Hideki Nakayama

Kumamoto University, Kumamoto, Kumamoto Prefecture, Japan

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Publications (38)112.9 Total impact

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    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 · 3.34 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; DOI:10.1111/apm.12344 · 1.92 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; · 6.63 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 utilized 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 immunological response were evaluated using enzyme-linked ImmunoSpot (ELISPOT) and pentamer assays. The peptides were subcutaneously administered weekly with IFA. The primary endpoints were evaluated based on 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) 4.9 vs. 3.5 month, 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 · 8.19 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; 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 · 2.77 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; DOI:10.1111/jop.12140 · 1.87 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; DOI:10.1016/j.ajoms.2013.09.011
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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 · 3.30 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; DOI:10.1038/labinvest.2013.95 · 3.96 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; DOI:10.1038/hr.2013.46 · 2.94 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 · 2.80 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Radiotherapy as well as chemotherapy in head and neck cancer induces severe oral mucositis. Even after healing of the mucositis, however, the oral mucosa looking atrophic is known to be susceptible to injury and infection. In order to investigate such vulnerability of mucosa, we immunohistochemically studied the expressions of Ki-67, proliferating cell nuclear antigen (PCNA), cyclin D1, nuclear factor (NF)-kB, and keratinocyte growth factor (KGF) receptor in the oral mucosal keratinocytes undergoing preoperative concurrent chemoradiotherapy for oral cancer, compared with those of the oral mucosa without such therapy. As a result, the expressions of Ki-67, PCNA, and cyclin D1 were decreased in the chemoradiotherapy-treated oral keratinocytes. Interestingly, NF-kB expression, which is known to be enhanced in oral mucositis, was reduced after chemoradiotherapy. The chemoradiotherapy had no effect on the expression of KGF receptor in oral keratinocytes. In conclusion, the vulnerability of oral mucosa undergoing chemoradiation may be associated with reduced NF-kB expression and impaired growth activity.
    International Journal of Oral Science 11/2012; 9(2):33–37. DOI:10.1016/S1348-8643(12)00008-0 · 2.03 Impact Factor
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    ABSTRACT: We retrospectively evaluated the relationship between computed tomography (CT)- and histopathological findings of parotid and submandibular glands in six patients treated for advanced oral cancer. Eligibility criteria were a pathologic diagnosis of oral squamous cell carcinoma, preoperative chemoradiation therapy (CRT) with a total dose of 30 Gy and oral S-1 (80 mg/m²/day), the availability of morphological assessments by CT and of functional assessments with the Saxon test before- and 2 weeks after CRT, and the availability of histopathological slides of irradiated parotid and submandibular glands. In the histopathological interpretation, gland structures were divided into acinar-, duct-, and adipose cells and other tissues. The Mann-Whitney test and the Spearman rank correlation test were used to determine histopathological changes. After 30-Gy irradiation, saliva production and parotid and submandibular volumes were significantly decreased (P < 0.05 each). Histopathological analysis demonstrated that 30-Gy irradiation resulted in a loss of acinar cells although acinar cells in the submandibular gland were relatively retained; the median acinar rate in the parotid and submandibular glands was 1.1% and 19.0%, respectively. The CT values after CRT were inversely correlated with adipose ratios (r = -0.98, P < 0.01) and there was a strong correlation between CT values before and after CRT (r = 0.97, P < 0.01). Our results suggested that acinar cell loss is a main contributor to changes in the volume and function of irradiated human parotid and submandibular glands. The CT value may reflect the adipose ratio rather than salivary function.
    Journal of Radiation Research 04/2012; 53(3):492-6. DOI:10.1269/jrr.11115 · 1.45 Impact Factor
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    ABSTRACT: Nuclear factor-κB (NF-κB) activation contributes to the development of metastasis, thus leading to a poor prognosis in many cancers, including OSCC. However, little in vivo experimental data are available about the effects of NF-κB inhibition on OSCC metastasis. OSCC sublines were established from a GFP-expressing parental cell line, GSAS, and designated GSAS/N3 and N5 according to the in vivo passage number after cervical lymph node metastasis by a serial orthotopic transplantation model. In vitro migration and invasion were assessed in these cells, and the NF-κB activities and expression of NF-κB-regulated metastasis-related molecules were also examined. In in vivo experiments, the metastasis and survival of tumor-engrafted mice were monitored. Furthermore, the effects of a selective NF-κB inhibitor, NEMO-binding domain (NBD) peptide, on metastasis in GSAS/N5-engrafted mice were assessed, and engrafted tongue tumors were immunohistochemically examined. Highly metastatic GSAS/N3 and N5 cells showed an enhanced NF-κB activity, thus contributing to increased migration, invasion, and a poor prognosis compared with the parent cells. Furthermore, the expression levels of NF-κB-regulated metastasis-related molecules, such as fibronectin, β1 integrin, MMP-1, -2, -9, and -14, and VEGF-C, were upregulated in the highly metastatic cells. The NBD peptide suppressed metastasis and tongue tumor growth in GSAS/N5-inoculated mice, and was accompanied by the downregulation of the NF-κB-regulated metastasis-related molecules in engrafted tongue tumors. Our results suggest that the selective inhibition of NF-κB activation by NBD peptide may provide an effective approach for the treatment of highly metastatic OSCC.
    Cancer Science 12/2011; 103(3):455-63. DOI:10.1111/j.1349-7006.2011.02174.x · 3.53 Impact Factor
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    ABSTRACT: Lymph node metastasis is associated with resistance to conventional therapy and poor survival of patients with oral squamous cell carcinoma (OSCC). Although lymphangiogenesis is well known to be associated with the occurrence of lymph node metastasis in various cancers, the precise mechanisms of lymphangiogenesis in OSCC are largely unknown. IL-6, a potent pro-inflammatory cytokine, has been shown to play active roles in various cancers, including OSCC. This study aimed to investigate the involvement of IL-6 signalling in lymphatic metastasis and to evaluate the efficacy of tocilizumab, a humanized anti-human IL-6 receptor antibody, as an anti-lymphangiogenic agent for OSCC. This investigation confirmed that levels of expression of IL-6 protein and VEGF-C mRNA in OSCC tissues were significantly correlated with lymph node metastasis in patients with OSCC, as assessed by immunohistochemical analysis and real-time quantitative RT–PCR. In vitro studies showed that IL-6 regulated VEGF-C mRNA expression in a human OSCC cell line, SAS cells, through the phosphoinositide 3-kinase-Akt pathway. In addition, treatment with tocilizumab led to markedly reduced VEGF-C mRNA expression and OSCC-related lymphangiogenesis in SAS xenografts. Together, these data suggest that tocilizumab acted as expected: it inhibited lymph node metastasis in OSCC by reducing tumour lymphangiogenesis. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    The Journal of Pathology 06/2011; 225(1):142 - 150. DOI:10.1002/path.2935 · 7.33 Impact Factor
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    ABSTRACT: To evaluate longitudinal changes in parotid volumes and saliva production over 2 years after 30 Gy irradiation. We retrospectively evaluated 15 assessable patients treated for advanced oral cancer. Eligibility criteria were a pathologic diagnosis of squamous cell carcinoma, preoperative radiation therapy with a total dose of 30 Gy delivered in 15 fractions, and the availability of longitudinal data of morphological assessments by computed tomography and functional assessments with the Saxon test spanning 2 years after radiation therapy. In the Saxon test, saliva production was measured by weighing a folded sterile gauze pad before and after chewing; the low-normal value is 2 g/2 min. Repeated-measures analysis of variance with Bonferroni adjustment for multiple comparisons was used to determine the longitudinal changes. The normalized ipsilateral parotid volumes 2 weeks and 6-, 12- and 24 months after radiation therapy were found to be 72.5, 63.7, 66.9 and 78.1%, respectively; the normalized contralateral volumes were 69.8, 64.6, 72.2 and 82.0%, respectively. The bilateral parotid volumes were significantly decreased after radiation therapy (P < 0.01). The nadir appeared at 6 months post-radiation therapy and the volumes substantially recuperated 24 months after radiation therapy (P < 0.01). Mean saliva production before radiation therapy was 3.7 g; the longitudinal changes after radiation therapy were 31.3, 38.0, 43.3 and 69.6%, respectively. Substantial recuperation of saliva production was observed 24 months after radiation therapy (P = 0.01). Although parotid volumes and saliva production were decreased after 30 Gy irradiation, we observed the recuperation of morphological and functional changes in the parotid glands 2 years after radiation therapy.
    Japanese Journal of Clinical Oncology 03/2011; 41(4):503-7. DOI:10.1093/jjco/hyq236 · 1.75 Impact Factor
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    ABSTRACT: Nucleostemin (NS) has been reported as essential for stem and cancer cell proliferation. To investigate the significance of NS in oral squamous cell carcinomas (OSCCs), we examined NS expression in neoplastic tissue of the tongue and in OSCC cell lines. Nucleostemin expression in the histological samples showed positive correlation with Ki-67 expression. Furthermore, NS expression was associated with cellular proliferation in OSCC cell lines using siRNA, which upregulated p27, a cyclin-dependent kinase inhibitor. Regarding OSCC differentiation, NS expression did not influence cornification or oral epithelial differentiation markers such as involucrin and cytokeratin19. Thus, NS is widely expressed in normal and neoplastic oral epithelial tissues, and is likely a marker of proliferation.
    Cancer Science 03/2011; 102(7):1418-23. DOI:10.1111/j.1349-7006.2011.01935.x · 3.53 Impact Factor
  • Nippon Koku Geka Gakkai zasshi 01/2010; 56(12):730-734. DOI:10.5794/jjoms.56.730

Publication Stats

316 Citations
112.90 Total Impact Points


  • 2004–2014
    • Kumamoto University
      • • Department of Oral and Maxillofacial Surgery
      • • Graduate School of Medical Sciences
      Kumamoto, Kumamoto Prefecture, Japan
  • 2001–2004
    • Kyushu University
      • • Department of Oral and Maxillofacial Surgery
      • • Faculty of Dental Science
      Hukuoka, Fukuoka, Japan