Shizuoka Cancer Center Hospital and Research Institute

Shizuoka-shi, Japan

Shizuoka Cancer Center Hospital and Research Institute

Shizuoka-shi, Japan
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Hitomi S.,Kyushu University | Ono K.,Kyushu University | Miyano K.,National Cancer Center Research Institute | Ota Y.,Shizuoka Cancer Center Hospital and Research Institute | And 8 more authors.
Journal of Neuroscience Methods | Year: 2015

Background: Stomatitis induces severe and painful hypersensitivity to pungency and physical contact during meals. Many studies have used anesthetized animals to examine evoked nociception in the oral mucosa, but no reports have used traditional behavioral assays to evaluate nociception in conscious animals. New methods: We developed two new methods of applying chemical or mechanical stimulation directly to the oral mucosa of the mandibular vestibule of conscious rats. Nociceptive evaluations were performed by measuring facial grooming time and the head withdrawal threshold to von Frey stimulations. (1) For the intraoral dropping method, rat mucosa was transiently exposed by hand, and a drop of a pungent solution was applied. (2) For the stable intraoral opening method, rat mucosa was long-term exposed following piercing surgery of the mental skin after habitual training for 2-3 weeks. Results: In the intraoral dropping method, the application of 100. μM capsaicin or 100. mM allyl isothiocyanate prolonged mouth-rubbing time. Capsaicin-induced mouth-rubbing time was further enhanced following the development of an acetic acid-induced ulcer. The stable intraoral opening method enabled stable measurements of the mechanical withdrawal threshold in the oral mucosa of conscious rats. Ulcer development decreased the mechanical threshold, whereas topical lidocaine treatment increased the threshold. Comparison with existing methods: These new methods enable the evaluations of motivational nocifensive behaviors in response to intraoral stimulations without any anesthetic effects. Conclusions: The intraoral dropping and stable intraoral opening methods can be used in combination with traditional behavioral assays to evaluate nociception in the oral mucosa of conscious rats. © 2014 Elsevier B.V.


PubMed | University of Arkansas for Medical Sciences, University of Liverpool, University of Houston, Woodland Hills Medical Center and 8 more.
Type: Journal Article | Journal: European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | Year: 2016

Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the larynx. There are a total of ten patients reported with paraneoplastic syndromes associated with laryngeal neuroendocrine carcinomas in the literature. Of these, nine died and the tenth is alive with liver metastases. There were five cases of small-cell neuroendocrine carcinoma, four cases of moderately differentiated neuroendocrine carcinoma, and one case of well-differentiated neuroendocrine carcinoma associated with paraneoplastic syndromes. As these syndromes have significant clinical relevance, physicians should be aware of the possible presence of paraneoplastic syndromes in the diagnostic process of patients with neuroendocrine carcinoma of the larynx.


PubMed | University of Michigan, Institute of Oncology, Hospital Universitario Central Of Asturias, University of Groningen and 6 more.
Type: Journal Article | Journal: European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery | Year: 2016

While small cell neuroendocrine carcinomas (SCNCs) most often arise in the lung, extrapulmonary SCNCs arise in a variety of locations-including the head and neck region. In particular, laryngeal SCNCs-while rare tumors-are nevertheless recognized as distinct lesions. The rarity of laryngeal SCNC gives rise to two distinct difficulties: first (particularly with small biopsy specimens), laryngeal SCNC can be difficult to diagnose by routine light microscopy; second, limited experience with these tumors can make the crafting of a treatment plan for individual patients difficult. As regards the first problem, pathologic diagnosis is greatly enhanced by the application of immunohistochemistry. The second problem-crafting a successful treatment strategy-presents a much larger difficulty. It is tempting to extrapolate from experience with the (more common) pulmonary SCNC in search of a strategy applicable to laryngeal SCNC; such an extrapolation, however, may not be uniformly successful. In particular, while a combination of radiation therapy and chemotherapy appears to be as valuable in the treatment of extrapulmonary as it is in the treatment of pulmonary SCNC, prophylactic cranial irradiation (PCI)-which has enjoyed some success in the treatment of some patients with pulmonary SCNC-does not appear to have similar utility in patients with laryngeal SCNC. Accordingly, the use of PCI does not appear to have a role to play at this point in time in the treatment of patients with laryngeal SCNC.


PubMed | University of Arkansas for Medical Sciences, University of Liverpool, University of Washington, University of Houston and 12 more.
Type: | Journal: Head & neck | Year: 2016

Neuroendocrine neoplasms of the sinonasal region, which are relatively uncommon but clinically very important, are reviewed here in the light of current knowledge. Using a definition for neuroendocrine based on phenotypic, histologic, immunohistochemical, and electron microscopic features rather than histogenetic criteria, sinonasal neuroendocrine carcinomas are examined with a particular emphasis on the small-cell and large-cell subtypes. This is followed by revisiting olfactory neuroblastoma because it is also a tumor that shows a neuroendocrine phenotype. Kadish clinical and Hyams histologic grading systems as prognosticators of olfactory neuroblastoma are also considered in detail. Finally, controversies regarding sinonasal undifferentiated carcinoma as a neuroendocrine tumor are discussed and a possible relationship with high-grade olfactory neuroblastoma is explored. Genetic events and current management of these tumors are also outlined. 2015 Wiley Periodicals, Inc. Head Neck 38: E2259-E2266, 2016.


PubMed | Shizuoka Cancer Center Research Institute, Japan SRL Inc. and Shizuoka Cancer Center Hospital and Research Institute
Type: Journal Article | Journal: Anticancer research | Year: 2016

The identification of additional therapeutic targets by clinical molecular profiling is necessary to expand the range of molecular-targeted cancer therapeutics. This study aimed to identify novel functional tumor-specific single nucleotide variants (SNVs) in the kinase domain of receptor tyrosine kinases (RTKs), from whole-exome sequencing (WES) data.SNVs were selected from WES data of multiple cancer types using both cancer-related databases and the index reflecting molecular evolution. Immunoblotting and luciferase assay were performed to assess the function of selected SNVs.Among the seven selected SNVs, two, namely neurotrophic receptor tyrosine kinase 1 (NTRK1) V710A and fms related tyrosine kinase 3 (FLT3) K868N, detected in kinase subdomain IX, were investigated. These SNVs inhibited the autophosphorylation of the respective RTKs, thereby reducing the activity of extracellular signal-regulated kinases.RTK subdomain IX is a promising target for the molecular design of kinase inhibitors.


Hatakeyama K.,Shizuoka Cancer Center Research Institute | Ohshima K.,Shizuoka Cancer Center Research Institute | Fukuda Y.,Tokyo University of Agriculture and Technology | Ogura S.-I.,Tokyo Institute of Technology | And 3 more authors.
Proteomics | Year: 2011

Splicing variation enhances proteome diversity and modulates cancer-associated proteins. Thus, the identification of alternative splice forms is significant for discovery of new cancer-related biomarkers. However, relatively few screening approaches of alternative splicing via proteomics have been reported. In the present study, we describe a combined analysis with proteome and transcriptome to simultaneously identify cancer-related splicing variants and splicing variant-derived protein fragments that are differentially expressed in a highly metastatic gastric cancer cell line MKN45P versus its parental cell line MKN45. We found three potential alternative-spliced genes using MS-based shotgun method and two different microarray platforms. Among them, aldolase C, fructose-bisphosphate (ALDOC) was predicted to have novel alternative splice forms. We successfully identified and validated novel splice forms of ALDOC gene by RT-PCR and DNA sequencing analyses, the expression level of which were higher in MKN45P than in MKN45. Furthermore, the protein fragment derived from the validated splicing variant was identified using custom-built data set including sequences of ALDOC variants in MS/MS analysis. Our combined analysis will be a promising technique for screening of cancer-related splicing variants and their protein isoforms. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | Yokohama College of Pharmacy, Olympus Corporation, Shizuoka Cancer Center Research Institute, Ochanomizu University and Shizuoka Cancer Center Hospital and Research Institute
Type: | Journal: International immunopharmacology | Year: 2016

Beta-tricalcium phosphate (-TCP) is widely used for bone substitution in clinical practice. Particles of calcium phosphate ceramics including -TCP act as an inflammation mediators, which is an unfavorable characteristic for a bone substituent or a prosthetic coating material. It is thought that the stimulatory effect of -TCP on the immune system could be utilized as an immunomodulator. Here, in vitro effects of -TCP on primary cultured murine dendritic cells (DCs) and macrophages were investigated. -TCP particles enhanced expression of costimulatory surface molecules, including CD86, CD80, and CD40 in DCs, CD86 in macrophages, and MHC class II and class I molecules in DCs. DEC205 and CCR7 were up-regulated in -TCP-treated DCs. Production of cytokines and chemokines, including CCL2, CCL3, CXCL2, and M-CSF, significantly increased in DCs; CCL2, CCL3, CCL4, CCL5, CXCL2, and IL-11ra were up-regulated in macrophages. The results of the functional assays revealed that -TCP caused a prominent reduction in antigen uptake by DCs, and that conditioned medium from DCs treated with -TCP facilitated the migration of splenocytes in the transwell migration assay. Thus, -TCP induced phenotypical and functional maturation/activation of DCs and macrophages; these stimulating effects may contribute to the observed in vivo effect where -TCP induced extensive migration of immune cells. When compared to lipopolysaccharide (LPS), an authentic TLR ligand, the stimulatory effect of -TCP on the immune systems is mild to moderate; however, it may have some advantages as a novel immunomodulator. This is the first report on the direct in vitro effects of -TCP against bone marrow-derived DCs and macrophages.


Yamada H.,Hamamatsu University School of Medicine | Shinmura K.,Hamamatsu University School of Medicine | Ito H.,Showa University | Kasami M.,Shizuoka Cancer Center Hospital and Research Institute | And 9 more authors.
Cancer Science | Year: 2011

Germline point or small frameshift mutations of the CDH1 (E-cadherin) gene are known to cause familial gastric cancer (FGC), but the frequency of CDH1 mutations is low in Japanese patients with FGC. Because recent studies have reported germline large genomic deletions of CDH1 in European and Canadian patients with FGC, in the present study we examined DNA samples from 13 Japanese patients with FGC to determine whether similar germline changes were present in CDH1 in this population. Using a sequencing analysis, a 1-bp deletion (c.1212delC), leading to the production of a truncated protein (p.Asn405IlefsX12), was found in an FGC family; immunohistochemical analysis revealed the loss of CDH1 protein expression in the tumors in this family. Using a combination of multiplex ligation-dependent probe amplification (MLPA) and RT-PCR analyses, we also found a large genomic deletion (c.164-?-387+?del), leading to the loss of exon 3 and the production of a truncated protein (p.Val55GlyfsX38), in another FGC family. The functional effects of the detected mutations were examined using a slow aggregation assay. Significant impairment of cell-cell adhesion was detected in CHO-K1 cells expressing Ile405fsX12- and Gly55fsX38-type CDH1 compared with cells expressing wild-type CDH1. Our results suggest that the p.Asn405IlefsX12 and p.Val55GlyfsX38 mutations of the CDH1 gene contribute to carcinogenesis in patients with FGC. This is the first report of CDH1 germline truncating mutations in Japanese patients with FGC. Screening for large germline rearrangements should be included in CDH1 genetic testing for FGC. © 2011 Japanese Cancer Association.


Oba H.,Saitama Cancer Center | Nishida K.,Saitama Cancer Center | Takeuchi S.,Nippon Medical School | Akiyama H.,Saitama Cancer Center | And 3 more authors.
Endocrine Pathology | Year: 2013

We report a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). We performed immunohistochemical analysis of 17 neuropeptides and human gonadotropin-alpha (hCGα), a trophoblastic peptide that promotes the proliferation of neuroendocrine cells. A 51-year-old woman with no history of smoking was found to have a nodule in the right middle lobe. Upon examination, the nodule was found to comprise diffuse linear and nodular neuroendocrine cell hyperplasia (NECH), numerous pulmonary tumorlets merging with one peripheral carcinoid, and an additional central carcinoid. Immunohistochemical analysis revealed diffuse but intense expression of the general neuroendocrine markers CD56, synaptophysin, and chromogranin A, together with gastrin-releasing peptide (GRP), calcitonin, and hCGα throughout the carcinoids, tumorlets, and NECH. Positive staining was also noted for adrenocorticotropic hormone, corticotropin-releasing hormone, met-enkephalin, vasoactive intestinal polypeptide, neurotensin, and growth hormone-releasing hormone in a few isolated cells of the carcinoids and the tumorlets, but staining for these proteins was entirely negative in the NECH lesions. The presence of these neuropeptides in neuroendocrine tumors might explain the presence of neuropeptide-producing tumors of the lungs, cases of which have been reported over the last 30 years. The preoperative serum proGRP level was high but returned to normal after surgical intervention, indicating that GRP was produced and secreted by carcinoids, tumorlets, and/or NECH lesions. It is also probable that neuroendocrine cells secreted GRP into the interstitium in a paracrine manner, leading to the development of dense fibrosis around the tumorlets. During the preoperative and postoperative periods, no evidence of bronchiolitis obliterans was noted, in contrast to some previously reported cases of DIPNECH. © 2013 Springer Science+Business Media New York.


Kusafuka K.,Shizuoka Cancer Center Hospital and Research Institute | Maeda M.,Toyohashi Municipal Hospital | Honda M.,Shizuoka Cancer Center Hospital and Research Institute | Nakajima T.,Shizuoka Cancer Center Hospital and Research Institute
Medical Molecular Morphology | Year: 2012

Salivary duct carcinoma (SDC) is a highly aggressive salivary gland carcinoma, and the mucin-rich variant of SDC (mSDC) is extremely rare. We report herein one case of salivary mSDC, showing predominantly signet-ring cell features. The patient was an 84-year-old Japanese woman, who noticed swelling in the left submandibular region. The tumor consisted of two components: one was of mSDC, which contained numerous signet-ring cells in large mucinous lakes, whereas the other was of preexisting pleomorphic adenoma (PA), which showed a hyalinized nodule. mSDC was markedly positive for mucin staining. Signetring cells in the mSDC component were immunopositive for androgen receptor, gross cystic disease fluid protein-15, MUC1, MUC2, MUC5AC, MUC5B, and MUC6, but negative for Her-2 and myoepithelial markers. This case was diagnosed as mSDC with the signet-ring cell feature ex PA. We discuss herein the significance of the signet-ring cell feature in mSDC and the mucin pattern of mSDC. © 2012 The Japanese Society for Clinical Molecular Morphology.

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