研究者詳細 - 西原　広史

論文 - 西原　広史

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EXO1 homozygous deletion suppresses the hydroxyurea sensitivity in anaplastic meningioma with extracranial metastases

Yoshimura S., Ohta T., Makita K., Yamamuro S., Ochai Y., Sumi K., Shijo K., Yoshino A., Homma T., Sugitani M., Yuzawa S., Nishihara H., Tanaka S.

International Journal of Clinical and Experimental Medicine （International Journal of Clinical and Experimental Medicine） 9 （ 9 ） 18618 - 18625 2016年09月

研究論文（学術雑誌）, 共著, ISSN 1940-5901

© 2016, E-Century Publishing Corporation. All rights reserved. Background: Anaplastic meningioma is exceedingly rare, and its clinicopathological features are distinctive. Distant meningioma metastases have previously been reported to be very rare. The most common site of metastasis is the lung, which accounts for 61% of all meningioma metastases. The standard therapy for meningiomas is total resection and/or radiation therapy. Case Report: A 71-year-old man was admitted with headache and left hemiparesis. Magnetic resonance imaging (MRI) revealed mass lesions at the right frontal convexity and left occipital lobe. Following surgery, pathological examinations demonstrated an anaplastic meningioma. At 3 months after the operation and radiation therapy, lung tumor was removed. The pathological findings for the lung tumor resembled those of the brain tumor. A diagnosis of metastatic lung tumor from anaplastic meningioma was made. At 2 months after the lung surgery, MRI disclosed focal recurrence in the frontal convexity area and progression into the cavernous sinus. Abdominal CT detected a new metastatic lesion in the patient’s liver. He underwent adjuvant reirradiation consisting of whole brain radiotherapy. In addition, he received chemotherapy using angiogenesis receptor (bevacizumab). Chemotherapy with hydroxyurea was initiated after 2 courses of the bevacizumab chemotherapy, because his hepatic lesion had become more aggressive. The intracranial mass was reduced by 50% at 8 weeks after initiation of the hydroxyurea chemotherapy. However, there was no significant effect on the liver and lung metastases. Analysis and Conclusion: Extracranial metastases have been estimated to occur in only 0.1% of all meningiomas and most often in association with anaplastic meningiomas. While total resection and/ or radiation treatment provide the standard therapy for meningiomas, use of chemotherapy against meningiomas has been limited to distant metastases or based on out of surgical criteria. Several reports have demonstrated that hydroxyurea provides on effective chemotherapy for meningiomas including grade I cases. Hydroxyurea halts meningioma cell growth through arrest of the S-phase of the cell cycle, thus inducing apoptosis. Our analysis revealed EXO1 homozygous deletion at exons 8 and 10 in the patient’s extracranial metastatic meningioma. The findings suggested that EXO1 homozygous deletion may be associated with suppression of hydroxyurea sensitivity in anaplastic meningiomas. Hydroxyurea should be a justified therapeutic adaptation in cases of anaplastic meningioma without EOX1 homozygous deletion.

Relationship between left coronary artery bifurcation angle and restenosis after stenting of the proximal left anterior descending artery

Konishi T., Yamamoto T., Funayama N., Nishihara H., Hotta D.

Coronary Artery Disease （Coronary Artery Disease） 27 （ 6 ） 449 - 459 2016年09月

研究論文（学術雑誌）, 共著, ISSN 09546928

© 2016 Wolters Kluwer Health, Inc. All rights reserved. Introduction Restenosis after a percutaneous coronary intervention for proximal left anterior descending (pLAD) coronary artery disease remains a clinical challenge. However, the relationship between the left main trunk (LMT)/LAD bifurcation angle and the pLAD artery restenosis is unclear. This study examined the relationship between the LMT-LAD bifurcation angle and restenosis after stent implantation for pLAD disease. Methods We analysed the data of 177 consecutive patients who underwent stent implantation for pLAD disease, followed by coronary angiography between December 2008 and September 2013. The LMT-LAD bifurcation angle was measured in the left or the right anterior oblique caudal (CAU) angiographic view. Results and discussion Out of 177 patients, 12 developed in-stent restenosis and 21 developed in-segment restenosis. The mean angle in patients with in-stent restenosis (52.2°±14.5°) in the left anterior oblique CAU view was significantly larger than that in patients without restenosis (32.0°±18.1°; P<0.001). The LMT-LAD angle in the right anterior oblique CAU view was significantly larger in patients with in-segment restenosis (27.3°±14.3°) than in patients without restenosis (17.5°±10.1°; P<0.001). Moreover, by multivariate analysis, the LMT-LAD angle was an independent predictor of in-stent and in-segment restenosis, after adjustment for significant confounders such as diabetes, hypertension, dyslipidaemia, final minimum lesion diameter and lesion length. Conclusion This study suggests that a wide LMT-LAD angle is a predictor of restenosis after stent implantation for pLAD artery disease.

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Analysis of NAB2-STAT6 Gene Fusion in 17 Cases of Meningeal Solitary Fibrous Tumor/Hemangiopericytoma

Yuzawa S., Nishihara H., Wang L., Tsuda M., Kimura T., Tanino M., Tanaka S.

American Journal of Surgical Pathology （American Journal of Surgical Pathology） 40 （ 8 ） 1031 - 1040 2016年08月

共著, ISSN 01475185

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Solitary fibrous tumor/hemangiopericytoma (SFT/ HPC) is a mesenchymal tumor that can affect virtually any region of the body. SFT/HPC of the thoracic cavity and soft tissue has been histologically considered a single biological entity termed SFT; in fact, NAB2-STAT6 gene fusion was recently identified in both diseases. In contrast, meningeal SFT and HPC still need to be investigated in detail with regard to gene fusion variants. The aim of this study was to verify the frequency of NAB2-STAT6 fusion and the relationship between fusion variants and clinicopathologic findings of SFT/HPC, especially meningeal SFT/HPC. We examined the NAB2-STAT6 fusion by reverse transcription polymerase chain reaction with 4 cases of meningeal SFT and 13 cases of meningeal HPC. NAB2-STAT6 fusion transcripts were identified in 12 of 17 cases, including NAB2ex6-STAT6ex17 (4/17, 24%), NAB2ex6-STAT6ex16 and NAB2ex4-STAT6ex2 (3/17, 18%, respectively), and NAB2ex5- STAT6ex16 (2/17, 12%). Three cases showed a pseudopapillary pattern, and 2 of them carried NAB2ex6-STAT6ex17. In addition, our meta-analysis revealed that the major fusion variant in meningeal SFT/HPC was NAB2ex6-STAT6ex16/17 (29/54, 54%), which was also common in soft tissue and intraperitoneum/ retroperitoneum but rare in thoracic SFT. Fusion variant significantly correlated with age and histologic diagnosis in meningeal SFT/HPC but not with prognosis. Our results represented that meningeal SFT and HPC were in a single biological spectrum with NAB2-STAT6 gene fusion as was nonmeningeal SFT and further confirmed the organ-specific tumorigenic process and morphologic differences on the basis of fusion variants in meningeal SFT/HPC.

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Identification and analysis of CXCR4-positive synovial sarcoma-initiating cells

Kimura T., Wang L., Tabu K., Tsuda M., Tanino M., Maekawa A., Nishihara H., Hiraga H., Taga T., Oda Y., Tanaka S.

Oncogene （Oncogene） 35 （ 30 ） 3932 - 3943 2016年07月

研究論文（学術雑誌）, 共著, ISSN 09509232

Synovial sarcoma accounts for almost 10% of all soft tissue sarcomas, and its prognosis is poor with 5-year survival rates at 36%. Thus, new treatments and therapeutic targets for synovial sarcoma are required. Tumor-initiating cells have been defined by the ability for self-renewal and multipotent differentiation, and they exhibit higher tumorigenic capacity, chemoresistance and radiation resistance, expecting to be a new therapeutic target. In synovial sarcoma, the presence of such stemness remains largely unclear; thus, we analyzed whether synovial sarcoma possessed tumor-initiating cells and explored specific markers, and we discovered that synovial sarcoma cell lines possessed heterogeneity by way of containing a sphere-forming subpopulation highly expressing NANOG, OCT4 and SOX2. By expression microarray analysis, CXCR4 was identified to be highly expressed in the sphere subpopulation and correlated with stem-cell-Associated markers. Inhibition of CXCR4 suppressed the cell proliferation of synovial sarcoma cell lines in vitro. The tumor-initiating ability of CXCR4-positive cells was demonstrated by xenograft propagation assay. CXCR4-positive cells showed higher tumorigenicity than negative ones and possessed both self-renewal and multipotent differentiation ability. Immunohistochemical analysis of 39 specimens of synovial sarcoma patients revealed that CXCR4 strongly correlated with poor prognosis of synovial sarcoma. Thus, we conclude that CXCR4 is the marker of synovial sarcoma-initiating cells, a new biomarker for prognosis and a new potential therapeutic target.

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Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system

Yuzawa S., Nishihara H., Yamaguchi S., Mohri H., Wang L., Kimura T., Tsuda M., Tanino M., Kobayashi H., Terasaka S., Houkin K., Sato N., Tanaka S.

Modern Pathology （Modern Pathology） 29 （ 7 ） 708 - 716 2016年07月

研究論文（学術雑誌）, 共著, ISSN 08933952

© 2016 USCAP, Inc All rights reserved. Recent genetic analyses using next-generation sequencers have revealed numerous genetic alterations in various tumors including meningioma, which is the most common primary brain tumor. However, their use as routine laboratory examinations in clinical applications for tumor genotyping is not cost effective. To establish a clinical sequencing system for meningioma and investigate the clinical significance of genotype, we retrospectively performed targeted amplicon sequencing on 103 meningiomas and evaluated the association with clinicopathological features. We designed amplicon-sequencing panels targeting eight genes including NF2 (neurofibromin 2), TRAF7, KLF4, AKT1, and SMO. Libraries prepared with genomic DNA extracted from PAXgene-fixed paraffin-embedded tissues of 103 meningioma specimens were sequenced using the Illumina MiSeq. NF2 loss in some cases was also confirmed by interphase-fluorescent in situ hybridization. We identified NF2 loss and/or at least one mutation in NF2, TRAF7, KLF4, AKT1, and SMO in 81 out of 103 cases (79%) by targeted amplicon sequencing. On the basis of genetic status, we categorized meningiomas into three genotype groups: NF2 type, TRAKLS type harboring mutation in TRAF7, AKT1, KLF4, and/or SMO, and 'not otherwise classified' type. Genotype significantly correlated with tumor volume, tumor location, and magnetic resonance imaging findings such as adjacent bone change and heterogeneous gadolinium enhancement, as well as histopathological subtypes. In addition, multivariate analysis revealed that genotype was independently associated with risk of recurrence. In conclusion, we established a rapid clinical sequencing system that enables final confirmation of meningioma genotype within 7 days turnaround time. Our method will bring multiple benefits to neuropathologists and neurosurgeons for accurate diagnosis and appropriate postoperative management.

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Clinical impacts of mesothelin expression in gastrointestinal carcinomas.

Takahiro Einama, Futoshi Kawamata, Hirofumi Kamachi, Hiroshi Nishihara, Shigenori Homma, Fumihiko Matsuzawa, Tatsuzo Mizukami, Yuji Konishi, Munenori Tahara, Toshiya Kamiyama, Okio Hino, Akinobu Taketomi, Satoru Todo

World journal of gastrointestinal pathophysiology 7 （ 2 ） 218 - 22 2016年05月

共著, 査読有り

Mesothelin, C-ERC/mesothelin is a 40-kDa cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura, peritoneum, and pericardium. Moreover, mesothelin has been shown to be overexpressed in several human cancers, including virtually all mesothelioma and pancreatic cancer, approximately 70% of ovarian cancer and extra bile duct cancer, and 50% of lung adenocarcinomas and gastric cancer. The full-length human mesothelin gene encodes the primary product, a 71-kDa precursor protein. The 71-kDa mesothelin precursor is cleaved into two products, 40-kDa C-terminal fragment that remains membrane-bound via glycosylphosphatidylinositol anchor, and a 31-kDa N-terminal fragment, megakaryocyte potentiating factor, which is secreted into the blood. The biological functions of mesothelin remain largely unknown. However, results of recent studies have suggested that the mesothelin may play a role of cell proliferation and migration. In pancreatic cancer, mesothelin expression was immunohistochemically observed in all cases, but absent in normal pancreas and in chronic pancreatitis. Furthermore, the expression of mesothelin was correlated with an poorer patient outcome in several human cancers. The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy. The present review discusses the expression and function of mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.

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Novel signaling collaboration between TGF-β and adaptor protein Crk facilitates EMT in human lung cancer

Elmansuri A., Tanino M., Mahabir R., Wang L., Kimura T., Nishihara H., Kinoshita I., Dosaka-Akita H., Tsuda M., Tanaka S.

Oncotarget （Oncotarget） 7 （ 19 ） 27094 - 27107 2016年05月

研究論文（学術雑誌）, 共著, ISSN 1949-2553

The signaling adaptor protein Crk has been shown to play an important role in various human cancers. However, its regulatory machinery is not clear. Here, we demonstrated that Crk induced EMT in A549 human lung adenocarcinoma cells through differential regulation of Rac1/Snail and RhoA/Slug, leading to decreased expression of E-cadherin and increased N-cadherin, fibronectin, and MMP2 expression. Cancer cells with mesenchymal features produced TGF-β and also increased the levels of TGF-β receptor. TGF-β increased the endogenous levels of Crk and also augmented Crk-dependent expression of Snail and Slug, and conversely TGF-β receptor inhibitor suppressed the levels of Snail and Slug. Overexpression of Crk was observed at the invasive front of human lung cancer tissues and was significantly associated with poor prognosis. Thus, TGF-β and Crk collaborate to form a positive feedback loop to facilitate EMT, which may lead to the malignancy of human cancers possibly being affected by their microenvironment.

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Diagnostic value of liquid-based cytology with fine needle aspiration specimens for cervical lymphadenopathy

Bandoh N., Goto T., Akahane T., Ohnuki N., Yamaguchi T., Kamada H., Harabuchi Y., Tanaka S., Nishihara H.

Diagnostic Cytopathology （Diagnostic Cytopathology） 44 （ 3 ） 169 - 176 2016年03月

研究論文（学術雑誌）, 共著, ISSN 87551039

© 2016 Wiley Periodicals, Inc. Background Cervical lymphadenopathy is a symptom that is frequently seen among outpatients, and it is important to differentiate malignant lesions from reactive lymphoid hyperplasia. Fine needle aspiration (FNA) cytology has been widely used for the diagnosis of cervical lymphadenopathy. However, some limitations of the diagnostic accuracy using conventional smear (CS) cytology have been pointed out. The diagnostic value of liquid-based cytology (LBC) with FNA specimens has not yet been fully proven. Methods Forty-two patients with cervical lymphadenopathy who underwent FNA with CS cytology from 2007 to 2011 and 123 patients who underwent FNA with LBC utilizing LBCPREP2™ from 2011 to 2015 were studied. Diagnostic values were compared between the CS and the LBC groups. Results Of the total 165 patients representing the combined CS and LBC groups, 81 (49.1%) were diagnosed as benign lymph node and 84 (50.9%) were malignant diseases including 37 (22.4%) of metastatic carcinoma except for thyroid carcinoma, 30 (18.2%) of metastatic thyroid carcinoma, and 17 (10.3%) of malignant lymphoma. The overall statistical values including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the CS were 75%, 100%, 100%, 78.9%, and 87.1%, respectively, whereas those values for LBC were 91.2%, 100%, 100%, 90.7%, and 95.3%, respectively. The sensitivity of LBC for malignant diseases tended to be higher than that of CS cytology (p = 0.081). Conclusion LBC with FNA specimens from cervical lymphadenopathy is a useful and reliable method for the diagnosis of malignant diseases, especially of metastatic carcinomas, due to its increased sensitivity compared with CS cytology. Diagn. Cytopathol. 2016;44:169-176.

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Organ-specific efficacy of HSP90 inhibitor in multiple-organ metastasis model of chemorefractory small cell lung cancer

Takeuchi S., Fukuda K., Arai S., Nanjo S., Kita K., Yamada T., Hara E., Nishihara H., Uehara H., Yano S.

International Journal of Cancer （International Journal of Cancer） 138 （ 5 ） 1281 - 1289 2016年03月

共著, ISSN 00207136

© 2015 UICC. Small-cell lung cancer (SCLC) accounts for nearly 15% of lung cancer cases and exhibits aggressive clinical behavior characterized by rapid growth and metastatic spread to multiple organs. About 70% of patients with SCLC present with extensive disease and distant metastases at diagnosis. HSP90 is a 90-kDa molecular chaperone whose association is required for the stability and function of its numerous "client proteins." Here, we assessed the therapeutic potential of the HSP90 inhibitor 17-DMAG in SCLC. Notably, 17-DMAG hindered the viability of human SCLC cell lines - regardless of their chemosensitivity - via the decreased expression of client proteins, including the proto-oncogene c-Raf (also known as RAF1). In an in vivo imaging model of SCLC multiple-organ metastasis with the human SCLC cell line SBC-5, treatment with 17-DMAG remarkably inhibited the formation of metastatic sites in the liver, but was ineffective in hindering the progression of bone lesions. The latter was likely the result of activation of osteoclasts. IGF-1, which is supposed to be rich in bone environment, preserved c-Raf expression and maintained viability of SBC-5 cells treated with 17-DMAG. Furthermore, the combined use of a bisphosphonate with 17-DMAG significantly attenuated the progression of metastases in both the liver and the bone. These findings suggest that therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials. What's new? Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by increased incidence of multi-organ metastasis and acquired resistance to conventional chemotherapy. Here, the authors show that HSP90 inhibitor 17-DMAG efficiently inhibits the metastasis of chemorefractory SCLC cells to the liver, but worsens bone metastasis, indicating heterogeneity in 17-DMAG's anti-metastatic effect. Furthermore, they show that the combined use of a bisphosphonate with 17-DMAG significantly attenuates the progression of metastases in both the liver and the bone. The findings thus suggest that the therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials.

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A case of cerebral astroblastoma with rhabdoid features: a cytological, histological, and immunohistochemical study

Yuzawa S., Nishihara H., Tanino M., Kimura T., Moriya J., Kamoshima Y., Nagashima K., Tanaka S.

Brain Tumor Pathology （Brain Tumor Pathology） 33 （ 1 ） 63 - 70 2016年01月

研究論文（学術雑誌）, 共著, ISSN 14337398

© 2015, The Japan Society of Brain Tumor Pathology. Astroblastoma is a rare neuroepithelial neoplasm of unknown origin, usually occurring in children and young adults. Here we report a case of astroblastoma with uncommon features in an 18-year-old female. The tumor was a well-circumscribed cystic and solid mass with marked gadolinium enhancement in the right frontal lobe. Cytological examination showed polarized monopolar cells with diminished cohesiveness. Tumor cells possessed eccentric round to oval nuclei with abundant eosinophilic cytoplasm, sometimes having cytoplasmic processes. Histopathologically, the tumor showed perivascular pseudorosettes with prominent vascular sclerosis. Foam cells were frequently infiltrated around blood vessels and among tumor cells. In some areas, a solid growth pattern of plump tumor cells with abundant inclusion-like eosinophilic cytoplasm showing rhabdoid appearance was observed. The immunohistochemical study revealed strong and diffuse positivity for vimentin and epithelial membrane antigen. Tumor cells were focally positive for glial fibrillary acidic protein and cytokeratin AE1/AE3. Nuclear immunoreactivity for INI1 protein was evident. The Ki-67 labeling index was 10.8 %. This tumor was finally diagnosed as low-grade astroblastoma and the patient had no evidence of recurrence without postoperative radiotherapy or chemotherapy during the last 6 months of follow-up. This report describes novel cytological, histopathological, and immunohistochemical features of the rare tumor.

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Rapid immunocytochemistry based on alternating current electric field using squash smear preparation of central nervous system tumors

Moriya J., Tanino M., Takenami T., Endoh T., Urushido M., Kato Y., Wang L., Kimura T., Tsuda M., Nishihara H., Tanaka S.

Brain Tumor Pathology （Brain Tumor Pathology） 33 （ 1 ） 13 - 18 2016年01月

研究論文（学術雑誌）, 共著, ISSN 14337398

© 2015, The Japan Society of Brain Tumor Pathology. The role of intraoperative pathological diagnosis for central nervous system (CNS) tumors is crucial for neurosurgery when determining the surgical procedure. Especially, treatment of carmustine (BCNU) wafers requires a conclusive diagnosis of high-grade glioma proven by intraoperative diagnosis. Recently, we demonstrated the usefulness of rapid immunohistochemistry (R-IHC) that facilitates antigen–antibody reaction under alternative current (AC) electric field in the intraoperative diagnosis of CNS tumors; however, a higher proportion of water and lipid in the brain parenchyma sometimes leads to freezing artifacts, resulting in poor quality of frozen sections. On the other hand, squash smear preparation of CNS tumors for cytology does not affect the frozen artifacts, and the importance of smear preparation is now being re-recognized as being better than that of the tissue sections. In this study, we established the rapid immunocytochemistry (R-ICC) protocol for squash smears of CNS tumors using AC electric field that takes only 22 min, and demonstrated its usefulness for semi-quantitative Ki-67/MIB-1 labeling index and CD 20 by R-ICC for intraoperative diagnosis. R-ICC by AC electric field may become a substantial tool for compensating R-IHC and will be applied for broad antibodies in the future.

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Intraoperative localization of arteriovenous malformation of a jejunum with combined use of angiographic methods and indocyanine green injection: Report of a new technique

Ono H., Kusano M., Kawamata F., Danjo Y., Kawakami M., Nagashima K., Nishihara H.

International Journal of Surgery Case Reports （International Journal of Surgery Case Reports） 29 137 - 140 2016年

共著, ISSN 22102612

© 2016 The Author(s) Introduction The localization of small intestine sources of obscure gastrointestinal bleeding has been a challenge. The use of indocyanine green (ICG) is effective in aiding intraoperative localization if a bleeding lesion is identified on angiography. Case presentation A 95-year-old Japanese man presented with hematochezia. Selective angiography of the superior mesenteric artery (SMA) established an arteriovenous malformation (AVM). ICG injection into the feeding vessel was administered intraoperatively, and the demarcated segment of the jejunum was resected. Discussion Diluted ICG was injected in the SMA by intraoperative angiography, and the region could be easily and clearly visualized by the ICG fluorescence imaging; small patchy poolings of ICG were recognized. Ultimately, the region was diagnosed as an AVM of the jejunum. To the best of our knowledge, this is the first reported description of this technique. Conclusion Our new technique of combining selective angiography with intraoperative ICG injection and focused enterectomy is a safe, accurate, and cost-effective treatment.

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The infrastructure of the biobank system

Suzuki T., Hatakeyama H., Yasukawa S., Homma A., Nishihara H., Matsuno Y., Fukuda S.

Oto-Rhino-Laryngology Tokyo （Oto-Rhino-Laryngology Tokyo） 59 （ 6 ） 371 - 376 2016年

研究論文（学術雑誌）, 共著, ISSN 03869687

With the development of analysis technology, high-quality biological materials have been increasingly important for researches. Cryopreservation of fresh samples is recommended with regard to quality control. We consider that support system which enables closer cooperation with pathologists is essential for collection of tissue samples from specimens, lest the procedure should interfere with the pathological diagnosis. Thus, we manage to set up the platform of Biobank and establish its guideline for the acquisition, maintenance and provision of the quality of biological resources in a secure manner.

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Intraprocedural left ventricular free wall rupture diagnosed by left ventriculogram in a patient with infero-posterior myocardial infarction and severe aortic stenosis

Konishi T., Funayama N., Yamamoto T., Nishihara H., Hotta D., Kikuchi K., Yokoyama H., Ohori K.

BMC Cardiovascular Disorders （BMC Cardiovascular Disorders） 16 （ 1 ） 2016年

研究論文（学術雑誌）, 共著, ISSN 1471-2261

� 2016 The Author(s). Background: Left ventricular wall rupture remains a major lethal complication of acute myocardial infarction and hypertension is a well-known predisposing factor of cardiac rupture after myocardial infarction. Case presentation: An 87-year-old man was admitted to our hospital, diagnosed as acute myocardial infarction (AMI). The echocardiogram showed 0.67-cm 2 aortic valve, consistent with severe aortic stenosis (AS). A coronary angiography showed a chronic occlusion of the proximal left circumflex artery and a 99 % stenosis and thrombus in the mid right coronary artery. During percutaneous angioplasty of the latter, transient hypotension and bradycardia developed at the time of balloon inflation, and low doses of noradrenaline and etilefrine were intravenously administered as needed. The patient suddenly lost consciousness and developed electro-mechanical dissociation. Cardio-pulmonary resuscitation followed by insertion of an intra-aortic balloon pump (IABP) and percutaneous cardiopulmonary support were initiated. The echocardiogram revealed moderate pericardial effusion, though the site of free wall rupture was not distinctly visible. A left ventriculogram clearly showed an infero-posterior apical wall rupture. Surgical treatment was withheld because of the interim development of brain death. Conclusions: In this patient, who presented with severe AS, the administration of catecholamine to stabilize the blood pressure probably increased the intraventricular pressures considerably despite apparently normal measurements of the central aortic pressure. IABP, temporary pacemaker, or both are recommended instead of intravenous catecholamines for patients with AMI complicated with significant AS to stabilize hemodynamic function during angioplasty.

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Successful and Safe Retrieval of a Thrombus from the Lumen of a Guiding Catheter during Percutaneous Coronary Intervention

Konishi T, Funayama N, Nishihara H

Journal of Clinical Case Reports 6 2 2016年

共著, 査読有り

Authentic Vascular and Stromal Structure in Animal Disease Model for Nanomedicine

Hiroshi Nishihara, Mitsunobu R. Kano

Intracellular Delivery III 149 - 160 2016年

共著

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Prognostic impact of clinical variables on surgically resected small-cell lung cancer: Results of a retrospective multicenter analysis (FIGHT002A and HOT1301A)

Yokouchi H., Ishida T., Yamazaki S., Kikuchi H., Oizumi S., Uramoto H., Tanaka F., Harada M., Akie K., Sugaya F., Fujita Y., Fukuhara T., Takamura K., Kojima T., Harada T., Higuchi M., Matsuura Y., Honjo O., Minami Y., Watanabe N., Nishihara H., Suzuki H., Dosaka-Akita H., Isobe H., Nishimura M., Munakata M.

Lung Cancer （Lung Cancer） 90 （ 3 ） 548 - 553 2015年12月

研究論文（学術雑誌）, 共著, ISSN 01695002

© 2015 Elsevier Ireland Ltd. Objectives: Several American and Japanese guidelines recommend surgery for patients with c-stage I small-cell lung cancer (SCLC), whereas the European Society of Medical Oncology (ESMO) guidelines recommend surgery for patients with not only c-stage I but also c-stage II (T2N1) SCLC. In addition, previous studies identified various factors other than clinical stage that are related to survival in these patients. Thus, further validation and examination of the association of clinical stage and other clinical variables with survival are required for establishing practical management of early-stage SCLC. Patients and methods: We reviewed the clinical courses of 156 SCLC patients who had undergone surgery at 17 institutions between January 2003 and January 2013. Results: Clinical stages (tumor-node-metastasis [TNM] version 7) of the 156 patients were 98 cases in IA, 14 in IB, 16 in IIA, 7 in IIB, 18 in IIIA, and 3 in IIIB. Median overall survival (OS) was 33.3 months (95% confidence interval: 20.9-45.8). Multivariate analysis revealed that OS was longer in patients either at c-stage II and under, with a maximum tumor diameter of <20 mm, with preoperative diagnosis, without a history or presence of other types of cancer, or who underwent prophylactic cranial irradiation (PCI). Conclusion: These results indicate that a history or presence of other types of cancer might be a major decisive factor for surgery. Patients with c-stages I and II (c-T2N1) can be considered for surgery, and PCI may be useful in patients undergoing surgery in a practical setting, partly supporting the ESMO guidelines.

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Infective endocarditis presenting initially with ileus complicated by dehiscence of annuloplasty ring

Konishi T., Nishihara H., Ito T., Tanaka Y.

BMC Cardiovascular Disorders （BMC Cardiovascular Disorders） 15 （ 1 ） 2015年10月

研究論文（学術雑誌）, 共著, ISSN 1471-2261

© 2015 Konishi et al. Background: Infective endocarditis (IE) on an annuloplasty ring dehiscence is uncommon after mitral valve repair. Case Presentation: A 53-year-old man underwent mitral annuloplasty with a 24-mm ring for posterior mitral valve prolapse. He underwent repeat valve repair for recurrent mitral valve regurgitation 4 years later. He was re-hospitalised complaining of vomiting, nausea, general fatigue and left abdominal pain 2 months later, and presented with low-grade fever, leukocytosis and an elevated blood concentration of C-reactive protein. An abdominal computed tomography scan showed multiple embolisms in the liver, kidney and spleen. Transoesophageal echocardiography revealed mitral annuloplasty ring dehiscence and vegetations consistent with IE. The infected annuloplasty ring and vegetations were surgically excised. Blood cultures grew coagulasenegative staphylococcus aureus, consistent with the excised mitral valve histology. The postoperative course was uneventful, without recurrence of IE. Conclusions: Embolic ileus as initial manifestation of IE is rare and might confuse the diagnosis and delay its management. Gastrointestinal signs and symptoms may be the initial manifestations of systemic embolization from infective endocarditis. Transoesophageal echocardiography effectively identified the presence of vegetations and mitral annuloplasty ring dehiscence.

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Histologically confirmed case of cerebral vasculitis associated with Crohn's disease -a case report

Gekka M., Sugiyama T., Nomura M., Kato Y., Nishihara H., Asaoka K.

BMC Neurology （BMC Neurology） 15 （ 1 ） 2015年09月

研究論文（学術雑誌）, 共著, ISSN 1471-2377

© 2015 Gekka et al. Background: Extraintestinal manifestations in Crohn's disease (CD) are frequent and well recognized. However, neurological involvement secondary to CD is rare, and there have been few histologically confirmed cases of cerebral vasculitis secondary to CD. Case presentation: A 58-year-old left-handed man with a history of refractory CD who had fever of over 38 °C, progression of CD symptoms, and Gerstmann's syndrome consulted our hospital. Laboratory data showed elevation of C-reactive protein (CRP) and hypoproteinemia. T2-weighted magnetic resonance imaging (MRI) revealed a right parietal high-intensity lesion. Catheter angiography showed segmental multiple narrowing and occlusion in the distal part of the middle cerebral artery and anterior cerebral artery. Angiography also revealed multiple venous occlusions in the affected parietal area. To confirm the diagnosis, the patient underwent open biopsy, and histological examination revealed cerebral vasculitis. The patient was then started on high-dose prednisolone (60 mg/day) in addition to his previous therapy, which included mesalazine, adalimumab, and azathioprine. CRP elevation, hypoproteinemia, and gastrointestinal symptoms immediately improved after starting this treatment. Neurological status improved simultaneously with CD symptom improvement, and follow-up brain MRI revealed a reduction in the size of the right parietal lobe lesion. He returned to normal status and was discharged from our hospital 5 weeks after admission. Conclusion: This is an important case of histologically confirmed cerebral vasculitis associated with CD. The clinical course of our case clearly illustrates the relevance of the occurrence of cerebral vasculitis and the exacerbation of CD.

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Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs

Nakata A., Yoshida R., Yamaguchi R., Yamauchi M., Tamada Y., Fujita A., Shimamura T., Imoto S., Higuchi T., Nomura M., Kimura T., Nokihara H., Higashiyama M., Kondoh K., Nishihara H., Tojo A., Yano S., Miyano S., Gotoh N.

Scientific Reports （Scientific Reports） 5 （ 1 ） 2015年08月

研究論文（学術雑誌）, 共著

There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-β-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a β-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of β-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of β-catenin and treatment with a β-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate β-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-β-catenin pathway to improve the efficacy of EGFR-TKIs.

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西原　広史

論文 - 西原　広史