Hideki Nakayama

Kumamoto University, Kumamoto, Kumamoto, Japan

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Publications (65)182.37 Total impact

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  • [Show abstract] [Hide abstract]
    ABSTRACT: Clinical applications of a chemotherapeutic agent, 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) have been limited because of drug resistance. This study aimed to identify novel mechanisms of 5-FU resistance. Here we found increased osteopontin (OPN) gene expression in OSCC tissues with resistance to 5-FU-based chemoradiotherapy. OPN overexpression in OSCC cells led to 5-FU resistance and abrogated the prosurvival effect of the drug in a mouse xenograft model. OPN-induced 5-FU resistance required integrin αvβ3. Targeting integrin αvβ3 reversed the resistance in a 5-FU-resistant clone highly expressing OPN. Our data suggest that the OPN-integrin αvβ3 axis is crucial for 5-FU resistance in OSCC. Copyright © 2014. Published by Elsevier B.V.
    FEBS Letters 12/2014; 589(2). DOI:10.1016/j.febslet.2014.12.004 · 3.17 Impact Factor
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    ABSTRACT: It has been increasingly recognized that the tumour microenvironment is a critical factor involved in cancer progression. However, little is known about the clinical value of the stromal features in oral squamous cell carcinoma (OSCC). The purpose of this study was to determine the clinical significance of cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) in OSCC. OSCC specimens were obtained from 60 patients who underwent surgery following 5-fluorouracil-based chemoradiotherapy. Paraffin-embedded sections obtained from biopsy specimens were immunohistochemically analysed. The associations among CAFs, TAMs and various clinicopathological features were examined, and the effects of CAFs and TAMs on the prognosis were evaluated. In the group with a high level of CAFs, the incidence of advanced pT- and pN-stage cases was significantly higher than that in the group with the low level. A high TAMs tumour expression was significantly correlated with a poor response to preoperative chemoradiotherapy. A Kaplan–Meier analysis revealed that higher numbers of CAFs and TAMs were significantly correlated with a poor prognosis. These findings suggest that TAMs are a potential biomarker for predicting the clinical response to 5-FU-based chemoradiotherapy, and the expression status of the CAFs and TAMs may be useful for making treatment decisions to improve the survival of OSCC patients.
    Apmis 12/2014; 123(3). DOI:10.1111/apm.12344 · 2.04 Impact Factor
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    ABSTRACT: Dormant or slow-cycling disseminated tumor cells (DTCs) in bone marrow (BM) are resistant to conventional therapy in various cancers including head and neck squamous cell carcinoma (HNSCC), although the molecular mechanisms remain largely unknown. This study aimed to identify the intrinsic molecular mechanisms underlying drug resistance in BM-DTCs. We used in vivo selection of the human HNSCC cell line HEp3, which mimics non-proliferative BM-DTCs in mice, to establish BM-DTC-derived (BM-HEp3) and lung metastases-derived (Lu-HEp3) sublines. Both sublines had higher migration activity and shortened survival in a murine xenograft model compared with parental (P-HEp3) cells. Slow-cycling BM-HEp3 cells had intrinsically enhanced cisplatin resistance compared with Lu-HEp3 cells, which also manifested this resistance but proliferated rapidly. The drug resistance and slow-cycling state of BM-HEp3 cells depended on enhanced positive feedback of the signaling axis of stromal cell-derived factor-1 (SDF-1)-C-X-C chemokine receptor-4 (CXCR4) via their overexpression. Interestingly, BM-DTCs highly expressed transforming growth factor-beta 2 (TGF-β2) to maintain SDF-1-CXCR4 overexpression. Inhibition of SDF-1-CXCR4 signaling by down-regulating TGF-β2 fully reversed the drug resistance of BM-HEp3 cells via reactivation of cell proliferation. These data suggest that the intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance dependent on a slow-cycling state in BM-DTCs.
    Oncotarget 11/2014; 6(2). DOI:10.18632/oncotarget.2826 · 6.36 Impact Factor
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    ABSTRACT: Purpose: The peptides derived from ideal cancer-testis antigens, including LY6K, CDCA1, and IMP3 (identified using genome-wide cDNA microarray analyses), were used in immunotherapy for head and neck squamous cell cancer (HNSCC). In this trial, we analyzed the immune response to and safety and efficacy of vaccine therapy. Experimental design: A total of 37 patients with advanced HNSCC were enrolled in this trial of peptide vaccine therapy, and the OS, PFS, and immunologic response were evaluated using enzyme-linked ImmunoSpot (ELISPOT) and pentamer assays. The peptides were subcutaneously administered weekly with IFA. The primary endpoints were evaluated on the basis of differences between HLA-A*2402-positive [A24(+)] patients treated with peptide vaccine therapy and -negative [A24(-)] patients treated without peptide vaccine therapy among those with advanced HNSCC. Results: Our cancer vaccine therapy was well tolerated. The OS of the A24(+) vaccinated group (n = 37) was statistically significantly longer than that of the A24(-) group (n = 18) and median survival time (MST) was 4.9 versus 3.5 months, respectively; P < 0.05. One of the patients exhibited a complete response. In the A24(+) vaccinated group, the ELISPOT assay identified LY6K-, CDCA1-, and IMP3-specific CTL responses in 85.7%, 64.3%, and 42.9% of the patients, respectively. The patients showing LY6K- and CDCA1-specific CTL responses demonstrated a longer OS than those without CTL induction. Moreover, the patients exhibiting CTL induction for multiple peptides demonstrated better clinical responses. Conclusions: The immune response induced by this vaccine may improve the prognosis of patients with advanced HNSCC.
    Clinical Cancer Research 11/2014; 21(2). DOI:10.1158/1078-0432.CCR-14-0202 · 8.72 Impact Factor
  • International journal of radiation oncology, biology, physics 09/2014; 90(1):S506-S507. DOI:10.1016/j.ijrobp.2014.05.1556 · 4.26 Impact Factor
  • H. Ito · H. Nakayama · T. Nishii · K. Imai · S. Murakami · M. Okada · M. Masuda
    Interactive Cardiovascular and Thoracic Surgery 06/2014; 18(suppl 1):S34-S34. DOI:10.1093/icvts/ivu167.129 · 1.16 Impact Factor
  • T. Nishii · T. Yokose · Y. Miyagi · H. Ito · K. Yamada · H. Nakayama · M. Masuda
    Interactive Cardiovascular and Thoracic Surgery 06/2014; 18(suppl 1):S19-S19. DOI:10.1093/icvts/ivu167.72 · 1.16 Impact Factor
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    ABSTRACT: Adenomatoid odontogenic tumors (AOTs) are rare, benign odontogenic tumors characterized by a progressively slow growing pattern and asymptomatic behavior. The most common presentation is a cystic mass involving an unerupted tooth (especially canine), and the usual site is the anterior maxillary region. These tumors are histopathologically thought to arise from the odontogenic epithelium with or without inductive changes in the connective tissue. We herein report a rare case of AOT-like tumor arising in the first premolar region to the first molar region of the maxilla. A 33-year-old male was referred to our hospital for further evaluation of a round radiolucent lesion of the maxilla. After performing a biopsy, which confirmed the diagnosis of AOT, surgical excision was performed under general anesthesia. The tumor was encapsulated and relatively large (approximately 30 mm in maximal diameter) for an AOT. Furthermore, an unusual finding of the root resorption of adjacent teeth was observed. The histopathological examination showed duct-like structures composed of regularly single- or double-layered cuboidal cells; however, there were no duct-like structures composed of columnar epithelial cells characteristic of AOT. On the other hand, the existence of melanocytes, ghost cells, and CK19-positive cells suggests that our case was a benign odontogenic tumor. Taking all findings into account, we diagnosed this patient with an AOT-like, benign odontogenic tumor. The patient's postoperative course was uneventful, and no signs of recurrence have been found 2 years after the operation.
    05/2014; 27(2). DOI:10.1016/j.ajoms.2014.05.001
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    ABSTRACT: Kaposi's sarcoma (KS) is one of the most common diseases seen in patients presenting with acquired immunodeficiency syndrome (AIDS); however, it is rare in Japan. We herein report a case of AIDS-associated KS of the tongue, which was initially misdiagnosed as recurrent hemangioma according to the initial histopathological diagnosis. The patient is a 42-year-old male who had been suffering from a painful vascular neoplasm-like mass on the dorsum of the tongue. The patient did not complain of any other distinct symptoms and a debulking operation was planned based on the clinical diagnosis of hemangioma. However, preoperative blood tests revealed the presence of syphilis and the human immunodeficiency virus and the patient was therefore diagnosed to have full-blown AIDS. Therefore, the patient's oral lesion was then instead suspected to be oral KS (OKS). A histopathological examination of the tongue biopsy specimen showed the typical findings of KS. Combination active antiretroviral therapy (cART) combined with liposomal doxorubicin was administered and the patient achieved a complete remission (CR). In conclusion, clinicians including oral surgeons, should take OKS into account in the diagnosis of vascular neoplasm-like masses of the tongue in adults since this complication may occur as a result of AIDS.
    04/2014; 26(2):170–174. DOI:10.1016/j.ajoms.2012.12.008
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    ABSTRACT: The tumor-associated microenvironment has been shown to protect tumor cells from treatment, and the extracellular matrix (ECM) is known to affect drug resistance as a key regulator of the tumor microenvironment. However, little is known about cell adhesion-mediated drug resistance (CAM‑DR) due to cell-ECM contact in patients with oral squamous cell carcinoma (OSCC). In the present study, we evaluated the ECM molecule fibronectin (FN) using DNA microarray data obtained from parental and 5-FU-resistant OSCC cell lines. We investigated the effects of cell adhesion to FN on 5-FU resistance in OSCC cells and examined the activation of FN receptor β1 integrin‑mediated survival regulators such as ILK, Akt and NF-κB. In addition, we investigated whether FNIII14, a 22-mer peptide derived from FN that potently prevents β1 integrin-mediated adhesion to FN, could overcome CAM-DR against 5-FU in OSCC cells and examined the activation of survival regulators and apoptosis-related molecules. Consequently, we obtained the following results. FN was extracellularly overexpressed in the 5-FU-resistant cells compared with that observed in the 5-FU-sensitive cells. Cell adhesion to FN enhanced 5-FU resistance and activated integrin-mediated ILK/Akt/NF-κB survival signaling in the 5-FU-resistant OSCC cells. Furthermore, the inhibition of cell adhesion to FN by FNIII14 enhanced chemosensitivity to 5-FU and apoptosis by suppressing ILK/Akt/NF-κB signaling in the 5-FU-resistant cells. These novel findings demonstrate that FN is a potentially useful biomarker and therapeutic target for improving the treatment of OSCC, particularly in the setting of 5-FU resistance.
    International Journal of Oncology 01/2014; 44(4). DOI:10.3892/ijo.2014.2265 · 3.03 Impact Factor
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    ABSTRACT: The deregulation of microRNA (miRNA) is associated with multiple processes involved in cancer progression. RNase III endonucleases, Dicer and Drosha, are key enzymes for miRNA biogenesis, and it has been reported that altered expressions of these molecules affect the clinical outcomes of patients with various cancers. However, the clinical value of measuring the levels of Dicer and Drosha in oral squamous cell carcinoma (OSCC) patients is unclear. The purpose of this study was to determine the clinical significance of the expressions of Dicer and Drosha in patients with OSCC. Oral squamous cell carcinoma specimens were obtained from 61 patients who underwent surgery following 5-fluorouracil-based chemoradiotherapy at Kumamoto University Hospital between October 2003 and January 2009. Paraffin-embedded sections obtained from biopsy specimens were immunohistochemically analyzed. The associations between Dicer, Drosha, and various clinicopathological features were examined, and the effects of Dicer and Drosha on the prognosis were evaluated. A low Dicer tumor expression was significantly correlated with the pathological response to chemoradiotherapy. Furthermore, a Cox regression analysis based on the overall survival revealed the Dicer expression status (hazard ratio, 0.34; P = 0.048) and pathological response to chemoradiotherapy (hazard ratio, 0.21; P = 0.014) to be significant prognostic factors in OSCC patients. On the other hand, the Drosha expression was not associated with any clinicopathological features or the prognosis. These results suggest that Dicer is a potential biomarker for predicting the clinical response to 5-FU-based chemoradiotherapy and the overall survival in patients with OSCC.
    Journal of Oral Pathology and Medicine 12/2013; 43(5). DOI:10.1111/jop.12140 · 1.93 Impact Factor
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    ABSTRACT: We report a rare case of giant cell tumor affecting the articular tubercle of the temporal bone. The patient was a 43-year-old woman who referred to our hospital with swelling of the left temporomandibular area and pain on opening her mouth. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a tumor mass involving the left mandibular ramus and condylar process, with bone destruction extending to the mandibular fossa. The mass was removed by gross total resection and curettage, and the defect was reconstructed by using mandibular reconstruction plates with condylar heads for the resected mandible bone. CT during follow-up showed that additional bone surrounded the titanium condylar head. During 12 years of clinical and radiological follow-up, the patient has manifested no evidence of recurrence. Masticatory function is well preserved, the maximum mouth opening is 32 mm, and the left artificial joint can move smoothly via a hinge movement of the mandible without ankylosis of the temporomandibular joint.
    11/2013; 27(2). DOI:10.1016/j.ajoms.2013.09.011
  • R. Murakami · N. Kai · Y. Fujita · H. Nakayama · M. Nagata · T. Saito · R. Toya · T. Hirai
    International Journal of Radiation OncologyBiologyPhysics 10/2013; 87(2):S428. DOI:10.1016/j.ijrobp.2013.06.1128 · 4.26 Impact Factor
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    ABSTRACT: Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin superfamily. Although its overexpression in various cancers was reported, little is known about its expression and clinical significance in oral squamous cell carcinoma (OSCC). This study aimed to elucidate the clinical significance of NGAL in OSCC. We immunohistochemically investigated NGAL expression in tumour cells and stromal cells in 96 OSCC tissues. NGAL expression in tumour cells significantly correlated with histological tumour cell differentiation, as shown by its specific distribution in the horn pearl-forming keratinized tumour cells, but not with other major clinicopathological parameters. We found NGAL(+) cells in the stroma that were predominantly myeloperoxidase-positive neutrophils. The number of such NGAL-expressing stromal cells was significantly associated with poor differentiation and reduced overall survival in OSCC. The prognostic value of stromal NGAL expression was significant in the univariate analysis while only a trend was found in the multivariate analyses. This study is the first to show the clinical significance of stromal NGAL expression, which may be an indicator of poor prognosis and more aggressive histological grade in OSCC. Our data suggest that NGAL expression in tumour cells and stroma is associated in different ways with OSCC differentiation. This article is protected by copyright. All rights reserved.
    Histopathology 09/2013; 64(3). DOI:10.1111/his.12293 · 3.45 Impact Factor
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    ABSTRACT: Notch signaling has been reported to be involved in several types of malignant tumors; however, the role and activation mechanism of Notch signaling in oral squamous cell carcinoma (OSCC) remains poorly characterized. The purpose of this study was to elucidate the pathological significance of Notch signaling and its activation mechanism in the development and progression of OSCC. In this study, we showed that the expression of Notch1 and intracellular Notch domain (NICD) are upregulated in OSCCs. In addition, Notch1 and NICD were found to be characteristically localized at the invasive tumor front. TNF-α, a major inflammatory cytokine, significantly activated Notch signaling in vitro. In a clinicopathological analysis, Notch1 expression correlated with both the T-stage and the clinical stage. Furthermore, loss of Notch1 expression correlated with the inhibition of cell proliferation and TNF-α-dependent invasiveness in an OSCC cell line. In addition, γ-secretase inhibitor (GSI) prevented cell proliferation and TNF-α-dependent invasion of OSCC cells in vitro. These results indicate that altered expression of Notch1 is associated with increased cancer progression and that Notch1 regulates the steps involved in cell metastasis in OSCC. Moreover, inactivating Notch signaling with GSI could therefore be a useful approach for treating patients with OSCC.Laboratory Investigation advance online publication, 12 August 2013; doi:10.1038/labinvest.2013.95.
    Laboratory Investigation 08/2013; 93(10). DOI:10.1038/labinvest.2013.95 · 3.68 Impact Factor
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    ABSTRACT: Inflammation has a role in the pathogenesis of atherosclerosis, which causes hypertension. Results from some studies have suggested links between periodontal disease and atherosclerosis, but links between periodontal disease and hypertension have been seldom studied. We investigated whether periodontal disease and serum antibody level were associated with hypertension. We studied 127 patients (93 men and 34 women, mean age 68±9 years) who were admitted with ischemic heart disease to our institution. A composite periodontal risk score was calculated from five periodontal vector scores. The levels of serum antibody against Porphyromonas gingivalis (Pg) were measured. Pulse pressure, mean blood pressure (BP) and pulse wave velocity were used as indices of atherosclerosis. We divided patients into two groups according to the levels of serum antibody against Pg: higher or equal to the median (high Pg antibody group) and lower than the median (low Pg antibody group).There was no difference in the use of antihypertensive agents between the two groups. The composite periodontal risk score (P=0.0003), systolic BP (P=0.030), diastolic BP (P=0.038), pulse pressure (P=0.050) and mean BP (P=0.055) were higher in the high Pg antibody group than in the low Pg antibody group. The composite periodontal risk score (r=0.320, P=0.0003), systolic BP (r=0.212, P=0.017), diastolic BP (r=0.188, P=0.035) and mean BP (r=0.225, P=0.011) correlated with the level of serum antibody against Pg, even after adjustment for age. An elevated antibody level against Pg indicates advanced periodontal disease and suggests advancement of atherosclerosis and hypertension.Hypertension Research advance online publication, 16 May 2013; doi:10.1038/hr.2013.46.
    Hypertension Research 05/2013; 36(9). DOI:10.1038/hr.2013.46 · 2.66 Impact Factor
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    ABSTRACT: Purpose We evaluated whether preoperative chemotherapy with S-1 and concurrent radiotherapy is feasible and efficacious in the treatment of advanced oral squamous cell carcinoma. Methods Participants comprised 39 patients with oral carcinoma (stage III, n = 15; stage IVA, n = 24). All patients received a total radiation dose of 40 Gy, in once-daily 2-Gy fractions, and received S-1 at 65 mg/m2/day for 5 consecutive days, over 4 consecutive weeks with concurrent radiotherapy. Results Hematological toxicity was mild and reversible. The most common non-hematological toxicity was grade 3 mucositis, but this was transient and tolerable. Radical surgery was performed for 37 patients, with the remaining 2 patients declining the surgery. Postoperatively, local failure developed in 1 patient, and neck failure in 2 patients. Distant metastases were identified in 4 patients. At a median follow-up of 38.0 months (range 23–88 months), locoregional control, disease-specific survival, and overall survival rates at 3 years were 91.5, 83.8, and 83.8 %, respectively. Conclusion Concurrent administration of S-1 and radiotherapy combined with surgery offers a well-tolerated method of successfully treating advanced oral squamous cell carcinoma. The locoregional control rate remains high even at 3 years of follow-up, and no serious adverse effects have been encountered.
    Cancer Chemotherapy and Pharmacology 02/2013; 71(4). DOI:10.1007/s00280-013-2101-5 · 2.77 Impact Factor
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    T Honda · T Kondo · S Murakami · H Saito · F Oshita · H Ito · M Tsuboi · H Nakayama · T Yokose · Y Kameda · T Isobe · K Yamada
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    ABSTRACT: Aim: To analyse the correlation between computed tomography (CT) findings of small lung adenocarcinomas and the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification of Lung Adenocarcinoma. Materials and methods: A retrospective review of 300 lung adenocarcinoma lesions (size ≤20 mm) after surgical resection in 295 consecutive patients was performed. Tumours were defined as air-containing type if the ratio of the maximum dimension of the tumour on mediastinal windows to the maximum dimension of the tumour on lung windows was ≤50%, and as solid-density type if the ratio was >50%. The incidence between CT findings (air bronchogram, vascular involvement, pleural tags, notches, and spiculation) and pathological findings were investigated. Results: Of the 142 air-containing lesions, 114 were adenocarcinoma in situ (AIS), 28 were minimally invasive adenocarcinoma (MIA), and none of the lesions were invasive adenocarcinoma. Of the 158 solid-density lesions, 30 were AIS, 24 were MIA, and 104 were invasive adenocarcinoma. Notches and pleural tags were commonly observed in cases of invasive adenocarcinoma (p < 0.05). Conclusions: In the air-containing type of small lung adenocarcinomas, AIS and MIA were observed but no cases of invasive adenocarcinoma were found. The presence of notches and pleural tags were a significant factor in invasive adenocarcinoma.
    Clinical Radiology 11/2012; 68(1). DOI:10.1016/j.crad.2012.09.002 · 1.76 Impact Factor
  • International Journal of Radiation OncologyBiologyPhysics 11/2012; 84(3):S461. DOI:10.1016/j.ijrobp.2012.07.1221 · 4.26 Impact Factor

Publication Stats

437 Citations
182.37 Total Impact Points


  • 2005–2014
    • Kumamoto University
      • Department of Oral and Maxillofacial Surgery
      Kumamoto, Kumamoto, Japan
    • The University of Tokushima
      • Department of Optical Science and Technology
      Tokusima, Tokushima, Japan
  • 2000–2012
    • Kanagawa Cancer Center
      Yokohama, Kanagawa, Japan
    • Kanto Rosai Hospital
      Kawasaki Si, Kanagawa, Japan
  • 2003–2005
    • Yokohama Rosai Hospital
      Yokohama, Kanagawa, Japan
  • 2000–2004
    • Kyushu University
      • Department of Oral and Maxillofacial Surgery
      Hukuoka, Fukuoka, Japan