H Kurita, N Uzawa, H Nakayama, T Abe, S Ibaraki, Y Ohyama, K Uchida, H Sato, S Miyabe, T Abé, N Kakimoto, A Kaida, T Sugiura, M Kioi, A Danjo, Naoya Kitamura, O Hasegawa, T Tanaka, N Ueda, T Hasegawa, S Asoda, H Katsuta, S Yanamoto, S Yamada, D Takeda, T Suzuki, Y Ohta and T Kirita : Japanese clinical practice guidelines for oral cancer, International Journal of Oral and Maxillofacial Surgery, 2024.
(要約)
The Japanese Society of Oral Oncology and Japanese Society of Oral and Maxillofacial Surgeons have jointly developed clinical practice guidelines for oral cancer (oral squamous cell carcinoma) to improve and standardize the quality of oral cancer treatment in Japan. The first, second, and third editions were published in 2009, 2013, and 2019, respectively, and the 2023 edition was recently developed. In the development of the 2023 edition, 60 clinical questions (CQs) were listed. Systematic reviews following the GRADE approach were performed for 11 of these CQs. This article outlines the 2023 edition and describes the most relevant guidelines and CQs for the diagnosis, treatment, follow-up, and supportive care of oral cancer patients in Japan.
Masahiro Iwamoto, Michiko Takahashi, Hiromichi Maeda, Hiroaki Takeuchi, Jumpei Uchiyama, Takako Ujihara, Keizo Nagasaki, Kazuhiro Hanazaki, Satoru Seo, Naoya Kitamura, Tetsuya Yamamoto and Shigenobu Matsuzaki : Analysis of the life cycle of Helicobacter pylori bacteriophage KHP40 belonging to the genus Schmidvirus, FEMS Microbiology Letters, 371, fnae082, 2024.
(要約)
Bacteriophage (phage) KHP40 was previously isolated from the supernatant of a culture of Helicobacter pylori KMT83 cells. In this study, we analysed the infection characteristics of KHP40, phage release pattern from KMT83 cells, and state of KHP40 DNA in KMT83 cells. The findings revealed that KHP40 phage showed varied adsorption efficiencies for different strains, long latent periods, and small burst sizes. Additionally, KHP40 activity was maintained at pH 2.5-12. KHP40 phages were released during the vegetative growth phase of the KMT83 cells. PCR analysis demonstrated that KHP40 DNA was stably maintained in KMT83 clones. Next-generation sequencing analysis revealed the presence of two distinct types of circular double-stranded DNA in H. pylori KMT83 cells. One was an H. pylori-specific DNA consisting of 1 578 403 bp, and the other was a 26 412-bp sequence that represented the episomal form of phage KHP40 DNA. Furthermore, defective KHP40-lysogenic DNA was detected in the H. pylori-specific DNA, the deleted portion of which appeared to have been transferred to another location in the bacterial genome. These findings indicate that KHP40 DNA exists in both episomal and defectively lysogenized states in KMT83 cells, and active phages are produced from KHP40-episomal DNA.
Yoji Nakase, Atsuko Hamada, Fumitaka Obayashi, Naoya Kitamura, Tsuyoshi Hata, Tetsuya Yamamoto and Tetsuji Okamoto : Establishment of induced pluripotent stem cells derived from patients and healthy siblings of a nevoid basal cell carcinoma syndrome family, In Vitro Cellular & Developmental Biology. Animal, 59, 6, 395-400, 2023.
(要約)
It is known that a nevoid basal cell carcinoma syndrome (NBCCS) is characterized by a combination of developmental abnormalities and a predisposition to form various tumors. Although it is possible to create disease models via gene editing, there are significant potential problems with this approach such as off-target mutations and differences in SNPs. On the other hand, since disease families share common SNPs, research using iPSCs derived from both patients and healthy siblings of the same disease family is very important. Thus, establishment of induced pluripotent stem cells derived from patients and healthy siblings of the same NBCCS family will be of great importance to study the etiology of this disease and to develop therapeutics. In this study, we generated hiPSCs using peripheral blood mononuclear cells derived from the patients and healthy siblings of familial NBCCS with the novel mutation in PTCH1_c.3298_3299insAAG in the feeder- and serum-free culture conditions using SeVdp. In addition, disease-specific hiPSCs such as those expressing the PTCH1_c.3298_3299insAAG mutation could be powerful tools for revealing the genotype-phenotype relationship and pathogenicity of NBCCS.
Naoya Kitamura, Yumiko Hashida, Tomonori Higuchi, Seiji Ohno, Shinya Sento, Eri Sasabe, Ichiro Murakami, Tetsuya Yamamoto and Masanori Daibata : Detection of Merkel cell polyomavirus in multiple primary oral squamous cell carcinomas, Odontology, 111, 4, 971-981, 2023.
(要約)
Oral microbiome studies have mainly focussed on bacteria, with the relationship between viruses and oral cancers remaining poorly understood. Oral cancers can develop even in the absence of any history of daily smoking or drinking. Oral cancer patients frequently have multiple primary cancers in the oral cavity and other organs, such as the upper gastrointestinal tract. Merkel cell polyomavirus (MCPyV) is a novel oncovirus identified from a subtype of skin cancer in 2008. In this study, we investigated the potential involvement of MCPyV in the pathogenesis of oral squamous cell carcinoma (OSCC). Participants comprised 115 Japanese patients with OSCC (single primary: 109 tumours in 109 patients; multiple primaries: 16 tumours in 6 patients) treated in our department between 2014 and 2017. DNA was extracted from formalin-fixed paraffin-embedded specimens of primary lesions. MCPyV DNA copy counts were analysed by quantitative real-time polymerase chain reaction. Twenty-four of the 115 patients (20.9%) were positive for MCPyV DNA. No association was found between presence or absence of MCPyV DNA and clinical characteristics other than number of primary lesions. The MCPyV DNA-positive rate was significantly higher for multiple primary OSCCs (62.5%, 10/16 tumours) than for single primary OSCCs (16.5%, 18/109 tumours; P < 0.001). Furthermore, MCPyV DNA load was significantly higher for patients with multiple primaries (P < 0.05). MCPyV was observed more frequently and DNA load was significantly higher with multiple primary OSCCs than with single primary OSCC. MCPyV may play some role as an oncovirus for multiple primary OSCCs.
(キーワード)
Humans / Carcinoma, Squamous Cell / Merkel cell polyomavirus / Squamous Cell Carcinoma of Head and Neck / Polyomavirus Infections / DNA, Viral / Mouth Neoplasms / Head and Neck Neoplasms / Neoplasms, Multiple Primary
Satoru Kisoda, Yasuhiro Mouri, Naoya Kitamura, Tetsuya Yamamoto, Keiko Miyoshi and Yasusei Kudo : The role of partial-EMT in the progression of head and neck squamous cell carcinoma., Journal of Oral Biosciences, 64, 2, 176-182, 2022.
(要約)
In this review, we highlight the features of partial-EMT in HNSCC by summarizing previous studies. Moreover, we discuss the therapeutic potential for targeting partial-EMT.
(キーワード)
Carcinoma, Squamous Cell / Epithelial-Mesenchymal Transition / Head and Neck Neoplasms / Humans / Lymphatic Metastasis / Squamous Cell Carcinoma of Head and Neck
Eri Sasabe, Ayumi Tomomura, Hangyu Liu, Shinya Sento, Naoya Kitamura and Tetsuya Yamamoto : Epidermal growth factor/epidermal growth factor receptor signaling blockage inhibits tumor cell-derived exosome uptake by oral squamous cell carcinoma through macropinocytosis, Cancer Science, 113, 2, 609-621, 2022.
(要約)
Various cell types secrete exosomes into their surrounding extracellular space, which consequently affect the function and activity of recipient cells. Numerous studies have showed that tumor cell-derived exosomes play important roles in tumor growth and progression. Although a variety of endocytic pathways are reportedly involved in the cellular uptake of exosomes, detailed mechanisms remain unknown. The present study demonstrated that treatment with recombinant epidermal growth factor (EGF) time- and dose-dependently promoted cellular uptake of oral squamous cell carcinoma (OSCC) cell-derived exosomes into OSCC cells themselves. Conversely, EGF receptor (EGFR) knockdown and treatment with EGFR inhibitors, including erlotinib and cetuximab, abrogated OSCC cell uptake of exosomes. The macropinocytosis inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA) blocked the effects of active EGF/EGFR signaling on uptake of OSCC cell-derived exosomes. These EGFR inhibitors also suppressed OSCC cell-derived exosome-induced proliferation, migration, invasion, stemness, and chemoresistance of OSCC cells. Taken together, the data presented herein suggest that EGFR inhibitors might inhibit the malignant potential of OSCC cells through direct inhibition of not only EGFR downstream signaling pathway but also cellular uptake of OSCC cell-derived exosomes through macropinocytosis.
(キーワード)
Cell Line, Tumor / Cell Movement / Cell Proliferation / Drug Resistance, Neoplasm / Epidermal Growth Factor / ErbB Receptors / Exosomes / Humans / Mouth Neoplasms / Neoplastic Stem Cells / Pinocytosis / Protein Kinase Inhibitors / シグナル伝達 (signal transduction) / Squamous Cell Carcinoma of Head and Neck
Tomohiro Nishimori, Tomonori Higuchi, Yumiko Hashida, Takako Ujihara, Ayuko Taniguchi, Fumiya Ogasawara, Naoya Kitamura, Ichiro Murakami, Kensuke Kojima and Masanori Daibata : Development of a novel cell line-derived xenograft model of primary herpesvirus 8-unrelated effusion large B-cell lymphoma and antitumor activity of birabresib in vitro and in vivo, Cancer Medicine, 10, 24, 8976-8987, 2021.
(要約)
Primary human herpesvirus 8 (HHV8)-unrelated effusion large B-cell lymphoma is a clinical disease entity distinct from HHV8-positive primary effusion lymphoma (PEL). However, the lack of experimental HHV8-unrelated effusion large B-cell lymphoma models continues to hinder the pathophysiologic and therapeutic investigations of this disorder. The lymphoma cells were obtained from the pleural effusion of a patient with primary HHV8-unrelated effusion large B-cell lymphoma and cultured in vitro. We established a novel HHV8-unrelated effusion large B-cell lymphoma cell line, designated Pell-1, carrying a c-MYC rearrangement with features distinct from those of HHV8-positive PEL. Moreover, we developed an HHV8-unrelated effusion large B-cell lymphoma cell line-derived xenograft model. Pell-1 cells induced profuse lymphomatous ascites and subsequently formed intra-abdominal tumors after intraperitoneal implantation into irradiated nonobese diabetic/severe combined immunodeficient mice. Thus, this xenograft mouse model mimicked the clinical phenomena observed in patients and recapitulated the sequential stages of aggressive HHV8-unrelated effusion large B-cell lymphoma. The bromodomain and extraterminal domain (BET) inhibitors JQ1 and birabresib (MK-8628/OTX015) reduced the proliferation of Pell-1 cells in vitro through the induction of cell cycle arrest and apoptosis. The antitumor effect of BET inhibition was also demonstrated in vivo, as birabresib significantly reduced ascites and suppressed tumor progression without apparent adverse effects in the xenografted mice. These preclinical findings suggest the therapeutic potential of targeting c-MYC through BET inhibition in HHV8-unrelated effusion large B-cell lymphoma.
Naoya Kitamura, Eri Sasabe, Shinya Sento, Katsuhito Kiyasu, Kosuke Nakaji, Masanori Daibata and Tetsuya Yamamoto : Vertebral fracture and splenomegaly in a head and neck cancer producing granulocyte colony-stimulating factor: A case report of systemic complications associated with a cytokine-producing solid tumor, Molecular and Clinical Oncology, 15, 4, 202, 2021.
(要約)
Granulocyte colony-stimulating factor (G-CSF)-producing tumors are rare and are associated with a poor prognosis when they occur in the lungs and the head and neck region. Positron emission tomography/computed tomography has been reported to show systemic specific accumulation of fluorodeoxyglucose in these cases, but the systemic complications associated with the cytokines produced are not well known. We herein present the case of a G-CSF-producing maxillary sinus squamous cell carcinoma in a 73-year-old Japanese woman with a vertebral fracture and splenomegaly. These findings are known severe adverse events of high-dose recombinant human G-CSF treatment. The aim of the present study was to further discuss the hypothesis that cytokines produced by solid tumors may induce spinal vertebral fracture and splenomegaly.
Naoya Kitamura, Shinya Sento, Yasumasa Yoshizawa, Eri Sasabe, Yasusei Kudo and Tetsuya Yamamoto : Current Trends and Future Prospects of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma., International Journal of Molecular Sciences, 22, 1, 240, 2020.
(要約)
In recent years, advances in drug therapy for head and neck squamous cell carcinoma (HNSCC) have progressed rapidly. In addition to cytotoxic anti-cancer agents such as platinum-based drug (cisplatin and carboplatin) and taxane-based drugs (docetaxel and paclitaxel), epidermal growth factor receptor-tyrosine kinase inhibitors (cetuximab) and immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) antibodies (nivolumab and pembrolizumab) have come to be used. The importance of anti-cancer drug therapy is increasing year by year. Therefore, we summarize clinical trials of molecular targeted therapy and biomarkers in HNSCC from previous studies. Here we show the current trends and future prospects of molecular targeted therapy in HNSCC.
Yoji Nakase, Atsuko Hamada, Naoya Kitamura, Tsuyoshi Hata, Shigeaki Toratani, Tetsuya Yamamoto and Tetsuji Okamoto : Novel PTCH1 mutations in Japanese familial nevoid basal cell carcinoma syndrome, Human Genome Variation, 7, 1, 38, 2020.
(要約)
Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is inherited in an autosomal dominant manner and is characterized by a combination of developmental abnormalities and a predisposition to tumor formation. Hedgehog receptor Patched 1 (PTCH1) has been identified as the mutated gene in NBCCS. We identified the PTCH1_c.3298_3299insAAG_p.1099_1100insE mutation in the transmembrane region, which comprises a sterol transporter whose abnormal function is reportedly related to pathogenicity.
Kharisma Perdani Kusumahstuti, Tadashi Watabe, Naoya Kitamura and Tetsuya Yamamoto : Diffuse bone marrow uptake related to granulocyte colony-stimulating factor-producing maxillary sinus carcinoma on 4-borono-2-18F-fluoro-L-phenylalanine positron emission tomography/computed tomography, World Journal of Nuclear Medicine, 20, 2, 188-191, 2020.
(要約)
Granulocyte colony-stimulating factor (G-CSF) can be produced by tumor cells and is known to promote tumor growth, thereby potentially accelerating disease progression. Squamous cell carcinoma (SCC) at maxillary sinus is aggressive growth with poor prognosis. Maxillary sinus carcinomas are rare and can be clinically silent in the early stages or manifest with the same signs and symptoms of more common illnesses, leading to their delayed diagnosis of disease. Hypermetabolic uptake of F-fluorodeoxyglucose (F-FDG) but not of 4-borono-2-F-fluoro- L-phenylalanine (F-FBPA), in the bone marrow of patients with G-CSF-producing tumors without bone marrow involvement during positron emission tomography (PET), has been reported. The present case report describes our first experience of bone marrow uptake in PET/computed tomography examination usingF-FBPA, high uptake seen in the bone marrow of a patient with a G-CSF-secreting SCC of the maxillary sinus that it relapsed following chemoradiation therapy and surgical resection of the tumor.
Natsumi Fujiwara, Naoya Kitamura, Kaya Yoshida, Tetsuya Yamamoto, Kazumi Ozaki and Yasusei Kudo : Involvement of Fusobacterium Species in Oral Cancer Progression: A Literature Review Including Other Types of Cancer, International Journal of Molecular Sciences, 21, 17, 6207, 2020.
(要約)
Chronic inflammation caused by infections has been suggested to be one of the most important cause of cancers. It has recently been shown that there is correlation between intestinal bacteria and cancer development including metastasis. As over 700 bacterial species exist in an oral cavity, it has been concerning that bacterial infection may cause oral cancer. However, the role of bacteria regarding tumorigenesis of oral cancer remains unclear. Several papers have shown that species deriving the oral cavities, especially, play a crucial role for the development of colorectal and esophageal cancer. is a well-known oral bacterium involved in formation of typical dental plaque on human teeth and causing periodontal diseases. The greatest characteristic of is its ability to adhere to various bacteria and host cells. Interestingly, is frequently detected in oral cancer tissues. Moreover, detection of is correlated with the clinical stage of oral cancer. Although the detailed mechanism is still unclear, species have been suggested to be associated with cell adhesion, tumorigenesis, epithelial-to-mesenchymal transition, inflammasomes, cell cycle, etc. in oral cancer. In this review, we introduce the reports focused on the association of species with cancer development and progression including oral, esophageal, and colon cancers.
Naoya Kitamura, Eri Sasabe, Shigenobu Matsuzaki, Masanori Daibata and Tetsuya Yamamoto : Characterization of two newly isolated Staphylococcus aureus bacteriophages from Japan belonging to the genus Silviavirus, Archives of Virology, 165, 10, 2355-2359, 2020.
(要約)
Two Staphylococcus aureus bacteriophages, KSAP7 and KSAP11, were isolated from sewage and characterized. Based on morphology and DNA sequences, they were assigned to the genus Silviavirus, subfamily Twortvirinae, family Herelleviridae, whose members are hypothesized to be suitable for bacteriophage therapy. The KSAP7 and KSAP11 genomes were 137,950 and 138,307 bp in size, respectively. Although their DNA sequences were almost identical, evidence of site-specific DNA rearrangements was found in two regions. Changes in the number of PIEPEK amino acid sequence repeats encoded by orf10 and the insertion/deletion of a 541-bp sequence that includes a possible tail-related gene were identified.
Riki Tomita, Naoya Kitamura, Yasumasa Yoshizawa, Eri Sasabe, Yasusei Kudo and Tetsuya Yamamoto : A case of large varix including partially organizing thrombosis on the oral floor, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 32, 4, 313-315, 2020.
Shinya Sento, Yasusei Kudo, Kenji Hibiya, Naozumi Ishimaru, Eri Sasabe, Naoya Kitamura and Tetsuya Yamamoto : Hyalinizing clear cell carcinoma of the anterior lingual salivary gland: A case report and review of the literature, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 32, 4, 267-274, 2020.
Y. Yoshizawa, R. Tomita, Naoya Kitamura and T. Yamamoto : Two cases of medication-related osteonecrosis of the jaw with extension to the cranial base, Oral Surgery, 13, 2, 147-156, 2020.
Eri Sasabe, Ayumi Tomomura, Naoya Kitamura and Tetsuya Yamamoto : Metal nanoparticles-induced activation of NLRP3 inflammasome in human oral keratinocytes is a possible mechanism of oral lichenoid lesions, Toxicology In Vitro, 62, 104663, 2020.
(要約)
The NLRP3 inflammasome has been implicated in the pathogenesis of various inflammatory diseases and is activated by particulate stimulants. Oral epithelial keratinocytes are frequently exposed to metal nanoparticles. In this study, we examined the effects of gold, silver, and palladium nanoparticles, which are frequently used for dental metal alloys on cell proliferation, cytotoxicity, autophagy, lysosomal functions, and NLRP3 inflammasome activation using the immortalized human oral keratinocyte cell line RT-7. The metal nanoparticles were agglomerated in the membrane vesicles in RT-7 cells and suppressed cell proliferation and increased lactate dehydrogenase activity as well as the proportion of apoptotic cells. Silver and palladium nanoparticles induced autophagy and lysosomal dysfunctions and all metal nanoparticles tested triggered the secretion of IL-1β through caspase-1 activation. Furthermore, the epithelium obtained from patients with oral lichenoid lesions (OLLs) had robust NLRP3, ASC, caspase-1, and IL-1β-positive keratinocytes and cDNA microarray showed significant elevation in the mRNA levels of NLRP3. These results suggest that internalized metal nanoparticles in oral mucosal epithelial cells activate the NLRP3 inflammasome through the induction of lysosomal damage and autophagy dysfunction. This process may be involved in the pathogenesis of OLL and suggest its potential as an alternative target for OLL therapy.
Naoya Kitamura, E Sasabe, H Kitaoka and T Yamamoto : Unilateral necrosis of the tongue caused by embolisation of cholesterol crystals, The British Journal of Oral & Maxillofacial Surgery, 56, 4, 340-342, 2018.
(要約)
Cholesterol crystals embolise when an aortic atherosclerotic lesion ruptures and cholesterol crystals are scattered and obstruct small peripheral arterioles. Risk factors include both iatrogenic factors such as intravascular catheterisation, and spontaneous factors for atherosclerosis such as aging, hypertension, dyslipidaemia, and smoking. We describe the case of an 83-year-old Japanese man who developed unilateral, superficial necrosis of the tongue as a result of spontaneous embolisation of cholesterol crystals.
(キーワード)
Aged, 80 and over / Embolism, Cholesterol / Humans / 男性 (male) / Necrosis / Tongue / Tongue Diseases
To evaluate the efficacy of palonosetron in preventing acute and delayed nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC) in oral cancer patients. Oral cancer patients receiving HEC were enrolled; among the 40 patients, 87 courses of chemotherapy were administered. On day 1, 0.75 mg palonosetron was intravenously administrated just before chemotherapy. The primary endpoint was the proportion of patients with a complete response (CR) and the secondary endpoint was the proportion of patients with complete control (CC) during the acute and delayed phase. During the acute phase, 86 of 87 courses (98.9%) had CR and 84 of 87 courses (96.6%) had CC. During the delayed phase, 84 of 87 courses (96.6%) had CR and 70 of 87 courses (80.5%) had CC. Palonosetron is effective at preventing HEC-induced chemotherapy-induced nausea and vomiting (CINV) in oral cancer chemotherapeutic regimens in the acute and delayed phases.
Eri Sasabe, Ayumi Tomomura, Riki Tomita, Shinya Sento, Naoya Kitamura and Tetsuya Yamamoto : Ephrin-B2 reverse signaling regulates progression and lymph node metastasis of oral squamous cell carcinoma, PLoS ONE, 12, 11, e0188965, 2017.
(要約)
Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck and frequently metastasizes to cervical lymph nodes. Aggressive local invasion and metastasis of OSCC are significant factors for poor prognosis. In this study, we investigated whether ephrin-B2 expressed in OSCC contributed to tumor progression and lymph node metastasis. Clinical specimens from patients with OSCC had robust ephrin-B2-positive tumor cells and ephrin-B2 protein level was associated with clinical stage, lymph node metastasis, and poor survival outcomes. We also determined that ephrin-B2 protein level was increased in OSCC cell lines compared to normal human oral keratinocytes and that its levels were associated with the migratory and invasive potential of OSCC cell lines. Transfection of an EFNB2-specific small interfering RNA (siRNA) into SAS-L1 cells significantly reduced proliferation, attachment, migration, and invasion through phosphorylation of the epidermal growth factor receptor, FAK, ERK1/2, p38, AKT, and JNK1/2 pathways. Furthermore, knockdown of EFNB2 significantly suppressed adhesion and transmigration of SAS-L1 cells toward human lymphatic endothelial cells. In addition, the growth rate of tumor xenografts and cervical lymph node metastases of OSCC were suppressed by local injection of EFNB2 siRNA. These results suggest that ephrin-B2 overexpression and activation of the ephrin-B2 reverse signaling pathway in tumor microenvironment in OSCC facilitates progression and lymph node metastasis via enhancement of malignant potential and interaction with surrounding cells.
Tomohiro Yamada, Seiji Ohno, Naoya Kitamura, Eri Sasabe and Tetsuya Yamamoto : SPARC is associated with carcinogenesis of oral squamous epithelium and consistent with cell competition, Medical Molecular Morphology, 48, 3, 129-137, 2015.
(要約)
The matricellular protein, secreted protein acidic and rich in cysteine (SPARC) is thought to be involved in cell competition. The objective of this study is to investigate the role of SPARC in cancerization of oral squamous epithelium. Clinical specimens from 57 pre- and early cancerous lesion, 66 invasive squamous cell carcinoma (SCC) and controls were immunostained with SPARC. Clinical features and SPARC expression were evaluated. Furthermore, effects of SPARC knockdown and overexpression were examined in oral cancer and keratinocyte cell lines. Leukoplakia, carcinoma in situ, and early invasive SCC had more SPARC-positive cells than normal mucous epithelium. However, there were no significant differences between leukoplakia, carcinoma in situ, and early SCC, and there were no correlations between SPARC immunoreactivity and prognosis of invasive oral SCCs. Cell proliferation was down-regulated by SPARC siRNA, and enhanced by SPARC transformed keratinocytes. But SPARC overexpression did not enhance cell migration activity. SPARC is induced by dysplastic cells in the early stage of cancerization, and may improve survival capability, but is not involved in malignancy. SPARC may act to escape from elimination by cell competition.
Tomohiro Yamada, Naoya Kitamura, Eri Sasabe and Tetsuya Yamamoto : Plasmablastic lymphoma of the upper gingiva in an HIV-negative elderly patient, Oral and Maxillofacial Surgery Cases, 1, 2, 19-24, 2015.
(要約)
AbstractPlasmablastic lymphoma (PBL) is a highly aggressive variant of diffuse large B-cell lymphoma and is usually treated by chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens. However, elderly patients tend to have difficulty with the chemotherapy. We successfully treated an HIV-negative elderly PBL patient with surgery alone. An 87-year-old Japanese man was referred to our hospital because of gingival swelling of the left maxilla. After several examinations, a multilobular 3-cm tumor of the left maxilla and lymph node swelling on the left side of the neck were revealed. The patient was HIV negative and human T-cell leukemia virus negative. He was diagnosed with PBL, or undifferentiated carcinoma/sarcoma, and we performed surgical therapy, radical neck dissection, and a partial maxillectomy. The surgical margin of the resected specimen was negative for tumor cells, and 6 of 27 lymph nodes contained tumor cells. Histologically, the tumor consisted of basophilic large cells with deviated nuclei. Together with the immunohistochemical findings, the final diagnosis was PBL. The patient and his family did not agree to chemotherapy. Nineteen months after surgery, he is fine and no signs of recurrence were observed. Surgery-only therapy may be a reasonable alternative for elderly PBL patients.
(キーワード)
Oral / RD1-811 / Gingiva / Maxilla / HIV negative / Surgery / Plasmablastic lymphoma
Naoya Kitamura, Riki Tomita, Mayo Yamamoto, Yasumasa Yoshizawa, Eri Sasabe, Tomohiro Yamada and Tetsuya Yamamoto : Complete remission of Merkel cell carcinoma on the upper lip treated with radiation monotherapy and a literature review of Japanese cases, World Journal of Surgical Oncology, 13, 152, 2015.
(要約)
Merkel cell carcinoma is a rare and aggressive neuroendocrine-derived skin cancer arising most commonly on the sun-exposed head and neck skin of elderly and immunocompromised patients. Although a combination of wide excision and adjuvant radiotherapy is the optimal therapeutic approach for Merkel cell carcinoma, radiation monotherapy has recently been recommended for unresectable tumors. We report here a case of Merkel cell carcinoma treated with radiation monotherapy and reviewed Merkel cell carcinoma cases treated with radiotherapy alone in Japan. A 75-year-old man was referred for treatment of a tumor on the upper lip with a swollen submental lymph node. The histopathological diagnosis from biopsied material was Merkel cell carcinoma (T3N1bM0, stage IIIB). The submental lymph node was extirpated and radiation monotherapy was applied according to the 2014 National Comprehensive Cancer Network Guidelines because the Eastern Cooperative Oncology Group Performance Status of the patient was grade 3 and the patient and his family did not desire surgery. The primary site and bilateral upper neck regions were irradiated with 45 Gy followed by 20 Gy irradiation for the primary site alone. Three months after radiotherapy, the tumor seemed to have completely remitted. Approximately 1 year after radiotherapy, no evidence of local recurrence or late metastasis has been noted. Radiation monotherapy should be considered as a curative treatment for Merkel cell carcinoma, particularly in situations where extensive surgery is not favored.
Tomohiro Yamada, Mayu Takahashi, Manabu Matsumoto, Makoto Toi, Seiji Ohno, Naoya Kitamura, Eri Sasabe and Tetsuya Yamamoto : Mucinous Cystadenoma in the Upper Lip: Report of Two Cases, International Journal of Surgical Pathology, 22, 4, 364-368, 2014.
(要約)
Mucinous cystadenoma of the salivary gland is a very rare disease, and only a few cases have been reported. We report here 2 cases of mucinous cystadenoma in the upper lip. The first case was a 57-year-old man and the second was a 42-year-old woman. The tumors were painless nodules with a smooth-surfaced mucosa, and surgical excisions were performed. Histologically, the tumors were surrounded by a fibrous capsule and were composed of multiple cysts lined with columnar epithelial cells. The tumor cells contain mucous substances that reacted with periodic acid-Schiff base and Alcian blue. Immunohistochemical staining revealed that the tumor cells expressed cytokeratin (AE1/3 and CK7), but their immunoreactivity with MIB-1 (Ki-67) was less than 3%. They had negative immunoreactivity for neuroectoderm markers, S-100 protein, and myoepithelial markers, p63, α-smooth muscle actin, and calponin, except for the accompanying myoepithelial-like cells. No recurrences were noted after surgery at 7 years and 1 year, respectively.
Tomohiro Yamada, Azumi Hirata, Eri Sasabe, Tomohide Yoshimura, Seiji Ohno, Naoya Kitamura and Tetsuya Yamamoto : TCDD disrupts posterior palatogenesis and causes cleft palate, Journal of Cranio-Maxillo-Facial Surgery, 42, 1, 1-6, 2014.
(要約)
Dioxins (e.g. 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) cause cleft palate at a high rate. A post-fusional split may contribute to the pathogenesis, and tissue fragility may be a concern. The objective of this study was to investigate the effects of TCDD on the palatal epithelium, bone and muscle, which contribute to tissue integrity. ICR mice (10-12 weeks old) were used. TCDD was administered on E12.5 at 40 mg/kg. Immunohistochemical staining for AhR, ER-α, laminin, collagen IV, osteopontin, Runx2, MyoD, and desmin were performed. Furthermore, western blot analysis for osteopontin, Runx2, MyoD, and desmin were performed to evaluate protein expression in the palatal tissue. Immunohistologically, there was little difference in the collagen IV and laminin localization in the palatal epithelium between control versus TCDD-treated mice. Runx2 and osteopontin immunoreactivity decreased in the TCDD-treated palatal bone, and MyoD and desmin decreased in the TCDD-treated palatal muscle. AhR and ER-α immunoreactivity were localized to the normal palatal bone, but ER-α was diminished in the TCDD-treated palate. On western blot analysis, Runx2, MyoD, and desmin were all downregulated in the TCDD-treated palate. TCDD may suppress palatal osteogenesis and myogenesis via AhR, and cause cleft palates via a post-fusional split mechanism, in addition to a failure of palatal fusion.
Tomohiro Yamada, Tomohide Yoshimura, Naoya Kitamura, Eri Sasabe, Seiji Ohno and Tetsuya Yamamoto : Low-grade myofibroblastic sarcoma of the palate, International Journal of Oral Science, 4, 3, 170-173, 2012.
(要約)
Low-grade myofibroblastic sarcoma (LGMS) is a rare, malignant tumor with myofibroblastic differentiation. Despite it being classified as a distinct entity by the World Health Organization, a few cases were reported in the oral and maxillofacial region. Here, a LGMS developed on the palate of a 73-year-old man who presented with a 1-cm tumor on the posterior border of the palate. Based on the histological and immunohistochemical features, a diagnosis of LGMS was established. The tumor was resected, and no recurrence was observed over 2 years. Although the tongue is the most preferred site for LGMS, it may occur in any region of the oral cavity.
Tomohiro Yamada, Moritoshi Uchida, Kang Kwang-Lee, Naoya Kitamura, Tomohide Yoshimura, Eri Sasabe and Tetsuya Yamamoto : Correlation of metabolism/hypoxia markers and fluorodeoxyglucose uptake in oral squamous cell carcinomas, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 113, 4, 464-471, 2012.
(要約)
The objective of this study was to analyze the relationship between the uptake of (18)F-2-fluoro-2-deoxy-d-glucose (FDG) by positron emission tomography-computerized tomography (PET-CT) and glucose metabolism/hypoxia markers in oral squamous cell carcinoma (OSCC). Thirty-six patients with OSCC (tongue [n = 23], buccal mucosa [n = 7], and floor of the mouth [n = 6]) were assessed and underwent incisional biopsy and subsequently received FDG-PET-CT. Expressions of hypoxia-inducible factor 1α (HIF-1α), glucose transporter protein 1 (GLUT-1), hexokinase-II (HK-II), and glucose-6-phosphatase (G6Pase) were immunohistochemically quantified, and FDG uptake was evaluated by the maximum standardized uptake values (SUV(max)) at the primary tumor site. FDG uptake was found to be significantly correlated with the T classification of OSCC but not with other clinicopathologic characteristics, such as the N classification, clinical type, and histologic grade of malignancy. In the early-stage (T1 and T2) tumor, FDG uptake was significantly associated with the expression levels of GLUT-1, HK II, and HIF-1α, and the expression levels of GLUT-1 and HK-II significantly correlated with HIF-1α expression levels. However, there were no correlations between the expression levels of these molecules and SUV(max) in the late-stage (T3 and T4) tumor. FDG uptake was significantly associated with the expression levels of glucose metabolism-related molecules, such as GLUT-1, HK II, and HIF-1α, especially in early-stage tumors.
Tomohide YOSHIMURA, Seiji OHNO, Naoya Kitamura, Eri SASABE, Tomohiro YAMADA and Tetsuya YAMAMOTO : A case of intravascular papillary endothelial hyperplasia in the alveolar mucosa, Journal of The Japanese Stomatological Society, 61, 2, 233-236, 2012.
H Satake, T Yamada, Naoya Kitamura, T Yoshimura, E Sasabe and T Yamamoto : Post-surgical unilateral temporomandibular joint dislocation treated by open reduction followed by orthodontic treatment, International Journal of Oral and Maxillofacial Surgery, 40, 3, 335-338, 2011.
(要約)
A case of prolonged unilateral temporomandibular joint (TMJ) dislocation, which was treated by open surgical reduction and post-surgical orthodontic therapy, is presented. A 58-year-old woman presented complaining of facial asymmetry and malocclusion. She had received surgery for a malignant tumour in the right retromolar region 7 years previously. It was considered that contraction of the pterygoid muscle by surgical injury caused anterior meniscal displacement and TMJ dislocation. Since manual manipulation failed, direct open reduction was performed after separation of the lateral pterygoid muscle from the condylar head and removal of the intra-articular scar tissues. Although the condylar head was returned to the glenoid fossa, optimal occlusion was not obtained because of compensatory tooth movement and inclination. Satisfactory occlusion and symmetric facial appearance were brought about by post-surgical orthodontic therapy.
Chika Koike, Taketoshi Mizutani, Taiji Ito, Yasuhito Shimizu, Nobutake Yamamichi, Takashi Kameda, Eiji Michimukai, Naoya Kitamura, Tetsuji Okamoto and Hideo Iba : Introduction of wild-type patched gene suppresses the oncogenic potential of human squamous cell carcinoma cell lines including A431, Oncogene, 21, 17, 2670-2678, 2002.
(要約)
Defects in a developmental signaling pathway involving the mammalian homologue of the Drosophila segment polarity gene, patched are associated with human tumors such as basal cell carcinoma, medulloblastoma and squamous cell carcinoma. Loss of heterozygosity (LOH) in some of these tumor cells suggests that patched functions as a tumor suppressor gene. To evaluate the biological significance of patched mutations in human sporadic tumor cells, we constructed a VSV-G pseudotyped retrovirus vector carrying the wild-type patched gene and transduced it into two human squamous cell carcinoma (SCC) cell lines, A431 and KA, that express only mutant patched mRNA. When SSC cells were transduced with Ptc virus, colony forming activity in soft agar was drastically reduced and these cells recovered anchorage independent growth when Sonic hedgehog (Shh), the ligand of Patched (Ptc), was added into the soft agar culture. Expression of exogenous patched, however, had no effect on anchorage independent growth of Ras-transformed NIH3T3 cells or SCC cell line, NA, which expresses wild-type patched mRNA. Cyclopamine, a specific inhibitor of the Shh/Ptc/Smo signaling pathway, efficiently suppressed anchorage independent growth of A431 and KA cells. These results indicate that loss of patched function plays a major role in the acquisition of oncogenic potential in these SCCs and further that Ptc virus would be an effective reagent for suppressing tumorigenicity of such SCCs.
Eiji Michimukai, Naoya Kitamura, Yan Zhang, Hua Wang, Yoshiko Hiraishi, Ken-Saku Sumi, Yasutaka Hayashido, Shigeaki Toratani and Tetsuji Okamoto : Mutations in the human homologue of the drosophila segment polarity gene patched in oral squamous cell carcinoma cell lines, In Vitro Cellular & Developmental Biology. Animal, 37, 7, 459-464, 2001.
(要約)
In the present study, we have analyzed tumor deoxyribonucleic acid from oral squamous cell carcinoma (OSCC) cells for patched mutations using an exon-by-exon single strand conformation polymorphism assay and direct sequencing. We found two missense mutations which affected the conserved residue in the transmembrane domains of the gene product and in the intracellular loop at the C-terminal residue implicated in regulating the smoothened molecule. In addition, we demonstrated that the N-terminal fragment of sonic hedgehog (Shh-N) stimulates the growth of normal epithelial cells, the OSCC cell line, NA, and the salivary gland adenocarcinoma cell lines, HSG and HSY, which have no detectable mutation in patched. On the other hand, Shh has no effect on human SCC cells (UE, KA, KO, NI, A431 cells) that have mutations in patched. These results strongly suggest that an Shh-patched signaling is involved in the cell growth of oral epithelial cells and in the tumorigenesis of OSCCs.
Seiichiro Kamimura, Keisuke Ishitani, Morozumi R., Tatsuya Fujii and Naoya Kitamura : Two cases of chronic rhinosinusitis associated with EGPA exhibiting different responses to mepolizumab, European rhinologic society 2025, Budapest, Hungary, Jun. 2025.
2.
Yukio Yoshioka, Takaaki Okanishi, Yuma Ishida, Kanako Sugawara, Kie Nakatani, Jumpei Shirakawa, Eri Sasabe, Naoya Kitamura and Tetsuya Yamamoto : Two cases of mandibular reconstruction using the custom-made plates made in Japan, 16th Asian Congress of Oral & Maxillofacial Surgery, Chennai, India, Jul. 2024.
3.
Naoya Kitamura, Yumiko Hashida, Tomonori Higuchi, Eri Sasabe, Masanori Daibata and Tetsuya Yamamoto : Detection of Merkel cell polyomavirus in multiple primary oral squamous cell carcinomas, Taiwanese Association of Oral & Maxillofacial Surgeons, The 35th Annual Conference on Oral and Maxillofacial Surgery, Taipei, Mar. 2023.