Faculty Profiles - NAGATSUKA Hitoshi

Papers - NAGATSUKA Hitoshi

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Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer Reviewed International journal

Saori Yoshida, Hotaka Kawai, Takanori Eguchi, Shintaro Sukegawa, May Wathone Oo, Chang Anqi, Kiyofumi Takabatake, Keisuke Nakano, Kuniaki Okamoto, Hitoshi Nagatsuka

CELLS 8 ( 7 ) 2019.7

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

CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis, thereby supporting tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To uncover the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as tumor angiogenic inhibition triggered necrosis (TAITN), which was induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic areas with the induction of hypoxia-inducible factor-1a in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.

DOI： 10.3390/cells8070761

ハニカムTCPの幾何学構造による血管新生を介した選択的骨・軟骨組織形成制御

高畠清文, 辻極秀次, 浜田芽衣, 河合穂高, 吉田沙織, 大森悠加, 中野敬介, 長塚仁

日本口腔科学会雑誌 68 ( 2 ) 179 - 179 2019.7

Locally injected ivabradine inhibits carrageenan-induced pain and inflammatory responses via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels Reviewed International journal

Saki Miyake, Hitoshi Higuchi, Yuka Honda-Wakasugi, Maki Fujimoto, Hotaka Kawai, Hitoshi Nagatsuka, Shigeru Maeda, Takuya Miyawaki

PLoS ONE 14 ( 5 ) e0217209 2019.5

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

Background Recently, attention has been focused on the role of hyperpolarization-activated cyclic nucleotide- gated (HCN) channels in the mechanism of and as a treatment target for neuropathic and inflammatory pain. Ivabradine, a blocker of HCN channels, was demonstrated to have an effect on neuropathic pain in an animal model. Therefore, in the present study, we evaluated the effect of ivabradine on inflammatory pain, and under the hypothesis that ivabradine can directly influence inflammatory responses, we investigated its effect in in vivo and in vitro studies. Methods After approval from our institution, we studied male Sprague-Dawley rats aged 8 weeks. Peripheral inflammation was induced by the subcutaneous injection of carrageenan into the hindpaw of rats. The paw-withdrawal threshold (pain threshold) was evaluated by applying mechanical stimulation to the injected site with von Frey filaments. Ivabradine was subcutaneously injected, combined with carrageenan, and its effect on the pain threshold was evaluated. In addition, we evaluated the effects of ivabradine on the accumulation of leukocytes and TNF-alpha expression in the injected area of rats. Furthermore, we investigated the effects of ivabradine on LPS-stimulated production of TNF-alpha in incubated mouse macrophage- like cells. Results The addition of ivabradine to carrageenan increased the pain threshold lowered by carrageenan injection. Both lamotrigine and forskolin, activators of HCN channels, significantly reversed the inhibitory effect of ivabradine on the pain threshold. Ivabradine inhibited thecarrageenan-induced accumulation of leukocytes and TNF-alpha expression in the injected area. Furthermore, ivabradine significantly inhibited LPS-stimulated production of TNFalpha in the incubated cells. Conclusion The results of the present study demonstrated that locally injected ivabradine is effective against carrageenan-induced inflammatory pain via HCN channels. Its effect was considered to involve not only an action on peripheral nerves but also an anti-inflammatory effect.

DOI： 10.1371/journal.pone.0217209

Notch signaling affects oral neoplasm cell differentiation and acquisition of tumor-specific characteristics Reviewed International journal

Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Saori Yoshida, Hatsuhiko Maeda, Toshiyuki Kawakami, Hitoshi Nagatsuka

International Journal of Molecular Sciences 20 ( 8 ) 2019.4

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

Histopathological findings of oral neoplasm cell differentiation and metaplasia suggest that tumor cells induce their own dedifferentiation and re-differentiation and may lead to the formation of tumor-specific histological features. Notch signaling is involved in the maintenance of tissue stem cell nature and regulation of differentiation and is responsible for the cytological regulation of cell fate, morphogenesis, and/or development. In our previous study, immunohistochemistry was used to examine Notch expression using cases of odontogenic tumors and pleomorphic adenoma as oral neoplasms. According to our results, Notch signaling was specifically associated with tumor cell differentiation and metaplastic cells of developmental tissues. Notch signaling was involved in the differentiation of the ductal epithelial cells of salivary gland tumors and ameloblast-like cells of odontogenic tumors. However, Notch signaling was also involved in squamous metaplasia, irrespective of the type of developmental tissue. In odontogenic tumors, Notch signaling was involved in epithelial–mesenchymal interactions and may be related to tumor development and tumorigenesis. This signaling may also be associated with the malignant transformation of ameloblastomas. Overall, Notch signaling appears to play a major role in the formation of the characteristic cellular composition and histological features of oral neoplasms, and this involvement has been reviewed here.

DOI： 10.3390/ijms20081973

動物モデルを用いた高転移臓器における転移促進的微小環境の検討

河合穂高, 辻極秀次, メイワト・ウ, 吉田沙織, 高畠清文, 中野敬介, 長塚仁

日本病理学会会誌 108 ( 1 ) 293 - 293 2019.4

口腔扁平上皮癌におけるCXCR4の腫瘍血管新生への関与

吉田沙織, 河合穂高, Chang Anqi, 高畠清文, 浜田芽衣, 藤井昌江, 中野敬介, 長塚仁

日本病理学会会誌 108 ( 1 ) 335 - 335 2019.4

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma Reviewed International journal

Rieko Shimizu, Soichiro Ibaragi, Takanori Eguchi, Daisuke Kuwajima, Shinichi Kodama, Takashi Nishioka, Tatsuo Okui, Kyoichi Obata, Kiyofumi Takabatake, Hotaka Kawai, Kisho Ono, Kuniaki Okamoto, Hitoshi Nagatsuka, Akira Sasaki

International Journal of Oncology 54 ( 1 ) 283 - 294 2019.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Epidermal growth factor (EGF) is overexpressed in many cancers and is associated with worse prognosis. EGF binds to its cell surface receptor (EGFR), which induces EGFR phosphorylation. Phosphorylated EGFR (p-EGFR) is translocated into the nucleus, which increases cancer cell activity. Nicotine, which is one of the main components of tobacco, is absorbed through pulmonary alveoli and mucosal epithelia in the head and neck region by smoking and moves into the blood. Nicotine in blood binds to nicotinic acetylcholine receptor (nAChR) in the central nervous system and serves a crucial role in tobacco addiction. Although nAChR localization is thought to be limited in the nervous system, nAChR is present in a wide variety of non-neuronal cells, including cancer cells. Recent studies suggest that nicotine contributes to the metastasis and resistance to anti-cancer drugs of various cancer cells. However, it remains unknown whether head and neck squamous cell carcinoma (HNSCC) cells can utilize nicotine-nAChR signaling to metastasize and acquire resistance to anti-cancer drugs, even though the mucosal epithelia of the head and neck region are the primary sites of exposure to tobacco smoke. To the best of our knowledge, the present study is the first to demonstrate the role of nicotine in metastasis and anti-EGFR-therapy resistance of HNSCC. The present findings demonstrated that nicotine increased proliferation, migration, invasion, p-EGFR nuclear translocation and protein kinase B (Akt) phosphorylation in HNSCC cells. It was also demonstrated that nicotine restored cetuximab-inhibited proliferation, migration and invasion of HNSCC cells. Finally, an in vivo experiment revealed that nicotine increased lymph node metastasis of xenografted tumors, whereas an nAChR inhibitor suppressed lymph node metastasis and p-EGFR nuclear localization of xenografted tumors. Taken together, these results demonstrated that nicotine induced nuclear accumulation of p-EGFR, and activation of Akt signaling. These signaling pathways elevated the activities of HNSCC cells, causing lymph node metastasis and serving a role in cetuximab resistance.

DOI： 10.3892/ijo.2018.4631

Immunohistochemistry of YAP and dNp63 and survival analysis of patients bearing precancerous lesion and oral squamous cell carcinoma Reviewed International journal

Sawako Ono, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka

International Journal of Medical Sciences 16 ( 5 ) 766 - 773 2019

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

Background: Yes-associated protein (YAP) is a candidate oncogene in various human cancers, and recently, it has been reported that YAP expression and its activity was enhanced by ΔNp63. However, the role of YAP and ΔNp63 expression in carcinogenesis and progression of oral squamous cell carcinoma (OSCC) has been unknown. Therefore, we investigated how YAP and ΔNp63 influence carcinogenesis and progression of OSCC. Methods: We performed immunohistochemical analyses in whole tissue samples to investigate YAP and ΔNp63 expression in normal oral mucosa, epithelial hyperplasia, oral epithelial dysplasia (OED; low/high grade), carcinoma in situ (CIS), and OSCC. Furthermore, in OSCC, we analyzed clinical significance by using Kaplan-Meier survival analysis. Results: In normal oral mucosa and epithelial hyperplasia, YAP expression was primarily confined to the basal and parabasal layers, but YAP expression was elevated in OED, CIS, and OSCC. In OED, YAP and ΔNp63 expression levels were markedly higher in high grade than in low grade. In OSCC groups, YAP and ΔNp63 expression patterns tended to differ according to histopathological differentiation of OSCC. Furthermore, the YAP high expression group, which showed YAP staining in >50% positive cells with strong cytoplasmic staining or >10% positive cells with nuclear reactivity, showed a tendency to have a poor survival rate. Conclusion: YAP and ΔNp63 expression levels correlated with grade of oral OED. Additionally, YAP expression was associated with OSCC survival rate. Our results suggested that YAP and ΔNp63 expression might serve as predictive markers to distinguish OSCC development and progression.

DOI： 10.7150/ijms.29995

In vivo tissue response of endodontic bio-ceramic materials

Teresita Romano, María Victoria Jammal, Keisuke Nakano, Ana García Rusco, Jorge Olmos Fassi, Silvia Kozuszko, Kiyofumi Takabatake, Hitoshi Nagatsuka, Liliana Raquel Missana

Journal of Hard Tissue Biology 28 ( 1 ) 1 - 6 2019

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL HARD TISSUE BIOLOGY

In order to evaluate the biocompatibility and mineral repair capacity, mineral trioxide aggregate (MTA), portland cement normal setting (PCn) and fast setting (PCf) and calcium hydroxide-based paste (Calen) filled silicone tube were implanted into the dorsal subcutaneous connective tissues of 25 Wistar rats. Animals were euthanized at 24, 72 hours, 7, 15 and 30 days. Implants with surrounding tissues were fixed with 10% buffer formaldehyde and processed for histological routine techniques. Slides (5 µm serial cuts) were stained with H&E and Von Kossa stains for morphological, qualitative and quantitative analysis by light microscopy. Calen showed severe and moderate inflammatory response and granuloma-tous reaction with psammoma body-like formation. PCn and MTA have similar behavior, with mild inflammatory reaction from 8% and 4%, respectively. Even though, PCn and MTA demonstrated analogous biological reaction, MTA developing thick artificial mineral precipitation (p = 0,007). All sealers demonstrated a similar inflammatory response at all time periods studied (p = 0.678).

DOI： 10.2485/jhtb.28.1

Whitish-Yellow Tumor on its Characteristic Cut Surface: A Case Report of Congenital Granular Cell Epulis

Kenichi Mizutani, Munenori Mukai, Hitoshi Nagatsuka, Sohsuke Yamada

Clinical Pathology 12 2019

Publishing type：Research paper (scientific journal)

Introduction: Congenital granular cell epulis is a rare and benign lesion in newborn. There are some papers of the entity; however, there are very few reports focusing on its macroscopic view. Case Presentation: A 0-day-old boy was noted to have a mass consisting of multiple nodules on maxillary gingiva, and it was excised. The mass was measured about 2 cm in its greatest diameter. Surface of cross-section was characteristically whitish-yellow and very smooth. Histopathologically, the lesion was composed of a proliferation of large polygonal cells with demarcated cell membrane, granular cytoplasm, and small uniform nuclei. Immunohistochemically, these cells were negative for S100. The diagnosis was concluded as congenital granular cell epulis. Discussion and Conclusion: We reported a typical case of congenital granular cell epulis. It is noteworthy that the cross-section observed in this case was very characteristically whitish-yellow and smooth.

DOI： 10.1177/2632010X19831257

An in vitro three-dimensional co-culture system for ameloblastoma modelling Reviewed

Soo Leng Lee, Zainal Ariff Abdul Rahman, Hidetsugu Tsujigiwa, Mei Hamada, Kiyofumi Takabatake, Keisuke Nakano, Hitoshi Nagatsuka, Chong Huat Siar

Sains Malaysiana 48 ( 8 ) 1697 - 1706 2019

Language：English Publishing type：Research paper (scientific journal) Publisher：UNIV KEBANGSAAN MALAYSIA

Ameloblastoma, the most clinically significant odontogenic epithelial tumor, is a locally-invasive and destructive lesion in the jawbones. However, the nature of this infiltrativeness and destructive behavior remains ill-understood. To address this, we established an in vitro three-dimensional (3D) co-culture system to simulate an amelobastoma disease model aimed at investigating the interactions between tumor cells and osteoblasts. Osteoblastic cell lines (KUSA/A1 and MC3T3-E1) and one stromal cell line (ST2) were separately co-seeded with ameloblastoma-derived cell line (AM-1) in a collagen scaffold (representing the extracellular bone matrix) and incubated with mineralization medium. Immunohistochemistry, double immunofluorescence and mineralization assay were performed. Only AM-1/KUSA-A1 co-culture showed a significant increase in AM-1 cell count, suggesting that heterotypic cell-cell interaction promotes tumoral cell growth, while formation of visible AM-1 epithelial nest-like structures resembling ameloblastoma cells in their native state, suggest morphodifferentiation. A RANK-high, RANKL-low and osteoprotegerin-low immunoprofile in co-culture AM-1 cells implies deregulated osteoclastogenesis. Mineralization assays showed diminished calcification in AM-1/KUSA-A1 co-culture extracellular matrix suggesting an altered local bone metabolism. In contrast, KUSA/A1 monocultures showed abundant extracellular matrix calcification. Taken together, these results suggest that a 3D co-culture system as an amelobastoma disease model provides insights that bidirectional ameloblastoma-osteoblastic interactions might play a role in modulating tumor growth and osteoclastogenesis.

DOI： 10.17576/jsm-2019-4808-15

Biomechanical loading comparison between titanium and unsintered hydroxyapatite/poly-L-lactide plate system for fixation of mandibular subcondylar fractures Reviewed International journal

Shintaro Sukegawa, Takahiro Kanno, Norio Yamamoto, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

Materials 12 ( 9 ) 2019

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

Osteosynthesis absorbable materials made of uncalcined and unsintered hydroxyapatite (u-HA) particles, poly-l-lactide (PLLA), and u-HA/PLLA are bioresorbable, and these plate systems have feasible bioactive osteoconductive capacities. However, their strength and stability for fixation in mandibular subcondylar fractures remain unclear. This in vitro study aimed to assess the biomechanical strength ofu-HA/PLLAbioresorbable plate systems after internal fixation of mandibular subcondylar fractures. Tensile and shear strength were measured for each u-HA/PLLA and titanium plate system. To evaluate biomechanical behavior, 20 hemimandible replicas were divided into 10 groups, each comprising a titanium plate and a bioresorbable plate. A linear load was applied anteroposteriorly and lateromedially to each group to simulate the muscular forces in mandibular condylar fractures. All samples were analyzed for each displacement load and the displacement obtained by the maximum load. Tensile and shear strength of the u-HA/PLLA plate were each approximately 45% of those of the titanium plates. Mechanical resistance was worst in the u-HA/PLLA plate initially loaded anteroposteriorly. Titanium plates showed the best mechanical resistance during lateromedial loading. Notably, both plates showed similar resistance when a lateromedially load was applied. In the biomechanical evaluation of mandibular condylar fracture treatment, the u-HA/PLLA plates had sufficiently high resistance in the two-plate fixation method.

DOI： 10.3390/ma12091557

Feasible advantage of bioactive/bioresorbable devices made of forged composites of hydroxyapatite particles and poly-L-lactide in alveolar bone augmentation: A preliminary study Reviewed International journal

Shintaro Sukegawa, Hotaka Kawai, Keisuke Nakano, Takahiro Kanno, Kiyofumi Takabatake, Hitoshi Nagatsuka, Yoshihiko Furuki

International Journal of Medical Sciences 16 ( 2 ) 311 - 317 2019

Language：English Publishing type：Research paper (scientific journal) Publisher：IVYSPRING INT PUBL

Purpose: We aimed to document the clinical usefulness of uncalcined and unsintered hydroxyapatite (u-HA) particles and poly-L-lactide (PLLA) composite materials and their advantageous properties. Methods: Between April 2016 and March 2018, five patients required anterior maxillary alveolar ridge augmentation using fixation with u-HA/PLLA screws for an onlay block bone graft harvested from the mandibular ramus at our institute. Bone biopsies were obtained from the dental implantation site following bone healing for histomorphometric and immunohistochemical (IHC) measurements. Results: Many stromal cells were positive for Osterix, RUNX2, and SOX9 but were negative for CD68. On cell counting, based on IHC staining for Osterix, RUNX2, SOX9 and CD68 from peripheral u-HA/PLLA screw or bone areas, both areas consistently showed no significant difference in terms of Osterix, RUNX2, and SOX9. Hematoxylin-eosin staining revealed direct bone connection to the biomaterials, and no inflammatory cells infiltrated the areas surrounding the bone or artificial material. Area between the bone and u-HA/PLLA screw was seamless with no boundary. Round small cells and immature fibroblasts were noted. The new bone showed the presence of bone lamellae, normal osteocytes, and osteoblasts. Conclusion: The u-HA/PLLA materials showed excellent biodegradability and bioactive osteoconductivity. In addition, this material induced no apparent inflammatory or foreign body reactions following implantation, and it directly bonded to the human bone. Therefore, this u-HA/PLLA material seems ideal and most suitable for use as a substitute for osteosynthesis.

DOI： 10.7150/ijms.27986

Differentiation and roles of bone marrow-derived cells on the tumor microenvironment of oral squamous cell carcinoma Reviewed International journal

Chang Anqi, Kiyofumi Takabatake, Hotaka Kawai, O. O. May Wathone, Saori Yoshida, Masae Fujii, Haruka Omori, Shintaro Sukegawa, Keisuke Nakano, Hidetsugu Tsujigiwa, Zheng Jinhua, Hitoshi Nagatsuka

Oncology Letters 18 ( 6 ) 6628 - 6638 2019

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

The stroma affects the properties and dynamics of the tumor. Previous studies have demonstrated that bone marrow-derived cells (BMDCs) possess the capability of differentiating into stromal cells. However, the characteristics and roles of BMDCs in oral squamous cell carcinoma remain unclear. The current study therefore investigated their locations and features by tracing green fluorescent protein (GFP)-labeled BMDCs in a transplantation mouse model. After irradiation, BALB-c nu-nu mice were injected with bone marrow cells from C57BL/6-BALB-C-nu/nu-GFP transgenic mice. These recipient mice were then injected subcutaneously in the head with human squamous cell carcinoma-2 cells. Immunohistochemistry for GFP, Vimentin, CD11b, CD31 and α-smooth muscle actin (SMA), and double-fluorescent immunohistochemistry for GFP-Vimentin, GFP-CD11b, GFP-CD31 and GFP-α-SMA was subsequently performed. Many round-shaped GFP-positive cells were observed in the cancer stroma, which indicated that BMDCs served a predominant role in tumorigenesis. Vimentin(+) GFP(+) cells may also be a member of the cancer-associated stroma, originating from bone marrow. Round or spindle-shaped CD11b(+) GFP(+) cells identified in the present study may be macrophages derived from bone marrow. CD31(+)GFP(+) cells exhibited a high tendency towards bone marrow-derived angioblasts. The results also indicated that spindle-shaped α-SMA(+) GFP(+) cells were not likely to represent bone marrow-derived cancer-associated fibroblasts. BMDCs gathering within the tumor microenvironment exhibited multilineage potency and participated in several important processes, such as tumorigenesis, tumor invasion and angiogenesis.

DOI： 10.3892/ol.2019.11045

Do the presence of mandibular third molar and the occlusal support affect the occurrencand the mode of mandibular condylar fractures? Reviewed

Shintaro Sukegawa, Masato Saika, Takahiro Kanno, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

Journal of Hard Tissue Biology 28 ( 4 ) 377 - 382 2019

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL HARD TISSUE BIOLOGY

To investigate the influence of occlusal support and the presence and position of mandibular third molars on the incidence of mandibular condylar fractures. Records of 222 patients who presented with mandibular fracture at the Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, from 2006 to 2019 were retrospectively analyzed. The following variables were investigated: age, sex, cause of fracture, the presence and state (impaction and angula-tion) of mandibular third molars, the site of mandibular fracture, and the presence of occlusal support for molars. Various risk factors for mandibular condylar head and subcondylar fractures were investigated. The majority of fractures were caused by a fall. The risk of mandibular subcondylar fractures was significantly higher in patients with occlusal support and mandibular third molars. The risk of mandibular condylar head fractures was significantly higher in patients without occlusal support or mandibular third molars. The position and angulation of mandibular third molars did not show significant difference between occurrences of head or subcondylar fractures. This study demonstrated that occlusal support and the presence of mandibular third molars significantly increased the risk of subcondylar fractures. One the contrary, their absence increased the risk of condylar head fractures.

DOI： 10.2485/jhtb.28.377

舌扁平上皮癌における新TNM分類(UICC:第8版)の実用性

吉田祥子, 岸本晃治, 村瀬友里香, 伊原木聰一郎, 吉岡徳枝, 奥井達雄, 長塚仁, 佐々木朗

日本口腔腫瘍学会誌 30 ( 4 ) 151 - 157 2018.12

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

UICCのTNM分類は、口腔癌の進行度評価の基準にされているが、2016年に第8版へ改訂され、T分類では浸潤の深さ(Depth of Invasion:DOI)が、N分類では被膜外進展(Extra Nodal Extension:ENE)が導入された。本研究では、当科で手術を行った舌扁平上皮癌症例107例において、第7版と第8版TNM分類により評価を行い、TNM分類改訂と頸部リンパ節後発転移(以下後発転移)および生存率との関連について検討を行った。TNM分類改訂により、17例(15.9%)にcTの変更を、6例(5.6%)にpTの変更を認めた。後発転移数・後発転移率は、cT1とpT1では低下し、cT2とpT2では増加した。また、第7版でcT4a、pT4aの2例が、第8版ではcT3、pT3に変更されたため、第8版は第7版と比較してcT3、pT3の生存率が低下した。第7版でpN2bの3例が、第8版ではpN3bに分類され、3例とも経過不良であった。当科の舌扁平上皮癌症例におけるTNM分類の第7版から第8版への見直しは、主にStage上昇につながった。そして、第8版TNM分類は、舌扁平上皮癌の進行度をより的確に後発転移と生存率へ反映させるため、実用的であると考えられた。(著者抄録)

ニコチンは口腔扁平上皮癌細胞のセツキシマブ耐性を促進する

清水理恵子, 伊原木聰一郎, 江口傑徳, 奥井達雄, 高畠清文, 河合穂高, 小野喜章, 岡元邦彰, 長塚仁, 佐々木朗

岡山歯学会雑誌 37 ( 2 ) 80 - 81 2018.12

口腔扁平上皮癌におけるPD-L1発現傾向の臨床病理学的解析

吉田沙織, 浜田芽衣, 藤井昌江, 河合穂高, 高畠清文, 中野敬介, 長塚仁, 安田政実

岡山歯学会雑誌 37 ( 2 ) 86 - 86 2018.12

Significance of PD-L1 expression in tongue cancer development Reviewed International journal

Saori Yoshida, Hitoshi Nagatsuka, Keisuke Nakano, Yasunao Kogashiwa, Yasuhiro Ebihara, Mitsutake Yano, Masanori Yasuda

International Journal of Medical Sciences 15 ( 14 ) 1723 - 1730 2018.10

Language：English Publishing type：Research paper (scientific journal) Publisher：IVYSPRING INT PUBL

Aims: Immunohistochemistry of PD-L1 has been recently established as a surrogate method to predict if immunotherapy targeting PD-L1/PD-1 has a significant effect on suppression of cancers such as lung non-small cell carcinoma, melanoma, and renal cell carcinoma. Here we performed immunohistochemistry for PD-L1 expression in squamous cell carcinoma (SCC) of the tongue to investigate the potential correlation between PD-L1 expression and clinicopathological factors and whether PD-L1 expression would be associated with prognosis. Methods: Tissue microarray cores of paraffin-embedded blocks from 135 cases with surgically resected tongue SCC were immunohistochemically analysed for PD-L1 expression. Results: We observed a positive correlation between PD-L1 expression and tongue SCC pT1 and pT2 tumours, but a negative correlation with pT2, pT3 and pT4 tumours. We also observed a positive correlation with lymph node metastasis. However, no positive correlation was demonstrated between PD-L1 expression and overall survival. Conclusions: PD-L1 tends to be overexpressed at the early stage of tongue SCC, showing a close correlation with initial development of tongue. However, PD-L1 expression may not affect prognosis.

DOI： 10.7150/ijms.27860

Effects of the geometrical structure of a honeycomb TCP on relationship between bone/ cartilage formation and angiogenesis Reviewed International journal

Hiroyuki Matsuda, Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Satoko Watanabe, Satoshi Ito, Hotaka Kawai, Mei Hamada, Saori Yoshida, Keisuke Nakano, Hitoshi Nagatsuka

International Journal of Medical Sciences 15 ( 14 ) 1582 - 1590 2018.10

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

A number of biomaterials have been developed, some of which already enjoy widespread clinic use. We have devised a new honeycomb tricalcium phosphate (TCP) containing through-and-through holes of various diameters to control cartilage and bone formation. However, the way in which the geometric structure of the honeycomb TCP controls cartilage and bone tissue formation separately remains unknown. In addition, an association has been reported between bone formation and angiogenesis. Therefore, in the present study, we investigated the relationship between angiogenesis and various hole diameters in our honeycomb TCP over time in a rat ectopic hard tissue formation model. Honeycomb TCPs with hole diameters of 75, 300, and 500 µm were implanted into rat femoral muscle. Next, ectopic hard tissue formation in the holes of the honeycomb TCP was assessed histologically at postoperative weeks 1, 2, and 3, and CD34 immunostaining was performed to evaluate angiogenesis. The results showed that cartilage formation accompanied by thin and poor blood vessel formation, bone marrow-like tissue with a branching network of vessels, and vigorous bone formation with thick linear blood vessels occurred in the TCPs with 75-µm, 300-µm, and 500-µm hole diameters, respectively. These results indicated that the geometrical structure of the honeycomb TCP affected cartilage and bone tissue formation separately owing to the induced angiogenesis and altered oxygen partial pressure within the holes.

DOI： 10.7150/ijms.28452

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