Faculty Profiles - FUJIWARA Toshiyoshi

MISC - FUJIWARA Toshiyoshi

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StageIII大腸癌根治術後の再発予測におけるMGMTプロモーター領域のメチル化解析の有用性

母里淑子, 永坂岳司, 竹原裕子, 吉田一博, 重安邦俊, 楳田祐三, 田澤大, 貞森裕, 藤原俊義

日本消化器外科学会総会 68回 O - 39 2013.7

温阻血再灌流+70%肝切除におけるHMGB1の動態解析と制御

杉原正大, 貞森裕, 佐藤太祐, 吉田龍一, 楳田祐三, 篠浦先, 田澤大, 永坂岳司, 八木孝仁, 藤原俊義

日本消化器外科学会総会 68回 RS - 54 2013.7

A novel synergistic effect of iron depletion on antiangiogenic cancer therapy

Toshiaki Ohara, Kazuhiro Noma, Shinichi Urano, Shinichiro Watanabe, Seishi Nishitani, Yasuko Tomono, Fumiaki Kimura, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF CANCER 132 ( 11 ) 2705 - 2713 2013.6

Language：English Publisher：WILEY-BLACKWELL

Iron is an essential element for both normal and cancer cells in humans. Treatment to reduce iron levels has been shown to suppress tumor growth in vivo. However, iron depletion monotherapy by iron decreased treatment has not been thought to be superior to ordinary chemotherapy and is not part of the standard therapeutic strategy for the treatment of cancer. Iron depletion is also known to reduce serum hemoglobin and oxygen supply to the tissue, which indicates that iron depletion may induce angiogenesis. Therefore, we hypothesized that iron depletion with antiangiogenic therapy can have a novel therapeutic effect in the treatment of cancer. Human nonsmall cell carcinoma cell lines A549 and H1299 were used in our study. An iron-deficient diet and an iron chelator were used to simulate an iron-depleted condition. The antitumor effects of iron depletion and antiangiogenic therapy were determined on A549 xenograft mice. The iron-depleted condition produced by an iron-deficient diet suppressed tumor growth. Tumor tissue from the iron-deficient diet group showed that cancer cell proliferation was suppressed and hypoxia was induced. Microvessel density of this group was increased which suggested that the iron-depleted condition induced angiogenesis. Bevacizumab administration had a synergetic effect on inhibiting the tumor growth on Day 39. An iron-depleted condition inhibited cancer cell proliferation and reciprocally induced angiogenesis. Bevacizumab synergistically enhanced the iron-depleted antitumor effect. Treatment to deplete iron levels combined with anti-angiogenic therapy could induce a novel therapeutic effect in the treatment of cancer.

DOI： 10.1002/ijc.27943

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Peptide intra-tumor injection for cancer immunotherapy Enhancement of tumor cell antigenicity is a novel and attractive strategy

Daisuke Nobuoka, Toshiaki Yoshikawa, Toshiyoshi Fujiwara, Tetsuya Nakatsura

HUMAN VACCINES & IMMUNOTHERAPEUTICS 9 ( 6 ) 1234 - 1236 2013.6

Language：English Publisher：LANDES BIOSCIENCE

One of the problems in antigen-specific cancer immunotherapy is the low density of the tumor antigen-derived peptide endogenously presented on tumor cell surface major histocompatibility complex class I molecules. To overcome this, we are engaged in research on peptide intra-tumor injection to enhance tumor cell antigenicity. In in vivo studies using immunodeficient mice, the peptide injected into a solid mass of subcutaneous tumor was revealed to be loaded onto human leukocyte antigen class I molecules of tumor cells. In a peptide vaccine model and an adoptive cell transfer model using C57BL/6 mice, peptide intra-tumor injection was effective in terms of tumor growth inhibition and prolongation of survival time. Moreover, an antigen-spreading effect was detected after peptide intra-tumor injection. Peptide intra-tumor injection is an effective method of enhancing tumor cell antigenicity. It can induce additional peptide loading onto tumor cells, making tumor cells more antigenic for specific cytotoxic T-lymphocyte activity. Peptide intra-tumor injection may be a useful option for improvement of antigen-specific immunotherapy against solid tumors.

DOI： 10.4161/hv.23990

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Appendicitis during pregnancy

75 ( 6 ) 622 - 625 2013.6

CD14 upregulation as a distinct feature of non-alcoholic fatty liver disease after pancreatoduodenectomy

Daisuke Satoh, Takahito Yagi, Takeshi Nagasaka, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Masashi Utsumi, Takehiro Tanaka, Hiroshi Sadamori, Toshiyoshi Fujiwara

World Journal of Hepatology 5 ( 4 ) 189 - 195 2013.4

Language：English

Aim: to investigate the pathogenesis of non-alcoholic fatty liver disease (nafld) after pancreatoduodenectomy (pd). methods: a cohort of 82 patients who underwent pd at okayama university hospital between 2003 and 2009 was enrolled and the clinicopathological features were compared between patients with and without nafld after pd. computed tomography (ct) images were evaluated every 6 mo after pd for follow-up. hepatic steatosis was diagnosed on ct when hepatic attenuation values were 40 hounsfield units. liver biopsy was performed for 4 of 30 patients with nafld after pd who consented to undergo biopsies. to compare nafld after pd with nafld associated with metabolic syndrome, liver samples were obtained from 10 patients with nafld associated with metabolic syndrome [fatty liver, n = 5
non-alcoholic steatohepatitis (nash), n = 5] by percutaneous ultrasonography-guided liver biopsy. double-fluorescence immunohistochemistry was applied to examine cd14 expression as a marker of lipopolysaccharide (lps)-sensitized macrophage cells (kupffer cells) in liver biopsy specimens. results: the incidence of postoperative nafld was 36.6% (30/82). univariate analysis identified cancer of the pancreatic head, sex, diameter of the main pancreatic duct, and dissection of the nerve plexus as factors associated with the development of nafld after pd. those patients who developed nafld after pd demonstrated significantly decreased levels of serum albumin, total protein, cholesterol and triglycerides compared to patients without nafld after pd, but no glucose intolerance or insulin resistance. liver biopsy was performed in four patients with nafld after pd. all four patients showed moderate-to-severe steatosis and nash was diagnosed in two. numbers of cells positive for cd68 (a marker of kupffer cells) and cd14 (a marker of lpssensitized kupffer cells) were counted in all biopsy specimens. the number of cd68+ cells in specimens of nafld after pd was significantly increased from that in specimens of nafld associated with metabolic syndrome specimens, which indicated the presence of significantly more kupffer cells in nafld after pd than in nafld associated with metabolic syndrome. similarly, more cd14+ cells, namely, lps-sensitized kupffer cells, were observed in nafld after pd than in nafld associated with metabolic syndrome. regarding nash, more cd68+ cells and cd14+ cells were observed in nash after pd specimens than in nash associated with metabolic syndrome. this showed that more kupffer cells and more lps-sensitized kupffer cells were present in nash after pd than in nash associated with metabolic syndrome. these observations suggest that after pd, kupffer cells and lps-sensitized kupffer cells were significantly upregulated, not only in nash, but also in simple fatty liver. conclusion: nafld after pd is characterized by both malnutrition and the up-regulation of cd14 on kupffer cells. gut-derived endotoxin appears central to the development of nafld after pd. © 2013 Baishideng.

DOI： 10.4254/wjh.v5.i4.189

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Multicenter phase II study of S-1 and docetaxel combination chemotherapy for advanced or recurrent gastric cancer patients with peritoneal dissemination

Kunitoshi Shigeyasu, Shunsuke Kagawa, Futoshi Uno, Masahiko Nishizaki, Hiroyuki Kishimoto, Akira Gochi, Toshikazu Kimura, Takaomi Takahata, Yasuyuki Nonaka, Motoki Ninomiya, Toshiyoshi Fujiwara

Cancer Chemotherapy and Pharmacology 71 ( 4 ) 937 - 943 2013.4

Language：English

Purpose: Peritoneal dissemination is the most frequent and life-threatening mode of metastasis and recurrence in patients with gastric cancer. A multicenter phase II study was designed to evaluate the efficacy and tolerability of S-1 and docetaxel combination chemotherapy regimen for the treatment of advanced or recurrent gastric cancer patients with peritoneal dissemination. Methods: Nineteen patients with histologically confirmed unresectable or recurrent gastric cancer with peritoneal dissemination were enrolled. Oral S-1 at 80 mg/m2/day was administered twice daily for 2 weeks, followed by 1 drug-free week. Docetaxel infusion at 40 mg/m2 was performed on day 1, simultaneous with S-1 administration. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary endpoints were the response rates and safety status. Results: Patients received a median of 4 cycles of the S-1 and docetaxel regimen (range 1-43). The disease control rate was 73.7 % (14/19). Median overall survival was 459 days (15.3 months), while median time to progression was 212 days (7.1 months). Neutropenia was the most common type of toxicity (n = 7, 36.8 %). Conclusions: Combination chemotherapy with S-1 and docetaxel is a tolerable and effective treatment for advanced or recurrent gastric cancer patients with peritoneal dissemination. © 2013 Springer-Verlag Berlin Heidelberg.

DOI： 10.1007/s00280-013-2086-0

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Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy

Daisuke Nobuoka, Toshiaki Yoshikawa, Mari Takahashi, Tatsuaki Iwama, Kazutaka Horie, Manami Shimomura, Shiro Suzuki, Noriko Sakemura, Munehide Nakatsugawa, Hiroshi Sadamori, Takahito Yagi, Toshiyoshi Fujiwara, Tetsuya Nakatsura

CANCER IMMUNOLOGY IMMUNOTHERAPY 62 ( 4 ) 639 - 652 2013.4

Language：English Publisher：SPRINGER

Antigen-specific cancer immunotherapy is a promising strategy for improving cancer treatment. Recently, many tumor-associated antigens and their epitopes recognized by cytotoxic T lymphocytes (CTLs) have been identified. However, the density of endogenously presented antigen-derived peptides on tumor cells is generally sparse, resulting in the inability of antigen-specific CTLs to work effectively. We hypothesize that increasing the density of an antigen-derived peptide would enhance antigen-specific cancer immunotherapy. Here, we demonstrated that intratumoral peptide injection leads to additional peptide loading onto major histocompatibility complex class I molecules of tumor cells, enhancing tumor cell recognition by antigen-specific CTLs. In in vitro studies, human leukocyte antigen (HLA)-A*02:01-restricted glypican-3(144-152) (FVGEFFTDV) and cytomegalovirus(495-503) (NLVPMVATV) peptide-specific CTLs showed strong activity against all peptide-pulsed cell lines, regardless of whether the tumor cells expressed the antigen. In in vivo studies using immunodeficient mice, glypican-3(144-152) and cytomegalovirus(495-503) peptides injected into a solid mass were loaded onto HLA class I molecules of tumor cells. In a peptide vaccine model and an adoptive cell transfer model using C57BL/6 mice, intratumoral injection of ovalbumin(257-264) peptide (SIINFEKL) was effective for tumor growth inhibition and survival against ovalbumin-negative tumors without adverse reactions. Moreover, we demonstrated an antigen-spreading effect that occurred after intratumoral peptide injection. Intratumoral peptide injection enhances tumor cell antigenicity and may be a useful option for improvement in antigen-specific cancer immunotherapy against solid tumors.

DOI： 10.1007/s00262-012-1366-6

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Novel photoimmunotherapy (PIT) targeting cancer-associated fibroblasts (CAFs) for esophageal cancer.

Shinichiro Watanabe, Kazuhiro Noma, Shinichi Urano, Toshiaki Ohara, Yuuri Hashimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

CANCER RESEARCH 73 ( 8 ) 2013.4