Faculty Profiles - FUJIWARA Toshiyoshi

MISC - FUJIWARA Toshiyoshi

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A novel apoptotic mechanism of genetically engineered adenovirus-mediated tumour-specific p53 overexpression through E1A-dependent p21 and MDM2 suppression

Yasumoto Yamasaki, Hiroshi Tazawa, Yuuri Hashimoto, Toru Kojima, Shinji Kuroda, Shuya Yano, Ryosuke Yoshida, Futoshi Uno, Hiroyuki Mizuguchi, Akira Ohtsuru, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

EUROPEAN JOURNAL OF CANCER 48 ( 14 ) 2282 - 2291 2012.9

Language：English Publisher：ELSEVIER SCI LTD

Oncolytic viruses engineered to replicate in tumour cells but not in normal cells could be used as tumour-specific vectors carrying the therapeutic genes. We previously developed a telomerase-specific oncolytic adenovirus, OBP-301, that causes cell death in human cancer cells with telomerase activities. Here, we further modified OBP-301 to express the wild-type p53 tumour suppressor gene (OBP-702), and investigated whether OBP-702 induces stronger antitumour activity than OBP-301. The antitumour effect of OBP-702 was compared to that of OBP-301 on OBP-301-sensitive (H358 and H460) and OBP-301-resistant (T.Tn and HSC4) human cancer cells. OBP-702 suppressed the viability of both OBP-301-sensitive and OBP-301-resistant cancer cells more efficiently than OBP-301. OBP-702 caused increased apoptosis compared to OBP-301 or a replication-deficient adenovirus expressing the p53 gene (Ad-p53) in H358 and T.Tn cells. Adenovirus E1A-mediated p21 and MDM2 downregulation was involved in the apoptosis caused by OBP-702. Moreover, OBP-702 significantly suppressed tumour growth in subcutaneous tumour xenograft models compared to monotherapy with OBP-301 or Ad-p53. Our data demonstrated that OBP-702 infection expressed adenovirus E1A and then inhibited p21 and MDM2 expression, which in turn efficiently induced apoptotic cell death. This novel apoptotic mechanism suggests that the p53-expressing OBP-702 is a promising antitumour reagent for human cancer and could improve the clinical outcome. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ejca.2011.12.020

Synergistic interaction of telomerase-specific oncolytic virotherapy and chemotherapeutic agents for human cancer

Toshiyoshi Fujiwara, Shunsuke Kagawa, Hiroshi Tazawa

Current Pharmaceutical Biotechnology 13 ( 9 ) 1809 - 1816 2012.7

Language：English

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. Telomerase activation is considered to be a critical step in carcinogenesis through the maintenance of telomeres, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector, in which the hTERT promoter element drives expression of E1 genes, OBP-301 (Telomelysin). Since only tumor cells that express telomerase activity would 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. OBP-301 alone exhibited substantial antitumor effects both in animal models and in clinical trials
data regarding combination therapy with OBP-301 and chemotherapeutic agents are preliminary but encouraging. This article reviews synergistic interaction of virotherapy and chemotherapy, and illustrates the potential application for the treatment of human cancer. © 2012 Bentham Science Publishers.

DOI： 10.2174/138920112800958887

Circulating tumour cells detected by a novel adenovirus-mediated system may be a potent therapeutic marker in gynaecological cancers

M. Takakura, S. Kyo, M. Nakamura, Y. Maida, Y. Mizumoto, Y. Bono, X. Zhang, Y. Hashimoto, Y. Urata, T. Fujiwara, M. Inoue

BRITISH JOURNAL OF CANCER 107 ( 3 ) 448 - 454 2012.7

Language：English Publisher：NATURE PUBLISHING GROUP

BACKGROUND: Recently developed detection system for circulating tumour cells (CTCs) using a telomerase-specific replicative adenovirus generated nonspecific green fluorescent protein (GFP) signals because of the co-presence of white blood cells (WBCs) nonspecifically infected by viruses. Here, we established a unique detection system for CTCs that completely excludes nonspecific signals.
METHODS: Blood obtained from the patients was subjected to haemolytic processes to eliminate red blood cells. The cell pellets were then infected with OBP-401, fixed, incubated with fluorescence-labelled anti-CD45 antibody to mark white blood WBCs, and examined on slides under a microscope.
RESULTS: Preparatory experiments with cancer cells artificially added to healthy donor samples confirmed that CD45 labelling could distinguish GFP-positive cancer cells from WBCs. In 53 patients with gynaecological cancers, CTCs were detected in 21 patients (39.6%) when CD45-positive cells were excluded as WBCs among GFP-positive cells. No CTCs were detected in samples from healthy volunteers. There was no significant correlation between CTC counts and known clinicopathological factors. The CTCs rapidly vanished after surgery or chemotherapy in most patients whose treatments were effective. In contrast, the persistence of CTCs even after treatments was tightly associated with poor response to the treatments (P<0.005).
CONCLUSION: The presence of CTCs in our system may potentially be a novel therapeutic marker in gynaecological cancers. British Journal of Cancer (2012) 107, 448-454. doi: 10.1038/bjc.2012.276 www.bjcancer.com Published online 26 June 2012 (C) 2012 Cancer Research UK

DOI： 10.1038/bjc.2012.276

Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer

Hui-fang Hao, Munenori Takaoka, Xiao-hong Bao, Zhi-gang Wang, Yasuko Tomono, Kazufumi Sakurama, Toshiaki Ohara, Takuya Fukazawa, Tomoki Yamatsuji, Toshiyoshi Fujiwara, Yoshio Naomoto

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 423 ( 4 ) 744 - 749 2012.7

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2012.06.030

Branched-chain amino acid-enriched nutrients improve nutritional and metabolic abnormalities in the early post-transplant period after living donor liver transplantation

Ryuichi Yoshida, Takahito Yagi, Hiroshi Sadamori, Hiroaki Matsuda, Susumu Shinoura, Yuzo Umeda, Daisuke Sato, Masashi Utsumi, Takeshi Nagasaka, Nami Okazaki, Ai Date, Ayako Noguchi, Akemi Tanaka, Yuko Hasegawa, Yachiyo Sakamoto, Toshiyoshi Fujiwara

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 19 ( 4 ) 438 - 448 2012.7

Language：English Publisher：SPRINGER TOKYO

Malnutrition and metabolic disorder of patients undergoing living donor liver transplantation (LDLT) can affect post-transplant prognosis. The aim of this study was to establish whether perioperative usage of branched-chain amino-acid (BCAA)-enriched nutrients improve metabolic abnormalities of patients undergoing LDLT.
We designed a randomized pilot study (UMIN registration number; 000004323). Twenty-five consecutive adult elective LDLT recipients were enroled and divided into two groups: the BCAA group (BCAA-enriched nutrients, n = 12) and the control group (standard diet, n = 13). Metabolic and nutritional parameters, including BCAA-to-tyrosine ratio (BTR), retinol binding protein (RBP), and prealbumin were regularly measured from 1 week before to 4 weeks after LDLT. Non-protein respiratory quotient (npRQ) was measured before and 4 weeks after LDLT.
BTR and RBP improved considerably in the BCAA group compared with the controls. npRQ significantly increased from 1 week before LDLT to 4 weeks after LDLT in the BCAA group (0.77 +/- A 0.05 to 0.84 +/- A 0.06, P = 0.002), but not in the control group (0.78 +/- A 0.04 to 0.81 +/- A 0.05).
Supplementation with BCAA-enriched nutrients might improve persistent nutritional and metabolic disorders associated with end-stage liver disease in the early post-transplant period, and consequently shorten the post-transplant catabolic phase after LDLT. A larger multicenter trial is needed to confirm these findings.

DOI： 10.1007/s00534-011-0459-5

Esophageal Cancer Exhibits Resistance to a Novel IGF-1R Inhibitor NVP-AEW541 with Maintained RAS-MAPK Activity

Xiao-Hong Bao, Munenori Takaoka, Hui-Fang Hao, Zhi-Gang Wang, Takuya Fukazawa, Tomoki Yamatsuji, Kazufumi Sakurama, Dong-Sheng Sun, Takeshi Nagasaka, Toshiyoshi Fujiwara, Yoshio Naomoto

ANTICANCER RESEARCH 32 ( 7 ) 2827 - 2834 2012.7

Language：English Publisher：INT INST ANTICANCER RESEARCH

Aim: To assess the effects of a novel type 1 insulin-like growth factor receptor (IGF-1R) inhibitor, NVP-AEW541, on cell proliferation and signal transduction of esophageal cancer. Materials and Methods: Cell proliferation assay and western blot were conducted to assess the antitumor effects of NVP-AEW541. Genetic modification of RAS by expression vector was applied for overexpression of mutant RAS. Results: More than 2 mu mol/l of NVP-AEW541 was required to effectively, inhibit the proliferation of esophageal cancer NVP-AEW541 potently blocked the activation of IGF-IR and protein kinase B (PKB, also known as AKT), but not of mitogen-activated protein kinase kinase (MEK) and extracellular-signal-regulated kinases (ERK). Active RAS was not reduced by NVP-AEW541 in esophageal cancer cells TE-1, suggesting that insensitivity of esophageal cancer to NVP-AEW541 is due to the maintained RAS-MAPK activity, which did not arise from RAS mutation. Moreover, the transduction of mutant RAS reduced the sensitivity of TE-1 cells to NVP-AEW541. Conclusion: Stimulation of RAS-MAPK pathway is associated with resistance to NVP-AEW541 in esophageal cancer. Combining NVP-AEW541 with inhibitors/antibodies against RAS-MAPK signaling molecules might be more effective for use against esophageal cancer.

Synergistic Interaction of Telomerase-Specific Oncolytic Virotherapy and Chemotherapeutic Agents for Human Cancer

Toshiyoshi Fujiwara, Shunsuke Kagawa, Hiroshi Tazawa

CURRENT PHARMACEUTICAL BIOTECHNOLOGY 13 ( 9 ) 1809 - 1816 2012.7

Language：English Publishing type：Book review, literature introduction, etc. Publisher：BENTHAM SCIENCE PUBL LTD

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. Telomerase activation is considered to be a critical step in carcinogenesis through the maintenance of telomeres, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector, in which the hTERT promoter element drives expression of E1 genes, OBP-301 (Telomelysin). Since only tumor cells that express telomerase activity would 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. OBP-301 alone exhibited substantial antitumor effects both in animal models and in clinical trials; data regarding combination therapy with OBP-301 and chemotherapeutic agents are preliminary but encouraging. This article reviews synergistic interaction of virotherapy and chemotherapy, and illustrates the potential application for the treatment of human cancer.

DOI： 10.2174/138920112800958887

The hTERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic Microenvironment

Yuuri Hashimoto, Hiroshi Tazawa, Fuminori Teraishi, Toru Kojima, Yuichi Watanabe, Futoshi Uno, Shuya Yano, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

PLOS ONE 7 ( 6 ) 1 - 10 2012.6

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1 alpha and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.

DOI： 10.1371/journal.pone.0039292

Carcinosarcoma of the Gallbladder Manifesting as Cholangitis Due to Hemobilia

Hiroshi Sadamori, Hiroyasu Fujiwara, Takehiro Tanaka, Hiroyuki Yanai, Daisuke Satoh, Takahito Yagi, Toshiyoshi Fujiwara

JOURNAL OF GASTROINTESTINAL SURGERY 16 ( 6 ) 1278 - 1281 2012.6

Language：English Publisher：SPRINGER

Carcinosarcomas of the gallbladder are rare tumors that are characterized by malignant epithelial and mesenchymal components, and preoperative diagnosis of carcinosarcoma of the gallbladder remains difficult.
We recently encountered a case of carcinosarcoma of the gallbladder with osteoid and chondroid differentiation, manifesting as cholangitis due to hemobilia.
Preoperative computed tomography and magnetic resonance imaging indicated the cause of cholangitis and provided qualitative information regarding the two components of the tumor.

DOI： 10.1007/s11605-012-1836-3

Long-term outcome of induction chemoradiotherapy with docetaxel and cisplatin followed by surgery for non-small-cell lung cancer with mediastinal lymph node metastasis

Shinichi Toyooka, Katsuyuki Kiura, Mitsuhiro Takemoto, Takahiro Oto, Nagio Takigawa, Toshiyoshi Fujiwara, Shinichiro Miyoshi, Hiroshi Date

INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 14 ( 5 ) 565 - 569 2012.5

Language：English Publisher：OXFORD UNIV PRESS

The purpose of this study was to show the long-term outcome of induction chemoradiotherapy, using docetaxel and cisplatin with concurrent radiotherapy followed by surgery for non-small-cell lung cancer (NSCLC) with mediastinal nodal metastasis. Between January 2000 and July 2006, 22 consecutive NSCLC patients with pathologically proven mediastinal nodal metastasis were treated with tri-modality therapy. The regimen consisted of docetaxel and cisplatin plus concurrent radiation at a dose of 40-46 Gy. The induction therapy was followed by surgery 4-6 weeks later. The pulmonary resections were composed of a lobectomy in 19 patients, including 3 with a sleeve lobectomy, a bilobectomy in 2 patients and a left pneumonectomy in 1 patient. With a median follow-up duration of 8.7 years, the 3-year and 7-year overall survival (OS) rates for the entire population were 72.7 and 63.6%, respectively. Our results suggest that tri-modality therapy is promising for NSCLC patients with mediastinal nodal metastasis.

DOI： 10.1093/icvts/ivs028

Chemotherapy of methioninase-synchronized S/G2 phase-blocked cancer cells identified by cell cycle-specific fluorescent reporters

Shuya Yano, Shukuan Li, Qinghong Han, Yuying Tan, Toshiyoshi Fujiwara, Robert M. Hoffman

JOURNAL OF CLINICAL ONCOLOGY 30 ( 15 ) 2012.5

腺様嚢胞癌細胞株におけるテロメラーゼ特異的腫瘍融解ウイルスの抗腫瘍効果の検討

佐藤大典, 栗原祐史, 近藤誠二, 代田達夫, 浦田泰生, 藤原俊義, 新谷悟

頭頸部癌 38 ( 2 ) 225 - 225 2012.5

Resection of Metachronous Lymph Node Metastases from Hepatocellular Carcinoma after Hepatectomy: Report of Four Cases

Masashi Utsumi, Hiroaki Matsuda, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Satoh, Masaaki Hashimoto, Takahito Yagi, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 66 ( 2 ) 177 - 182 2012.4

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

We report 4 cases of surgical resection of metachronous lymph node (LN) metastases from hepatocellular carcinoma (HCC) following hepatectomy. Clinicopathological features and results of LN dissection were investigated in the 4 patients. One patient was found to have a single metastasis in the mediastinal LNs, another had multiple metastases in the mediastinal and abdominal LNs, and the other 2 had single metastases in the abdominal LN. The locations of the abdominal LN metastases were behind the pancreas head in 2 patients and around the abdominal aorta in 1 patient. They all underwent surgical resection of metastatic LNs and had no postoperative complications. The 3 patients whose LN metastases were solitary have been alive for more than 2 years after LN resection, and one of them is free from recurrence. The patient with multiple LN metastases died 13 months after LN resection due to carcinomatosis. With the expectation of long-term survival, a single metachronous LN metastasis from HCC after hepatectomy should be resected in patients without uncontrollable intrahepatic or extrahepatic tumors.

DOI： 10.18926/AMO/48268

Iron chelator contributes to anti-angiogenic therapy via selective induction of VEGF-A

Toshiaki Ohara, Kazuhiro Noma, Seishi Nishitani, Shinichiro Watanabe, Yasuko Tomono, Yuuri Hashimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

CANCER RESEARCH 72 2012.4

Inhibitory effect of oncolytic adenovirus on transforming growth factor-beta-induced epithelial-mesenchymal transition in human cancer cells

Yuuri Hashimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 72 2012.4

Ataxia-Telangiectasia Mutated and the Mre11-Rad50-NBS1 Complex: Promising Targets for Radiosensitization

Shinji Kuroda, Yasuo Urata, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 66 ( 2 ) 83 - 92 2012.4

Language：English Publishing type：Book review, literature introduction, etc. Publisher：OKAYAMA UNIV MED SCHOOL

Radiotherapy plays a central part in cancer treatment, and use of radiosensitizing agents can greatly enhance this modality. Although studies have shown that several chemotherapeutic agents have the potential to increase the radiosensitivity of tumor cells, investigators have also studied a number of molecularly targeted agents as radiosensitizers in clinical trials based on reasonably promising preclinical data. Recent intense research into the DNA damage-signaling pathway revealed that ataxia-telangiectasia mutated (ATM) and the Mre11-Rad50-NBS1 (MRN) complex play central roles in DNA repair and cell cycle checkpoints and that these molecules are promising targets for radiosensitization. Researchers recently developed three ATM inhibitors (KU-55913, CGK733, and CP466722) and an MRN complex inhibitor (mirin) and showed that they have great potential as radiosensitizers of tumors in preclinical studies. Additionally, we showed that a telomerase-dependent oncolytic adenovirus that we developed (OBP-301 [telomelysin]) produces profound radiosensitizing effects by inhibiting the MRN complex via the adenoviral E1B55kDa protein. A recent Phase I trial in the United States determined that telomelysin was safe and well tolerated in humans, and this agent is about to be tested in combination with radiotherapy in a clinical trial based on intriguing preclinical data demonstrating that telomelysin and ionizing radiation can potentiate each other. In this review, we highlight the great potential of ATM and MRN complex inhibitors, including telomelysin, as radiosensitizing agents.

DOI： 10.18926/AMO/48258

Preventive Effect of Omental Flap in Pancreaticoduodenectomy against Postoperative Pseudoaneurysm Formation

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

HEPATO-GASTROENTEROLOGY 59 ( 114 ) 578 - 583 2012.3

Language：English Publisher：H G E UPDATE MEDICAL PUBLISHING S A

Background/Aims: An omental flap covering the splanchnic vessels might reduce postoperative intra-abdominal hemorrhage after pancreaticoduodenectomy. However, the efficiency of such a procedure remains to be verified. The purpose of this study was to determine the effect of mental flap placement in pancreaticoduodenectomy on the incidence of postoperative pseudoaneurysms. Methodology: Of 229 consecutive patients who underwent pancreaticoduodenectomy, the most recent 157 patients received the omental flap, while the initial 72 patients had no omental flap placement. Various preoperative factors were considered in the evaluation (age, gender, body mass index, primary disease and concurrent disease), as well as operative factors (operation time, blood loss, operative procedures, pancreatic texture, size of pancreatic duct and surgeon's experience). Results: Eighty-one patients (35.4%) developed pancreatic fistula. Nine patients (3.9%) developed postoperative pseudoaneurysm. Among the patients with pancreatic fistula, those without omental flap developed pseudoaneurysms more frequently (21.7%) than those with omental flap placement (5.2%). Multivariate analysis identified pancreatic fistula, no use of mental flap and hypertension, in that order, as predisposing factors for a pseudoaneurysm. The omental flap significantly prevented pseudoaneurysms (p=0.021; OR=0.151; 95% CI, 0.030-0.751). Conclusions: Omental flap placement over splanchnic vessels could be a feasible and efficient surgical procedure to prevent postoperative pseudoaneurysms following pancreaticoduodenectomy.

DOI： 10.5754/hge11452

Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

Daisuke Nobuoka, Yutaka Motomura, Hirofumi Shirakawa, Toshiaki Yoshikawa, Toshimitsu Kuronuma, Mari Takahashi, Kohei Nakachi, Hiroshi Ishii, Junji Furuse, Naoto Gotohda, Shinichiro Takahashi, Toshio Nakagohri, Masaru Konishi, Taira Kinoshita, Hiroyuki Komori, Hideo Baba, Toshiyoshi Fujiwara, Tetsuya Nakatsura

INTERNATIONAL JOURNAL OF ONCOLOGY 40 ( 1 ) 63 - 70 2012.1

Language：English Publisher：SPANDIDOS PUBL LTD

Glypican-3 (GPC3), a carcinoembryonic antigen, is an ideal target for anticancer immunotherapy against hepatocellular carcinoma (HCC). In this study, we attempted to compare the induction of the GPC3-specific T-cell-mediated immune response after locoregional therapies in HCC patients and tumor-bearing mice. Twenty-seven HCC patients treated with locoregional therapies, including radiofrequency ablation (RFA), surgical resection and transcatheter arterial chemoembolization (TACE), were prospectively enrolled in this study. Additionally, we performed RFA experiments using a mouse model. GPC3-specific T-cell response was investigated pretreatment and post-treatment by an interferon-gamma enzyme-linked immunospot assay using peripheral blood mononuclear cells from HCC patients and lymph node cells from tumor-bearing mice. Circulating GPC3-specific cytotoxic T lymphocytes (CTLs) were increased in 5 of 9 patients after RFA and in 4 of 9 patients after TACE, but in only 1 of 9 patients after surgical resection. All 7 patients with GPC3-expressing HCCs exhibited an increase in GPC3-specific CTLs after RFA or TACE, whereas none of the 7 patients did after surgical resection. The number of increased GPC3-specific CTLs after RFA was significantly larger than that after surgical resection (P=0.023). Similarly, the frequency of GPC3-specific CTLs after RFA was significantly greater than that after surgical resection in the mouse model (P=0.049). We validated for the first time the stronger effect on the immune system brought by RFA compared with surgical resection for HCC patients and tumor-bearing mice. Combined treatment of RFA and immunotherapy is a reasonable strategy against HCC.

DOI： 10.3892/ijo.2011.1202

胃癌術後脊椎転移による横断性脊髄障害を呈した1例.

河野藍子, 香川俊輔, 岸本浩行, 宇野太, 西崎正彦, 大岩雅彦, 藤原俊義

癌と化学療法 39 ( 12 ) 2357 - 2359 2012

Language：Japanese Publisher：(株)癌と化学療法社

症例は45歳、男性。心窩部痛・体重減少を主訴に発見された進行胃癌に対して幽門側胃切除術、D2、Roux-en Y再建を行い、術後診断はpT4aN3bCY1、stage IVであった。術後S-1による化学療法を施行中、術後3ヵ月に背部痛が出現した。PET-CTではTh4-6の骨転移を指摘された。直ちに骨転移に対し放射線療法を開始したが、第5治療日より脊髄横断症状を呈し座位保持も不能となった。その後、癒着性の小腸イレウスが発症し小腸部分切除術を施行することとなり、同時に直腸肛門機能低下による排便困難に対しS状結腸ストーマ造設を併施した。その結果、排便の自己管理が可能になり、さらに放射線治療の完遂ならびに、その後の化学療法と緩和治療が在宅で可能であった。胃癌の骨転移はまれであるが、その予後は極めて不良である。胃癌の骨転移の特徴・対策を知り、早期診断と集学的治療は重要であり、本症例の経験に文献的考察を加え報告する。(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00296&link_issn=&doc_id=20121206360200&doc_link_id=%2Fab8gtkrc%2F2012%2F003912%2F200%2F2357-2359%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2012%2F003912%2F200%2F2357-2359%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Gastric aberrant pancreas with acute pancreatitis treated with surgery

124 ( 1 ) 59 - 62 2012

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