Faculty Profiles - FUJIWARA Toshiyoshi

MISC - FUJIWARA Toshiyoshi

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A long-term control of gastrointestinal stromal tumor with sunitinib

Futoshi Uno, Yasuhiro Fujiwara, Toshiyoshi Fujiwara

Japanese Journal of Cancer and Chemotherapy 40 ( 9 ) 1241 - 1244 2013

Language：Japanese Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

The patient was a 70-year-old woman with gastrointestinal stromal tumor (GIST) of the small intestine, accompanied by liver metastasis. Multiple liver metastases were pointed out 3 months after R0 surgery (jejunectomy and hepatectomy). Although she was given radiofrequency ablation (RFA) therapy and imatinib, metastatic tumors progressed. In a further examination at our institution 21 months after R0 surgery, multiple liver, bone, and lung metastases were indicated, and she was given sunitinib once daily at a 50 mg in 6-week courses, with 4 weeks on and 2 weeks off treatment. Although sunitinib dosage was decreased to 25 mg/day because of adverse events, 21 courses of this treatment were administrered, and it took 137 weeks to progress her disease with this sunitinib treatment. At our institution, seven cases of GIST were treated with sunitinib, and the median time to progression was 30-weeks. That was almost the same result as for Japan and international clinical trials. Sunitinb treatment may be one of the most important therapeutic options for unresectable imatinib-resistant GIST.

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下部直腸・肛門部疾患の診断と治療非上皮性悪性腫瘍.

稲田涼, 藤田伸, 谷口浩和, 宇野太, 永坂岳司, 藤原俊義

臨床消化器内科 2013

A Case of Local Recurrence of Anal Canal Mucinous Adenocarcinoma at Five Years After an Initial Surgery

Hamada Yuki, Inada Ryo, Mori Yoshiko, Kondo Yoshitaka, Nagasaka Takeshi, Fujiwara Toshiyoshi

Nihon Gekakei Rengo Gakkaishi (Journal of Japanese College of Surgeons) 38 ( 5 ) 1086 - 1090 2013

Language：Japanese Publisher：Japanese College of Surgeons

A 61-year-old man underwent curative abdominoperineal resection with lateral lymph node dissection for anal canal mucinous adenocarcinoma at our hospital. Histopathological findings were pA, pN0, pH0, pP0, pM0, pStage Ⅱ, curA on the Japanese Classification of Colorectal Carcinoma, the seventh edition. Five years after the surgery, he complained of perineal pain and CT/MRI scans revealed a substantial recurrent tumor in the pelvis, measuring 90mm in diameter without other metastatic lesions. On the diagnosis of local recurrence of anal canal mucinous adenocarcinoma, we performed total pelvic exenteration (TPE), to eradicate the tumor in an en bloc fashion. He was discharged on the 25^th postoperative day without intra- and postoperative complications. Histopathologically, the specimens showed mucinous adenocarcinoma suggesting local recurrence of the primary tumor, and the radial margin was negative for cancer. The patient is doing well without any re-recurrence 28 months after TPE. Colorectal mucinous adenocarcinoma is a poor prognostic disease, compared with differentiated adenocarcinoma, and most of local recurrence arises within three years. We report a case of local recurrence of anal canal mucinous adenocarcinoma at five years after the initial surgery with good course and survival after TPE.

DOI： 10.4030/jjcs.38.1086

CiNii Article

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肝臓癌における除鉄併用ソラフェニブ療法の可能性

浦野真一, 大原利章, 勝部亮一, 友野靖子, 木村文昭, 野間和広, 白川靖博, 藤原俊義

日本鉄バイオサイエンス学会学術集会プログラム・抄録集 37th 2013

予後および病態評価が可能な新規食道癌同所移植性モデル

大原利章, 白川靖博, 野間和広, 浦野真一, 前田直見, 田辺俊介, 櫻間教文, 田澤大, 藤原俊義

日本消化器癌発生学会総会プログラム・抄録集 24th 2013

遺伝子異常と癌の多様性癌遺伝子と癌抑制遺伝子の多様性と治療への応用.

藤原俊義

臨床と研究 90 ( 1 ) 38 - 42 2013

肝切除後の肝移植(生体及び脳死ドナー).

八木孝仁, 藤原俊義

手術 67 ( 7 ) 1071 - 1076 2013

消化器がんの分子病態に基づいた治療開発.

藤原俊義

第100回日本消化器病学会中国支部例会記念誌 181 - 187 2013

Molecular targeted therapies and gastroenterological neoplasia

125 ( 2 ) 145 - 152 2013

肺癌の遺伝子治療の現状．

藤原俊義

呼吸と循環 61 ( 6 ) 574 - 580 2013

次世代型制限増殖アデノウイルスを利用した血中循環がん細胞検出法の開発.

櫻井文教, 藤原俊義, 水口裕之

薬学雑誌 133 ( 3 ) 291 - 296 2013

80歳以上の超高齢者食道癌症例に対する外科治療の安全性確保への取り組み

田邊俊介, 白川靖博, 前田直見, 勝部亮一, 櫻間教文, 野間和広, 藤原俊義

日本消化器外科学会雑誌(Web) 46 ( Supplement1 ) 2013

同時性/異時性多発大腸癌における遺伝子変異の特徴

永坂岳司, 母里淑子, 豊岡伸一, 藤原俊義

日本人類遺伝学会大会プログラム・抄録集 58th 2013

Genetically engineered oncolytic adenovirus induces autophagic cell death through an E2F1-microRNA-7-epidermal growth factor receptor axis

Hiroshi Tazawa, Shuya Yano, Ryosuke Yoshida, Yasumoto Yamasaki, Tsuyoshi Sasaki, Yuuri Hashimoto, Shinji Kuroda, Masaaki Ouchi, Teppei Onishi, Futoshi Uno, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF CANCER 131 ( 12 ) 2939 - 2950 2012.12

Language：English Publisher：WILEY-BLACKWELL

Autophagy is known to have a cytoprotective role under various cellular stresses; however, it also results in robust cell death as an important safeguard mechanism that protects the organism against invading pathogens and unwanted cancer cells. Autophagy is regulated by cell signalling including microRNA (miRNA), a post-transcriptional regulator of gene expression. Here, we show that genetically engineered telomerase-specific oncolytic adenovirus induced miR-7 expression, which is significantly associated with its cytopathic activity in human cancer cells. Virus-mediated miR-7 upregulation depended on enhanced expression of the E2F1 protein. Ectopic expression of miR-7 suppressed cell viability and induced autophagy by inhibiting epidermal growth factor receptor (EGFR) expression. Our results suggest that oncolytic adenovirus induces autophagic cell death through an E2F1-miR-7-EGFR pathway in human cancer cells, providing a novel insight into the molecular mechanism of an anticancer virotherapy.

DOI： 10.1002/ijc.27589

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Jejunal interposition reconstruction with a stomach preserving esophagectomy improves postoperative weight loss and reflux symptoms for esophageal cancer patients

Eiji Yamada, Yasuhiro Shirakawa, Tomoki Yamatsuji, Leon Sakuma, Munenori Takaoka, Takako Yamada, Kazuhiro Noma, Kazufumi Sakurama, Yasuhiro Fujiwara, Shunsuke Tanabe, Takeshi Nagasaka, Toshiyoshi Fujiwara, Yoshio Naomoto

JOURNAL OF SURGICAL RESEARCH 178 ( 2 ) 700 - 707 2012.12

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Background: Conventional reconstruction after an esophagectomy uses a gastric tube, which commonly causes several postoperative complaints such as gastric acid reflux in long-term survival cases. Intestinal interposition between the remnant esophagus and the stomach is an option to reduce complaints, and in this study, the advantages of jejunal interposition reconstruction with a stomach preserving esophagectomy (SPE) were assessed.
Materials and methods: Eleven cases of jejunal interposition with an SPE and 16 cases with gastric tube reconstruction as a control were subject to a comparison of operation time, amount of bleeding, postoperative quality of life, and endoscopic findings.
Results: The SPE group had a longer operation time (SPE: 560 +/- 121 min, control 414 +/- 83 min, P = 0.038), whereas there was no significant difference in blood loss. Postoperative weight loss was significantly recovered in the SPE group (SPE versus control = 94.0 +/- 5.4% versus 87.5 +/- 4.7% at 3 mo, P = 0.017; 97.2 +/- 7.5% versus 85.0 +/- 5.2% at 6 mo, P = 0.010), and there was a significant decrease in the occurrence of reflux symptoms such as heartburn, odynophagia, and cough when jejunal interposition with an SPE was done. Furthermore, reflux esophagitis and Barrett's epithelium were found in six out of 12 cases (50%) of the control group by postoperative endoscopy, while no cases in the SPE group had either condition (P < 0.01).
Conclusions: This reconstruction method is a promising option to improve postoperative quality of life, mainly due to the long-term elimination of reflux esophagitis, which assists in the recovery of postoperative weight loss. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jss.2012.07.057

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Surgical rationalization of living donor liver transplantation by abolition of hepatic artery reconstruction under a fixed microscope

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

CLINICAL TRANSPLANTATION 26 ( 6 ) 877 - 883 2012.11

Language：English Publisher：WILEY-BLACKWELL

The small diameter of the hepatic artery is one of the complexities of living donor liver transplantation (LDLT). We analyzed whether the direct suture technique using surgical loupes can simplify the operative process for LDLT compared with fixed microscopic reconstruction. We applied the direct technique to rationalize the operative process and abolished routine microsurgery from 2004. Two hundred and nine LDLT with a postoperative period over 34 months were carried out from 1996 to 2008. The patients were divided into two groups: the micro group (children: 20, adults: 72) and the non-micro group (children: 12, adults: 97). Running anastomosis was undertaken in the non-micro group. The anastomotic size of the children was significantly smaller than that of the adults, but larger than 2 mm (2.38 +/- 0.4 vs. 2.7 +/- 0.47 mm, p = 0.0005). By appropriate choice of the proximal artery, direct anastomosis is possible even in children. Early complications occurred in seven cases in the micro group, but none occurred in the non-micro group (p < 0.05). Significant reductions were observed in operation time (p < 0.0001), blood loss (p < 0.05), and hospital stay (p < 0.01) in the non-micro group. Non-microscopic anastomosis is useful for the rationalization of LDLT.

DOI： 10.1111/j.1399-0012.2012.01651.x

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Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells

Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Shuya Yano, Teppei Onishi, Tsuyoshi Sasaki, Yasuhiro Shirakawa, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER IMMUNOLOGY IMMUNOTHERAPY 61 ( 11 ) 1905 - 1916 2012.11

Language：English Publisher：SPRINGER

Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to long-term tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2-positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibody-dependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab-resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deficient adenovirus vector had no apparent effect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers.

DOI： 10.1007/s00262-012-1249-x

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Enhanced antitumor efficacy of telomerase-specific oncolytic adenovirus with valproic acid against human cancer cells

Y. Watanabe, Y. Hashimoto, S. Kagawa, H. Kawamura, K. Nagai, N. Tanaka, Y. Urata, T. Fujiwara

CANCER GENE THERAPY 19 ( 11 ) 767 - 772 2012.11

Language：English Publisher：NATURE PUBLISHING GROUP

Replication-selective oncolytic viruses are being developed for human cancer therapy. We previously developed an attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site. OBP-301 can replicate in, and causes selective lysis of, human cancer cells. Valproic acid (VPA), which is an effective antiepileptic drug, is known to inhibit the histone deacetylase activities. We determined whether the antitumor effect of OBP-301 could be enhanced by VPA in human lung cancer cells. In an in vitro cell viability assay, OBP-301 infection killed four human lung cancer cell lines, H1299, H1299-R5 (a subline of H1299 with a low level of the coxsackievirus and adenovirus receptor (CAR) expression), H460, and A549, more efficiently in the presence of VPA than in its absence. VPA treatment increased CAR expression in all the four lung cancer cells. Consistent with their CAR upregulation, the infection efficiency of adenoviruses in the presence of VPA was significantly higher than that in its absence. The molecular mechanism of this combined effect could be explained by an increase in adenovirus infectivity via VPA-mediated upregulation of CAR. These results suggest that treatment with OBP-301 in combination with VPA is a promising strategy for human lung cancer.

DOI： 10.1038/cgt.2012.57

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進行肝細胞癌の治療高度脈管浸潤を伴う進行肝細胞癌の治療戦略

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

日本臨床外科学会雑誌 73 ( 増刊 ) 409 - 409 2012.10

同時性肝内転移、膵転移を伴った肝原発solitary fibrous tumorの一例

杭瀬崇, 楳田祐三, 貞森裕, 篠浦先, 吉田龍一, 佐藤太祐, 内海方嗣, 藤智和, 八木孝仁, 藤原俊義

日本臨床外科学会雑誌 73 ( 増刊 ) 696 - 696 2012.10

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