研究者詳細 - 藤原　俊義

MISC - 藤原　俊義

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F-18 FDG PET/CT Contributes to More Accurate Detection of Lymph Nodal Metastasis From Actively Proliferating Esophageal Squamous Cell Carcinoma

Shunsuke Tanabe, Yoshio Naomoto, Yasuhiro Shirakawa, Yasuhiro Fujiwara, Kazufumi Sakurama, Kazuhiro Noma, Munenori Takaoka, Tomoki Yamatsuji, Takao Hiraki, Yoshihiro Okumura, Masahiko Mitani, Mitsumasa Kaji, Susumu Kanazawa, Toshiyoshi Fujiwara

CLINICAL NUCLEAR MEDICINE 36 ( 10 ) 854 - 859 2011年10月

記述言語：英語出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Purpose: Evaluating the status of disease progression is critical for planning a therapeutic strategy for esophageal cancer. In this regard, F-18 fluorodeoxyglucose-labeled positron emission tomography (PET) is one of the most useful diagnostic modalities. However, there is room to improve its diagnostic performance, such as distinguishing lymph nodal metastases from false positives. In this study, we examined the diagnostic accuracy of fluorodeoxyglucose PET accompanied by computed tomography imaging (PET/CT) to detect regional lymph nodal metastasis from esophageal squamous cell carcinoma (ESCC).
Methods: A total of 102 patients diagnosed as ESCC were subjected to this study. These patients had a preoperative PET/CT examination to evaluate the existence of metastasis. The values of maximum standardized uptake value (SUVmax) in primary tumors and in metastasized lymph nodes were measured to analyze their relationship with various clinicopathologic characteristics including the status of tumor cell proliferation, which was assessed by immunohistochemistry for Ki-67.
Results: The SUVmax of the primary tumor was positively correlated with tumor size and vessel invasion, and was positively related with the SUVmax of lymph nodal metastasis, especially in cases of poorly differentiated ESCC. The SUVmax of metastasized lymph nodes was higher in larger-sized metastasized lymph nodes, whereas the Ki-labeling index of lymph nodal metastasis was positively related with the SUVmax per unit area (SUVmax/mm(2)). The diagnostic accuracy of PET/CT (87.3%) was higher than that of conventional CT scans (78.4%).
Conclusions: The improved diagnostic accuracy of PET/CT can be explained by its ability to detect actively progressive metastasis at an early phase regardless of size.

DOI： 10.1097/RLU.0b013e318217adc9

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当院における頭頸部癌・食道癌領域におけるPEGの適応と現状

田辺俊介, 白川靖博, 野間和広, 前田直見, 大原利章, 櫻間教文, 浅野博昭, 岸本浩行, 宇野太, 西崎正彦, 佃和憲, 香川俊輔, 藤原俊義, 小野田友男, 勝井邦彰, 片山敬久, 吉尾浩太郎, 武本充広

Gastroenterological Endoscopy 53 ( Suppl.2 ) 2784 - 2784 2011年9月

Tumor-selective adenoviral-mediated GFP genetic labeling of human cancer in the live mouse reports future recurrence after resection

Hiroyuki Kishimoto, Ryoichi Aki, Yasuo Urata, Michael Bouvet, Masashi Momiyama, Noriaki Tanaka, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 10 ( 16 ) 2737 - 2741 2011年8月

記述言語：英語出版者・発行元：LANDES BIOSCIENCE

We have previously developed a telomerase-specific replicating adenovirus expressing GFP (OBP-401), which can selectively label tumors in vivo with GFP. Intraperitoneal (i.p.) injection of OBP-401 specifically labeled peritoneal tumors with GFP, enabling fluorescence visualization of the disseminated disease and real-time fluorescence surgical navigation. However, technical problems of removing all cancer cells still remain, even with fluorescence-guided surgery. In this study, we report that in vivo OBP-401 labeling of tumors with GFP before fluorescence-guided surgery reports cancer recurrence after surgery. Recurrent tumor nodules brightly expressed GFP, indicating that initial OBP-401-GFP labeling of peritoneal disease was genetically stable such that proliferating residual cancer cells still express GFP. In situ tumor labeling with a genetic reporter has important advantages over antibody and other non-genetic labeling of tumors, since residual disease remains labeled during recurrence and can be further resected under fluorescence guidance.

DOI： 10.4161/cc.10.16.16756

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末梢型と肝門型肝内胆管癌における術式の検討

佐藤太祐, 楳田祐三, 貞森裕, 松田浩明, 篠浦先, 吉田龍一, 内海方嗣, 杭瀬崇, 菊池寛次, 八木孝仁, 藤原俊義

岡山医学会雑誌 123 ( 2 ) 168 - 168 2011年8月

Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells

Toshiaki Ohara, Munenori Takaoka, Shinichi Toyooka, Yasuko Tomono, Toshio Nishikawa, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

CANCER SCIENCE 102 ( 7 ) 1344 - 1349 2011年7月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of < 1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0)/G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3); P < 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P < 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival. (Cancer Sci 2011; 102: 1344-1349)

DOI： 10.1111/j.1349-7006.2011.01967.x

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高度脈管侵襲を伴う肝細胞癌に対する治療戦略高度脈管侵襲肝癌に対する治療戦略 Vp3/4、Vv2/3進行肝癌の治療成績

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

日本消化器外科学会総会 66回 200 - 200 2011年7月

当院で切除した膵内分泌腫瘍に対する治療成績

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

日本消化器外科学会総会 66回 314 - 314 2011年7月

Efficient virotherapy for osteosarcoma by telomerase-specific oncolytic adenovirus

Guidong Li, Hiroyuki Kawashima, Akira Ogose, Takashi Ariizumi, Yongjun Xu, Tetsuo Hotta, Yasuo Urata, Toshiyoshi Fujiwara, Naoto Endo

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 137 ( 6 ) 1037 - 1051 2011年6月

記述言語：英語出版者・発行元：SPRINGER

A telomerase-specific oncolytic adenovirus, Telomelysin, can selectively kill cancer cells, and be attenuated in normal cells. We herein describe the oncolytic effect of Telomelysin on human osteosarcoma both in vitro and in vivo.
The anti-tumor effects of Telomelysin were evaluated on human osteosarcoma cell lines in vitro and in a mouse xenograft model of human osteosarcoma in vivo. The replication efficiencies of Telomelysin in human osteosarcoma cell lines and normal cell lines and in osteosarcoma xenografts were determined by the expression levels of E1 mRNA and E1A protein using real-time quantitative PCR, Western blot analysis and immunohistochemistry. The in vitro telomerase-specific replication and the viral infection rate were also confirmed by TelomeScan (Telomelysin-GFP), using fluorescent microscopy and flow cytometry, respectively. The cell viabilities were examined by XTT assay, and the tumor volumes were measured every 2 days. The induction of apoptosis was assessed by Western blot analysis, as well as by TUNEL assay.
TelomeScan and Telomelysin were efficiently replicated in human osteosarcoma cell lines and led to a dose- and time-dependent expression of GFP, E1 mRNA and E1A protein. Telomelysin infection induced marked cytolysis and apoptosis in osteosarcoma cell lines in vitro. Neither cytotoxicity nor apoptosis were induced in normal human cell lines. In the human osteosarcoma cell xenograft model, intratumoral injection of Telomelysin resulted in increased viral replication, significant tumor growth suppression and distinct apoptotic cell death.
This study indicated that virotherapy with Telomelysin may provide a promising strategy for the treatment of human osteosarcoma.

DOI： 10.1007/s00432-010-0969-6

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IS-9-3 乳癌のトラスツズマブ耐性機構の解析とHER2細胞外ドメイン発現によるADCC活性増強を介した感受性誘導(IS-9 国際シンポジウム(9)Translational research in breast cancer treatment,第111回日本外科学会定期学術集会)

吉田亮介, 田澤大, 矢野修也, 大西哲平, 宇野太, 香川俊輔, 藤原俊義

日本外科学会雑誌 112 ( 1 ) 202 - 202 2011年5月

PS-091-7 腹膜播種を伴う進行・再発胃癌患者を対象としたDocetaxelとS-1の併用化学療法の検討(臨床第II相試験)(PS-091 ポスターセッション(91)胃:化学療法-3,第111回日本外科学会定期学術集会)

宇野太, 香川俊輔, 西崎正彦, 合地明, 木村臣一, 高畑隆臣, 野中泰幸, 二宮基樹, 藤原俊義

日本外科学会雑誌 112 ( 1 ) 663 - 663 2011年5月

Enhanced Safety Profiles of the Telomerase-Specific Replication-Competent Adenovirus by Incorporation of Normal Cell-Specific microRNA-Targeted Sequences

Kumiko Sugio, Fuminori Sakurai, Kazufumi Katayama, Katsuhisa Tashiro, Hayato Matsui, Kenji Kawabata, Atsushi Kawase, Masahiro Iwaki, Takao Hayakawa, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi

CLINICAL CANCER RESEARCH 17 ( 9 ) 2807 - 2818 2011年5月

記述言語：英語出版者・発行元：AMER ASSOC CANCER RESEARCH

Purpose: Oncolytic adenoviruses (Ad) have been actively pursued as potential agents for cancer treatment. Among the various types of oncolytic Ads, the telomerase-specific replication-competent Ad (TRAD), which possesses an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, has shown promising results in human clinical trials; however, the E1 gene is also slightly expressed in normal cells, leading to replication of TRAD and cellular toxicity in normal cells.
Experimental Design: To overcome this problem, we utilized a microRNA (miRNA)-regulated gene expression system. Four copies of complementary sequences for miR-143, -145, -199a, or let-7a, which have been reported to be exclusively downregulated in tumor cells, were incorporated into the 3'-untranslated region of the E1 gene expression cassette.
Results: Among the TRAD variants (herein called TRADs) constructed, TRADs containing the sequences complementary to miR-143, -145, or -199a showed efficient oncolytic activity comparable to the parental TRAD in the tumor cells. On the other hand, replication of the TRADs containing the miRNA complementary sequences was at most 1,000-fold suppressed in the normal cells, including primary normal cells. In addition, to suppress the replication of the TRADs in hepatocytes as well as other normal cells, we constructed a TRAD containing 2 distinct complementary sequences for miR-199a and liver-specific miR-122a (TRAD-122a/199aT). TRAD-122a/199aT exhibited more than 10-fold reduction in viral replication in all the normal cells examined, including primary hepatocytes.
Conclusions: This study showed that oncolytic Ads containing the sequences complementary to normal cell-specific miRNAs showed significantly improved safety profiles without altering tumor cell lysis activity. Clin Cancer Res; 17(9); 2807-18. (C)2011 AACR.

DOI： 10.1158/1078-0432.CCR-10-2008

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再発肝細胞癌の治療方針再肝切除・RFAの有効性とSalvage transplantation導入の見極め

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

日本外科学会雑誌 112 ( 臨増1-2 ) 356 - 356 2011年5月

大腸癌肝転移の外科的治療戦略術前・術後化学療法の意義と問題点

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

日本外科学会雑誌 112 ( 臨増1-2 ) 360 - 360 2011年5月

Telomerase-specific oncolytic virotherapy for human gastrointestinal cancer

Toshiyoshi Fujiwara, Yasuhiro Shirakawa, Shunsuke Kagawa

EXPERT REVIEW OF ANTICANCER THERAPY 11 ( 4 ) 525 - 532 2011年4月

記述言語：英語掲載種別：書評論文，書評，文献紹介等出版者・発行元：EXPERT REVIEWS

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Human telomerase is highly active in more than 85% of primary cancers, regardless of their tissue origins, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (OBP-301), in which the hTERT promoter element drives the expression of El genes. Since only tumor cells that express telomerase activity are able to activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with gastrointestinal tumors. In this article we show that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human gastrointestinal malignancies.

DOI： 10.1586/ERA.10.200

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

Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Futoshi Uno, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 71 2011年4月

大腸癌肝転移の外科治療術前・術後化学療法の効果

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

岡山医学会雑誌 123 ( 1 ) 76 - 76 2011年4月

手術手技膵頭十二指腸切除術における血管床に対する大網弁被覆の意義

松田浩明, 八木孝仁, 藤原俊義

手術 65 ( 3 ) 349 - 352 2011年3月

Glutamine depletion induces murine neonatal melena with increased apoptosis of the intestinal epithelium

Takayuki Motoki, Yoshio Naomoto, Junji Hoshiba, Yasuhiro Shirakawa, Tomoki Yamatsuji, Junji Matsuoka, Munenori Takaoka, Yasuko Tomono, Yasuhiro Fujiwara, Hiroshi Tsuchita, Mehmet Gunduz, Hitoshi Nagatsuka, Noriaki Tanaka, Toshiyoshi Fujiwara

WORLD JOURNAL OF GASTROENTEROLOGY 17 ( 6 ) 717 - 726 2011年2月

記述言語：英語出版者・発行元：BAISHIDENG PUBLISHING GROUP INC

AIM: To investigate the possible biological outcome and effect of glutamine depletion in neonatal mice and rodent intestinal epithelial cells.
METHODS: We developed three kinds of artificial milk with different amounts of glutamine; Complete amino acid milk (CAM), which is based on maternal mouse milk, glutamine-depleted milk (GDM), and glutaminerich milk (GRM). GRM contains three-fold more glutamine than CAM. Eighty-seven newborn mice were divided into three groups and were fed with either of CAM, GDM, or GRM via a recently improved nipple-bottle system for seven days. After the feeding period, the mice were subjected to macroscopic and microscopic observations by immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU) and Ki-67 as markers of cell proliferation, and for cleaved-caspase-3 as a marker of apoptosis. Moreover, IEC6 rat intestinal epithelial cells were cultured in different concentrations of glutamine and were subject to a 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate cell proliferation assay, flow cytometry, and western blotting to examine the biological effect of glutamine on cell growth and apoptosis.
RESULTS: During the feeding period, we found colonic hemorrhage in six of 28 GDM-fed mice (21.4%), but not in the GRM-fed mice, with no differences in body weight gain between each group. Microscopic examination showed destruction of microvilli and the disappearance of glycocalyx of the intestinal wall in the colon epithelial tissues taken from GDM-fed mice. Intake of GDM reduced BrdU incorporation (the average percentage of BrdU-positive staining; GRM: 13.8%, CAM: 10.7%, GDM: 1.14%, GRM vs GDM: P < 0.001, CAM vs GDM: P < 0.001) and Ki-67 labeling index (the average percentage of Ki-67-positive staining; GRM: 24.5%, CAM: 22.4% GDM: 19.4%, GRM vs GDM: P = 0.001, CAM vs GDM: P =0.049), suggesting that glutamine depletion inhibited cell proliferation of intestinal epithelial cells. Glutamine deprivation further caused the deformation of the nuclear membrane and the plasma membrane, accompanied by chromatin degeneration and an absence of fat droplets from the colonic epithelia, indicating that the cells underwent apoptosis. Moreover, immunohistochemical analysis revealed the appearance of cleaved caspase-3 in colonic epithelial cells of GDM-fed mice. Finally, when IEC6 rat intestinal epithelial cells were cultured without glutamine, cell proliferation was significantly suppressed after 24 h (relative cell growth; 4 mmol/L: 100.0% 36.1%, 0 mmol/L: 25.3% 25.0%, P < 0.05), with severe cellular damage. The cells underwent apoptosis, accompanied by increased cell population in sub-GO phase (4 mmol/L: 1.68%, 0.4 mmol/L: 1.35%, 0 mmol/L: 5.21%), where dying cells are supposed to accumulate.
CONCLUSION: Glutamine is an important alimentary component for the maintenance of intestinal mucosa. Glutamine deprivation can cause instability of the intestinal epithelial alignment by increased apoptosis. (C) 2011 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v17.i6.717

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A Prognostic Model and Treatment Strategy for Intrahepatic Recurrence of Hepatocellular Carcinoma after Curative Resection

Yuzo Umeda, Hiroaki Matsuda, Hiroshi Sadamori, Hiroyoshi Matsukawa, Takahito Yagi, Toshiyoshi Fujiwara

WORLD JOURNAL OF SURGERY 35 ( 1 ) 170 - 177 2011年1月

記述言語：英語出版者・発行元：SPRINGER

Background The aim of this study was to evaluate the prognostic factors for intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resection.
Methods Of 297 patients with HCC who underwent curative resection between 1998 and 2007, 145 had intrahepatic recurrence, and 125 of these were enrolled in this study. We analyzed the relationships between overall survival after HCC recurrence and 20 variables at initial hepatectomy and recurrence.
Results Recurrent HCC was treated by repeat hepatectomy (Re-Hr, n = 29), radiofrequency ablation (RFA, n = 58), or transarterial chemoembolization (TAE, n = 38). Complete tumor control (CTC) by Re-He and RFA was selected for 70% of patients. RFA-treated patients had more tumors, smaller tumors, and poorer liver function at recurrence than the Re-Hr group. The overall 1-, 3-, and 5-year post-recurrence survival rates (SR) were 93.1, 66.8, 58.1%; 94.7, 75.1, 48.3%; and 80.1, 22.5, 0%, respectively, in the Re-Hr, RFA, and TAE groups. The SR was better for Re-Hr and RFA than for TAE (p < 0.0001). Outcomes were similar in Re-Hr and RFA, regardless of recurrent tumor size. Multivariate analysis identified Child-Pugh grade B, AFP >= 100 ng/ml at recurrence, recurrent tumor size >= 3 cm, tumor number >= 3, and CTC as significant prognostic factors for overall post-recurrence survival. A scoring system using 1 point for each patient-background factor provided a well-categorized predictive model. The overall 3-/5-year post-recurrence SRs were 83.1/59.3%, 64.1/41.9%, 42.0/18.0%, and 13.6/0% at risk number (R) R0, R1, R2, and R3/4, respectively (p < 0.05).
Conclusions Significant prognostic factors for intrahepatic recurrent HCC are poor hepatic reserve, AFP, recurrent tumor size and number, and CTC. Selection of treatment modality for intrahepatic recurrence requires the clinician to be mindful of the predictive factors and to control tumors aggressively by adequate treatment, selected by balancing various conditions.

DOI： 10.1007/s00268-010-0794-8

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テロメラーゼ依存的腫瘍融解アデノウイルス製剤による放射線感受性増強作用

黒田新士, 藤原俊哉, 白川靖博, 山崎泰源, 矢野修也, 宇野太, 田澤大, 橋本悠里, 渡辺雄一, 野間和広, 浦田泰生, 香川俊輔, 藤原俊義

岡山医学会雑誌 123 ( 2 ) 103 - 109 2011年1月

記述言語：日本語出版者・発行元：岡山医学会

DNA修復機能阻害は放射線感受性を増強させるため，DNA修復に関与する因子の阻害剤は放射線増感剤となり得る．我々の開発したテロメラーゼ依存的腫瘍融解アデノウイルス製剤OBP-301（テロメライシン）は，アデノウイルスE1B55kDaタンパクを介して細胞のDNA修復に重要な役割を果たすMRN複合体（Mre11，Rad50，NBS1）を分解する機能を有する．このMRN複合体の分解によりATM（ataxia-telangiectasia mutated）の活性化が抑制され結果的にDNA修復機構が阻害される．我々はOBP-301と放射線との併用が強力な相乗効果を生み出すことをマウスの皮下腫瘍モデルおよび食道癌同所性モデルにおいて証明した．これらの結果はOBP-301が将来有望な放射線増感剤となり得ることだけでなく，E1B55kDaタンパクを産生する腫瘍融解アデノウイルス製剤と放射線との併用が悪性腫瘍に対する有力な治療戦略となり得ることを示す．

DOI： 10.4044/joma.123.103

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