Publications by authors named "Yasuaki Harabuchi"

155 Publications

19th International Symposium on Epstein-Barr Virus and Associated Diseases, 29-30 July 2021, Asahikawa, Japan.

Cancers (Basel) 2022 Jun 14;14(12). Epub 2022 Jun 14.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa 078-8510, Japan.

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.
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http://dx.doi.org/10.3390/cancers14122924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221456PMC
June 2022

A retrospective study of parotid gland tumors at a single institution.

Oncol Lett 2022 Jul 13;24(1):207. Epub 2022 May 13.

Department of Otolaryngology-Head and Neck Surgery, Hokuto Hospital, Obihiro, Hokkaido 080-0833, Japan.

The aim of the present study was to analyze the clinical characteristics, surgical treatments and clinical outcome of patients with parotid gland tumors and to compare the results with those cited in the literature. A retrospective study was conducted in 140 patients (male, n=77; female, n=63) with parotid gland tumors who underwent parotidectomy at Hokuto Hospital Department of Otolaryngology-Head and Neck Surgery (Obihiro, Japan) between April 2007 and December 2021. Of the 140 patients enrolled, 118 (84.3%) patients had benign tumors, including 63 (45%) patients with pleomorphic adenomas and 43 (30.7%) patients with Warthin tumors, and 22 patients (15.7%) had parotid carcinoma. Comparison of the three groups of patients with parotid gland tumors indicated that pack years as an indicator of smoking status were significantly higher in patients with Warthin tumors than in those with parotid carcinomas (P=0.011) or pleomorphic adenoma (P<0.001). Fine-needle aspiration cytology (FNAC) was non-diagnostic for only 6 (4.3%) of 140 patients. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of FNAC by both conventional smear and liquid-based cytology (LBC) for parotid carcinomas were 70, 99, 93.3, 94.4 and 82.9%, respectively. Among the 22 patients with parotid carcinoma, extended total/total and superficial parotidectomy were performed in 10 (45%) and 11 (50%) cases, respectively. Total and selective neck dissection of the area from level II to I, II and III were performed in 6 (24%) and 7 (32%) patients, respectively. Postoperative radiotherapy (50 Gy) was performed in 15 (68%) patients. The overall survival (OS) and disease-free survival (DFS) rates at 5 years were 51.5 and 76.4%, respectively. Univariate analysis revealed that age >65 years was significantly associated with poorer 5-year OS (P<0.001) and DFS (P<0.001). Multivariate analysis revealed that an age of more than 65 years combined with high-grade histologic malignancy was associated with worse DFS (P=0.02; hazard ratio, 3.628; 95% confidence interval, 1.283-9.514). In conclusion, the clinical characteristics and treatment outcomes of parotid gland tumors were consistent with the results of previous reports. Smoking may be closely related to the pathogenesis of Warthin tumors. LBC potentially provides improved accuracy in FNAC.
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http://dx.doi.org/10.3892/ol.2022.13328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9178697PMC
July 2022

Central-part laryngectomy after laryngotracheal separation to manage pharyngocutaneous fistula: A case report and retrospective analysis of 12 cases.

Auris Nasus Larynx 2022 May 11. Epub 2022 May 11.

Department of Otolaryngology-Head and Neck surgery, Asahikawa Medical University, 2-1-1-1, Midorigaoka-Higashi, Asahikawa 078-8510, Japan.

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.
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http://dx.doi.org/10.1016/j.anl.2022.04.011DOI Listing
May 2022

A case of primary histiocytic sarcoma arising from a neck lymph node.

Ear Nose Throat J 2022 Apr 20:1455613221097200. Epub 2022 Apr 20.

Department of Otolaryngology-Head and Neck Surgery, 38051Asahikawa Medical University, Asahikawa, Japan.

Histiocytic sarcoma (HS) is an aggressive and rare hematological malignancy. Its treatment has not been established, and most patients die within 2 years of diagnosis. Resection can provide a favorable prognosis for solitary lesions. We present the case of an 80-year-old Japanese man with HS. He presented a history of a slow-growing painless mass in the lower part of his right jaw. Ultrasonography showed a swollen lymph node in the vicinity of the right submandibular gland. Contrast-enhanced computed tomography revealed a heterogeneous, low-contrast mass on the right of the neck. Magnetic resonance imaging revealed a heterogeneously enhanced mass in gadolinium-enhanced T1-weighted images. The fine needle biopsy showed spindle-shaped cells and HS was suspected. Fluorodeoxyglucose positron emission tomography revealed uptake by the tumor alone. The patient underwent right upper neck dissection and resection of the submandibular salivary glands. No postoperative adjuvant treatment was administered, but 2-year survival was achieved. Histopathological examination showed proliferation of large, pleomorphic atypical cells without differentiation into lymphocytes, which proved their differentiation into histiocytes. A bone marrow biopsy showed no evidence of monocytic leukemia. Thus, a diagnosis of HS was made. With local treatment alone, our patient achieved long-term survival, maintaining his quality of life.
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http://dx.doi.org/10.1177/01455613221097200DOI Listing
April 2022

Pharmacotherapy focusing on for the management of otitis media with effusion in children: Systematic review and meta-analysis.

Auris Nasus Larynx 2022 Oct 24;49(5):748-754. Epub 2022 Mar 24.

Department of Otorhinolaryngology, Showa University School of Medicine.

Objective: To examine the evidence for treating children with otitis media with effusion with pharmacotherapy.

Data Sources: For the systematic review, data were retrieved from PubMed, Cochrane database, and the Japan Medical Abstracts Society Database (1st January 1995 through 31th May 2019).

Study Selection: Articles addressing pharmacotherapy for the management of otitis media with effusion in children were selected in English.

Data Extraction: The database was searched using the keywords "Otitis Media with effusion or secretory otitis media" and the following medical agents: carbocysteine, antihistamines, leukotriene receptor antagonist, and steroid nasal spray.

Data Synthesis: After a critical review of 18 studies, studies addressing steroid nasal spray were eligible for quantitative synthesis. Intranasal steroids for OME showed no benefit with OR 1.155 (95% CI 0.834-1.598) within one month. Conversely, intranasal steroids have effects for OME with OR 1.858 (95% CI 1.240-2.786) for more than one month.

Conclusions: We found evidence of benefit from treatment of OME in children with intranasal steroids and S-carboxymethylcysteine at longer-term follow-up.
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http://dx.doi.org/10.1016/j.anl.2022.03.017DOI Listing
October 2022

IL-2 complex recovers steroid-induced inhibition in immunochemotherapy for head and neck cancer.

Transl Oncol 2022 Apr 2;18:101358. Epub 2022 Feb 2.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan.

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.
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http://dx.doi.org/10.1016/j.tranon.2022.101358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8819385PMC
April 2022

Removal of Coin Cell Lithium Battery Lodged in the Pediatric Pharyngoesophageal Junction by Rigid Esophagoscopy; a Case Report.

Arch Acad Emerg Med 2022 1;10(1):e4. Epub 2022 Jan 1.

Department of Otolaryngology-Head & Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.

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.
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http://dx.doi.org/10.22037/aaem.v10i1.1430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8771150PMC
January 2022

Role of Palatine Tonsil and Epipharyngeal Lymphoid Tissue in the Development of Glomerular Active Lesions () in Immunoglobulin A Nephropathy.

Int J Mol Sci 2022 Jan 10;23(2). Epub 2022 Jan 10.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa 078-8510, Japan.

Hematuria is an essential symptom of immunoglobulin A nephropathy (IgAN). Although the etiology of hematuria in IgAN has not been fully elucidated, it is thought that the rupture of the glomerular basement membranes caused by intra-capillary leukocyte influx, so-called glomerular vasculitis, is the pathological condition responsible for severe hematuria. Glomerular vasculitis are active lesions that exist in the glomeruli of acute phase IgAN and it is important because it is suspected to make the transition to segmental glomerular sclerosis (SGS) as a repair scar lesion in the chronic phase, and the progression of SGS would eventually lead to glomerular obsolescence. Worsening of hematuria concomitant with acute pharyngitis is common in patients with IgAN; therefore, elucidating the relationship between the immune system of Waldeyer's ring, including the palatine tonsil and epipharyngeal lymphoid tissue, and the may lead to understanding the nature of IgAN. The epipharynx is an immunologically activated site even under normal conditions, and enhanced activation of innate immunity is likely to occur in response to airborne infection. Hyperactivation of innate immunity via upregulation of Toll-like receptors in the interfollicular area of the palatine tonsil and epipharyngeal lymphoid tissue, followed by enhanced fractalkine/CX3CR1 interactions, appears to play an important role in the development of in IgAN. As latent but significant epipharyngitis is present in most patients with IgAN, it is plausible that acute upper respiratory infection may contribute as a trigger for the innate epipharyngeal immune system, which is already upregulated in a chronically inflamed environment. Given that epipharyngitis and its effects on IgAN are not fully understood, we propose that the so-called "epipharynx-kidney axis" may provide an important focus for future research.
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http://dx.doi.org/10.3390/ijms23020727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8775943PMC
January 2022

Immunomodulation via FGFR inhibition augments FGFR1 targeting T-cell based antitumor immunotherapy for head and neck squamous cell carcinoma.

Oncoimmunology 2022 3;11(1):2021619. Epub 2022 Jan 3.

Department of Otolaryngology-Head & Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.

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 and . 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 (FGFR1) 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.
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http://dx.doi.org/10.1080/2162402X.2021.2021619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741288PMC
January 2022

Nation-wide survey of the treatment trend of microscopic polyangiitis and granulomatosis with polyangiitis in Japan using the Japanese Ministry of Health, Labour and Welfare Database.

Mod Rheumatol 2021 Oct 7. Epub 2021 Oct 7.

Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.

Objectives: In Japan, clinical records of patients with intractable diseases, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), are compiled into a database. This study aimed to understand the current treatment status and changes in treatment regimens from our previous survey.

Methods: Using data from 2012 and 2013, patients with new-onset MPA and GPA were extracted and analysed.

Results: We analysed 1278 MPA and 215 GPA patients. The average age was 71.7 and 62.7 years, respectively. Methylprednisolone pulse therapy was used in 51.2% of MPA patients and 40.5% of GPA patients; the initial prednisolone-equivalent glucocorticoid dose was 39.5 mg/day in MPA and 46.6 mg/day in GPA. Concomitant intravenous or oral cyclophosphamide (CY) was administered to 22.6% of MPA and 56.3% of GPA. Young age, bloody sputum, low serum creatinine, and high C-reactive protein levels were independently associated with CY use in MPA. Compliance with treatment protocol for Japanese patients with myeloperoxidase (MPO)-anti-neutrophilic cytoplasmic antibody-associated vasculitis study criteria or the 2011 clinical practice guidelines for rapidly progressive glomerulonephritis was 42.7% and 49.7%, respectively.

Conclusions: MPA was more prevalent than GPA in the registry. Compared to patients with GPA, MPA patients were older and used CY less frequently. No apparent changes in treatment trends were observed from the previous survey.
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http://dx.doi.org/10.1093/mr/roab088DOI Listing
October 2021

Concurrent chemoradiotherapy with cisplatin and docetaxel for head and neck squamous cell carcinoma.

Clin Otolaryngol 2022 01 26;47(1):228-233. Epub 2021 Oct 26.

Department of Otolaryngology-Head & Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.

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http://dx.doi.org/10.1111/coa.13876DOI Listing
January 2022

CD47 blockade enhances the efficacy of intratumoral STING-targeting therapy by activating phagocytes.

J Exp Med 2021 11 24;218(11). Epub 2021 Sep 24.

Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.

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.
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http://dx.doi.org/10.1084/jem.20200792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480673PMC
November 2021

Extranodal NK/T-Cell Lymphoma, Nasal Type: Genetic, Biologic, and Clinical Aspects with a Central Focus on Epstein-Barr Virus Relation.

Microorganisms 2021 Jun 25;9(7). Epub 2021 Jun 25.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa 078-8510, Japan.

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.
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http://dx.doi.org/10.3390/microorganisms9071381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304202PMC
June 2021

Sclerosing Polycystic Adenosis Arising in the Parotid Gland Without PI3K Pathway Mutations.

Head Neck Pathol 2022 Mar 2;16(1):282-287. Epub 2021 Jun 2.

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center At Shreveport, 1501 Kings Highway, Shreveport, LA, 71103, USA.

A 15-year-old old Japanese male with a 2-month history of swelling of his left subauricular area was admitted to our department. A thumb-sized, hard mass with mild tenderness was palpated on the left parotid gland. Ultrasonography revealed a well-circumscribed, hypoechoic mass exhibiting heterogeneity in the left parotid gland measuring 1.7 × 1.5 × 1.3 cm. Computed tomography scan revealed a well-circumscribed, solid mass exhibiting slight peripheral enhancement in the left parotid gland. Magnetic resonance imaging revealed a hypointense mass in the left parotid gland on both T1- and T2-weighted images. Clinicoradiologic findings suggested a benign or low-grade malignant parotid tumor. The patient underwent left superficial parotidectomy with adequate safety margins. The facial nerve was identified and preserved. Neither facial paralysis nor tumor recurrence was observed as of 1 year postoperatively. Histologically, the nodule consisted of a vaguely nodular arrangement of variably sized ducts and acini in a hyalinized fibrous background with focal myxoid changes. The ductal/acinar component exhibited a bilayered arrangement of cuboidal luminal and flattened abluminal cells exhibiting a variety of epithelial proliferative patterns, including micropapillary and cribriform. Areas of oncocyte-like changes with intracellular coarse eosinophilic granules, apocrine-like feature, foamy/vacuolated changes, and clear cells were noted in the proliferating epithelium. Immunohistologically, the luminal cells were positive for gross cystic disease fluid protein-15. The Ki-67 labeling index was 2-3%. The histologic features and immunohistologic profile were consistent with sclerosing polycystic adenosis. Targeted next-generation sequencing of 160 cancer-related genes using the surgical specimen revealed no mutations, including known significant mutations in PTEN, PIK3CA, or PIK3R1.
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http://dx.doi.org/10.1007/s12105-021-01339-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018941PMC
March 2022

Endoscopic Resection of a Massive Pleomorphic Adenoma of the Nasal Septum.

Ear Nose Throat J 2021 May 31:1455613211020972. Epub 2021 May 31.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.

Pleomorphic adenoma is a benign tumor that commonly arises from the major salivary glands, such as the parotid and submandibular glands. However, they rarely originate from the nasal cavity. Herein, we describe the case of a 49-year-old woman who presented with nasal obstruction. Preoperative evaluation revealed a giant pleomorphic adenoma attached to the nasal septum. Transnasal endoscopic removal was successfully performed using a specimen retrieval bag. We performed an endoscopic complete en-bloc resection of a large pleomorphic adenoma in the nasal cavity, using a specimen retrieval bag. There were no complications seen, no local recurrences after 2 years of follow-up, and the patient satisfaction was high. We therefore recommend that this technique of using specimen retrieval bags can be favorably utilized for endoscopic removal of large nasal tumors like pleomorphic adenoma.
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http://dx.doi.org/10.1177/01455613211020972DOI Listing
May 2021

Laryngeal recurrence of extranodal NK/T cell lymphoma.

EJHaem 2021 Aug 29;2(3):667-668. Epub 2021 May 29.

Department of Otolaryngology, Head and Neck Surgery Asahikawa Medical University Asahikawa Japan.

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http://dx.doi.org/10.1002/jha2.233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9176005PMC
August 2021

A stealth antigen SPESP1, which is epigenetically silenced in tumors, is a suitable target for cancer immunotherapy.

Cancer Sci 2021 Jul 3;112(7):2705-2713. Epub 2021 Jun 3.

Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.

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.
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http://dx.doi.org/10.1111/cas.14973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253266PMC
July 2021

Interruption of MDM2 signaling augments MDM2-targeted T cell-based antitumor immunotherapy through antigen-presenting machinery.

Cancer Immunol Immunother 2021 Dec 18;70(12):3421-3434. Epub 2021 Apr 18.

Department of Otolaryngology-Head & Neck Surgery, Asahikawa Medical University, Asahikawa, 078-8510, Japan.

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 (MDM2) 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.
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http://dx.doi.org/10.1007/s00262-021-02940-5DOI Listing
December 2021

Diffuse-Type Tenosynovial Giant Cell Tumor Arising in the Temporomandibular Joint Extending to the External Auditory Canal: A Case Report and Literature Review.

Ear Nose Throat J 2021 Mar 23:1455613211002954. Epub 2021 Mar 23.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Japan.

A 74-year-old Japanese woman with a 1-year history of right preauricular pain and a 2-month history of bleeding from the right ear was admitted to our department. Tumor was observed in the anterior wall in the right external auditory canal. Bony swelling of the right preauricular area was palpated. Computed tomography revealed an ill-defined, osteogenic tumor around the mandibular condyle with a destructive bony lesion involving the temporal bone. Magnetic resonance imaging revealed a 2.0 × 1.5 × 1.3-cm solid tumor around the mandibular condyle, exhibiting a low-intensity signal on T1-weighted imaging and an isointense central area surrounded by low-signal intensity on T2-weighted imaging. Histological examination of biopsy specimens revealed diffuse-type tenosynovial giant cell tumor (D-TGCT). After the feeding arteries for the tumor were embolized, the patient underwent surgery with combined temporal craniotomy and mandibular condylectomy. The soft and cystic tumor with calcification located in the extradural space was totally resected along with the mandibular condyle. No facial paralysis or recurrence was evident as of 6 months postoperatively. To date, only 23 cases of D-TGCT arising in the temporomandibular joint (TMJ) with ear involvement have been reported since 2011. We report successful resection of a rare case of D-TGCT arising in the TMJ.
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http://dx.doi.org/10.1177/01455613211002954DOI Listing
March 2021

Severe laryngeal edema caused by Pseudoterranova species: A case report.

Medicine (Baltimore) 2021 Jan;100(4):e24456

Department of Otolaryngology-Head and Neck Surgery.

Rationale: Severe laryngeal edema can cause upper airway obstruction, which is fatal. Pseudoterranova, an uncommon nematode of the family Anisakidae, predominantly invades the stomach after ingestion of the nematodes in raw or undercooked marine fish. There have been a few reports of development of severe laryngeal edema caused by the nematode invading the base of the tongue.

Patient Concerns: A 69-year-old Japanese woman complained of stuffy and scratchy throat for 8 hours and reported eating sashimi, fresh slices of raw jacopever, 4 days before the first visit.

Diagnosis: Endoscopy revealed a white-yellowish wriggling worm at the left side of the base of the tongue and severe edema of the larynx.

Interventions: The worm was extracted using endoscopic forceps. The patient was hospitalized and treated with intravenous injection of an antibiotic and steroid.

Outcomes: The symptoms and laryngeal edema disappeared the next day. The worm was identified as a 4th-stage larva of Pseudoterranova spp based on morphologic features. The serum Anisakis-specific IgE antibody level was high, at 38.6 UA/mL.

Lessons: Clinicians should be aware of the possibility of severe laryngeal edema due to invasion by anisakid nematodes in the pharyngolaryngeal area in cases involving previous ingestion of raw or uncooked marine fish.
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http://dx.doi.org/10.1097/MD.0000000000024456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850652PMC
January 2021

A critical role of STING-triggered tumor-migrating neutrophils for anti-tumor effect of intratumoral cGAMP treatment.

Cancer Immunol Immunother 2021 Aug 28;70(8):2301-2312. Epub 2021 Jan 28.

Department of Pathology, Asahikawa Medical University, Asahikawa, Hokkaido, 078-8510, Japan.

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.
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http://dx.doi.org/10.1007/s00262-021-02864-0DOI Listing
August 2021

Expression of placenta-specific 1 and its potential for eliciting anti-tumor helper T-cell responses in head and neck squamous cell carcinoma.

Oncoimmunology 2020 12 29;10(1):1856545. Epub 2020 Dec 29.

Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.

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 (PLAC1) 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 PLAC1 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.
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http://dx.doi.org/10.1080/2162402X.2020.1856545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781841PMC
December 2020

Response to PD-1 blockade in a patient with mucosal melanoma of the middle ear: Case report.

Clin Case Rep 2020 Dec 29;8(12):3468-3471. Epub 2020 Oct 29.

Department of Otolaryngology-Head & Neck Surgery Asahikawa Medical University Asahikawa Japan.

PD-1 blockade is a feasible approach in treating mucosal malignant melanomas of the middle ear.
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http://dx.doi.org/10.1002/ccr3.3424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752406PMC
December 2020

Effects of early nutritional intervention by a nutritional support team for patients with head and neck cancer undergoing chemoradiotherapy or radiotherapy.

Head Neck 2021 02 5;43(2):514-519. Epub 2020 Oct 5.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.

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.
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http://dx.doi.org/10.1002/hed.26502DOI Listing
February 2021

Exceptional Response to PD-1 Blockade as First-Line Therapy in Head and Neck Squamous Cell Carcinoma.

ORL J Otorhinolaryngol Relat Spec 2020;82(6):343-350. Epub 2020 Sep 3.

Department of Otolaryngology-Head & Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.

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.
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http://dx.doi.org/10.1159/000509485DOI Listing
March 2021

An accessory tongue in a child: A clinical case.

Auris Nasus Larynx 2021 Dec 17;48(6):1214-1216. Epub 2020 Aug 17.

Department of Otolaryngology-Head and Neck surgery, Asahikawa Medical University, Asahikawa, Japan. Electronic address:

A 20-month-old male patient presented with a tumor on his tongue. The tumor was detected at birth with an initial size of 5 mm; thereafter, it gradually grew larger. The patient had no symptoms, but he frequently touched the tumor, as he grew older. The authors performed a tumor resection under general anesthesia, and the histopathological diagnosis confirmed that it was an accessory tongue, with the same components as that of a normal tongue. An accessory tongue regularly grows bigger as a patient grows older, resulting in dysphagia and articulation disorder. Younger patients should get accessory tongues surgically resected as soon as they are old enough to receive general anesthesia.
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http://dx.doi.org/10.1016/j.anl.2020.08.005DOI Listing
December 2021

Clinical characteristics, the diagnostic criteria and management recommendation of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) proposed by Japan Otological Society.

Auris Nasus Larynx 2021 Feb 5;48(1):2-14. Epub 2020 Aug 5.

Department of Otolaryngology, Miyazaki University Faculty of Medicine, Miyazaki, Japan.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a form of necrotizing vasculitis with few or no immune deposits. It primarily affects small and medium blood vessels. AAV is classified into three categories, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangitis (EGPA), and two major ANCAs, proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA are involved in their pathogenesis. Intractable otitis media frequently occurs in patients with GPA, MPA or EGPA, although all patients show similar clinical features, regardless of the type of AAV. Furthermore, approximately 15% patients with otitis media caused by AAV do not show ANCA positivity, histopathological evidence, or any other AAV-related lesions at the initial visit; therefore, these patients do not fulfill the ordinary diagnostic criteria for systemic AAV. Thus, we first proposed that this condition could be categorized as "otitis media with AAV (OMAAV)". Subsequently, the Japanese Otological Society (JOS) conducted a nationwide survey between December 2013 and February 2014 and identified 297 patients with OMAAV. The survey revealed that OMAAV is a disease that initially occurs in the middle ear and subsequently spreads to other organs such as the lungs and kidneys, with eventual involvement of all body organs. Severe sequelae such as facial palsy, hypertrophic pachymeningitis, complete deafness, and subarachnoid hemorrhage resulting in death can also occur. In this review, we introduce the clinical features, diagnostic criteria, and treatment strategies recommended by JOS for early diagnosis and treatment of OMAAV.
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http://dx.doi.org/10.1016/j.anl.2020.07.004DOI Listing
February 2021

Kimura Disease Presenting with Buccal Mass: A Case Report and Literature Review.

Head Neck Pathol 2021 Jun 25;15(2):657-662. Epub 2020 Jul 25.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.

A 52-year-old man with a 2-year history of left buccal swelling was admitted to our department. An elastic hard oral mass was palpated under the intact buccal mucosa. A CT scan with enhancement revealed a solid mass measuring 2.0 × 1.5 × 1.3 cm between the left masseter muscle and the maxilla. Laboratory examination showed elevated peripheral blood eosinophil count of 1070/μL (12.3%) and serum immunoglobulin (Ig)E level of 1374 IU/mL. Histologic examination of transorally excised mass revealed lymphoid follicular hyperplasia with reactive germinal centers and eosinophilic infiltration with eosinophilic micro-abscesses in the germinal centers. Abundant IgE deposition in a reticular fashion was observed in the germinal centers and c-kit positive mast cells was observed in the paracortical area in the excised mass. The patient was diagnosed with Kimura disease (KD) and treated with oral prednisolone, tapering from 10 mg/day for approximately 8 months. Eosinophil count and serum IgE level decreased to 435/μL (5%) and 520 IU/dL, respectively. He is free from symptoms at the time of this submission. KD, a rare, benign, and chronic inflammatory disorder, occurs predominantly in young male adults in Asia. Patients with KD who presents with buccal mass are relatively rare. Immunohistologic analyses suggested that an allergic reaction played an important role in the etiology of KD in this case.
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http://dx.doi.org/10.1007/s12105-020-01206-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134605PMC
June 2021

Spontaneous Pneumomediastinum: Unusual Cause of Sore Throat.

J Pediatr 2020 09 8;224:176-177. Epub 2020 Jun 8.

Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.

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http://dx.doi.org/10.1016/j.jpeds.2020.06.010DOI Listing
September 2020

Resection of a desmoid-type fibromatosis with a CTNNB1 p.S45P mutation using a cervico-thoracic approach: A case report and literature review.

Auris Nasus Larynx 2021 Aug 4;48(4):777-782. Epub 2020 Jun 4.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan.

Desmoid-type fibromatosis (DF) is a rare, locally infiltrative, and fibroblastic proliferative disease. DF usually arises from abdominal fascial tissue, but in rare cases, it can occur in extra-abdominal areas. A 73-year-old Japanese male complained of a painless, left anterior neck mass of 3-month duration. Computed tomography revealed the mass measured 9 × 7 × 6 cm and extended to the anterior mediastinum, with invasion of the left clavicle. En bloc resection of the tumor with the left sternoclavicular joint and the medial portion of the left clavicle was performed by cervico-thoracic approach with L-shaped partial sternotomy. Histopathologic examination showed fascicular growth of spindle-shaped cells separated by abundant collagen. Immunohistologic examination revealed nuclear staining of β-catenin and cytoplasmic staining of vimentin. Genetic analysis of 160 cancer-related genes by next-generation sequencing (NGS) demonstrated only a missense mutation in the CTNNB1 gene (c.133T>C, p.S45P). DF extending from the neck to the anterior mediastinum is rare. We report the complete resection of a large-sized DF with the clavicular invasion. A low-frequency CTNNB1 mutation of DF was identified. Genetic analysis with NGS was beneficial for the diagnosis.
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http://dx.doi.org/10.1016/j.anl.2020.05.004DOI Listing
August 2021
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