Details of a Researcher - NISHIHARA, Hiroshi

Papers - NISHIHARA, Hiroshi

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A randomized phase II trial of erlotinib vs. S-1 as a third- or fourth-line therapy for patients with wild-type EGFR non-small cell lung cancer (HOT1002).

Yasuyuki Ikezawa, Hajime Asahina, Satoshi Oizumi, Masahiro Watanabe, Kei Takamura, Yasutaka Kawai, Noriyuki Yamada, Toshiyuki Harada, Ichiro Kinoshita, Yuka Fujita, Eisaku Miyauchi, Takahiro Ogi, Toraji Amano, Megumi Furuta, Jun Sakakibara-Konishi, Hiroshi Nishihara, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura

Cancer chemotherapy and pharmacology (SPRINGER) 80 ( 5 ) 955 - 963 2017.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 03445704

PURPOSE: A high proportion of patients with wild-type EGFR non-small cell lung cancer (NSCLC) receive third-line therapy and beyond, with no prospective randomized trials addressing the issue. This study aimed to select the most suitable regimen as a third- or fourth-line therapy for wild-type EGFR NSCLC. METHODS: This multicenter, randomized phase II study in Japan included patients with recurrent or advanced NSCLC with wild-type or unknown EGFR, who progressed after two or three previous chemotherapies. The patients were randomly assigned to erlotinib (150 mg/day, days 1-21) or S-1 (80-120 mg/day, days 1-14) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), toxicity, and quality of life (QOL). RESULTS: From 2011 to 2016, 37 patients were randomly assigned to receive erlotinib (E arm, n = 19) and S-1 (S arm, n = 18). This study was terminated prematurely because of poor patient accrual. DCR/ORR were 42.1%/15.8% in the E arm and 66.7%/16.7% in the S arm. Median PFS/OS were 1.6 months/8.0 months in the E arm and 3.3 months/12.2 months in the S arm. In both groups, the most commonly reported grade 3-4 toxicities were fatigue, anorexia, and nausea. One grade 5 pneumonitis occurred in the S arm. No significant difference was seen in QOL. CONCLUSIONS: S-1 as a third- or fourth-line therapy for wild-type EGFR NSCLC showed numerically better clinical outcomes than erlotinib. CLINICAL TRIAL REGISTRATION NO: UMIN000005308.

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The Anti-tumor Effect of Cabozantinib on Ovarian Clear Cell Carcinoma In Vitro and In Vivo

Makiko Nakatani, Hidemichi Watari, Takashi Mitamura, Lei Wang, Yutaka Hatanaka, Kanako C. Hatanaka, Kohei Honda, Toshiyuki Nomura, Hiroshi Nishihara, Shinya Tanaka, Noriaki Sakuragi

ANTICANCER RESEARCH (INT INST ANTICANCER RESEARCH) 37 ( 11 ) 6125 - 6132 2017.11

Research paper (scientific journal), Joint Work, ISSN 02507005

Background: Several reports have shown that the overexpression of the MET proto-oncogene, receptor tyrosine kinase (MET), was more frequently observed in clear cell carcinoma (CCC) than in non-CCC. We evaluated the antitumor activity of cabozantinib, that targets MET. Materials and Methods: A gene expression analysis of tumors from human ovarian cancers was carried out by transcriptome sequencing. An in vitro 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay (MTT assay) and in vivo experiments were performed to determine the activity of cabozantinib. Results: The MET levels were higher in tumors with CCC than high-grade serous carcinoma (2.2-fold). Cabozantinib inhibited cell viability and phosphorylation of AKT and MAPK under the treatment of hepatocyte growth factor in RMG-I CCC cells. The tumors removed from mice given cabozantinib of 10 mg/kg weighed 70% less than control on day 15, and the immunohistochemical reactivity of phosphorylated MET was reduced compared with control mice. Conclusion: Cabozantinib contributes to tumor reduction, and phosphorylated MET represents an attractive target of CCC.

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Biopsy-proven case of Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system.

Kohei Kano, Takayuki Katayama, Shiori Takeguchi, Asuka Asanome, Kae Takahashi, Tsukasa Saito, Jun Sawada, Masato Saito, Ryogo Anei, Kyousuke Kamada, Naoyuki Miyokawa, Hiroshi Nishihara, Naoyuki Hasebe

Neuropathology : official journal of the Japanese Society of Neuropathology (WILEY) 37 ( 3 ) 259 - 264 2017.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 09196544

A 75-year-old woman was admitted to our hospital with rapidly deteriorating consciousness disturbance. She had a 7-year history of rheumatoid arthritis (RA), which had been treated with methotrexate (MTX) and prednisolone. Brain T2-weighted MRI showed diffuse high-intensity lesions in the cerebral subcortical and deep white matter, bilateral basal ganglia and thalamus. A cerebrospinal fluid examination revealed elevated protein levels and positive Epstein-Barr virus (EBV) DNA. Human immunodeficiency virus was negative. Brain biopsy showed perivascular lymphocytic infiltration in the parenchyma and meninx with EBV-encoded small RNA (EBER). Since this case did not fulfill the criteria for chronic active EBV infection (CAEBV), she was diagnosed with Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system. High-dose methylprednisolone, acyclovir, ganciclovir and foscarnet were not effective. Although EBV is a causative agent of infectious mononucleosis (IM), lymphomas and nasopharyngeal carcinomas, vasculitic pathology of the central nervous system with EBV reactivation in the elderly is rare. Immunosuppressive drugs such as steroids and MTX are widely used to treat autoimmune disorders, but may exacerbate the reactivation of EBV. This is the first case of biopsy-proven EBV-positive/HIV-negative vasculitis during the treatment of RA with MTX and steroids. This case indicates that EBV-associated vasculitis needs to be considered as a differential diagnosis of CNS vasculitis.

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PCTAIRE1/CDK16/PCTK1 is overexpressed in cutaneous squamous cell carcinoma and regulates p27 stability and cell cycle.

Teruki Yanagi, Hiroo Hata, Eri Mizuno, Shinya Kitamura, Keisuke Imafuku, Shinichi Nakazato, Lei Wang, Hiroshi Nishihara, Shinya Tanaka, Hiroshi Shimizu

Journal of dermatological science (ELSEVIER IRELAND LTD) 86 ( 2 ) 149 - 157 2017.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 09231811

BACKGROUND: PCTAIRE1 (also known as cyclin-dependent kinase 16 (Cdk16) and PCTK1) is a Cdk family protein that has been implicated in spermatogenesis. We recently revealed the function of PCTAIRE1 in the tumorigenesis of malignancies, including breast and prostate cancers; however, the tumorigenic function of PCTAIRE1 in cutaneous squamous cell carcinoma (SCC) remains unclear. OBJECTIVE: In this study, we investigated the role of PCTAIRE1 in the tumorigenesis of cutaneous SCCs. METHODS AND RESULTS: In cutaneous/oral SCC A431, DJM-1, HSC-3 cells, PCTAIRE1 gene-knockdown was found to diminish cell proliferation as assessed by cell counting and clonogenic assays. FACS analyses of annexin V-PI staining and DNA content showed PCTAIRE1 knockdown to cause G2/M arrest followed by apoptosis. The depletion of PCTAIRE1 was found to lead to the accumulation of tumor suppressor p27 and down-regulation of c-Myc. In tumor xenografts of A431 cells, the conditional knockdown of PCTAIRE1 restores p27 protein expression and suppresses tumor growth. Clinically, in primary tumors from patients with SCC, PCTAIRE1 is more highly expressed in malignant lesions than in adjacent normal epidermis. Conversely, expression levels of p27 are significantly lower in SCC than in normal epidermis. CONCLUSIONS: Our findings reveal a crucial function for PCTAIRE1 in regulating p27, c-Myc levels and tumor growth in cutaneous SCC cells, suggesting that PCTAIRE1 could be a novel target for skin tumor treatment.

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Regulation of endothelial Fas expression as a mechanism of promotion of vascular integrity by mural cells in tumors

Ryosuke Kamei, Hiroyoshi Y. Tanaka, Takao Kawano, Chiharu Morii, Sayaka Tanaka, Hiroshi Nishihara, Caname Iwata, Mitsunobu R. Kano

CANCER SCIENCE (WILEY) 108 ( 5 ) 1080 - 1088 2017.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 13479032

Angiogenesis is a multi-step process that culminates in vascular maturation whereby nascent vessels stabilize to become functional, and mural cells play an essential role in this process. Recent studies have shown that mural cells in tumors also promote and maintain vascular integrity, with wide-reaching clinical implications including the regulation of tumor growth, metastases, and drug delivery. Various regulatory signaling pathways have been hitherto implicated, but whether regulation of Fas-dependent apoptotic mechanisms is involved has not yet been fully investigated. We first compared endothelial FAS staining in human pancreatic ductal adenocarcinomas and colon carcinomas and show that the latter, characterized by lower mural cell coverage of tumor vasculature, demonstrated higher expression of FAS than the former. Next, in an invitro coculture system of MS-1 and 10T1/2 cells as endothelial and mural cells respectively, we show that mural cells decreased endothelial Fas expression. Then, in an invivo model in which C26 colon carcinoma cells were inoculated together with MS-1 cells alone or with the further addition of 10T1/2 cells, we demonstrate that mural cells prevented hemorrhage. Finally, knockdown of endothelial Fas sufficiently recapitulated the protection against hemorrhage seen with the addition of mural cells. These results together suggest that regulation of endothelial Fas signaling is involved in the promotion of vascular integrity by mural cells in tumors.

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Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation

Shinji Takeuchi, Koji Fukuda, Tadaaki Yamada, Sachiko Arai, Satoshi Takagi, Genichiro Ishii, Atsushi Ochiai, Shotaro Iwakiri, Kazumi Itoi, Hisanori Uehara, Hiroshi Nishihara, Naoya Fujita, Seiji Yano

CANCER SCIENCE (WILEY) 108 ( 4 ) 696 - 703 2017.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 13479032

Malignant pleural mesothelioma (MPM) is characterized by dissemination and aggressive growth in the thoracic cavity. Podoplanin (PDPN) is an established diagnostic marker for MPM, but the function of PDPN in MPM is not fully understood. The purpose of this study was to determine the pathogenetic function of PDPN in MPM. Forty-seven of 52 tumors (90%) from Japanese patients with MPM and 3/6 (50%) MPM cell lines tested positive for PDPN. Knocking down PDPN in PDPN-high expressing MPM cells resulted in decreased cell motility. In contrast, overexpression of PDPN in PDPN-low expressing MPM cells enhanced cell motility. PDPN stimulated motility was mediated by activation of the RhoA/ROCK pathway. Moreover, knocking down PDPN with short hairpin (sh) RNA in PDPN-high expressing MPM cells resulted in decreased development of a thoracic tumor in mice with severe combined immune deficiency (SCID). In sharp contrast, transfection of PDPN in PDPN-low expressing MPM cells resulted in an increase in the number of Ki-67-positive proliferating tumor cells and it promoted progression of a thoracic tumor in SCID mice. Interestingly, PDPN promoted focus formation invitro, and a low level of E-cadherin expression and YAP1 activation was observed in PDPN-high MPM tumors. These findings indicate that PDPN is a diagnostic marker as well as a pathogenetic regulator that promotes MPM progression by increasing cell motility and inducing focus formation. Therefore, PDPN might be a pathogenetic determinant of MPM dissemination and aggressive growth and may thus be an ideal therapeutic target.

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THE ADAPTOR PROTEIN CRK-INDUCED ERBB2 EXPRESSION PROMOTES TUMOR PROGRESSION AND METASTASIS OF BLADDER CANCER VIA EXOSOMES

Yoshida Kazuhiko, Tsuda Masumi, Matsumoto Ryuji, Semba Shingo, Kimura Taichi, Tanino Mishie, Nishihara Hiroshi, Kondo Tsunenori, Tanabe Kazunari, Tanaka Shinya

JOURNAL OF UROLOGY 197 ( 4 ) E1175 2017.04

Joint Work, Accepted, ISSN 0022-5347

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[Clinical Biobank: A Novel System to Support Cancer Clinical Sequencing in Japan].

Hiroshi Nishihara

Rinsho byori. The Japanese journal of clinical pathology 65 ( 2 ) 167 - 172 2017.02

Single Work, Accepted, ISSN 0047-1860

The development of genomic medicine has enabled us to perform contemporary clinical sequencing, while the acquisition of high-quality biospecimens and the appropriate handling of these materials are indispensable. We started Clinical Biobank, a novel system for on-demand-type banking, in 2014. During the 22 months from August 2014, we stored around 6,000 biospecimens from 1,700 patients, and most of them were obtained for diverse clinical research. The quality and amount of extracted DNA and RNA from PFPE samples were markedly high; thus, these samples are adequate for targeted amplicon sequencing using MiSeq (Illumina). In addition, we recently established the Division of Clinical Cancer Genetics for personalized cancer medicine. We obtain biospecimens including blood and tissue fixed using the PAXgene Tissue system, and the samples are immediately analyzed for targeted amplicon sequencing using MiSeq. The rest of the samples are stored after adequate procedures in a -80 degree freezer. We obtain DNA and RNA from PAX-fixed paraffin- embedded samples with a high quality and sufficient amounts for clinical sequencing after pathological evalua- tion. For three months, we examined 40 cancer patients and performed targeted exome sequencing. As a result, detection rates of actionable and druggable gene mutations were around 85 and 50%, respectively. We have also established the Clinical Biobank Study Group in Japan, collaborating with several universities and cancer centers. We believe that this novel biospecimen repository system will help to effectively estab- lish cancer clinical sequencing throughout Japan.

Clinicopathological evaluation of Sox10 expression in diffuse-type gastric adenocarcinoma.

Marin Kato, Hiroshi Nishihara, Hideyuki Hayashi, Taichi Kimura, Yusuke Ishida, Lei Wang, Masumi Tsuda, Mishie Ann Tanino, Shinya Tanaka

Medical oncology (Northwood, London, England) (HUMANA PRESS INC) 34 ( 1 ) 8 - 8 2017.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 13570560

Sox10, one of the transcription factors, regulates Wnt/β-catenin signaling in diverse developmental processes in normal tissues. Sox10 is also expressed in variable solid tumors such as breast cancer, salivary tumor, hepatocellular carcinoma, ovarian tumor, nasopharyngeal carcinoma, prostate cancer, and digestive cancer. The role of Sox10 during tumorigenesis is still controversial, especially in digestive cancers; thus, we performed clinicopathological evaluation of Sox10 expression in 41 cases of diffuse-type gastric adenocarcinoma (DGA). We examined the expression of Sox10 by immunohistochemical staining and real-time quantitative reverse transcriptase PCR and evaluated the correlation between Sox10 expression and clinicopathological factors. A low-level expression of Sox10 was significantly associated with high-level venous invasion by immunohistochemical evaluation, while it was significantly associated with high-level lymphatic permeation when analyzed by real-time PCR assay. Survival analysis of 41 cases indicated that high level of vascular permeation was a statistically poor prognostic factor, suggesting that derogation of Sox10 would lead to unfavorable patients' outcome through the acceleration of vascular invasion. In this study, we revealed the clinical benefit of evaluation of Sox10 expression to predict the risk of vascular permeation which yields patients' poor prognosis in DGA.

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Expression of Notch1 and Numb in small cell lung cancer.

Hajime Kikuchi, Jun Sakakibara-Konishi, Megumi Furuta, Hiroshi Yokouchi, Hiroshi Nishihara, Shigeo Yamazaki, Hidetaka Uramoto, Fumihiro Tanaka, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Toshiyuki Harada, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Satoshi Oizumi, Hiroyuki Suzuki, Takashi Ishida, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Mitsuru Munakata, Masaharu Nishimura

Oncotarget (IMPACT JOURNALS LLC) 8 ( 6 ) 10348 - 10358 2017

Research paper (scientific journal), Joint Work, Accepted, ISSN 1949-2553

Notch signaling in tumorigenesis functions as an oncogene or tumor suppressor according to the type of malignancy. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC(hazard ratio = 0.503, P = 0.023). High Notch1 expression, but not Numb expression, is associated with favorable prognosis in SCLC.

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The Complete Remission of Acquired Immunodeficiency Syndrome-associated Isolated Central Nervous System Lymphomatoid Granulomatosis: A Case Report and Review of the Literature.

Yasuhiro Kano, Minori Kodaira, Atsuhito Ushiki, Makoto Kosaka, Mitsunori Yamada, Kunihiko Shingu, Hiroshi Nishihara, Masayuki Hanaoka, Yoshiki Sekijima

Internal medicine (Tokyo, Japan) (JAPAN SOC INTERNAL MEDICINE) 56 ( 18 ) 2497 - 2501 2017

Joint Work, Accepted, ISSN 09182918

A 49-year-old man presented with gradually progressive aphasia one month after being diagnosed with acquired immunodeficiency syndrome (AIDS). Brain magnetic resonance imaging showed multiple brain lesions with punctate and linear enhancement. A polymerase chain reaction detected Epstein-Barr virus (EBV) in the patient's cerebrospinal fluid. A diagnosis of isolated central nervous system lymphomatoid granulomatosis (CNS-LYG) was made based on the brain biopsy findings. The complete remission of CNS-LYG was achieved by anti-retroviral therapy (ART) alone. In the present case, the development of AIDS-associated CNS-LYG was considered to have been initiated by the reactivation of EBV in the CNS under immunosuppressive conditions. The patient's condition improved with the reconstitution of the patient's immune system.

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Proposal for a Prospective Registry for Moyamoya Disease in Japan.

Ken Kazumata, Masaki Ito, Haruto Uchino, Hiroshi Nishihara, Kiyohiro Houkin

Neurologia medico-chirurgica (JAPAN NEUROSURGICAL SOC) 57 ( 2 ) 66 - 72 2017

Research paper (scientific journal), Joint Work, Accepted, ISSN 04708105

The number of clinical research papers published worldwide on moyamoya disease (MMD) has increased recently. However, the majority of the literature comprises retrospective single-center studies collecting data on small numbers of patients. Several multi-center studies are ongoing in Japan; however, the current data are insufficient for comprehensively outlining the various characteristics of MMD. To enhance our knowledge on epidemiologic, vascular, and genetic aspects of MMD, a prospective multicenter registry will be established in Japan that will help to streamline clinical research as well as improve clinical treatments and long-term outcomes. Patients with MMD or secondary moyamoya syndrome referred to the participating centers will be invited to the registry. Demographic and physiological parameters, along with neuroimaging data will be collected chronologically. Clinical events, including neurological, medical, and surgical interventions will be recorded. Whole blood samples will be collected. Extra- and intra-cranial vascular tissue, and/or cerebrospinal fluid will also be collected from patients who undergo surgical revascularization. These biospecimens will be stored at the repositories and utilized for genome-wide association studies for identifying genetic variants, as well as tissue-specific proteomic, and/or molecular analyses. Ethics approval will be obtained at all facilities collecting biospecimens. The registry will provide descriptive statistics on functional outcomes, surgical techniques used, medications, and neurological events stratified according to patients' clinical characteristics. We expect this study to provide novel insights in the management of MMD patients and design better therapies.

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Prognostic Value of Eosinophil to Leukocyte Ratio in Patients with ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

Takao Konishi, Naohiro Funayama, Tadashi Yamamoto, Toru Morita, Daisuke Hotta, Hiroshi Nishihara, Shinya Tanaka

Journal of atherosclerosis and thrombosis (JAPAN ATHEROSCLEROSIS SOC) 24 ( 8 ) 827 - 840 2017

Research paper (scientific journal), Joint Work, Accepted, ISSN 13403478

AIM: Leukocyte profile has been related to clinical outcome in patients with ST-segment elevation (STE) myocardial infarction (MI). However, whether eosinophil to leukocyte ratio (ELR) predicts clinical outcome in patients who have undergone primary percutaneous coronary intervention (PCI) remains unclear. Therefore, we examined the prognostic value of ELR in this patient population. METHODS: We retrospectively analyzed the data of 331 consecutive patients who underwent primary PCI for STEMI between January 2009 and March 2015. All leukocyte types were counted and ELR was calculated for all patients 24 h after hospital admission. The primary study endpoint was major adverse cardiac events (MACEs) within up to one year of follow-up duration. RESULTS: MACEs including cardiac deaths in 9.4% of the patients, MI in 1.5%, and target lesion or vessel revascularization in 10.3%, occurred within one year in 68 patients (20.5%). The mean ELR was significantly lower in patients with MACEs than in patients without MACEs (0.20±0.51 vs.0.49±0.66, respectively; p＜0.001). An ELR ＜0.1 at 24 h was identified as the best cut-off value for mortality prediction. Multivariate analysis identified that an ELR ＜0.1 (odds ratio [OR]=0.38; 95% confidence interval [CI]=0.22-0.67; p＜0.001) and chronic kidney disease (OR=2.38; CI=1.33-4.24; p=0.003) are independent predictors of MACEs. CONCLUSION: In primary PCI patients with STEMI, ELR at 24 h was an independent predictor of MACEs in addition to the usual coronary risk factors and commonly used biomarkers.

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Immunohistochemical profiling of receptor tyrosine kinases, MED12, and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker.

Hiroshi Yokouchi, Hiroshi Nishihara, Toshiyuki Harada, Takashi Ishida, Shigeo Yamazaki, Hajime Kikuchi, Satoshi Oizumi, Hidetaka Uramoto, Fumihiro Tanaka, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Aya Goto, Hiroyuki Suzuki, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura, Mitsuru Munakata

Oncotarget (IMPACT JOURNALS LLC) 8 ( 24 ) 39711 - 39726 2017

Research paper (scientific journal), Joint Work, Accepted, ISSN 1949-2553

The limited number of available treatments for patients with small-cell lung cancer (SCLC) has prompted us to further investigate the biology of SCLC by molecular profiling. We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-βRII) by immunohistochemistry (IHC). Of the 125 evaluable samples, all tumors expressed MED12, and 123 samples (98.4%) expressed TGF-βRII. MED12 was highly expressed in the nucleus in 92% of the positive samples while TGF-βRII was highly expressed in the cytoplasm in 55% of the positive samples. High c-kit expression was an independent favorable prognostic marker confirmed by multivariate analysis (hazard ratio: 0.543, 95% confidence interval: 0.310-0.953, p = 0.033). Both the relapse free-survival and overall survival of patients who underwent adjuvant chemotherapy were statistically longer in those with high c-kit expression (n = 38) than those with intermediate, low, or no c-kit expression (n = 19) (not reached vs 11.6 months, p = 0.021; not reached vs 25.9 months, p = 0.028). IHC for c-kit may offer a prognostic marker for early-stage SCLC, and the results for MED12 and TGF-βRII may suggest the biological characteristics of SCLC. Further investigation of the roles of their related molecules in early stage SCLC is required.

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ANCA-Negative Granulomatosis with Polyangiitis Presenting with Hypertrophic Cranial Pachymeningitis, Abducens Nerve Palsy, and Stenosis of the Internal Carotid Artery.

Shohei Harabuchi, Nobuyuki Bandoh, Rika Yasukawa, Michihisa Kono, Takashi Goto, Yasuaki Harabuchi, Hidetoshi Ikeda, Hajime Kamada, Hiroshi Nishihara

Case reports in otolaryngology 2017 9687383 - 9687383 2017

Joint Work, Accepted

We report a rare case of granulomatosis with polyangiitis (GPA) presenting with hypertrophic cranial pachymeningitis (HCP), abducens nerve palsy, and stenosis of the internal carotid artery (ICA). A 59-year-old Japanese man presented with a year history of nasal obstruction and a 2-month history of slight headache. Histopathological examination of the granulomatous mucosa in the ethmoid sinuses resected by endoscopic sinus surgery revealed necrotizing vasculitis with multinucleated giant cells. The patient was diagnosed with the limited form of GPA as a result of the systemic examination. He declined immunosuppressive treatment. Eighteen months after the diagnosis of GPA, he presented with diplopia and severe headache. Though nasal findings indicating GPA were not observed in the nasal cavity, CT scan revealed a lesion of the right sphenoid sinus eroding the bone of the clivus. Gadolinium-enhanced MRI of the brain showed thickening of the dura mater around the right cavernous sinus and clivus. Magnetic resonance angiography and cerebral angiography revealed narrowing at the C5 portion of the ICA. Intravenous methylprednisolone pulse therapy followed by oral prednisolone and cyclophosphamide resolved headache and dramatically improved HCP and stenosis of the ICA.

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A case of giant cell-rich solitary fibrous tumor in the external auditory canal

Sayaka Yuzawa, Satoshi Tanikawa, Isamu Kunibe, Hiroshi Nishihara, Kazuo Nagashima, Shinya Tanaka

PATHOLOGY INTERNATIONAL (WILEY-BLACKWELL) 66 ( 12 ) 701 - 705 2016.12

Research paper (scientific journal), Joint Work, ISSN 13205463

We present a rare case of giant cell-rich solitary fibrous tumor (SFT) arising at the left external auditory canal in a 31-year-old woman. The tumor was well-circumscribed and composed of spindle-shaped cells with abundant collagenous bands. Scattered multinucleate giant cells were observed, some of which lined pseudovascular spaces. Although a focal mild-hypercellular area was observed, mitoses were rare and necrosis was absent. Interstitial mast cells were scattered, especially in the hypercellular area. Immunohistochemically, CD34, vimentin, and Bcl-2 presented diffuse positivity. Moreover, both mononuclear spindle cells and multinucleate cells showed nuclear STAT6 positivity, while NAB2-STAT6 fusion gene could not be detected by reverse transcription polymerase chain reaction using formalin-fixed specimen. These findings suggest the pathological diagnosis of giant cell-rich SFT, previously known as giant cell angiofibroma, which is a rare variant of SFT with multinucleate giant cells and occurs predominantly in orbital region. Although giant cell-rich SFTs of extra-orbital sites have been reported, to our knowledge, this is the first case arising in the external auditory canal. Giant cell-rich SFT should be considered as a differential diagnosis of spindle cell lesion with multinucleate giant cells, and STAT6 immunohistochemistry should be performed to distinguish this rare tumor from other mesenchymal neoplasms.

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Severe mitral regurgitation due to mitral leaflet aneurysm diagnosed by three-dimensional transesophageal echocardiography: a case report

Takao Konishi, Naohiro Funayama, Tadashi Yamamoto, Daisuke Hotta, Kenjiro Kikuchi, Katsumi Ohori, Hiroshi Nishihara, Shinya Tanaka

BMC CARDIOVASCULAR DISORDERS (BIOMED CENTRAL LTD) 16 ( 1 ) 2016.11

Research paper (scientific journal), Joint Work, ISSN 1471-2261

Background: A small mitral valve aneurysm (MVA) presenting as severe mitral regurgitation (MR) is uncommon.
Case presentation: A 47-year-old man with a history of hypertension complained of exertional chest discomfort. A transthoracic echocardiogram (TTE) revealed the presence of MR and prolapse of the posterior leaflet. A 6mm in diameter MVA, not clearly visualized by TTE, was detected on the posterior leaflet on a three-dimensional (3D) transesophageal echocardiography (TEE). The patient underwent uncomplicated triangular resection of P2 and mitral valve annuloplasty, and was discharged from postoperative rehabilitation, 2 weeks after the operation. Histopathology of the excised leaflet showed myxomatous changes without infective vegetation or signs of rheumatic heart disease.
Conclusions: A small, isolated MVA is a cause of severe MR, which might be overlooked and, therefore, managed belatedly. 3D TEE was helpful in imaging its morphologic details.

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A novel treatment strategy for pancreatic cancer based on gene profiles

Hayashi H., Nishihara H.

Japanese Journal of Cancer and Chemotherapy 43 ( 11 ) 1326 - 1331 2016.11

Accepted, ISSN 03850684

Pancreatic cancer has one of the highest rates of mortality among malignancies and the development of promising future therapies is strongly required. Recently, the utility of gene aberrations as biomarkers for determining therapeutic strategies has been demonstrated in several types of cancer. The detection of druggable mutations that aid in the selection of effective molecular targeting drugs is feasible in clinical settings for certain cancers. On the other hand, personalized therapy for pancreatic cancer guided by genomic biomarkers has not yet been realized and suitable molecular targets for the disease have been unclear until now. KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcino-genesis. However, it is considered difficult to develop treatment strategies to target genetic aberrations of these four genes. In recent years, genome sequencing has progressively revealed the molecular biological characteristics of pancreatic cancer, including the discovery of novel potential therapeutic targets and low-frequency druggable genetic aberrations. Gene profile-based novel treatment strategies and subsequent attempts to realize precision medicine for pancreatic cancer are steadily ongoing in an effort to achieve improved treatment outcomes.

Aldo-keto reductase 1C1 induced by interleukin-1β mediates the invasive potential and drug resistance of metastatic bladder cancer cells.

Ryuji Matsumoto, Masumi Tsuda, Kazuhiko Yoshida, Mishie Tanino, Taichi Kimura, Hiroshi Nishihara, Takashige Abe, Nobuo Shinohara, Katsuya Nonomura, Shinya Tanaka

Scientific reports (Scientific Reports) 6 34625 - 34625 2016.10

Research paper (scientific journal), Joint Work

In treating bladder cancer, determining the molecular mechanisms of tumor invasion, metastasis, and drug resistance are urgent to improving long-term patient survival. One of the metabolic enzymes, aldo-keto reductase 1C1 (AKR1C1), plays an essential role in cancer invasion/metastasis and chemoresistance. In orthotopic xenograft models of a human bladder cancer cell line, UM-UC-3, metastatic sublines were established from tumors in the liver, lung, and bone. These cells possessed elevated levels of EMT-associated markers, such as Snail, Slug, or CD44, and exhibited enhanced invasion. By microarray analysis, AKR1C1 was found to be up-regulated in metastatic lesions, which was verified in metastatic human bladder cancer specimens. Decreased invasion caused by AKR1C1 knockdown suggests a novel role of AKR1C1 in cancer invasion, which is probably due to the regulation of Rac1, Src, or Akt. An inflammatory cytokine, interleukin-1β, was found to increase AKR1C1 in bladder cancer cell lines. One particular non-steroidal anti-inflammatory drug, flufenamic acid, antagonized AKR1C1 and decreased the cisplatin-resistance and invasion potential of metastatic sublines. These data uncover the crucial role of AKR1C1 in regulating both metastasis and drug resistance; as a result, AKR1C1 should be a potent molecular target in invasive bladder cancer treatment.

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Genetic landscape of meningioma

Sayaka Yuzawa, Hiroshi Nishihara, Shinya Tanaka

BRAIN TUMOR PATHOLOGY (SPRINGER JAPAN KK) 33 ( 4 ) 237 - 247 2016.10

Joint Work, ISSN 14337398

Meningioma is the most common intracranial tumor, arising from arachnoid cells of the meninges. Monosomy 22 and inactivating mutations of NF2 are well-known genetic alterations of meningiomas. More recently, mutations in TRAF7, AKT1, KLF4, SMO, and PIK3CA were identified by next-generation sequencing. We here reviewed 553 meningiomas for the mutational patterns of the six genes. NF2 aberration was observed in 55 % of meningiomas. Mutations of TRAF7, AKT1, KLF4, PIK3CA, and SMO were identified in 20, 9, 9, 4.5, and 3 % of cases, respectively. Altogether, 80 % of cases harbored at least one of the genetic alterations in these genes. NF2 alterations and mutations of the other genes were mutually exclusive with a few exceptions. Clinicopathologically, tumors with mutations in TRAF7/AKT1 and SMO shared specific features: they were located in the anterior fossa, median middle fossa, or anterior calvarium, and most of them were meningothelial or transitional meningiomas. TRAF7/KLF4 type meningiomas showed different characteristics in that they occurred in the lateral middle fossa and median posterior fossa as well as anterior fossa and median middle fossa, and contained a secretory meningioma component. We also discuss the mutational hotspots of these genes and other genetic/cytogenetic alterations contributing to tumorigenesis or progression of meningiomas.

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