Faculty Profiles - FUJIWARA Toshiyoshi

MISC - FUJIWARA Toshiyoshi

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VF-079-4 下大静脈合併切除再建を併施した切除不能肝芽腫に対する生体肝移植(VF ビデオフォーラム,第113回日本外科学会定期学術集会)

吉田龍一, 藤智和, 河合毅, 内海方嗣, 信岡大輔, 佐藤大祐, 楳田祐三, 篠浦先, 貞森裕, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 495 - 495 2013.3

PD-3-6 生体肝移植の短期・晩期予後向上に向けた治療戦略個別化の可能性(PD パネルディスカッション,第113回日本外科学会定期学術集会)

楳田祐三, 八木孝仁, 貞森裕, 内海方嗣, 篠浦先, 吉田龍一, 佐藤太祐, 信岡大輔, 藤智和, 保田裕子, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 236 - 236 2013.3

PS-227-1 当院で治療を行った膵神経内分泌腫瘍35症例の画像所見と病理組織学的所見の検討(PS ポスターセッション,第113回日本外科学会定期学術集会)

内海方嗣, 藤智, 河合毅, 佐藤太祐, 信岡大輔, 吉田龍一, 楳田祐三, 篠浦先, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 837 - 837 2013.3

PS-082-3 血清鉄コントロールを用いた新たな肝細胞癌治療戦略(PS ポスターセッション,第113回日本外科学会定期学術集会)

大原利章, 白川靖博, 浦野真一, 前田直見, 渡邊伸一郎, 田辺俊介, 野間和広, 能祖一裕, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 634 - 634 2013.3

VF-018-3 生体肝移植ドナーにおける無血肝切除技術と胆道合併症の予防対策(VF ビデオフォーラム,第113回日本外科学会定期学術集会)

貞森裕, 八木孝仁, 篠浦先, 楳田祐三, 吉田龍一, 佐藤太祐, 信岡大輔, 内海方嗣, 杉原正大, 藤智和, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 436 - 436 2013.3

PS-089-4 サイトケラチン19発現は肝細胞癌の上皮間葉移行と肝外転移を予測する(PS ポスターセッション,第113回日本外科学会定期学術集会)

横道直佑, 永坂岳司, 西田直生志, 楳田祐三, 母里淑子, 森川達也, 久保田暢人, 吉田一博, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 644 - 644 2013.3

WS-17-7 テロメラーゼ活性を指標とする血中遊離癌細胞の高感度検出法の開発と遺伝子解析技術への応用(WS ワークショップ,第113回日本外科学会定期学術集会)

重安邦俊, 橋本悠里, 宇野太, 永坂岳司, 田澤大2), 香川俊輔, 水口裕之, 浦田泰生, 藤原俊義

日本外科学会雑誌 114 ( 2 ) 338 - 338 2013.3

Telomerase-specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic mice

Wei-Hsiang Lin, Shiou-Hwei Yeh, Wan-Jen Yang, Kun-Huei Yeh, Toshiyoshi Fujiwara, Aisuke Nii, Stanley Shi-Chung Chang, Pei-Jer Chen

INTERNATIONAL JOURNAL OF CANCER 132 ( 6 ) 1451 - 1462 2013.3

Language：English Publisher：WILEY-BLACKWELL

The telomerase-specific replication-competent oncolytic adenovirus, Telomelysin, was developed for virus-mediated preferential lysis of tumor cells. Its selectivity is derived from a human telomerase reverse transcriptase (hTERT) promoter-driven active viral replication, which occurs in cancer cells with high telomerase activity but not in normal cells lacking such activity. Because the TERT activity is elevated in most cases of hepatocellular carcinoma (HCC), the current study aims to investigate whether Telomelysin can be used for treatment of HCC. The oncolytic effect of Telomelysin has been investigated both in vitro using cell culture and in vivo using an immunocompetent in situ orthotopic HCC model. In this model, HCC developed spontaneously in the liver of HBx transgenic mice, which is pathologically and genetically similar to human HCC. In cell culture assay, Telomelysin lyses HCC cell lines at a low multiplicity of infection (MOI), ranging 0.77-6.35 (MOI [PFU/cell]). In the orthotopic HCC model, Telomelysin showed a potent oncolytic effect on HCC but spared normal liver tissue. Dose escalation analysis identified a safety dose of 1.25 X 108 PFU for this model. The effect of multiple injections of Telomelysin was also evaluated in this immunocompetent HCC model. We found that the virus replicates in HCC after a second intratumoral injection despite an immune response induced by the previous injection. This preclinical study shows that Telomelysin can be used for treatment of human HCC at an appropriate dosage and that its tumor-killing activity persists after multiple injections.

DOI： 10.1002/ijc.27770

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Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice. International journal

Toshio Nishikawa, Munenori Takaoka, Toshiaki Ohara, Yasuko Tomono, Huifang Hao, Xiaohong Bao, Takuya Fukazawa, Zhigang Wang, Kazufumi Sakurama, Yasuhiro Fujiwara, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

Cancer biology & therapy 14 ( 3 ) 230 - 6 2013.3

Language：English

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

DOI： 10.4161/cbt.23294

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Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

Joe Hasei, Tsuyoshi Sasaki, Hiroshi Tazawa, Shuhei Osaki, Yasuaki Yamakawa, Toshiyuki Kunisada, Aki Yoshida, Yuuri Hashimoto, Teppei Onishi, Futoshi Uno, Shunsuke Kagawa, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

MOLECULAR CANCER THERAPEUTICS 12 ( 3 ) 314 - 325 2013.3

Language：English Publisher：AMER ASSOC CANCER RESEARCH

Tumor suppressor p53 is a multifunctional transcription factor that regulates diverse cell fates, including apoptosis and autophagy in tumor biology. p53 overexpression enhances the antitumor activity of oncolytic adenoviruses; however, the molecular mechanism of this occurrence remains unclear. We previously developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301, that kills human osteosarcoma cells, but some human osteosarcoma cells were OBP-301-resistant. In this study, we investigated the antitumor activity of a p53-expressing oncolytic adenovirus, OBP-702, and the molecular mechanism of the p53-mediated cell death pathway in OBP-301-resistant human osteosarcoma cells. The cytopathic activity of OBP-702 was examined in OBP-301-sensitive (U2OS and HOS) and OBP-301-resistant (SaOS-2 and MNNG/HOS) human osteosarcoma cells. The molecular mechanism in the OBP-702-mediated induction of two cell death pathways, apoptosis and autophagy, was investigated in OBP-301-resistant osteosarcoma cells. The antitumor effect of OBP-702 was further assessed using an orthotopic OBP-301-resistant MNNG/HOS osteosarcoma xenograft tumor model. OBP-702 suppressed the viability of OBP-301-sensitive and -resistant osteosarcoma cells more efficiently than OBP-301 or a replication-deficient p53-expressing adenovirus (Ad-p53). OBP-702 induced more profound apoptosis and autophagy when compared with OBP-301 or Ad-p53. E1A-mediated miR-93/106b upregulation induced p21 suppression, leading to p53-mediated apoptosis and autophagy in OBP-702-infected cells. p53 overexpression enhanced adenovirus-mediated autophagy through activation of damage-regulated autophagy modulator (DRAM). Moreover, OBP-702 suppressed tumor growth in an orthotopic OBP-301-resistant MNNG/HOS xenograft tumor model. These results suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy to induce dual apoptotic and autophagic cell death pathways via regulation of miRNA and DRAM in human osteosarcoma cells. Mol Cancer Ther; 12(3); 314-25. (C)2012 AACR.

DOI： 10.1158/1535-7163.MCT-12-0869

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下大静脈合併切除再建を併施した切除不能肝芽腫に対する生体肝移植

吉田龍一, 藤智和, 河合毅, 内海方嗣, 信岡大輔, 佐藤大祐, 楳田祐三, 篠浦先, 貞森裕, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 495 - 495 2013.3

当院で治療を行った膵神経内分泌腫瘍35症例の画像所見と病理組織学的所見の検討

内海方嗣, 藤智, 河合毅, 佐藤太祐, 信岡大輔, 吉田龍一, 楳田祐三, 篠浦先, 貞森裕, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 837 - 837 2013.3

温阻血再灌流+肝切除モデルにおけるHMGB1の動態解析および肝再生機序の解明

杉原正大, 貞森裕, 西堀正洋, 佐藤康晴, 田澤大, 吉田龍一, 楳田祐三, 篠浦先, 永坂岳司, 八木孝仁, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 637 - 637 2013.3

同時性多臓器転移を有する大腸癌の治療戦略遺伝子情報を用いた多臓器転移大腸癌の検討および治療戦略の構築

稲田涼, 永坂岳司, 母里淑子, 楳田祐三, 森川達也, 久保田暢人, 近藤喜太, 宇野太, 貞森祐, 八木孝仁, 三嶋秀行, 藤原俊義

日本外科学会雑誌 114 ( 臨増2 ) 261 - 261 2013.3

In Vivo Imaging of Transplanted Islets Labeled with a Novel Cationic Nanoparticle

Koichi Oishi, Yoshitaka Miyamoto, Hiroaki Saito, Katsutoshi Murase, Kenji Ono, Makoto Sawada, Masami Watanabe, Yasufumi Noguchi, Toshiyoshi Fujiwara, Shuji Hayashi, Hirofumi Noguchi

PLoS ONE 8 ( 2 ) 2013.2

Language：English

To monitor pancreatic islet transplantation efficiency, reliable noninvasive imaging methods, such as magnetic resonance imaging (MRI) are needed. Although an efficient uptake of MRI contrast agent is required for islet cell labeling, commercially-available magnetic nanoparticles are not efficiently transduced into cells. We herein report the in vivo detection of transplanted islets labeled with a novel cationic nanoparticle that allowed for noninvasive monitoring of islet grafts in diabetic mice in real time. The positively-charged nanoparticles were transduced into a β-cell line, MIN6 cells, and into isolated islets for 1 hr. MRI showed a marked decrease in the signal intensity on T1- and T2-weighted images at the implantation site of the labeled MIN 6 cells or islets in the left kidneys of mice. These data suggest that the novel positively-charged nanoparticle could be useful to detect and monitor islet engraftment, which would greatly aid in the clinical management of islet transplant patients. © 2013 Oishi et al.

DOI： 10.1371/journal.pone.0057046

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Risk factors for organ/space surgical site infection after hepatectomy for hepatocellular carcinoma in 359 recent cases

Hiroshi Sadamori, Takahito Yagi, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Satoh, Daisuke Nobuoka, Masashi Utsumi, Kazuhiro Yoshida, Toshiyoshi Fujiwara

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 20 ( 2 ) 186 - 196 2013.2

Language：English Publisher：SPRINGER JAPAN KK

Surgical site infections (SSIs), particularly organ/space SSIs, remain a common cause of major morbidity after hepatectomy for hepatocellular carcinoma (HCC).
Risk factors for SSIs were analyzed in 359 patients who underwent hepatectomy for HCC between 2001 and 2010. The causative bacteria, management, outcome, and characteristics of organ/space SSIs were investigated.
Anatomic hepatectomy was performed for 296 patients (82.5%), and repeat hepatectomy was carried out for 59 patients (16.4%). SSIs developed in 52 patients (14.5%; incisional, 24 cases; organ/space, 31 cases [3 patients showed both incisional and organ/space SSIs]). No in-hospital mortality related to incisional or organ/space SSIs was encountered. Independent risk factors for SSIs were repeat hepatectomy and operative time a parts per thousand yen280 min. Independent risk factors for organ/space SSIs were repeat hepatectomy and bile leakage. Methicillin-resistant Staphylococcus aureus was detected more frequently in organ/space SSIs after repeat hepatectomy than after initial hepatectomy.
Repeat hepatectomy and bile leakage represent independent risk factors for organ/space SSIs after hepatectomy for HCC. Establishing treatment strategies is important for preventing postoperative bile leakage and reducing the high rate of organ/space SSIs after repeat hepatectomy.

DOI： 10.1007/s00534-011-0503-5

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Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability

Yuzo Umeda, Takeshi Nagasaka, Yoshiko Mori, Hiroshi Sadamori, Dong-Sheng Sun, Susumu Shinoura, Ryuich Yoshida, Daisuke Satoh, Daisuke Nobuoka, Masashi Utsumi, Kazuhiro Yoshida, Takahito Yagi, Toshiyoshi Fujiwara

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 20 ( 2 ) 223 - 233 2013.2

Language：English Publisher：SPRINGER JAPAN KK

The discovery of practical biomarkers is important to realize personalized medicine for patients with malignant neoplasias, including colorectal cancer (CRC).
The aim of this study was to determine reliable prognostic biomarkers by the analysis of patients with resectable colorectal liver metastases (CRLM).
Genomic DNA was obtained from the CRLM tissues of a cohort of 126 patients with CRLM with curative hepatic resection. The KRAS/BRAF mutation spectrum and microsatellite instability (MSI) status were successfully analyzed in 100 of the 126 CRLM tissues and these findings were examined in relation to the patients' clinical outcomes.
The cohort of 100 CRLM patients consisted of 46 with synchronous and 54 with metachronous liver metastasis. Overall survival and disease-free survival at 5 years were 57.4 and 24.9 %, respectively. MSI analysis revealed that none of the 100 CRLM specimens showed any evidence of MSI. By KRAS/BRAF mutation analysis, the analyzed CRLM patients were divided into 3 groups; KRAS-mutant (KRAS-Mt; n = 27), BRAF-mutant (BRAF-Mt; n = 3), and wild-types of both genes (Wild-type; n = 70). In the survival analysis, both KRAS-Mt and BRAF-Mt patients showed significantly poorer prognoses compared with Wild-type patients. Furthermore, although the population with the BRAF mutation was small, this mutation had a significant negative impact on disease-free survival.
In this study, all tumors in the cohort of CRLM patients were non-MSI tumors, suggesting MSI cancer in primary CRC would rarely reveal metastatic potential. KRAS and BRAF mutations are suggested to be poor prognostic factors in CRLM. Genetic information has an essential role as a prognostic marker and could contribute to the decisions on treatment strategy for CRLM.

DOI： 10.1007/s00534-012-0531-9

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Bloodless Donor Hepatectomy in Living Donor Liver Transplantation: Counterclockwise Liver Rotation and Early Hanging Maneuver

Hiroshi Sadamori, Takahito Yagi, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Satoh, Daisuke Nobuoka, Masashi Utsumi, Kazuhiro Yoshida, Toshiyoshi Fujiwara

JOURNAL OF GASTROINTESTINAL SURGERY 17 ( 1 ) 203 - 206 2013.1

Language：English Publisher：SPRINGER

Living donor hepatectomy is important because it determines donor safety and recipient outcome.
We applied the counter-clockwise liver rotation method and the hanging maneuver from an early stage in two major types of living donor operations.
Twenty-eight living donors underwent these procedures with significant reduction in blood loss. Right hepatectomy was performed in 14 of the donors and extended left hepatectomy was performed in the other 14 donors.
These techniques facilitate safe and bloodless living donor hepatectomy.

DOI： 10.1007/s11605-012-1907-5

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A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus

T. Sasaki, H. Tazawa, J. Hasei, S. Osaki, T. Kunisada, A. Yoshida, Y. Hashimoto, S. Yano, R. Yoshida, S. Kagawa, F. Uno, Y. Urata, T. Ozaki, T. Fujiwara

GENE THERAPY 20 ( 1 ) 112 - 118 2013.1

Language：English Publisher：NATURE PUBLISHING GROUP

Adenovirus serotype 5 (Ad5) is frequently used as an effective vector for induction of therapeutic transgenes in cancer gene therapy or of tumor cell lysis in oncolytic virotherapy. Ad5 can infect target cells through binding with the coxsackie and adenovirus receptor (CAR). Thus, the infectious ability of Ad5-based vectors depends on the CAR expression level in target cells. There are conventional methods to evaluate the CAR expression level in human target cells, including flow cytometry, western blotting and immunohistochemistry. Here, we show a simple system for detection and assessment of functional CAR expression in human tumor cells, using the green fluorescent protein (GFP)-expressing telomerase-specific replication-competent adenovirus OBP-401. OBP-401 infection induced detectable GFP expression in CAR-expressing tumor cells, but not in CAR-negative tumor cells, nor in CAR-positive normal fibroblasts, 24 h after infection. OBP-401-mediated GFP expression was significantly associated with CAR expression in tumor cells. OBP-401 infection detected tumor cells with low CAR expression more efficiently than conventional methods. OBP-401 also distinguished CAR-positive tumor tissues from CAR-negative tumor and normal tissues in biopsy samples. These results suggest that GFP-expressing telomerase-specific replication-competent adenovirus is a very potent diagnostic tool for assessment of functional CAR expression in tumor cells for Ad5-based antitumor therapy. Gene Therapy (2013) 20, 112-118; doi:10.1038/gt.2011.213; published online 12 January 2012

DOI： 10.1038/gt.2011.213

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Risk factors for major morbidity after liver resection for hepatocellular carcinoma

H. Sadamori, T. Yagi, S. Shinoura, Y. Umeda, R. Yoshida, D. Satoh, D. Nobuoka, M. Utsumi, T. Fujiwara

BRITISH JOURNAL OF SURGERY 100 ( 1 ) 122 - 129 2013.1

Language：English Publisher：WILEY-BLACKWELL

Background: Bile leakage, and organ and/or space surgical-site infection (SSI) are common causes of major morbidity after partial hepatectomy for hepatocellular carcinoma (HCC). The purpose of this study was to analyse risk factors for major morbidity and to explore strategies for its reduction after partial hepatectomy for HCC. Methods: Risk factors for bile leakage and organ/space SSI were analysed in patients who underwent partial hepatectomy for HCC between 2001 and 2010. The causes, management and outcomes of intractable bile leakage requiring endoscopic therapy or percutaneous transhepatic biliary drainage were analysed. In addition, causative bacteria, outcomes and characteristics of organ/space SSI were investigated. Risk factors were identified using multivariable analysis. Results: Some 359 patients were included in the analysis. The prevalence of bile leakage and organ/space SSI was 12.8 and 8.6 per cent respectively. Repeat hepatectomy and an operating time of at least 300 min were identified as independent risk factors for bile leakage. The main causes of intractable bile leakage were latent strictures of the biliary system caused by previous treatments for HCC and intraoperative injury of the hepatic duct during repeat hepatectomy. Independent risk factors for organ/space SSI were repeat hepatectomy and bile leakage. Methicillin-resistant Staphylococcus aureus was detected more frequently in organ/space SSI after repeat hepatectomy than after initial partial hepatectomy. Conclusion: Repeat hepatectomy and prolonged surgery were identified as risk factors for bile leakage after liver resection for HCC. Bile leakage and repeat hepatectomy increased the risk of organ/space SSI. Copyright (c) 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/bjs.8957

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