamethasone decreased the activation marker CD69 expression on NK cells. CONCLUSION: This is the first report that shows the negative affect of steroids in cancer treatment using therapeutic antibody. Attention needs to be paid for using steroids in tumor treatment.

DOI： 10.1002/hed.23906

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Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL.

DOI： 10.2217/imt.15.103

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Other Link： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=26642249

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HER-3 expression has been reported to act as an important oncoprotein in head and neck squamous cell carcinoma. This protein is known to control tumor proliferation and acquisition of resistance by tumor cells towards EGFR inhibitors, therefore, development of a HER-3-targeted therapy is desirable. In this study, we found that HER-3 expression on tumor cells was increased after EGFR inhibition. To establish a novel therapeutic approach for HER-3-positive head and neck carcinoma, we identified a HER-3 helper epitope that could elicit effective helper T cell responses to the naturally processed HER-3-derived epitope presented in a HER-3 expressing tumors. This epitope induced potent cytolytic activity of CD4 T cells against such tumor cells. Moreover, pan HER-family tyrosine kinase inhibitor augmented the responses of HER-3-reactive CD4 T cells via upregulation of HLA-DR protein on the surface of tumor cells. Our results supports the validity of CD4 T cell-dependent HER-3-targeted therapy combined with a broad inhibitor of HER-family.

DOI： 10.1038/srep16280

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Other Link： https://www.nature.com/articles/srep16280

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Nasal natural killer/T-cell lymphoma (NNKTL) is associated with Epstein-Barr virus and has a poor prognosis because of local invasion and/or multiple dissemination. Various chemokines play a role in tumor proliferation and invasion, and chemokine receptors including the C-C chemokine receptor 4 (CCR4) are recognized as potential targets for treating hematologic malignancies. The aim of the present study was to determine whether specific chemokines are produced by NNKTL. We compared chemokine expression patterns in culture supernatants of NNKTL cell lines with those of other lymphoma or leukemia cell lines using chemokine protein array and ELISA. Chemokine (C-C motif) ligand (CCL) 17 and CCL22 were highly produced by NNKTL cell lines as compared to the other cell lines. In addition, CCL17 and CCL22 were readily observed in the sera of NNKTL patients. The levels of these chemokines were significantly higher in patients than in healthy controls. Furthermore, we detected the expression of CCR4 (the receptor for CCL17 and CCL22) on the surface of NNKTL cell lines and in tissues of NNKTL patients. Anti-CCR4 monoclonal antibody (mAb) efficiently induced antibody-dependent cellular cytotoxicity mediated by natural killer cells against NNKTL cell lines. Our results suggest that CCL17 and CCL22 may be important factors in the development of NNKTL and open up the possibility of immunotherapy of this lymphoma using anti-CCR4 mAb.

DOI： 10.1007/s00262-015-1675-7

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Other Link： http://link.springer.com/content/pdf/10.1007/s00262-015-1675-7.pdf

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Background: The expression of c-Met and its ligand HGF plays a critical role in cell proliferation and is involved in numerous malignancies. Because c-Met expression and its role in NK/T-cell lymphoma remain unclear, we studied the expression and function of c-Met in NK/T-cell lymphoma cells. In addition, we investigated the possibility that c-Met could function as a tumor-associated antigen for helper T lymphocytes (HTLs). Methods: We evaluated whether HGF and c-Met were expressed in NK/T-cell lymphoma and the capacity of predicted c-Met HTL epitopes to induce antitumor responses in vitro. In addition, c-Met inhibitor was evaluated for the ability to inhibit TGF-β production in tumor and subsequently increase HTL recognition. Results: c-Met and HGF were expressed in NK/T-cell lymphoma cell lines, nasal NK/T-cell lymphoma specimens and patient serum samples. Moreover, HGF was shown to promote NK/T cell lymphoma (NKTCL) proliferation in an autocrine manner. Furthermore, we have identified three novel c-Met HTL epitopes that were restricted by several HLA-DR molecules. Notably, peptide-induced HTL lines directly recognized and killed c-Met expressing NK/T-cell lymphomas and various epithelial solid tumors. The c-Met specific HTLs could also recognize dendritic cells (DCs) pulsed with c-Met expressing tumor cell lysates. In addition, we observed that c-Met inhibition augmented HTL recognition by decreasing TGF-β production by tumor cells. Lastly, autophagy partly regulated the HTL responses against tumors. Conclusions: We identified novel c-Met HTL epitopes that can elicit effective antitumor responses against tumors expressing c-Met. Our results provide the rationale of combining c-Met targeting therapy and immunotherapy for NKTCLs and epithelial tumors.

DOI： 10.4161/2162402X.2014.976077

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Other Link： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=2015169489

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BACKGROUND: EGFR-targeted therapy is an attractive option for head and neck squamous cell carcinoma patients. We have recently reported the use of EGFR inhibitors as an adjunct treatment to enhance HLA-DR expression in tumor cells to improve cancer immunotherapy. Nevertheless, we observed that EGFR inhibitors resulted in decreased anti-tumor responses, regardless of upregulation of HLA-DR expression on the tumor cell. In this study, we specifically investigated the mechanisms by which EGFR inhibition modulated anti-tumor responses. METHODS: An EGFR inhibitor erlotinib was used to assess the modulation of anti-tumor responses by tumor antigen-specific helper T cells. We then examined whether administration of the EGFR inhibitor altered tumor cytokine profiles and expression of immune-related molecules on tumor cells. RESULTS: Despite the augmented HLA-DR expression on a gingival cancer cell line by EGFR inhibition, anti-tumor responses of EGFR reactive helper T cell clones against tumor cells were decreased. EGFR inhibition did not change the expression of CD80, CD86, or PD-L1 on the tumor cells. Conversely, production of transforming growth factor beta (TGF-β) and prostaglandin E2 was increased by EGFR inhibition, indicating that these immunosuppressive molecules were involved in diminishing tumor recognition by T cells. Significantly, attenuation of HTL responses against tumors after EGFR inhibition was reversed by the addition of anti-TGF-β antibody or COX2 inhibitors. CONCLUSIONS: Targeting TGF-β and prostaglandin E2 may allow for improved outcomes for cancer patients treated with combination immunotherapy and EGFR inhibitors.

DOI： 10.1186/s12967-014-0265-3

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Posttranslational modifications regulate the function and stability of proteins, and the immune system is able to recognize some of these modifications. Therefore, the presence of posttranslational modifications increases the diversity of potential immune responses to a determinant antigen. The stimulation of tumor-specific CD4(+) helper T lymphocytes (HTLs) is considered important for the production of anti-tumor antibodies by B cells and for the generation and persistence of CD8(+) cytotoxic T lymphocytes, and in some instances, HTLs can directly reduce tumor cell growth. Identification of MHC class II-restricted peptide epitopes from tumor-associated antigens including those generated from posttranslational protein modifications should enable the improvement of peptide-based cancer immunotherapy. We describe here an MHC class II binding peptide from the tumor protein p53, which possesses an acetylated lysine at position 120 (p53110-124/AcK120) that is effective in eliciting CD4(+) T cell responses specific for the acetylated peptide. Most importantly, the acetylated peptide-reactive CD4 HTLs recognized the corresponding naturally processed posttranslational modified epitope presented by either dendritic cells loaded with tumor cell lysates or directly on tumors expressing p53 and the restricting MHC class II molecules. Treatment of tumor cells with a histone deacetylase inhibitor augmented their recognition by the p53110-124/AcK120-reactive CD4(+) T cells. These findings prove that the epitope p53110-124/AcK120 is immunogenic for anti-tumor responses and is likely to be useful for cancer immunotherapy.

DOI： 10.1007/s00262-014-1533-z

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Other Link： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=2014228829

Authorship：Lead author   Language：Japanese   Publisher：JAPAN SOCIETY OF IMMUNOLOGY AND ALLERGOLOGY IN OTOLARYNGOLOGY  

Overexpression of tumor antigens is commonly observed in head and neck squamous cell carcinoma (HNSCC) that is a fatal and common disease in Japan. Although some tumor antigen molecules on HNSCC have been elucidated, effective immunotherapy using these antigens for HNSCC has not been developed. We previously showed that tumor antigen-specific helper T cells had the ability to kill HNSCC cell lines. Moreover, immune modulators such as EGFR inhibitors could upregulate these antitumor T cell responses. In this review, we present the current understanding of helper T-cell mediated anti-tumor immunity and molecule-targeted therapies that can augment anti-tumor T-cell responses. A detailed understanding of anti-tumor immunity and the mechanisms of immune enhancers may provide a platform for establishing combinatorial immunotherapy with adjuvants in treatment for HNSCC.

DOI： 10.5648/jjiao.32.185

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Other Link： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=20141225

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Background:Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related morbidity and mortality worldwide. Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. T-cell-based immunotherapy has been proposed as a novel therapeutic approach to improve the clinical outcome for HNSCC. In this study, we report human epidermal receptor (HER) family epitopes that induced CD4 T-cell responses to HNSCC. The results provide support for a novel strategy to treat HNSCC by combining EGFR-targeted therapy with T-cell-based immunotherapy. Methods:We evaluated the capacity of predicted CD4 T-cell peptide epitopes from EGFR to induce antitumour immune responses in vitro. In addition, EGFR inhibitors were evaluated for their ability to augment tumour MHC class II expression in HNSCC cell lines and subsequently increase T-cell recognition.Results:Among several predicted peptide epitopes, EGFR 875-889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed. In addition, the CD4 T cells were capable of directly recognising and killing HNSCC cells expressing EGFR and the appropriate HLA class II molecule. T cells reactive with the EGFR 875-889 epitope could be detected in the blood of HNSCC patients. EGFR 875-889 -reactive CD4 T cells were also able to recognise several peptide analogues derived from homologous regions of EGFR family members, HER-2, HER-3 and c-MET. Finally, we examined the effects of EGFR tyrosine kinase inhibition or EGFR-blocking antibodies on CD4 T-cell tumour reactivity. Treatment of tumour cells with the EGFR inhibitors enhanced tumour recognition by EGFR 875-889 -reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells.Conclusion:We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR 875-889 functions as a promiscuous helper T-cell epitope that can elicit effective antitumour T-cell responses against tumours expressing HER family members and c-MET. These observations should facilitate the translation of T-cell-based immunotherapy into the clinic for the treatment of HNSCC and provide a rational basis for EGFR inhibition, immune-targeted combination therapy. © 2013 Cancer Research UK. All rights reserved.

DOI： 10.1038/bjc.2013.577

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Renal cell carcinoma (RCC) occasionally metastasizes to a variety of regions including bone and liver, but nasal and paranasal sinal metastases are rare. No standard treatment currently exists, because of the small number of cases, so treatment varies for each patient. Sorafenib is a novel small molecular inhibitor of several kinases for malignancy, especially for RCC and hepatocellular carcinoma. We report herein on a case of nasal and paranasal metastatic RCC treated with VEGF targeted therapy (sorafenib) and radiotherapy.

DOI： 10.5631/jibirin.106.423

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Other Link： http://id.ndl.go.jp/bib/024650788

Language：Japanese   Publisher：耳鼻咽喉科展望会  

DOI： 10.11453/orltokyo.56.128

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Human T cell leukemia virus type 1 (HTLV-1) induced adult T cell leukemia/lymphoma (ATLL) is usually a fatal lymphoproliferative malignant disease. Thus, the enhancement of T cell immunity to ATLL through the development of therapeutic vaccines using characterized T cell peptide epitopes could be of value. We isolated and characterized HLA-DR-bound peptides from HTLV-1-transformed T cells by fractionating on reverse-phase high performance liquid chromatography and Edman NH(2)-terminal sequencing and were able to identify five independent peptide sequences. One of the identified peptide sequences corresponded to a fragment of the human interleukin-9 receptor alpha (IL-9Rα), which is commonly expressed by HTLV-1-infected T cell lymphoma cells. Using a synthetic peptide corresponding to the identified IL-9Rα sequence, we generated antigen-specific CD4 helper T lymphocytes in vitro, which were restricted by HLA-DR15 or HLA-DR53 molecules and could recognize and kill HTLV-1+, IL-9Rα+ T cell lymphoma cells. These results indicate that IL-9Rα functions as T cell leukemia/lymphoma-associated antigen for CD4 T cells and that synthetic peptides such as the one described here could be used for T cell-based immunotherapy against IL-9Rα positive ATLL.

DOI： 10.1007/s00262-012-1284-7

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

Mumps virus infections primarily involve the parotid glands and most frequently affect school-aged children. Mumps has many complications, such as meningitis, but laryngeal edema is not a common one. We present four cases of mumps with laryngeal edema. The patients were a 39-year-old male, 23-yearold female, 29-year-old female and 31-year-old female. They came to our hospital complaining of submandibular and subaural regional swelling and dyspnea. In every case, fiberscopic findings revealed edema of the arytenoid. Laboratory examination showed normal WBC, slightly high CRP and high serum amylase. Their mumps titers were positive for immunoglobulin M and G. The patients were admitted to our hospital and were started on intravenous steroids. In one case, because of progressive dyspnea, a tracheotomy was needed. All symptoms of laryngeal edema improved within 3 days. In previous reports in the literature, there were four cases of mumps with laryngeal edema which required a tracheotomy because of aggravation of dyspnea. If a patient with mumps complains of dyspnea, examination of the respiratory airway is important.

DOI： 10.5631/jibirin.105.277

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Other Link： http://id.ndl.go.jp/bib/023577759

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BACKGROUND: T-cell based immunotherapy for lung cancer (LC) could be a promising and novel therapeutic approach. Six-transmembrane epithelial antigen of the prostate (STEAP) and the polycomb group protein enhancer of zeste homolog 2 (EZH2) are highly expressed in LC and since the expression of molecules in normal tissue is significantly lower as compared to tumor cells, these proteins are considered as potential tumor-associated antigens (TAAs) for developing T-cell based immunotherapy. METHODS: We assessed the capacity of predicted CD4 T-cell epitopes from STEAP and EZH2 to induce anti-tumor immune responses to LC cell lines. RESULTS: Out of several predicted epitopes, two synthetic peptides, STEAP281-296 and EZH295-109, were effective in inducing CD4 T-cell responses that were restricted by HLA-DR1, DR15, or DR53 molecules, indicating that the peptides function as promiscuous T-cell epitopes. Moreover, STEAP281-296 and EZH295-109-reactive T-cells could directly recognize STEAP or EZH2 expressing LC cells in an HLA-DR restricted manner. In addition, some STEAP-reactive T-cells responded to STEAP+ tumor cell lysates presented by autologous dendric cells. Most significantly, both of these peptides were capable of stimulating in vitro T-cell responses in patients with LC. CONCLUSIONS: Peptides STEAP281-296 and EZH295-109 function as strong CD4 T-cell epitopes that can elicit effective anti-tumor T-cell responses against STEAP or EZH2 expressing LC. These observations may facilitate the translation of T-cell based immunotherapy into the clinic for the treatment of LC.

DOI： 10.1186/1479-5876-9-191

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We investigated the relationship between nasopharyngeal flora of pediatric patients and antibiotic consumption in a local community in Japan between 2000 and 2009 retrospectively. There was a clear relationship between the lower annual consumption rate of cephalosporins and the lower annual prevalence of non-susceptible strains of Streptococcus pneumoniae (SP). High prevalence of BLNAR (β-lactamase nonproducing ampicillin-resistant Haemophilus influenzae) has been one of the bacteriological features of Japan.

DOI： 10.1159/000324789

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Language：English   Book type：Scholarly book

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Total pages：xii, 234 p.   Language：English  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：全日本病院出版会  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：東京 : 先端医学社  

扁桃病巣疾患は扁桃を病巣としてほかの臓器に障害をきたす疾患群の総称であり、扁桃摘出術が奏効する。その病態が感染症ではなく扁桃を病巣とした自己免疫的・自己炎症的機序と明らかになってきたことから、最近では病巣感染症よりも扁桃病巣疾患もしくはTIASとよばれるようになった。本疾患群にはIgA腎症や掌蹠膿疱症、胸肋鎖骨過形成症、PFAPA症候群といったさまざまな難治性疾患が含まれている。本稿では、本疾患の歴史およびこれまで解明されてきた病態について概説する。(著者抄録)

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I032538138

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publisher：(有)科学評論社  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publisher：東京 : 日本臨床社  

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I031577955

Authorship：Last author   Language：Japanese   Publisher：東京 : 日本臨床社  

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I031577939

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Language：Japanese   Publisher：大阪 : 医薬ジャーナル社  

DOI： 10.20837/3201806748

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Other Link： https://ndlsearch.ndl.go.jp/books/R000000004-I029070594

Authorship：Last author   Language：Japanese   Publisher：(株)全日本病院出版会  

扁桃病巣疾患とは扁桃を病巣として他の臓器に障害をきたす疾患群の総称であり、扁桃摘出術が奏効する。扁桃病巣疾患は急性扁桃炎を含む急性上気道炎時に悪化することから扁桃病巣感染症としても知られているが、扁桃における自己免疫の活性化がその病態の機序として明らかになったため、近年では扁桃病巣疾患と呼ばれている。代表的疾患としてIgA腎症、掌蹠膿疱症、胸肋鎖骨過形成症(SAPHO症候群)、PFAPA症候群があり、扁桃摘出術(扁摘)の極めて高い有効性が報告されている。他に、尋常性乾癬、膿疱性乾癬、滴状乾癬、結節性紅斑、IgA血管炎などの皮膚疾患、慢性関節リウマチ、反応性関節炎などの骨関節疾患、加えてベーチェット病や炎症性腸疾患などの中には扁摘が著効を呈した症例も数多く報告されている。扁桃摘出術は耳鼻咽喉科医にとって初歩的な手術であり、積極的に手術を勧めることが求められる。(著者抄録)

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Authorship：Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：全日本病院出版会  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publisher：(有)科学評論社  

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DOI： 10.11477/mf.1411201432

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J02122&link_issn=&doc_id=20171101160010&doc_link_id=10.11477%2Fmf.1411201432&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1411201432&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publisher：(株)東京医学社  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(株)Gakken  

扁桃病巣疾患の概念、掌蹠膿疱症や乾癬に対する扁摘の有効性、扁摘の安全性、扁桃を病巣とした掌蹠膿疱症の発症機序について概説した。これまでの報告によって、扁摘は掌蹠膿疱症に対してきわめて有効であり、扁摘以外の治療法よりも優れていることが示されている。また、掌蹠膿疱症の発症機序として、扁桃の常在菌に対する過剰免疫応答による扁桃B細胞の熱ショックタンパク質などに対する抗体産生と扁桃T細胞の掌蹠皮膚へのホーミングが関与している可能性が示唆されている。扁摘は安全な手術であり、掌蹠膿疱症に対する治療として医療経済的にもきわめて有効といえる。

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：東京医学社  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(株)東京医学社  

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publisher：(株)東京医学社  

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Authorship：Last author   Language：Japanese   Publisher：(株)東京医学社  

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Event date： 2021.5

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2019.7

Language：Japanese   Presentation type：Oral presentation (invited, special)  

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Event date： 2019.6

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2019.4

Language：English   Presentation type：Poster presentation  

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Event date： 2019.3

Language：Japanese  

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Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2018

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2016.11

Language：English   Presentation type：Poster presentation  

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Event date： 2016.11

Language：English   Presentation type：Poster presentation  

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Event date： 2014.9

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2014.4

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2014.2

Language：Japanese   Presentation type：Oral presentation (invited, special)  

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Event date： 2013.10

Language：English   Presentation type：Oral presentation (general)  

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Event date： 2013.6

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2012.9

Language：English   Presentation type：Oral presentation (general)  

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Presentation type：Oral presentation (general)  

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Presentation type：Symposium, workshop panel (nominated)  

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Presentation type：Oral presentation (invited, special)  

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Presentation type：Symposium, workshop panel (nominated)  

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Presentation type：Poster presentation  

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Presentation type：Oral presentation (general)  

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Presentation type：Symposium, workshop panel (nominated)  

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Presentation type：Symposium, workshop panel (nominated)  

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Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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Presentation type：Symposium, workshop panel (nominated)  

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Presentation type：Symposium, workshop panel (nominated)  

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Presentation type：Symposium, workshop panel (nominated)  

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Presentation type：Oral presentation (general)  

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