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

Distant metastasis is an important prognostic factor for oral squamous cell carcinoma (OSCC). It involves the direct spread of tumor cells through blood vessels or via lymph nodes; however, there are currently no well-established treatments for its prevention in patients with OSCC. To investigate the impact of metronomic neoadjuvant chemotherapy on OSCC, we conducted a retrospective analysis of the efficacy of neoadjuvant chemotherapy with S-1 alone. Fifty-four patients underwent up-front surgery, while 106 received neoadjuvant chemotherapy with S-1 alone. A serious adverse event occurred in one of patient treated with neoadjuvant chemotherapy (1%); however, all patients underwent resection. The 5-year overall survival rate was higher with S-1 than with up-front surgery (96% vs. 81%, P = 0.002). Moreover, neoadjuvant chemotherapy significantly increased the overall survival rate of patients with poorly or moderately differentiated tumors, but not those with well-differentiated tumors. By analyzing a cohort of 523 head and neck squamous cell carcinoma (HNSCC) patients in the Cancer Genome Atlas, we identified genetic variants associated with histological differentiation. The frequency of pathogenic/likely pathogenic variants or deletions in 5 genes associated with HNSCC correlated with histological differentiation, some of which indicated the activation of the Wnt/β-catenin pathway in well-differentiated HNSCC. The vessel marker CD31 was highly expressed in poorly differentiated OSCC, whereas the anti-angiogenic molecule, LCN2, which is induced by the activation of the Wnt pathway, was highly expressed in well-differentiated OSCC. The present study showed that overall survival rates were higher in patients with poorly or moderately differentiated OSCC who received metronomic neoadjuvant chemotherapy, which was attributed to a difference in angiogenesis based on the characteristic landscape of pathogenic mutations according to histological differentiation.

DOI： 10.62347/EYNT8387

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Language：Japanese   Publisher：(公社)日本顎顔面インプラント学会  

Ichushi

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

Despite significant advancements in therapeutic approaches, oral neoplasms remain formidable and life‑threatening conditions that affect a substantial number of individuals worldwide. Within oral malignancies, a subset of cancer stem cells (CSCs) represent a crucial population responsible for tumor initiation and progression. The identification of reliable markers for the detection and characterization of CSCs in solid tumors, particularly in the context of oral cancers, remains an ongoing challenge. Stage‑specific embryonic antigen 3 (SSEA3), previously associated with mesenchymal stem cells and linked to the progression of breast neoplasms and poor prognosis, has yet to be comprehensively elucidated in the context of oral malignancies. The present study aimed to investigate the expression and properties of SSEA3 in 16 distinct subsets of human oral neoplastic cell lines, classified as either CD44 positive (+) or CD44 negative (‑). For the first time, SSEA3 was examined as an indicator of tumorigenicity and resistance to taxane‑derived chemotherapeutic agents. In the majority of oral neoplastic cell lines analyzed, SSEA3 was expressed in a small population of CD44(+) cells. Significantly, SSEA3(+) cells exhibited heightened proliferative activity and upregulated expression of genes associated with stem cells compared with SSEA3(‑) cells. The aforementioned findings suggested that SSEA3 may contribute to the evolution and progression of oral malignancies by fostering tumor growth. Furthermore, SSEA3(+) cells displayed increased sensitivity to taxane‑based pharmaceuticals, indicating the potential for SSEA3 to be a viable target in the treatment schema for oral cavity neoplasms. In conclusion, the present study provides novel insight into the role of SSEA3 in the progression and management of oral neoplasms, potentially paving the way for more effective therapeutic approaches.

DOI： 10.3892/or.2023.8619

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DOI： 10.1016/j.ajoms.2023.01.010

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The current study's objective was to elucidate some currently unknown biological indicators to evaluate the biological nature of cancer-associated fibroblasts (CAFs). For this purpose, four different CAFs, CAFS1, CAFS2, SCC17F and MO-1000, were established using surgical specimens from oral squamous cell carcinomas (OSCC) with different clinical malignant stages (CAFS1 and CAFS2, T2N0M0, stage II; SCC17F and MO-1000, T4aN2bM0, stage IVA). Fibroblasts unrelated to cancer (non-CAFs) were also prepared and used as controls. Initially, confirmation that these four fibroblasts were indeed CAFs was obtained by their mRNA expression using positive and negative markers for the CAF or fibroblasts. To elucidate possible unknown biological indicators, these fibroblasts were subjected to a cellular metabolic analysis by a Seahorse bioanalyzer, in conjugation with 3D spheroid cultures of the cells and co-cultures with a pancreas ductal carcinoma cell line, MIA PaCa-2. The mitochondrial and glycolytic functions of human orbital fibroblasts (HOF) were nearly identical to those of Graves'-disease-related HOF (GOF). In contrast, the characteristics of the metabolic functions of these four CAFs were different from those of human conjunctival fibroblasts (HconF), a representative non-CAF. It is particularly noteworthy that CAFS1 and CAFS2 showed markedly reduced ratios for the rate of oxygen consumption to the extracellular acidification rate, suggesting that glycolysis was enhanced compared to mitochondrial respiration. Similarly, the physical aspects, their appearance and stiffness, of their 3D spheroids and fibroblasts that were induced effects based on the cellular metabolic functions of MIA PaCa-2 were also different between CAFs and non-CAFs, and their levels for CAFS1 or SCC17F were similar to those for CAFS2 or MO-1000 cells, respectively. The findings reported herein indicate that cellular metabolic functions and the physical characteristics of these types of 3D spheroids may be valuable and useful indicators for estimating potential biological diversity among various CAFs.

DOI： 10.3390/cells12172160

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

The mortality rate of oral cancer has not improved over the past three decades despite remarkable advances in cancer therapies. Oral cancers contain a subpopulation of cancer stem cells (CSCs) that share characteristics associated with normal stem cells, including self-renewal and multi-differentiation potential. CSCs are tumorigenic, play a critical role in cancer infiltration, recurrence, and distant metastasis, and significantly contribute to drug resistance to current therapeutic strategies, including immunotherapy. Cytotoxic CD8+ T lymphocytes (CTLs) are key immune cells that effectively recognize peptide antigens presented by the major histocompatibility complex class I molecules. Increasing evidence suggests that cancer antigen-specific targeting by CTLs effectively regulates CSCs that drive cancer progression. In this study, we utilized data from public domains and performed various bioassays on human oral squamous cell carcinoma clinical samples and cell lines, including HSC-2 and HSC-3, to investigate the potential role of olfactory receptor family 7 subfamily C member 1 (OR7C1), a seven transmembrane G-protein-coupled olfactory receptor that is also expressed in nonolfactory tissues and was previously reported as a novel marker and target of colon cancer initiating cell-targeted immunotherapy, in CSC-targeted treatment against oral cancer. We found that the OR7C1 gene was expressed only in oral CSCs, and that CTLs reacted with human leukocyte antigen-A24-restricted OR7C1 oral CSC-specific peptides. Taken together, our findings suggest that OR7C1 represents a novel target for potent CSC-targeted immunotherapy in oral cancer.

DOI： 10.1111/cas.15873

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

The objective of the current study was to elucidate the clinicopathological significance and appearance of in vitro three-dimension (3D) spheroid models of oral malignant tumors that were prepared from four pathologically different squamous cell carcinoma (OSCC; low-grade; SSYP and MO-1000, intermediate-grade; LEM2) and oral adenosquamous carcinoma (OASC; high-grade; Mesimo) obtained from patients with different malignant stages. To characterize the biological significance of these cell lines themselves, two-dimensional (2D) cultured cells were subjected to cellular metabolic analysis by a Seahorse bioanalyzer alongside the measurement of the cytotoxicity of cisplatin (CDDP). The appearance of their 3D spheroids was then observed by phase contrast microscopy, and both 2D and 3D cultured cells were subject to trypsin digestion and qPCR analysis of factors related to oncogenic signaling and other related analyses. ATP-linked respiration and proton leaking were significantly different among the four cell lines, and the malignant stages of these cultures were significantly associated with increased ATP-linked respiration and decreased proton leakage. Alternatively, the appearances of these 3D spheroids were also significantly diverse among them, and their differences increased in the order of LEM2, MO-1000, SSYP, and Mesimo. Interestingly, these orders were exactly the same in that the efficacies of CDDP-induced cytotoxicity increased in the same order. qPCR analysis indicated that the levels of expression of oncogenic signaling-related factors varied among these four cell lines, and the values for fibronectin and a key regulator of mitochondrial biogenesis, PGC-1α, were prominently elevated in cultures of the worst malignant Mesimo cells. In addition, although 0.25% trypsin-induced destruction was comparable among all four 2D cultured cells, the values for the 3D spheroids were also substantially varied among these cultures. The findings reported herein indicate that cellular metabolic functions and 3D spheroid architectures may be valuable and useful indicators for estimating the pathological and drug-sensitive aspects of OSCC and OASC malignancies.

DOI： 10.3390/cancers15102793

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

DOI： 10.1016/j.ajoms.2022.11.004

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

Metronomic chemotherapy is defined as a high-frequency low-dose schedule of chemotherapy drug administration. Although metronomic chemotherapy is widely used, the mechanisms underlying resistance to metronomic chemotherapy remain unclear. Therefore, we herein conducted a single institutional phase I/II trial to assess the efficacy and safety of metronomic chemotherapy with bleomycin plus S-1, an oral 5-FU prodrug, in the neoadjuvant setting for patients with oral squamous cell carcinoma (OSCC). The response rate of well-differentiated OSCC to metronomic chemotherapy was significantly lower. We investigated differences in molecular profiles between poorly or moderately differentiated head and neck squamous cell carcinoma (HNSCC) and well-differentiated HNSCC from patients with HNSCC TCGA data. EphA4 expression positively correlated with histological differentiation. An upstream regulator analysis correlated with EphA4 expression identified pathways associated with decreased mTORC1 signaling and T cell activation, including TCR, CD3, CD28, and CD40LG. An EphA4 blocking peptide (KYL) induced mTOR activation in well-differentiated OSCC cell lines. Plasmacytoid dendritic cell and CD8+ T cell numbers were higher in the microenvironment of poorly or moderately differentiated HNSCC than in that of well-differentiated HNSCC. Well-differentiated HNSCC had the characteristics of "cold tumors" (immune-excluded tumors). Moreover, KYL used with chemotherapeutic drugs synergistically increased cancer cell death. Well-differentiated OSCC is depleted of immune cells, which may be partly explained by the receptor tyrosine kinase EphA4.

DOI： 10.1016/j.ejphar.2023.175611

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Authorship：Lead author,　Corresponding author   Language：English  

Odontogenic keratocysts (OKCs) often occur in the molars in the mandibular ramus; they often progress asymptomatically and are discovered only after widespread development. Some cases of OKC progress to the mandibular condyle; however, very few cases exist only in the condyle. To the best of our knowledge, in all of the previously reported cases, OKCs occurred in the mandibular ramus, which underwent resection. The present study reports the case of a 31-year-old man in whom an OKC (13x12x6 mm) occurred discretely in the base of the condyle, in which the condylar head was successfully preserved. The tumor was removed under general anesthesia using the approach of shaving the anterior surface of the mandible. The extraction cavity was managed using the packed open technique and with an obturator. Approximately 20 months post-operation, the patient remained recurrence-free. This report presents a rare case of an OKC in the mandibular condyle base region. Resection was performed under general anesthesia and the condylar process was successfully preserved.

DOI： 10.3892/etm.2023.11840

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Authorship：Lead author,　Corresponding author   Language：English  

Oral/dental surgical care in patients with chronic medical comorbidities, such as isovaleric acidemia (IVA), can be challenging. In addition to technical complications, different comorbidities also present a complex range of concerning factors/challenges, which can increase the incidence of morbidity and mortality associated with surgery. IVA, a congenital error of metabolism, is a rare organic acidemia with a predisposition towards acute acidosis and life-threatening metabolic decompensation during stressful conditions, such as prolonged fasting and surgery. In addition, schizophrenia, a major neurological disorder, can result in manifestation of severe dental or periodontal conditions, including pericoronitis. The condition is associated with significant risk factors of postoperative complications, such as dangerous behaviors and adverse interactions between antipsychotic drugs and anesthetic agents. A case of comorbid dental disease with two coexisting chronic and life-threatening medical conditions, one of which is rare, is an unusual encounter in oral/dental surgery that is seldomly published. Moreover, implementing a safe and effective surgical intervention in such patients requires several informed considerations. However, only a few reported experiences or guidelines exist, reporting appropriate perioperative management strategies to minimize risks. Hence, in this case report, our experience of managing one of these rare encounters of a 20-year-old man who suffered from bilaterally partially erupted third molars, associated with chronic pericoronitis and dental caries of both the maxilla wisdom teeth with coexisting IVA and schizophrenia comorbidities is described. Additionally, the presentation and anticipated complications of the comorbid disorders of the patient are briefly reviewed. In this case, the pericoronitis and dental caries were treated by surgically removing the impacted third molars and the antagonist maxilla wisdom teeth under regional anesthesia and application of antibiotics for 3 days. The patient recovered without any postoperative complications after 1 year of follow-up.

DOI： 10.3892/br.2022.1547

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

DOI： 10.1016/j.ajoms.2022.01.005

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Language：English  

Mixed tumour of the skin or chondroid syringoma (CS) is a rare and mostly benign neoplasm of the sweat glands. Although CS is frequently located on varied parts of the head and neck region, the lower lip is a rarely reported site. The present report describes a case of CS of the lower lip in a 58-year-old male as an expository case to further emphasise the need for proper diagnosis, appropriate treatment and prognostic evaluation. The patient presented with a round, non-tender, slightly hard and mobile mass beneath the mucocutaneous junction of his left lateral side of the lower lip. Radiology revealed a mass measuring 11x11x7 mm3 in size at a depth of ~2 mm. Furthermore, magnetic resonance T1- and T2-weighted images showed slightly low and high signal intensities, respectively. A provisional diagnosis of benign tumour of the lower lip was made, and surgical excision biopsy taken under local anaesthesia, while considering the patient's cosmetic appearance. Histopathology demonstrated features akin to apocrine gland, chondroid and myxoid stroma consistent with the diagnosis of benign CS. No evidence of recurrence or satellites were recorded after a follow-up of nearly 2 years. Although rare, a high index of suspicion for CS among other cutaneous adnexal tumours of the lower lip is necessary. In addition, interprofessional collaboration in the management of such oral tumours could enhance patient satisfaction amid prevailing intraoral and aesthetic concerns.

DOI： 10.3892/mco.2022.2502

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

Well-differentiated head and neck squamous cell carcinoma (HNSCC), accounts for approximately 10% of all HNSCCs and, while these cases are associated with good prognosis after surgery, these are resistant to chemotherapy. Here we designed a retrospective study to evaluate the effects of histological differentiation on tongue squamous cell carcinoma (TSCC) patients undergoing surgery or metronomic neoadjuvant chemotherapy. The metronomic neoadjuvant chemotherapy significantly improved overall survival of patients with poorly or moderately differentiated tumour, but not those with well-differentiated tumour. Analysis of the Cancer Genome Atlas (TCGA) showed that FAT1 mutations were significantly enriched in more differentiated HNSCC while ASPM mutations were significantly enriched among the poorly differentiated HNSCC. Interestingly, Wnt/β-catenin pathway was activated in well-differentiated HNSCC. Active β-catenin is translocated to the nucleus in the well-differentiated oral squamous cell carcinoma cell lines. Wnt inhibitor, Wnt974, were synergistic with methotrexate in killing well-differentiated oral squamous cell carcinoma (OSCC) cell lines. TCGA data analyses reveal a signature in patients with well-differentiated HNSCC who have no benefits from metronomic neoadjuvant chemotherapy, suggesting that there might be novel nosology and therapeutic candidates for improving HNSCC patient survival. Well-differentiated OSCC is synergistically killed by combination chemotherapy with Wnt inhibitor, making it promising therapeutic candidates.

DOI： 10.1080/1061186X.2021.1929256

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Language：Japanese   Publisher：(一社)日本有病者歯科医療学会  

Ichushi

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Language：Japanese   Publisher：(一社)日本有病者歯科医療学会  

Ichushi

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Language：Japanese   Publisher：(一社)日本口腔腫瘍学会  

Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J02382&link_issn=&doc_id=20210921320010&doc_link_id=%2Fdy8ortum%2F2021%2F003303%2F010%2F0151-0158%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy8ortum%2F2021%2F003303%2F010%2F0151-0158%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Ichushi

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：一般社団法人 日本口蓋裂学会  

2011年から2019年までの9年間に琉球大学病院歯科口腔外科を受診した口唇裂・口蓋裂一次症例183名について臨床統計学的解析を行った。また，2014年から開始した産科の往診システムの効果を検討し，以下の結果を得た。<br>1．9年間に当科を受診した一次症例は183名であった。<br>2．裂型別患者数では183名中，口唇（顎）裂が82名（44.8％），口唇口蓋裂が59名（32.2％），口蓋裂が42名（23.0％）であった。<br>3．男女比は，男性92名，女性91名で1.01：1とほぼ同数であった。<br>4．初診時年齢は，61名（33.3％）が生後7日未満に受診していた。<br>5．出生時体重は，平均2,978.4gで，3,000g〜3,499gが71名（39.4％）と最も多かった。<br>6．母親の出産時年齢は，平均31.5歳で，30歳から34歳が49名（29.3％）と最も多かった。<br>7．先天異常を合併した患者は，22名（12.0％）に認められた。<br>8．手術総件数は554件で，手術内訳は口唇形成術が130件（22.3％）と最も多かった。<br>9．2014年から開始した往診数は45件で，その活動は患者家族の精神的負担を軽減できた。

DOI： 10.11224/cleftpalate.46.33

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Oral and Maxillofacial Surgeons  

DOI： 10.5794/jjoms.67.194

Ichushi

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

Cytotoxic CD8+ T lymphocytes (CTLs) recognize peptides displayed by HLA class I molecules on cell surfaces, monitoring pathological conditions such as cancer. Difficulty in predicting HLA class I ligands is attributed to the complexity of the Ag processing pathway across the cytosol and the endoplasmic reticulum. By means of HLA ligandome analysis using mass spectrometry, we collected natural HLA class I ligands on a large scale and analyzed the source-protein sequences flanking the ligands. This comprehensive analysis revealed that the frequency of proline at amino acid positions 1-3 upstream of the ligands was selectively decreased. The depleted proline signature was the strongest among all the upstream and downstream profiles. Experiments using live cells demonstrated that the presence of proline at upstream positions 1-3 attenuated CTL responses against a model epitope. Other experiments, in which N-terminal-flanking Ag precursors were confined in the endoplasmic reticulum, demonstrated an inability to remove upstream prolines regardless of their positions, suggesting a need for synergistic action across cellular compartments for making the proline signature. Our results highlight, to our knowledge, a unique role and position of proline for inhibiting downstream epitope presentation, which provides a rule for defining natural peptide-HLA class I repertoire formation and CTL responses.

DOI： 10.4049/jimmunol.1900029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

DOI： 10.1186/s12903-018-0572-9

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

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

DOI： 10.1158/2326-6066.CIR-17-0518

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

DOI： 10.1111/jop.12606

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

DOI： 10.21873/anticanres.11898

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Inc.  

DOI： 10.1080/2162402X.2017.1293214

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

Other Link： http://search.jamas.or.jp/link/ui/2017258491

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Inc.  

DOI： 10.1080/2162402X.2016.1274476

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society for Clinical Immunology  

DOI： 10.2177/jsci.40.40

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

DOI： 10.1002/eji.201545835

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Language：Japanese   Publisher：日本臨床免疫学会  

<p>  がん幹細胞は高い腫瘍形成能と化学・放射線療法に対する治療抵抗性を併せもち，再発・転移の起点となる細胞成分である．我々はヒト大腸がんSW480細胞株からside population法でがん幹細胞成分を単離し，HLA-A24リガンドーム解析によりがん幹細胞に特異的なIV9ペプチドとそのソース遺伝子ASB4を同定した．ASB4は大腸・肺・腎・頭頚部がんに発現する一方で成人および胎児の正常組織に発現はみられず，がん特異性が高い遺伝子である．IV9合成ペプチドを用いるとHLA-A24陽性の大腸がん患者および正常人の末梢血からそれぞれ3/3名および2/3名でテトラマー陽性CTLが誘導できた．誘導したCTLクローンはIV9ペプチド提示細胞を特異的に認識し同時にSW480がん幹細胞を強く細胞傷害する．さらに，SW480細胞担がんマウスモデルにCTLクローンを静注すると腫瘍形成を有意に抑制した．以上から，HLA-A24リガンドーム解析により同定したIV9ペプチドは大腸がん幹細胞成分を特異標的とするCTL誘導が可能であり，魅力的な新規がんワクチン候補と考えられる．</p>

DOI： 10.2177/jsci.39.404a

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Other Link:： https://search.jamas.or.jp/link/ui/2018307809

CiNii Research

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Language：Japanese  

Other Link:： http://search.jamas.or.jp/link/ui/2017264471

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

Ichushi

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Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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Country：Japan

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Award type：Award from publisher, newspaper, foundation, etc.  Country：Japan

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Award type：Award from Japanese society, conference, symposium, etc.  Country：Japan

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Country：Japan

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