Updated on 2021/12/01

写真a

 
FUJIWARA Toshiyoshi
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
External link

Degree

  • Doctor(medicive) ( Okayama University )

 

Papers

  • Impact of lymph node dissection on clinical outcomes of intrahepatic cholangiocarcinoma: inverse probability of treatment weighting with survival analysis.

    Yuzo Umeda, Toshiharu Mitsuhashi, Toru Kojima, Daisuke Satoh, Kenta Sui, Yoshikatsu Endo, Masaru Inagaki, Masahiro Oishi, Takahito Yagi, Toshiyoshi Fujiwara

    Journal of hepato-biliary-pancreatic sciences   2021.9

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    BACKGROUND: Lymph node metastasis (LNM) has been established as a critical risk factor for prognosis in intrahepatic cholangiocarcinoma (ICC). The clinical implications of lymph-node dissection (LND) have been debated. This study aimed to clarify the prognostic impact of LND by multicenter-retrospective analysis. METHODS: A total of 310 ICC patients who had undergone curative resection between 2000 and 2016 were retrospectively analyzed. The prognostic impact of LND was estimated under an inverse probability of treatment weighting (IPTW) approach using propensity scores. RESULTS: LND was performed for 224 patients (72%), with LNM pathologically confirmed in 90 patients (40%). Prognosis was poorer for patients with LNM (median survival, 16.9 months) than for those without (57.2 months; p<0.0001). One-, 3-, and 5-year overall survival rates (OS) were comparable among the LND+ (81.6%, 48.0%, and 37.5%, respectively) and the LND- groups (81.6%, 55.4%, and 44.6%, respectively). However, advanced tumor, as characterized by larger tumor, multinodular lesions, and serosal invasion, was significantly more frequent in the LND+ group than in the LND- group. After IPTW adjusting for imbalances, 1-, 3-, and 5-year OS were better in the LND+ group (83.5%, 52.2%, and 42.8%, respectively) than in the LND- group (71.9%, 32.4%, and 23.4%, respectively; p=0.046). LND thus showed significant prognostic impact (hazard ratio = 0.58, 95%CI = |0.39|-|0.84|, p=0.005). Especially in hilar ICC, LND showed significant prognostic impact. However, peripheral ICC displayed no therapeutic benefit from LND. CONCLUSIONS: LND could have significant role to improve oncologic outcomes. Therapeutic LND should be implemented on the basis of tumor location and tumor advancement.

    DOI: 10.1002/jhbp.1038

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  • Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression. International journal

    Kazuhisa Sugiu, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Tadashi Komatsubara, Yusuke Mochizuki, Hiroya Kondo, Shuhei Osaki, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Koji Ueda, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    Cancer chemotherapy and pharmacology   88 ( 3 )   513 - 524   2021.9

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    BACKGROUND: Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53-expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells. MATERIALS AND METHODS: The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model. RESULTS: DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model. CONCLUSION: Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.

    DOI: 10.1007/s00280-021-04310-5

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  • Adult Bochdalek hernia following living donor left hepatectomy repaired by thoracoscopy-assisted surgery: A case report.

    Kosei Takagi, Takashi Kuise, Kazuhiro Yoshida, Ryuichi Yoshida, Yuzo Umeda, Toshiyoshi Fujiwara, Takahito Yagi

    Asian journal of endoscopic surgery   2021.8

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    Bochdalek hernia is a congenital diaphragmatic hernia (DH). Herein, we report a case of adult Bochdalek hernia following living donor hepatectomy repaired by thoracoscopy-assisted surgery. A 36-year-old man underwent living donor left hepatectomy. Four months later, the patient presented with acute epigastric pain. Computed tomography found the left-sided DH in which the stomach was incarcerated into the pleural cavity without ischemic changes. As endoscopic intervention was unsuccessful, the herniated stomach was repositioned by thoracoscopy-assisted surgery. The 3-cm hernia orifice was found to have a smooth edge with no hernia sac, suggesting Bochdalek hernia, and the defect was primarily closed. The patient was followed up for 20 months without hernia recurrence. This is the first presentation of a case of Bochdalek hernia following donor hepatectomy. In cases of early detected DH, primary repair via a transthoracic approach with thoracoscopy-assisted surgery is safe and feasible.

    DOI: 10.1111/ases.12981

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  • Robotic Radical Antegrade Modular Pancreatosplenectomy Using the Supracolic Anterior Superior Mesenteric Artery Approach. International journal

    Kosei Takagi, Yuzo Umeda, Ryuichi Yoshida, Takahito Yagi, Toshiyoshi Fujiwara

    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract   2021.8

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    BACKGROUND: Radical antegrade modular pancreatosplenectomy (RAMPS) is the standardized approach in open pancreatic resection for pancreatic body and tail cancer. However, few studies have described regarding robotic RAMPS for pancreatic cancer. We herein present our techniques of robotic RAMPS using the supracolic anterior superior mesenteric artery (SMA) approach with the ventral view. METHODS: The patient was a 75-year-old female with a diagnosis of pancreatic body cancer. Following neoadjuvant chemotherapy with gemcitabine plus nab-paclitaxel, robotic RAMPS was performed. Our techniques of robotic RAMPS include four steps: (1) gastrocolic ligament division, (2) dissection of superior and inferior border of the pancreas, (3) division of the pancreas, and (4) retroperitoneal dissection. RESULTS: The operative time was 251 min with an estimated blood loss of 10 mL. The uneventful postoperative course was observed. The final pathology confirmed R0 surgical resection. CONCLUSIONS: Robotic RAMPS using the supracolic anterior SMA approach is safe and feasible for pancreatic body and tail cancer. Standardization and precise anatomical knowledge are key elements of performing robotic RAMPS.

    DOI: 10.1007/s11605-021-05112-z

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  • CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. International journal

    Tomohiro Fujiwara, Mohamed A Yakoub, Andrew Chandler, Alexander B Christ, Guangli Yang, Ouathek Ouerfelli, Vinagolu K Rajasekhar, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Hiroshi Tazawa, Yildirim Dogan, Malcolm A S Moore, Toshiyoshi Fujiwara, Toshifumi Ozaki, Ed Purdue, John H Healey

    Molecular cancer therapeutics   20 ( 8 )   1388 - 1399   2021.8

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    Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell-modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.

    DOI: 10.1158/1535-7163.MCT-20-0591

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  • Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (Telomelysin) with radiotherapy in oesophageal cancer patients unfit for standard treatments. International journal

    Yasuhiro Shirakawa, Hiroshi Tazawa, Shunsuke Tanabe, Nobuhiko Kanaya, Kazuhiro Noma, Takeshi Koujima, Hajime Kashima, Takuya Kato, Shinji Kuroda, Satoru Kikuchi, Shunsuke Kagawa, Kuniaki Katsui, Susumu Kanazawa, Yasuo Urata, Toshiyoshi Fujiwara

    European journal of cancer (Oxford, England : 1990)   153   98 - 108   2021.8

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    PURPOSE: OBP-301 (Telomelysin) is an attenuated type-5 adenovirus that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 sensitises human cancer cells to ionising radiation by inhibiting DNA repair, and radiation enhances coxsackievirus and adenovirus receptor-mediated OBP-301 infection on the contrary. We assessed OBP-301 with radiotherapy in oesophageal cancer patients unfit for standard chemoradiation treatments. METHODS: A phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed oesophageal cancer patients deemed unfit to undergo surgery or chemotherapy. Study treatment consisted of OBP-301 administration by intratumoural needle injection using a flexible endoscope on days 1, 18 and 32. Radiotherapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. RESULTS: Of the 13 patients, 7, 3 and 3 patients were treated with 1010, 1011 and 1012 virus particles, respectively. Study group comprised 10 males and 3 females, with a median age of 82 years (range, 53-91 years). All patients developed a transient, self-limited lymphopenia. Distribution studies revealed transient virus shedding in the plasma. Eight patients had local complete response (CR); all of them exhibited no pathologically viable malignant cells in biopsy specimens, and 3 patients had a partial response. The objective response rate was 91.7%. The clinical CR rate was 83.3% in stage I and 60.0% in stage II/III. Histopathological examination revealed massive infiltration of CD8+ cells and increased PD-L1 expression. CONCLUSION: Multiple courses of endoscopic intratumoural OBP-301 injection with radiotherapy are feasible and provide clinical benefits in patients with oesophageal cancer unfit for standard treatments.

    DOI: 10.1016/j.ejca.2021.04.043

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  • Prediction of Early Recurrence After Surgery for Liver Tumor (ERASL): An International Validation of the ERASL Risk Models. International journal

    Berend R Beumer, Kosei Takagi, Bastiaan Vervoort, Stefan Buettner, Yuzo Umeda, Takahito Yagi, Toshiyoshi Fujiwara, Ewout W Steyerberg, Jan N M IJzermans

    Annals of surgical oncology   2021.7

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    BACKGROUND: This study aimed to assess the performance of the pre- and postoperative early recurrence after surgery for liver tumor (ERASL) models at external validation. Prediction of early hepatocellular carcinoma (HCC) recurrence after resection is important for individualized surgical management. Recently, the preoperative (ERASL-pre) and postoperative (ERASL-post) risk models were proposed based on patients from Hong Kong. These models showed good performance although they have not been validated to date by an independent research group. METHODS: This international cohort study included 279 patients from the Netherlands and 392 patients from Japan. The patients underwent first-time resection and showed a diagnosis of HCC on pathology. Performance was assessed according to discrimination (concordance [C] statistic) and calibration (correspondence between observed and predicted risk) with recalibration in a Weibull model. RESULTS: The discriminatory power of both models was lower in the Netherlands than in Japan (C statistic, 0.57 [95% confidence interval {CI} 0.52-0.62] vs 0.69 [95% CI 0.65-0.73] for the ERASL-pre model and 0.62 [95% CI 0.57-0.67] vs 0.70 [95% CI 0.66-0.74] for the ERASL-post model), whereas their prognostic profiles were similar. The predictions of the ERASL models were systematically too optimistic for both cohorts. Recalibrated ERASL models improved local applicability for both cohorts. CONCLUSIONS: The discrimination of ERASL models was poorer for the Western patients than for the Japanese patients, who showed good performance. Recalibration of the models was performed, which improved the accuracy of predictions. However, in general, a model that explains the East-West difference or one tailored to Western patients still needs to be developed.

    DOI: 10.1245/s10434-021-10235-3

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  • Intracorporeal semi-hand-sewn Billroth I reconstruction in total laparoscopic distal gastrectomy.

    Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Kazuya Kuwada, Nobuo Takata, Yoshihiko Kakiuchi, Shuya Yano, Kazuhiro Noma, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Asian journal of endoscopic surgery   14 ( 3 )   640 - 643   2021.7

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    INTRODUCTION: Intracorporeal Billroth I (B-I) reconstruction using an endoscopic linear stapler (ELS) is widely performed in total laparoscopic distal gastrectomy. However, conventional procedures require many ELSs for anastomosis. Here, we introduce the novel intracorporeal semi-hand-sewn (SHS) B-I reconstruction. MATERIALS AND SURGICAL TECHNIQUE: After the transection of stomach and duodenum using ELS following adequate lymph node dissection, small entry holes were made on the anterior wall in the greater curvature of the stomach and the duodenal stump. The posterior walls of both the remnant stomach and the duodenum were attached with the ELS and fired to create the posterior wall of the B-I anastomosis. All the transection line of the duodenum and one-third of the transection line of the stomach were dissected; finally the anterior wall suturing at the anastomotic site was performed by the laparoscopic hand-sewn technique. DISCUSSION: SHS procedure was performed for 17 gastric cancer patients. There were no intraoperative complications or conversions to open surgery. One intra-abdominal abscess was observed although there was no anastomotic leakage. The median reconstruction time was 48 minutes (32-63). The SHS procedure was safe, feasible, and economical, although it requires sufficient laparoscopic suturing and ligation skill.

    DOI: 10.1111/ases.12887

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  • Gastroenteropancreatic neuroendocrine tumor of the accessory papilla of the duodenum: a case report. International journal

    Kosei Takagi, Yuzo Umeda, Ryuichi Yoshida, Kazuhiro Yoshida, Kazuya Yasui, Hiroki Sato, Takahito Yagi, Toshiyoshi Fujiwara

    Surgical case reports   7 ( 1 )   156 - 156   2021.6

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    BACKGROUND: Contrary to the increasing incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), GEP-NETs of the accessory papilla of the duodenum are extremely rare. Furthermore, there have been no recommendations regarding the treatment strategy for GEP-NETs of the accessory papilla of the duodenum. We present a case of GEP-NET of the accessory papilla of the duodenum successfully treated with robotic pancreatoduodenectomy. CASE PRESENTATION: A case of a 70-year-old complaining of no symptoms was diagnosed with GEP-NET of the accessory papilla of the duodenum. A 8-mm tumor was located at the submucosal layer with a biopsy demonstrating a neuroendocrine tumor grade 1. The patient underwent robotic pancreatoduodenectomy as curative resection for the tumor. The total operative time was 406 min with an estimated blood loss of 150 mL. The histological examination revealed a well-differentiated neuroendocrine tumor with low Ki-67 index (< 1%). In the posterior areas of the pancreas, the lymph node metastases were detected. The patient was followed up for 6 months with no recurrence postoperatively. CONCLUSIONS: Considering the potential risks of the lymph node metastases, the standard treatment strategy for GEP-NETs of the accessory papilla of the duodenum should be radical resection with pancreatoduodenectomy. Minimally invasive approach can be the alternative to the conventional open surgery.

    DOI: 10.1186/s40792-021-01241-4

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  • ASO Visual Abstract: Prediction of Early Hepatocellular Carcinoma Recurrence After Resection-An International Validation of the ERASL Risk Models. International journal

    Berend R Beumer, Kosei Takagi, Bastiaan Vervoort, Stefan Buettner, Yuzo Umeda, Takahito Yagi, Toshiyoshi Fujiwara, Ewout W Steyerberg, Jan N M IJzermans

    Annals of surgical oncology   2021.6

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    DOI: 10.1245/s10434-021-10132-9

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  • Immuno-hyperthermia effected by antibody-conjugated nanoparticles selectively targets and eradicates individual cancer cells. International journal

    Tetsuya Kagawa, Yuki Matsumi, Hiromichi Aono, Toshiaki Ohara, Hiroshi Tazawa, Kunitoshi Shigeyasu, Shuya Yano, Sho Takeda, Yasuhiro Komatsu, Robert M Hoffman, Toshiyoshi Fujiwara, Hiroyuki Kishimoto

    Cell cycle (Georgetown, Tex.)   1 - 11   2021.6

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    Hyperthermia has been used for cancer therapy for along period of time, but has shown limited clinical efficacy. Induction-heating hyperthermia using the combination of magnetic nanoparticles (MNPs) and an alternating magnetic field (AMF), termed magnetic hyperthermia (MHT), has previously shown efficacy in an orthotopic mouse model of disseminated gastric cancer. In the present study, superparamagnetic iron oxide nanoparticles (SPIONs), atype of MNP, were conjugated with an anti-HER2 antibody, trastuzumab and termed anti-HER2-antibody-linked SPION nanoparticles (anti-HER2 SPIONs). Anti-HER2 SPIONs selectively targeted HER2-expressing cancer cells co-cultured along with normal fibroblasts and HER2-negative cancer cells and caused apoptosis only in the HER2-expressing individual cancer cells. The results of the present study show proof-of-concept of anovel hyperthermia technology, immuno-MHT for selective cancer therapy, that targets individual cancer cells.AbbreviationsAMF:alternating magnetic fieldDDW:double distilled waterDMEM:Dulbecco's Modified Eagle's Mediumf:frequencyFBS:fetal bovine serumFITC:Fluorescein isothiocyanateGFP:green fluorescent proteinH:amplitudeHsp:heat shock proteinMHT:magnetic hyperthermiaMNPs:magnetic nanoparticlesPI:propidium iodideRFP:red fluorescent proteinSPION:superparamagnetic iron oxide (Fe3O4) nanoparticle.

    DOI: 10.1080/15384101.2021.1915604

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  • Preoperative prognostic nutritional index predicts postoperative infectious complications and oncological outcomes after hepatectomy in intrahepatic cholangiocarcinoma. International journal

    Tatsuo Matsuda, Yuzo Umeda, Tadakazu Matsuda, Yoshikatsu Endo, Daisuke Sato, Toru Kojima, Kenta Sui, Masaru Inagaki, Tetsuya Ota, Masayoshi Hioki, Masahiro Oishi, Masashi Kimura, Toshihiro Murata, Nobuhiro Ishido, Takahito Yagi, Toshiyoshi Fujiwara

    BMC cancer   21 ( 1 )   708 - 708   2021.6

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    BACKGROUND: In the surgical treatment of intrahepatic cholangiocarcinoma (ICC), postoperative complications may be predictive of long-term survival. This study aimed to identify an immune-nutritional index (INI) that can be used for preoperative prediction of complications. PATIENTS AND METHODS: Multi-institutional data from 316 patients with ICC who had undergone surgical resection were retrospectively analysed, with a focus on various preoperative INIs. RESULTS: Severe complications (Clavien-Dindo grade III-V) were identified in 66 patients (20.8%), including Grade V complications in 7 patients (2.2%). Comparison of areas under the receiver operating characteristic curve (AUCs) among various INIs identified the prognostic nutritional index (PNI) as offering the highest predictive value for severe complications (AUC = 0.609, cut-off = 50, P = 0.008). Multivariate analysis revealed PNI <  50 (odds ratio [OR] = 2.22, P = 0.013), hilar lesion (OR = 2.46, P = 0.026), and long operation time (OR = 1.003, P = 0.029) as independent risk factors for severe complications. In comparing a high-PNI group (PNI ≥ 50, n = 142) and a low-PNI group (PNI <  50, n = 174), the low-PNI group showed higher rates of both major complications (27% vs. 13.4%; P = 0.003) and infectious complications (14.9% vs. 3.5%; P = 0.0021). Furthermore, median survival time and 1- and 5-year overall survival rates were 34.2 months and 77.4 and 33.8% in the low-PNI group, respectively, and 52.4 months and 89.3 and 47.5% in the high-PNI group, respectively (P = 0.0017). CONCLUSION: Preoperative PNI appears useful as an INI correlating with postoperative severe complications and as a prognostic indicator for ICC.

    DOI: 10.1186/s12885-021-08424-0

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  • Hyperthermia generated by magnetic nanoparticles for effective treatment of disseminated peritoneal cancer in an orthotopic nude-mouse model. International journal

    Yuki Matsumi, Tetsuya Kagawa, Shuya Yano, Hiroshi Tazawa, Kunitoshi Shigeyasu, Sho Takeda, Toshiaki Ohara, Hiromichi Aono, Robert M Hoffman, Toshiyoshi Fujiwara, Hiroyuki Kishimoto

    Cell cycle (Georgetown, Tex.)   1 - 12   2021.6

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    Magnetic hyperthermia (MHT), which combines magnetic nanoparticles (MNPs) with an alternating magnetic field (AMF), holds promise as a cancer therapy. There have been many studies about hyperthermia, most of which have been performed by direct injection of MNPs into tumor tissues. However, there have been no reports of treating peritoneal disseminated disease with MHT to date. In the present study, we treated peritoneal metastasis of gastric cancer with MHT using superparamagnetic iron oxide (Fe3O4) nanoparticle (SPION) coated with carboxydextran as an MNP, in an orthotopic mouse model mimicking early peritoneal disseminated disease of gastric cancer. SPIONs of an optimal size were intraperitoneally administered, and an AMF (390 kHz, 28 kAm-1) was applied for 10 minutes, four times every three days. Three weeks after the first MHT treatment, the peritoneal metastases were significantly inhibited compared with the AMF-alone group or the untreated-control group. The results of the present study show that MHT can be applied as a new treatment option for disseminated peritoneal gastric cancer.Abbreviations: AMF: alternating magnetic field; Cy1: cytology-positive; DMEM: Dulbecco's Modified Eagle's Medium; FBS: fetal bovine serum; H&E: hematoxylin and eosin; HIPEC: hyperthermic intraperitoneal chemotherapy; MEM: Minimum Essential Medium; MHT: magnetic hyperthermia; MNPs: magnetic nanoparticles; P0: macroscopic peritoneal dissemination; RFP: red fluorescent protein; SPION: superparamagnetic iron oxide (Fe3O4) nanoparticle.

    DOI: 10.1080/15384101.2021.1919441

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  • Accreditation as a qualified surgeon improves surgical outcomes in laparoscopic distal gastrectomy.

    Satoru Kikuchi, Tetsuya Kagawa, Shinji Kuroda, Masahiko Nishizaki, Nobuo Takata, Kazuya Kuwada, Ryohei Shoji, Yoshihiko Kakiuchi, Toshiharu Mitsuhashi, Yuzo Umeda, Kazuhiro Noma, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Surgery today   2021.5

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    PURPOSE: The Endoscopic Surgical Skill Quantification System for qualified surgeons (QSs) was introduced in Japan to improve surgical outcomes. This study reviewed the surgical outcomes after initial experience performing laparoscopic distal gastrectomy (LDG) and evaluated the improvement in surgical outcomes following accreditation as a QS. METHODS: Eighty-seven consecutive patients who underwent LDG for gastric cancer by a single surgeon were enrolled in this study. The cumulative sum method was used to analyze the learning curve for LDG. The surgical outcomes were evaluated according to the two phases of the learning curve (learning period vs. mastery period) and accreditation (non-QS period vs. QS period). RESULTS: The learning period for LDG was 48 cases. Accreditation was approved at the 67th case. The operation time and estimated blood loss were significantly reduced in the QS period compared to the non-QS period (230 vs. 270 min, p < 0.001; 20.5 vs. 59.8 ml, p = 0.024, respectively). Furthermore, the major complication rate was significantly lower in the QS period than in the non-QS period (0 vs. 10.6%, p = 0.044). CONCLUSIONS: Experience performing approximately 50 cases is required to reach proficiency in LDG. After receiving accreditation as a QS, the surgical outcomes, including the complication rate, were improved.

    DOI: 10.1007/s00595-021-02309-2

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  • Clinical and epigenetic features of colorectal cancer patients with somatic POLE proofreading mutations. International journal

    Takashi Kawai, Akihiro Nyuya, Yoshiko Mori, Takehiro Tanaka, Hiroaki Tanioka, Kazuya Yasui, Toshiaki Toshima, Fumitaka Taniguchi, Kunitoshi Shigeyasu, Yuzo Umeda, Toshiyoshi Fujiwara, Makoto Okawaki, Yoshiyuki Yamaguchi, Ajay Goel, Takeshi Nagasaka

    Clinical epigenetics   13 ( 1 )   117 - 117   2021.5

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    BACKGROUND: Mutations in the POLE gene result in an ultra-hypermutated phenotype in colorectal cancer (CRC); however, the molecular characterisation of epigenetic alterations remains unclear. We examined the genetic and epigenetic profiles of POLE-mutant CRC to elucidate the clinicopathological features of the associated genetic and epigenetic alterations. RESULTS: Tumour tissues (1,013) obtained from a cohort of patients with CRC were analysed to determine associations between the proofreading domain mutations of POLE with various clinicopathological variables, microsatellite instability (MSI) status, BRAF and KRAS mutations, and the methylation status of key regions of MLH1, MGMT, and SFRP2 promoters by calculating the methylation scores (range 0-6). Only four cases (0.4%) exhibited pathogenic POLE hotspot mutations (two p.P286R [c.857C > G], one p.V411L [c.1231G > C], and p.S459F [c.1376C > T] each), which were mutually exclusive to BRAF and KRAS mutations and MSI. CRC patients were divided into four subgroups: patients with POLE mutations (POLE, 0.4%, n = 4), patients with both MSI and extensive methylation in MLH1 (MSI-M, 2.9%, n = 29), patients with MSI but no extensive methylation in MLH1 (MSI-U, 3.6%, n = 36), and patients without MSI (non-MSI, 93.2%, n = 944). The POLE group was younger at diagnosis (median 52 years, P < 0.0001), with frequent right-sided tumour localisation (frequency of tumours located in the right colon was 100%, 93.1%, 36.1%, and 29.9% in POLE, MSI-M, MSI-U, and non-MSI, respectively; P < 0.0001), and was diagnosed at an earlier stage (frequency of stages I-II was 100%, 72.4%, 77.8%, and 46.6% in POLE, MSI-M, MSI-U, and non-MSI, respectively, P < 0.0001). The mean methylation score in POLE was not different from that in MSI-U and non-MSI, but the methylation signature was distinct from that of the other subgroups. Additionally, although the examined number of POLE-mutant tumours was small, the number of CD8-positive cells increased in tumours with partial methylation in the MLH1 gene. CONCLUSIONS: CRC patients with POLE proofreading mutations are rare. Such mutations are observed in younger individuals, and tumours are primarily located in the right colon. Diagnosis occurs at an earlier stage, and distinct epigenetic alterations may be associated with CD8 cell infiltration.

    DOI: 10.1186/s13148-021-01104-7

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  • Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles. International journal

    Yoshihiko Kakiuchi, Shinji Kuroda, Nobuhiko Kanaya, Kento Kumon, Tomoko Tsumura, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Yuki Hamada, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

    Molecular therapy : the journal of the American Society of Gene Therapy   2021.5

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    Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. Here, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.

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  • SMAD4 Germline Pathogenic Variant-Related Gastric Juvenile Polyposis with Adenocarcinoma Treated with Laparoscopic Total Gastrectomy: A Case Report

    Yuya Sakurai, Satoru Kikuchi, Kunitoshi Shigeyasu, Yoshihiko Kakiuchi, Takehiro Tanaka, Hibiki Umeda, Masaki Sakamoto, Sho Takeda, Shuya Yano, Mashu Futagawa, Fumino Kato, Reimi Sogawa, Hideki Yamamoto, Shinji Kuroda, Yoshitaka Kondo, Fuminori Teraishi, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Akira Hirasawa, Toshiyoshi Fujiwara

    American Journal of Case Reports   22   2021.5

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    DOI: 10.12659/ajcr.932241

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  • Long-term survival without recurrence after surgery for gastric yolk sac tumor-like carcinoma: a case report. International journal

    Hibiki Umeda, Satoru Kikuchi, Shinji Kuroda, Shuya Yano, Takehiro Tanaka, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yuzo Umeda, Toshiyoshi Fujiwara

    Surgical case reports   7 ( 1 )   111 - 111   2021.5

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    BACKGROUND: Gastric yolk sac tumor (YST)-like carcinoma is extremely rare, and its prognosis is poor, because most patients have widespread metastases at the time of diagnosis. We report a case of gastric YST-like carcinoma with an adenocarcinoma component without metastases in which curative resection was performed. CASE PRESENTATION: A 77-year-old man complaining of melena and dizziness due to anemia was diagnosed with poorly differentiated adenocarcinoma in the gastric cardia, with a benign ulcer in the gastric body. He underwent total gastrectomy with D2 lymph node dissection for the tumor. Histological examination of the resected specimens revealed a mixture of reticular and glandular neoplastic components morphologically. In the reticular area, an endodermal sinus pattern and some Schiller-Duval bodies were confirmed. Gastric YST-like carcinoma with adenocarcinoma components, T2N0M0 Stage IB, was diagnosed. Immunohistochemical analysis showed that the YST was positive for carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP) and p53. In contrast, the adenocarcinoma was positive for p53 and negative for CEA and AFP. The patient remained healthy as of 7 years postoperatively, with no recurrence. CONCLUSIONS: Routine medical examinations or endoscopic examinations for accidental symptom may be helpful for early diagnosis and good prognosis for gastric YST-like carcinoma, although the prognosis is generally poor.

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  • Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma. International journal

    Yusuke Mochizuki, Hiroshi Tazawa, Koji Demiya, Miho Kure, Hiroya Kondo, Tadashi Komatsubara, Kazuhisa Sugiu, Joe Hasei, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    Cancer immunology, immunotherapy : CII   70 ( 5 )   1405 - 1417   2021.5

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    Immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1) antibody have recently improved clinical outcome in certain cancer patients; however, osteosarcoma (OS) patients are refractory to PD-1 blockade. Oncolytic virotherapy has emerged as novel immunogenic therapy to augment antitumor immune response. We developed a telomerase-specific replication-competent oncolytic adenovirus OBP-502 that induces lytic cell death via binding to integrins. In this study, we assessed the combined effect of PD-1 blockade and OBP-502 in OS cells. The expression of coxsackie and adenovirus receptor (CAR), integrins αvβ3 and αvβ5, and programmed cell death ligand 1 (PD-L1) was analyzed in two murine OS cells (K7M2, NHOS). The cytopathic activity of OBP-502 in both cells was analyzed using the XTT assay. OBP-502-induced immunogenic cell death was assessed by analyzing the level of extracellular ATP and high-mobility group box protein B1 (HMGB1). Subcutaneous tumor models for K7M2 and NHOS cells were used to evaluate the antitumor effect and number of tumor-infiltrating CD8+ cells in combination therapy. K7M2 and NHOS cells showed high expression of integrins αvβ3 and αvβ5, but not CAR. OBP-502 significantly suppressed the viability of both cells, in which PD-L1 expression and the release of ATP and HMGB1 were significantly increased. Intratumoral injection of OBP-502 significantly augmented the efficacy of PD-1 blockade on subcutaneous K2M2 and NHOS tumor models via enhancement of tumor-infiltrating CD8+  T cells. Our results suggest that telomerase-specific oncolytic virotherapy is a promising antitumor strategy to promote the efficacy of PD-1 blockade in OS.

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  • Efficacy and safety of short-term (3 days) enoxaparin in preventing venous thromboembolism after gastric cancer surgery: A single-center, prospective cohort study. International journal

    Shinji Kuroda, Satoru Kikuchi, Yoshihiko Kakiuchi, Megumi Watanabe, Kazuya Kuwada, Tomoko Tsumura, Masahiko Nishizaki, Shunsuke Kagawa, Shiro Hinotsu, Toshiyoshi Fujiwara

    International journal of surgery (London, England)   89   105946 - 105946   2021.5

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    BACKGROUND: Pharmacologic prophylaxis such as enoxaparin for venous thromboembolism (VTE) is rarely used in Japan, even following abdominal cancer surgery, for which it is recommended in relevant guidelines (at least 7 days of use) along with mechanical prophylaxis with intermittent pneumatic compression. Reasons for enoxaparin's unpopularity include concerns over postoperative bleeding and its inconvenience in clinical practice. Here, we conducted a prospective clinical study of short-term (3 days) use of enoxaparin, which is considered to minimally impact postoperative management without increasing bleeding risk. METHODS: Gastric cancer patients who underwent gastrectomy received enoxaparin for 3 days from postoperative day (POD) 1-4. The primary endpoint was the incidence of deep vein thrombosis (DVT), which was examined primarily via Doppler ultrasonography of the lower limbs between POD 8 and 14. The planned sample size was 70, which was calculated based on an estimated incidence rate of 9% and an upper limit of incidence rate of 20%, with alpha of 0.05 and beta of 0.2. RESULTS: A total of 70 gastric cancer patients were enrolled, and ultimately, 68 patients received the protocol intervention and DVT evaluation. Sixty-seven patients completed 6 enoxaparin injections, but 1 patient did not complete the course due to abdominal bleeding after initiation. The incidence of DVT was 4.4% (3/68), and the 95% upper confidence interval was 12.2%, lower than the 20% threshold we set as the upper limit of DVT incidence. DVT was detected only in the peripheral veins of the lower extremities in all 3 affected patients. The incidence of bleeding-related complications, which were not severe, was 1.5% (1/68). CONCLUSIONS: Short-term (3 days) use of enoxaparin was shown to be effective and safe for VTE prophylaxis, comparable to regular use (at least 7 days), in postoperative management of gastric cancer surgery.

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  • Dramatic Response to Carboplatin Plus Paclitaxel in Pancreatic Mucinous Cystadenocarcinoma with Liver Metastasis.

    Naohiro Oda, Masahiro Tabata, Masatoshi Uno, Yuzo Umeda, Hironari Kato, Toshio Kubo, Satoru Senoo, Takahito Yagi, Toshiyoshi Fujiwara, Yoshinobu Maeda, Katsuyuki Kiura

    Internal medicine (Tokyo, Japan)   2021.4

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    Mucinous cystic neoplasm (MCN) of the pancreas is a rare cystic tumor occurring in the pancreatic body and tail in young to middle-aged women that is pathologically characterized by an ovarian-like stroma. Chemotherapy for recurrent/advanced pancreatic MCN has been based on chemotherapy regimens for pancreatic ductal adenocarcinoma, but the prognosis is poor. We herein report a 37-year-old woman with pancreatic mucinous cystadenocarcinoma with liver metastasis that responded dramatically to carboplatin plus paclitaxel therapy (CBDCA + PTX). CBDCA + PTX may be a treatment option for recurrent/advanced pancreatic MCN with an ovarian-like stroma.

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  • Long-term Survival with a Rare Advanced Primary Gastrointestinal Malignant Melanoma Treated with Laparoscopic Surgery/Immune Checkpoint Inhibitor.

    Motochika Endo, Shuya Yano, Hiroaki Asano, Sho Takeda, Yuki Hamada, Yoshitaka Kondo, Shinji Kuroda, Kunitoshi Shigeyasu, Satoru Kikuchi, Takehiro Tanaka, Fuminori Teraishi, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Acta medica Okayama   75 ( 2 )   231 - 238   2021.4

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    Targeted therapies for malignant melanoma have improved patients' prognoses. A primary gastrointestinal malignant melanoma is very rare, with no standard treatment strategy. We treated a 78-year-old Japanese female with advanced primary gastrointestinal melanoma of the descending colon and gallbladder. We administered a multidisciplinary treatment: surgical resection of the descending colon and gallbladder tumors, resection of the metastatic lymph nodes behind the pancreas head, and immune checkpoint antibody-blockade therapy (nivolumab) for ~4 years. PET/CT demonstrated no recurrent lesion for > 3 years. Multidisciplinary therapies (e.g., surgery, chemotherapy, radiotherapy, target therapy, and immune checkpoint antibody-blockade therapy) can successfully treat primary gastrointestinal malignant melanoma.

    DOI: 10.18926/AMO/61906

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  • Laparoscopic Hepatectomy for the Patient with Hemophilia A with High Titer Factor VIII Inhibitor.

    Tatsuo Matsuda, Yuzo Umeda, Kazuhiro Yoshida, Tadakazu Matsuda, Masatoshi Uno, Masaya Abe, Noboru Asada, Yoshinobu Maeda, Takahito Yagi, Toshiyoshi Fujiwara

    Acta medica Okayama   75 ( 2 )   199 - 204   2021.4

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    We present the first case of laparoscopic left lateral segmentectomy for hepatocellular carcinoma (HCC) in a patient with hemophilia A, acquired hepatitis C, and high-titer factor VIII inhibitor, which was confirmed by preoperative diagnosis. He underwent laparoscopic left lateral segmentectomy with the administration of recombinant activated factor VII. Surgery could be performed with reduced intraoperative hemorrhage. He experienced postoperative intra-abdominal wall hemorrhage, which was successfully managed with red cell concentrates transfusion and administration of recombinant activated factor VII. Laparoscopic hepatectomy can be applied for hemophilia patients with high titer inhibitors.

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  • Nanog is a promising chemo-resistant stemness marker and therapeutic target by iron chelators for esophageal cancer. International journal

    Toru Narusaka, Toshiaki Ohara, Kazuhiro Noma, Noriyuki Nishiwaki, Yuki Katsura, Takuya Kato, Hiroaki Sato, Yasuko Tomono, Satoru Kikuchi, Hiroshi Tazawa, Yasuhiro Shirakawa, Akihiro Matsukawa, Toshiyoshi Fujiwara

    International journal of cancer   2021.3

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    Esophageal cancer is a disease showing poor prognosis. Although combination chemotherapy using cisplatin and 5-fluorouracil is standard for unresectable esophageal cancer, the response rate is 35%. Cancer stem cells (CSCs) and inflammation are reportedly responsible for the poor prognosis of esophageal cancer. However, comprehensive analyses have not been conducted and proposals for progress remain lacking. Iron is known to be a key factor in the stemness of CSCs. This study focused on the therapeutic potential of iron control using iron chelators for CSCs in esophageal cancer. Among 134 immunohistochemically analyzed cases, Nanog expression was high in 98 cases and low in 36 cases. High Nanog expression correlated with low overall and disease-free survivals. The iron chelators deferasirox (DFX) and SP10 suppressed the proliferation and expression of stemness markers in TE8 and OE33 cells. DFX and SP10 did not induce compensatory interleukin (IL)-6 secretion, although cisplatin did result in high induction. Moreover, BBI608 and SSZ, as other CSC-targeting drugs, could not suppress the expression of stemness markers. Together, Nanog expression appears related to poor prognosis in esophageal cancer patients, and inhibition of stemness and compensatory IL-6 secretion by iron chelators may offer a novel therapeutic strategy for esophageal cancer.

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  • Role of Tumor-Associated Macrophages in Sarcomas. International journal

    Tomohiro Fujiwara, John Healey, Koichi Ogura, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Miho Kure, Hiroshi Tazawa, Eiji Nakata, Toshiyuki Kunisada, Toshiyoshi Fujiwara, Toshifumi Ozaki

    Cancers   13 ( 5 )   2021.3

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    Sarcomas are complex tissues in which sarcoma cells maintain intricate interactions with their tumor microenvironment. Tumor-associated macrophages (TAMs) are a major component of tumor-infiltrating immune cells in the tumor microenvironment and have a dominant role as orchestrators of tumor-related inflammation. TAMs promote tumor growth and metastasis, stimulate angiogenesis, mediate immune suppression, and limit the antitumor activity of conventional chemotherapy and radiotherapy. Evidence suggests that the increased infiltration of TAMs and elevated expression of macrophage-related genes are associated with poor prognoses in most solid tumors, whereas evidence of this in sarcomas is limited. Based on these findings, TAM-targeted therapeutic strategies, such as inhibition of CSF-1/CSF-1R, CCL2/CCR2, and CD47/SIRPα, have been developed and are currently being evaluated in clinical trials. While most of the therapeutic challenges that target sarcoma cells have been unsuccessful and the prognosis of sarcomas has plateaued since the 1990s, several clinical trials of these strategies have yielded promising results and warrant further investigation to determine their translational benefit in sarcoma patients. This review summarizes the roles of TAMs in sarcomas and provides a rationale and update of TAM-targeted therapy as a novel treatment approach for sarcomas.

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  • 【胆膵領域のロボット支援下手術:ベストプラックティスを求めて】海外におけるロボット支援下膵頭十二指腸切除の現状

    高木 弘誠, 楳田 祐三, 吉田 龍一, 八木 孝仁, 藤原 俊義

    胆と膵   42 ( 3 )   217 - 221   2021.3

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    近年、内視鏡手術は肝胆膵外科領域で急速に普及しつつあり、高難度手術の膵頭十二指腸切除術においても腹腔鏡手術が定着し今後はロボット支援下手術への展開が期待されている。一方、欧米では、世界に先駆けてロボット支援下膵切除が導入され、とくに膵頭部領域の良性・悪性疾患に対するロボット支援下膵頭十二指腸切除(robotic pancreatoduodenectomy:RPD)は、その安全性と有効性の報告とともに、近年は腹腔鏡手術を凌駕して増加傾向にある。本邦においてもロボット支援下膵切除術が保険収載されたが、RPDの安全な導入には、肝胆膵外科手術の豊富な経験に加え、ロボット支援下手術の特性に精通する必要があるため、術前の系統的トレーニングが重要である。海外におけるわれわれの経験を基に、RPDの現状、トレーニングシステム、手術成績に関して報告する。(著者抄録)

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  • 【「課題解決型医療人養成プログラム「国内初の、肝移植を担う医療人養成-6大学連携プログラム-」の成果」】SNUC-LT Program外科履修生の成果と課題、キャリアパス形成

    高木 弘誠, 杭瀬 崇, 楳田 祐三, 藤原 俊義, 八木 孝仁

    移植   55 ( 4 )   361 - 369   2021.3

  • Surgical training model and safe implementation of robotic pancreatoduodenectomy in Japan: a technical note. International journal

    Kosei Takagi, Yuzo Umeda, Ryuichi Yoshida, Takahito Yagi, Toshiyoshi Fujiwara, Amer H Zureikat, Melissa E Hogg, Bas Groot Koerkamp

    World journal of surgical oncology   19 ( 1 )   55 - 55   2021.2

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    BACKGROUND: Growing evidence for the advantages of robotic pancreatoduodenectomy (RPD) has been demonstrated internationally. However, there has been no structured training program for RPD in Japan. Herein, we present the surgical training model of RPD and a standardized protocol for surgical technique. METHODS: The surgical training model and surgical technique were standardized in order to implement RPD safely, based on the Dutch training system collaborated with the University of Pittsburgh Medical Center. RESULTS: The surgical training model included various trainings such as basic robotic training, simulation training, biotissue training, and a surgical video review. Furthermore, a standardized protocol on the surgical technique was established to understand the tips, tricks, and pitfalls of RPD. CONCLUSIONS: Safe implementation of RPD can be achieved through the completion of a structured training program and learning surgical technique. A nationwide structured training system should be developed to implement the program safely in Japan.

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  • Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis. International journal

    Hiroki Kajioka, Shunsuke Kagawa, Atene Ito, Masashi Yoshimoto, Shuichi Sakamoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Yuzo Umeda, Kazuhiro Noma, Hiroshi Tazawa, Toshiyoshi Fujiwara

    Cancer letters   497   1 - 13   2021.1

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    Surgery is the only curative treatment option for pancreatic cancer, but patients often develop postoperative recurrence. Surgical invasiveness might be involved in the mechanism of recurrence. The associations among inflammation caused by surgery, neutrophils, and cancer metastasis were investigated. At first, neutrophil extracellular traps (NETs) were examined in clinical specimens, and NETs were observed around metastatic tumors. To explore how NETs were induced, neutrophils were cultured with pancreatic cancer or in cancer-conditioned medium. Neutrophils formed NETs when they were cultured with pancreatic cancer or even its conditioned medium. The effects of NETs on cancer cells were further investigated in vitro and in vivo. NETs induced the epithelial to mesenchymal transition in cancer cells and thereby promoted their migration and invasion. HMGB1 derived from NETs appeared to potentiate the malignancy of cancer cells. In a mouse model of liver metastasis with inflammation, NETs participated in the metastatic process by enhancing extravasation. Interestingly, thrombomodulin degraded HMGB1 and consequently inhibited the induction of NETs, thereby preventing pancreatic cancer metastasis to the liver. In conclusion, NETs interact reciprocally with pancreatic cancer cells, which play a pivotal role in inflammation-associated metastasis. Targeting NETs with thrombomodulin can be a novel strategy to improve the surgical outcome of pancreatic cancer patients.

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  • Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation. International journal

    Atene Ito, Shunsuke Kagawa, Shuichi Sakamoto, Kazuya Kuwada, Hiroki Kajioka, Masashi Yoshimoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara

    BMC cancer   21 ( 1 )   102 - 102   2021.1

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    BACKGROUND: Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. METHODS: The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. RESULTS: Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. CONCLUSION: EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.

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  • Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer. International journal

    Ryoichi Katsube, Kazuhiro Noma, Toshiaki Ohara, Noriyuki Nishiwaki, Teruki Kobayashi, Satoshi Komoto, Hiroaki Sato, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

    Scientific reports   11 ( 1 )   1693 - 1693   2021.1

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    Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

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  • Real-Time Fluorescence Image-Guided Oncolytic Virotherapy for Precise Cancer Treatment. International journal

    Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M Hoffman

    International journal of molecular sciences   22 ( 2 )   2021.1

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    Oncolytic virotherapy is one of the most promising, emerging cancer therapeutics. We generated three types of telomerase-specific replication-competent oncolytic adenovirus: OBP-301; a green fluorescent protein (GFP)-expressing adenovirus, OBP-401; and Killer-Red-armed OBP-301. These oncolytic adenoviruses are driven by the human telomerase reverse transcriptase (hTERT) promoter; therefore, they conditionally replicate preferentially in cancer cells. Fluorescence imaging enables visualization of invasion and metastasis in vivo at the subcellular level; including molecular dynamics of cancer cells, resulting in greater precision therapy. In the present review, we focused on fluorescence imaging applications to develop precision targeting for oncolytic virotherapy. Cell-cycle imaging with the fluorescence ubiquitination cell cycle indicator (FUCCI) demonstrated that combination therapy of an oncolytic adenovirus and a cytotoxic agent could precisely target quiescent, chemoresistant cancer stem cells (CSCs) based on decoying the cancer cells to cycle to S-phase by viral treatment, thereby rendering them chemosensitive. Non-invasive fluorescence imaging demonstrated that complete tumor resection with a precise margin, preservation of function, and prevention of distant metastasis, was achieved with fluorescence-guided surgery (FGS) with a GFP-reporter adenovirus. A combination of fluorescence imaging and laser ablation using a KillerRed-protein reporter adenovirus resulted in effective photodynamic cancer therapy (PDT). Thus, imaging technology and the designer oncolytic adenoviruses may have clinical potential for precise cancer targeting by indicating the optimal time for administering therapeutic agents; accurate surgical guidance for complete resection of tumors; and precise targeted cancer-specific photosensitization.

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  • Prognostic Utility of the Glasgow Prognostic Score for the Long-Term Outcomes After Liver Resection for Intrahepatic Cholangiocarcinoma: A Multi-institutional Study. International journal

    Kenta Sui, Takehiro Okabayashi, Yuzo Umeda, Masahiro Oishi, Toru Kojima, Daisuke Sato, Yoshikatsu Endo, Tetsuya Ota, Katsuyoshi Hioki, Masaru Inagaki, Tadakazu Matsuda, Ryuji Hirai, Masashi Kimura, Takahito Yagi, Toshiyoshi Fujiwara

    World journal of surgery   45 ( 1 )   279 - 290   2021.1

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    OBJECTIVE: The usefulness of the modified Glasgow prognostic score (GPS) as a prognostic tool remains unclear for patients undergoing curative surgery for intrahepatic cholangiocarcinoma (ICC). Therefore, this study investigated the prognostic usefulness of the GPS for patients who underwent ICC surgery. METHOD: All ICC patients who had a curative-intent hepatectomy at 17 institutions between 2000 and 2016 were included. The correlation was assessed between the preoperative GPS and the baseline characteristics of the patients, histopathological parameters, surgical parameters, and the postresection overall survival (OS). RESULT: There were 273 patients who met the eligibility criteria between the years 2000 and 2016. The postoperative OS rates at 1, 3, and 5 years were 83.8%, 56.3%, and 41.5%, respectively (median OS, 47.7 months). A multivariate analysis revealed the factors that were associated with a worse OS, which included an increased GPS (hazard ratio = 1.62; 95% confidence interval [CI]: 1.01-2.53; P = 0.03), an elevated carcinoembryonic antigen level (hazard ratio = 1.60; 95% CI: 1.06-2.41; P = 0.02), an elevated carbohydrate antigen 19-9 level (hazard ratio = 1.55; 95% CI: 1.05-2.30; P = 0.03), undifferentiated carcinoma (hazard ratio = 2.41; 95% CI: 1.56-3.67; P < 0.01), and positive metastasis to the lymph nodes (hazard ratio = 2.54; 95% CI: 1.76-3.67; P < 0.01). In ICC patients after a hepatectomy, an elevated GPS was associated with poorer OS, even if the tumour factors that affected GPS were eliminated by propensity-score matching. CONCLUSION: Preoperative GPS can be useful to predict the postoperative outcomes of ICC patients. Therefore, this relatively simple and inexpensive scoring system can be utilized to further refine patient stratification as well as to predict survival.

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  • 【消化器・一般外科領域の手術教育を考える】総論 手術教育における手術記録の活用法

    楳田 祐三, 杭瀬 崇, 吉田 龍一, 吉田 一博, 藤原 俊義, 八木 孝仁

    手術   75 ( 1 )   43 - 53   2021.1

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  • がん関連線維芽細胞由来IL-6制御による免疫応答の効率化バイオマーカーとしてのIL-6の可能性

    西脇 紀之, 野間 和広, 大原 利章, 河崎 健人, 赤井 正明, 小林 照貴, 加藤 卓也, 前田 直見, 菊地 覚次, 田辺 俊介, 田澤 大, 白川 靖博, 藤原 俊義

    日本分子腫瘍マーカー研究会誌   36   32 - 33   2021

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  • がん関連線維芽細胞由来IL-6制御による免疫応答の効率化バイオマーカーとしてのIL-6の可能性

    西脇 紀之, 野間 和広, 大原 利章, 河崎 健人, 赤井 正明, 小林 照貴, 加藤 卓也, 前田 直見, 菊地 覚次, 田辺 俊介, 田澤 大, 白川 靖博, 藤原 俊義

    日本分子腫瘍マーカー研究会誌   36   32 - 33   2021

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  • Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression. International journal

    Toshinori Omori, Hiroshi Tazawa, Yasuaki Yamakawa, Shuhei Osaki, Joe Hasei, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    PloS one   16 ( 4 )   e0250643   2021

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    Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.

    DOI: 10.1371/journal.pone.0250643

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  • Hemobilia after bile duct resection: perforation of pseudoaneurysm into intra-pancreatic remnant bile duct: a case report. International journal

    Kazuhiro Yoshida, Yuzo Umeda, Masaya Iwamuro, Kazuyuki Matsumoto, Hironari Kato, Mayu Uka, Yusuke Matsui, Ryuichi Yoshida, Takashi Kuise, Kazuya Yasui, Kosei Takagi, Hiroyuki Araki, Takahito Yagi, Toshiyoshi Fujiwara

    BMC surgery   20 ( 1 )   307 - 307   2020.12

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    BACKGROUND: Hemobilia occurs mainly due to iatrogenic factors such as impairment of the right hepatic or cystic artery, and/or common bile duct in hepatobiliary-pancreatic surgery. However, little or no cases with hemobilia from the intra-pancreatic remnant bile duct after bile duct resection (BDR) has been reported. Here, we report a case of massive hemobilia due to the perforation of psuedoaneurysm of the gastroduodenal artery (GDA) to the intra-pancreatic remnant bile duct after hepatectomy with BDR. CASE PRESENTATION: A 68-year-old male underwent extended right hepatectomy with BDR for gallbladder carcinoma. He presented with upper gastrointestinal bleeding 2 months after the initial surgery. Upper endoscopy identified a blood clot from the ampulla of Vater and simultaneous endoscopic balloon tamponade contributed to temporary hemostasis. Abdominal CT and angiography revealed a perforation of the psuedoaneurysm of the GDA to the intra-pancreatic remnant bile duct resulting in massive hemobilia. Subsequent selective embolization of the pseudoaneurysm with micro-coils could achieve complete hemostasis. He survived without any recurrence of cancer and bleeding. CONCLUSION: Hemobilia could occur in a patient with BDR due to perforation of the pseudoaneurysm derived from the GDA to the intra-pancreatic remnant bile duct. Endoscopic balloon tamponade was useful for a temporal hemostasis and a subsequent radiologic interventional approach.

    DOI: 10.1186/s12893-020-00981-8

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  • 周術期管理チーム介入後の高齢者大腸癌症例のアウトカムの検証 PERIO介入によりアウトカムは向上したか

    寺石 文則, 杉本 龍馬, 武田 正, 重安 邦俊, 矢野 修也, 近藤 喜太, 香川 俊輔, 藤原 俊義

    日本消化器外科学会総会   75回   P210 - 3   2020.12

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  • OS延長を目指した局所進行直腸癌に対するoxaliplatinを用いた術前化学放射線療法の治療成績

    武田 正, 寺石 文則, 重安 邦俊, 矢野 修也, 近藤 喜太, 西崎 正彦, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本消化器外科学会総会   75回   P135 - 6   2020.12

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  • プレシジョンメディシン時代に備えた大腸癌リンパ節郭清範囲の統一化

    矢野 修也, 重安 邦俊, 近藤 喜太, 寺石 文則, 黒田 新士, 菊地 覚次, 西崎 正彦, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本消化器外科学会総会   75回   P147 - 1   2020.12

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  • フェルカルボトランを用いた胃癌腹膜播種に対する磁気温熱療法

    松三 雄騎, 岸本 浩行, 香川 哲也, 矢野 修也, 重安 邦俊, 岡林 弘樹, 大原 利章, 田澤 大, 藤原 俊義

    日本消化器外科学会総会   75回   P077 - 3   2020.12

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  • 直腸癌術前後の白血球数は予防的回腸人工肛門の閉塞やHigh output stoma発症を予測する指標となる

    重安 邦俊, 小松 泰浩, 武田 正, 矢野 修也, 近藤 喜太, 寺石 文則, 西崎 正彦, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本消化器外科学会総会   75回   P129 - 1   2020.12

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  • フェルカルボトランを用いた胃癌腹膜播種に対する磁気温熱療法

    松三 雄騎, 岸本 浩行, 香川 哲也, 矢野 修也, 重安 邦俊, 岡林 弘樹, 大原 利章, 田澤 大, 藤原 俊義

    日本消化器外科学会総会   75回   P077 - 3   2020.12

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  • Short-term and long-term outcomes in living donors for liver transplantation: Cohort study. International journal

    Kosei Takagi, Yuzo Umeda, Ryuichi Yoshida, Nobuyuki Watanabe, Takashi Kuise, Kazuhiro Yoshida, Kazuya Yasui, Tatsuo Matsuda, Toshiyoshi Fujiwara, Takahito Yagi

    International journal of surgery (London, England)   84   147 - 153   2020.12

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    BACKGROUND: Although perioperative outcomes following donor hepatectomy (DH) have been reported, little is known about the long-term outcomes in living donors of liver transplantation. The aim of this study was to investigate the short-term and long-term outcomes following DH. METHODS: A total of 408 living donors who underwent DH between 1996 and 2019 were analyzed in this retrospective study, focusing on short-term outcomes with respect to the operation period (era) and the graft type, as well as long-term outcomes. RESULTS: The overall incidence of postoperative complications was 40.4%. These included minor (30.4%), major (10.0%), and biliary (14.0%) complications. Short-term outcomes after DH slightly improved over time, and outcomes did not differ significantly between the graft types. With regards to long-term outcomes, the incidence of surgery-related complications such as keloids, incisional hernias, and mechanical bowel obstructions was 6.6% over a median follow-up of 7.2 years. In addition, some donors developed comorbidities such as lifestyle diseases and cancers during the follow-up period. CONCLUSIONS: Our study confirmed an improvement of perioperative outcomes in living donors. There was no significant association between the graft type and postoperative outcomes. Donors could develop various morbidities during long-term follow-up. Therefore, a careful perioperative management and long-term follow-up should be provided to living donors.

    DOI: 10.1016/j.ijsu.2020.11.013

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  • The PVT1 lncRNA is a novel epigenetic enhancer of MYC, and a promising risk-stratification biomarker in colorectal cancer. International journal

    Kunitoshi Shigeyasu, Shusuke Toden, Tsuyoshi Ozawa, Takatoshi Matsuyama, Takeshi Nagasaka, Toshiaki Ishikawa, Debashis Sahoo, Pradipta Ghosh, Hiroyuki Uetake, Toshiyoshi Fujiwara, Ajay Goel

    Molecular cancer   19 ( 1 )   155 - 155   2020.11

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    Accumulating evidence suggests that dysregulation of transcriptional enhancers plays a significant role in cancer pathogenesis. Herein, we performed a genome-wide discovery of enhancer elements in colorectal cancer (CRC). We identified PVT1 locus as a previously unrecognized transcriptional regulator in CRC with a significantly high enhancer activity, which ultimately was responsible for regulating the expression of MYC oncogene. High expression of the PVT1 long-non-coding RNA (lncRNA) transcribed from the PVT1 locus was associated with poor survival among patients with stage II and III CRCs (p < 0.05). Aberrant methylation of the PVT1 locus inversely correlated with the reduced expression of the corresponding the PVT1 lncRNA, as well as MYC gene expression. Bioinformatic analyses of CRC-transcriptomes revealed that the PVT1 locus may also broadly impact the expression and function of other key genes within two key CRC-associated signaling pathways - the TGFβ/SMAD and Wnt/β-Catenin pathways. We conclude that the PVT1 is a novel oncogenic enhancer of MYC and its activity is controlled through epigenetic regulation mediated through aberrant methylation in CRC. Our findings also suggest that the PVT1 lncRNA expression is a promising prognostic biomarker and a potential therapeutic target in CRC.

    DOI: 10.1186/s12943-020-01277-4

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  • 癌関連線維芽細胞由来IL-6制御による免疫応答の効率化 "Drug repositioning"による癌治療の可能性

    西脇 紀之, 野間 和広, 大原 利章, 小林 照貴, 菊地 覚次, 田澤 大, 藤原 俊義

    日本癌学会総会記事   79回   OE12 - 7   2020.10

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  • 癌関連線維芽細胞を標的とした光免疫療法の新たな開発

    小林 照貴, 野間 和広, 河崎 健人, 赤井 正明, 西脇 紀之, 大原 利章, 田澤 大, 藤原 俊義

    日本癌学会総会記事   79回   OJ12 - 3   2020.10

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  • 胃癌サブタイプと癌関連線維芽細胞の相互作用

    李 云成, 田澤 大, 野間 和広, 大原 利章, 黒田 新士, 菊地 覚次, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   79回   OE14 - 7   2020.10

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  • 腫瘍融解ウイルスによるp53の発現増強は骨肉腫に対する全身性の抗腫瘍免疫反応を増強する

    近藤 宏也, 田澤 大, 出宮 光二, 久禮 美穂, 望月 雄介, 長谷井 嬢, 國定 俊之, 浦田 泰生, 尾崎 敏文, 藤原 俊義

    日本癌学会総会記事   79回   OE14 - 2   2020.10

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  • Boosting Replication and Penetration of Oncolytic Adenovirus by Paclitaxel Eradicate Peritoneal Metastasis of Gastric Cancer. International journal

    Wataru Ishikawa, Satoru Kikuchi, Toshihiro Ogawa, Motoyasu Tabuchi, Hiroshi Tazawa, Shinji Kuroda, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

    Molecular therapy oncolytics   18   262 - 271   2020.9

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    Peritoneal metastasis is the most frequent form of distant metastasis and recurrence in gastric cancer, and the prognosis is extremely poor due to the resistance of systemic chemotherapy. Here, we demonstrate that intraperitoneal (i.p.) administration of a green fluorescence protein (GFP)-expressing attenuated adenovirus with oncolytic potency (OBP-401) synergistically suppressed the peritoneal metastasis of gastric cancer in combination with paclitaxel (PTX). OBP-401 synergistically suppressed the viability of human gastric cancer cells in combination with PTX. PTX enhanced the antitumor effect of OBP-401 due to enhanced viral replication in cancer cells. The combination therapy increased induction of mitotic catastrophe, resulting in accelerated autophagy and apoptosis. Peritoneally disseminated nodules were selectively visualized as GFP-positive spots by i.p. administration of OBP-401 in an orthotopic human gastric cancer peritoneal dissemination model. PTX enhanced the deep penetration of OBP-401 into the disseminated nodules. Moreover, a non-invasive in vivo imaging system demonstrated that the combination therapy of i.p. OBP-401 administration with PTX significantly inhibited growth of peritoneal metastatic tumors and the amount of malignant ascites. i.p. virotherapy with PTX may be a promising treatment strategy for the peritoneal metastasis of gastric cancer.

    DOI: 10.1016/j.omto.2020.06.021

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  • Elimination of MYCN-Amplified Neuroblastoma Cells by Telomerase-Targeted Oncolytic Virus via MYCN Suppression. International journal

    Terutaka Tanimoto, Hiroshi Tazawa, Takeshi Ieda, Hiroshi Nouso, Morimichi Tani, Takanori Oyama, Yasuo Urata, Shunsuke Kagawa, Takuo Noda, Toshiyoshi Fujiwara

    Molecular therapy oncolytics   18   14 - 23   2020.9

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    Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. High-risk NB is characterized by MYCN amplification and human telomerase reverse transcriptase (hTERT) rearrangement, contributing to hTERT activation and a poor outcome. For targeting hTERT-activated tumors, we developed two oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in which the hTERT promoter drives expression of the viral E1 gene for tumor-specific virus replication. In this study, we demonstrate the therapeutic potential of the hTERT-driven oncolytic adenoviruses OBP-301 and OBP-702 using four human MYCN-amplified NB cell lines (IMR-32, CHP-134, NB-1, LA-N-5) exhibiting high hTERT expression. OBP-301 and OBP-702 exhibited a strong antitumor effect in association with autophagy in NB cells. Virus-mediated activation of E2F1 protein suppressed MYCN expression. OBP-301 and OBP-702 significantly suppressed the growth of subcutaneous CHP-134 tumors. Thus, these hTERT-driven oncolytic adenoviruses are promising antitumor agents for eliminating MYCN-amplified NB cells via E2F1-mediated suppression of MYCN protein.

    DOI: 10.1016/j.omto.2020.05.015

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  • FUCCI Real-Time Cell-Cycle Imaging as a Guide for Designing Improved Cancer Therapy: A Review of Innovative Strategies to Target Quiescent Chemo-Resistant Cancer Cells. International journal

    Shuya Yano, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M Hoffman

    Cancers   12 ( 9 )   2020.9

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    Progress in chemotherapy of solid cancer has been tragically slow due, in large part, to the chemoresistance of quiescent cancer cells in tumors. The fluorescence ubiquitination cell-cycle indicator (FUCCI) was developed in 2008 by Miyawaki et al., which color-codes the phases of the cell cycle in real-time. FUCCI utilizes genes linked to different color fluorescent reporters that are only expressed in specific phases of the cell cycle and can, thereby, image the phases of the cell cycle in real-time. Intravital real-time FUCCI imaging within tumors has demonstrated that an established tumor comprises a majority of quiescent cancer cells and a minor population of cycling cancer cells located at the tumor surface or in proximity to tumor blood vessels. In contrast to most cycling cancer cells, quiescent cancer cells are resistant to cytotoxic chemotherapy, most of which target cells in S/G2/M phases. The quiescent cancer cells can re-enter the cell cycle after surviving treatment, which suggests the reason why most cytotoxic chemotherapy is often ineffective for solid cancers. Thus, quiescent cancer cells are a major impediment to effective cancer therapy. FUCCI imaging can be used to effectively target quiescent cancer cells within tumors. For example, we review how FUCCI imaging can help to identify cell-cycle-specific therapeutics that comprise decoy of quiescent cancer cells from G1 phase to cycling phases, trapping the cancer cells in S/G2 phase where cancer cells are mostly sensitive to cytotoxic chemotherapy and eradicating the cancer cells with cytotoxic chemotherapy most active against S/G2 phase cells. FUCCI can readily image cell-cycle dynamics at the single cell level in real-time in vitro and in vivo. Therefore, visualizing cell cycle dynamics within tumors with FUCCI can provide a guide for many strategies to improve cell-cycle targeting therapy for solid cancers.

    DOI: 10.3390/cancers12092655

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  • リアルタイムイメージングによる予後不良間葉型大腸癌の治療抵抗性EMTマーカーの発現の時空間的意義

    三村 直毅, 矢野 修也, 田澤 大, 家田 偉史, 岡林 弘樹, 重安 邦俊, 武田 正, 吉田 一博, 寺石 文則, 楳田 祐三, 香川 俊輔, 藤原 俊義

    日本分子腫瘍マーカー研究会プログラム・講演抄録   40回   56 - 58   2020.9

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  • がん関連線維芽細胞由来IL-6制御による免疫応答の効率化バイオマーカーとしてのIL-6の可能性

    西脇 紀之, 野間 和広, 大原 利章, 河崎 健人, 赤井 正明, 小林 照貴, 加藤 卓也, 前田 直見, 菊地 覚次, 田辺 俊介, 田澤 大, 白川 靖博, 藤原 俊義

    日本分子腫瘍マーカー研究会プログラム・講演抄録   40回   72 - 73   2020.9

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  • 骨肉腫に対するp53誘導性腫瘍融解ウイルスを用いたアブスコパル効果・ワクチン効果の誘導

    出宮 光二, 田澤 大, 近藤 宏也, 久禮 美穂, 長谷井 嬢, 中田 英二, 国定 俊之, 藤原 俊義, 尾崎 敏文

    日本整形外科学会雑誌   94 ( 8 )   S1855 - S1855   2020.9

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  • 【肝胆膵外科におけるConversion Surgery】大腸癌肝転移に対するConversion Surgery

    楳田 祐三, 吉田 龍一, 杭瀬 崇, 吉田 一博, 藤原 俊義, 八木 孝仁

    手術   74 ( 10 )   1427 - 1434   2020.9

  • Fibroblast activation protein-α(FAP)を標的とした癌関連線維芽細胞(CAFs)に対する光免疫療法 Sunrise of targeting tumor microenvironment therapy

    小林 照貴, 野間 和広, 赤井 正明, 西脇 紀之, 鳴坂 徹, 河本 慧, 前田 直見, 大原 利章, 田辺 俊介, 田澤 大, 白川 靖博, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   SF - 8   2020.8

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  • 発生学・拡大視局所微細解剖に基づく最新の手術手技【Video】進行横行結腸癌に対する複雑な幅広いD3郭清手技を結腸の成り立ちから理解することにより単純化し定型手術として言語化する

    矢野 修也, 近藤 喜太, 寺石 文則, 黒田 新士, 重安 邦俊, 母里 淑子, 菊池 覚次, 藤本 卓也, 岸本 浩行, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   WS - 5   2020.8

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  • 噴門側胃切除術後再建法-食道残胃吻合 vs 食道空腸吻合-【食道残胃】噴門側胃切除術後標準再建法としての観音開き法再建の可能性

    黒田 新士, 西崎 正彦, 丁田 泰宏, 石田 道拡, 村岡 篤, 田中 則光, 羽藤 慎二, 菊地 覚次, 高田 暢夫, 庄司 良平, 重安 邦俊, 矢野 修也, 近藤 喜太, 田辺 俊介, 野間 和広, 寺石 文則, 香川 俊輔, 白川 靖博, 上川 康明, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   DB - 2   2020.8

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  • 局所進行直腸癌に対する術前治療における放射線治療の意義 放射線療法を併用しない術前化学療法との治療成績の比較

    寺石 文則, 藤本 卓也, 重安 邦俊, 矢野 修也, 近藤 喜太, 香川 俊輔, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   SF - 7   2020.8

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  • 肝内胆管癌における免疫微小環境と治療予後の関連性

    小西 大輔, 吉田 一博, 楳田 祐三, 重安 邦俊, 矢野 修也, 武田 正, 吉田 龍一, 杭瀬 崇, 藤 智和, 安井 和也, 松田 達雄, 田澤 大, 白川 靖博, 八木 孝仁, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   SF - 3   2020.8

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  • 直腸癌に対するtaTMEの意義-あり vs なし-【なし】解剖学的知識と内視鏡技術に卓越しなければtaTMEの意義はない

    近藤 喜太, 重安 邦俊, 矢野 修也, 寺石 文則, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   DB - 3   2020.8

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  • 腹腔内アプローチ困難と予想される症例に対する、taTMEの役割と安全性

    藤本 卓也, 近藤 喜太, 矢野 修也, 重安 邦俊, 母里 淑子, 寺石 文則, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   DP - 2   2020.8

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  • 病的肥満症に対する腹腔鏡下スリーブ状胃切除術導入と初期10例の治療成績

    香川 俊輔, 黒田 新士, 菊地 覚次, 高田 暢夫, 庄司 良平, 西崎 正彦, 寺石 文則, 近藤 喜太, 矢野 修也, 重安 邦俊, 野間 和広, 田辺 俊介, 白川 靖博, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   DP - 5   2020.8

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  • 癌微小環境が引き起こす腫瘍免疫抑制の解明 "Drug repositioning"による免疫応答賦活化の可能性

    西脇 紀之, 野間 和広, 赤井 正明, 小林 照貴, 鳴坂 徹, 河本 慧, 加藤 卓也, 前田 直見, 田辺 俊介, 大原 利章, 田澤 大, 白川 靖博, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   SF - 4   2020.8

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  • Systematic review on immunonutrition in partial pancreatoduodenectomy. International journal

    Kosei Takagi, Yuzo Umeda, Ryuichi Yoshida, Takahito Yagi, Toshiyoshi Fujiwara

    Langenbeck's archives of surgery   405 ( 5 )   585 - 593   2020.8

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    BACKGROUND: The effect of immunonutrition (IM) on postoperative outcomes has been investigated in gastrointestinal cancer surgery; however, strong evidence regarding IM in partial pancreatoduodenectomy (PD) is lacking. This study evaluated the effect of IM on short-term outcomes in patients undergoing PD. METHODS: A systematic literature review of randomized controlled trials was conducted to identify the studies investigating the IM effect on outcomes in PD. Random-effects meta-analyses were conducted to calculate the pooled risk ratio (RR). Studies were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Five studies were included in the meta-analysis. IM was associated with a lower incidence of overall complications (RR 0.74; 95% confidence interval (CI) 0.58, 0.94; P = 0.01; I2 = 0%) and infectious complications (RR 0.60; 95% CI 0.42, 0.84; P = 0.003; I2 = 0%). However, no significant association was noted in the incidence of major complications (RR 0.68; 95% CI 0.41, 1.12; P = 0.13), mortality (RR 0.79; 95% CI 0.16, 3.99; P = 0.78), postoperative pancreatic fistula (RR 0.92, 95% CI 0.59, 1.46; P = 0.74), and delayed gastric emptying (RR 1.09; 95% CI 0.55, 2.15; P = 0.81). CONCLUSIONS: IM administration in PD can prevent the incidence of overall and infectious complications postoperatively (GRADE recommendation: moderate). However, IM has no impact on major complications, mortality, and PD-specific complications (GRADE recommendation: low).

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  • 局所進行下部直腸癌に対する術前化学療法の治療成績

    寺石 文則, 高橋 一剛, 重安 邦俊, 矢野 修也, 母里 淑子, 近藤 喜太, 岸本 浩行, 香川 俊輔, 藤原 俊義

    日本大腸肛門病学会雑誌   73 ( 7 )   341 - 341   2020.7

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  • 肺癌と直腸癌の同時性重複癌にpembrolizumabが著効した1例

    岡 凌也, 寺石 文則, 杉本 龍馬, 武田 正, 垣内 慶彦, 高田 暢夫, 重安 邦俊, 菊地 覚次, 矢野 修也, 近藤 喜太, 黒田 新士, 香川 俊輔, 藤原 俊義

    日本臨床外科学会雑誌   81 ( 6 )   1202 - 1203   2020.6

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  • 整形トピックス 骨肉腫に対する抗PD-1抗体の効果増強をめざした腫瘍融解ウイルス併用複合免疫療法の開発

    望月 雄介, 田澤 大, 出宮 光二, 久禮 美穂, 長谷井 嬢, 中田 英二, 国定 俊之, 浦田 泰生, 藤原 俊義, 尾崎 敏文

    整形外科   71 ( 7 )   786 - 786   2020.6

  • Upregulation of microRNA-31 is associated with poor prognosis in patients with advanced colorectal cancer. International journal

    Nobuhito Kubota, Fumitaka Taniguchi, Akihiro Nyuya, Yuzo Umeda, Yoshiko Mori, Toshiyoshi Fujiwara, Hiroaki Tanioka, Atsushi Tsuruta, Yoshiyuki Yamaguchi, Takeshi Nagasaka

    Oncology letters   19 ( 4 )   2685 - 2694   2020.4

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    Colorectal cancer (CRC) manifests after the accumulation of genetic and epigenetic alterations along with tumor microenvironments. MicroRNA (miRNA/miR) molecules have been revealed to serve in critical roles in the progression various types of cancer, and their expression level is often an important diagnostic, predictive or prognostic biomarker. The aim of the present study was to evaluate the potential of miRNAs as prognostic biomarkers for patients with advanced CRC. miRNA arrays were performed on CRC specimens obtained from tumors with various molecular statuses [e.g. KRAS proto-oncogene, GTPase (KRAS)/B-Raf proto-oncogene, serine/threonine kinase (BRAF)/microsatellite instability (MSI)], and their paired normal mucosal specimens. The miRNA array revealed that miR-31-5p (miR-31) was specifically upregulated in CRCs with the BRAF V600E mutation, the results of which were supported by subsequent analysis of a dataset retrieved from The Cancer Genome Atlas (TCGA) database, which contained information regarding 170 patients with CRC including 51 BRAF-mutant CRCs. Of our cohort of 67 patients with stage IV CRC, 15 (22%) and 4 (6%) showed KRAS and BRAF V600E mutations, respectively. Since the median miR-31 expression was 3.45 (range, 0.004-6330.531), the cut-off value was chosen as 3.5, and all tumors were categorized into two groups accordingly (high-/low-miR-31 expression). The high miR-31 expression group (n=33) was significantly associated with a poorer mortality (univariate hazard ratio=2.12; 95% confidence interval, 0.23-0.95; P=0.03) and exhibited a shorter median survival time (MST; 20.1 months) compared with the low miR-31 expression group (n=34) (MST, 38.3 months; P=0.03), indicating that miR-31 is a promising prognostic biomarker for patients with advanced CRC. Thus, performing a functional analysis of miR-31 expression may lead to the development of new targeted therapies for the various genetic subtypes of CRC.

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  • 術前SOX療法を施行した進行胃癌症例の治療成績(Outcomes of preoperative S-1 plus oxaliplatin(SOX) therapy for advanced gastric cancer)

    香川 俊輔, 黒田 新士, 菊地 覚次, 高田 暢夫, 垣内 慶彦, 武田 正, 野間 和広, 田辺 俊介, 寺石 文則, 近藤 喜太, 矢野 修也, 重安 邦俊, 西崎 正彦, 白川 靖博, 藤原 俊義

    日本胃癌学会総会記事   92回   288 - 288   2020.3

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  • 術前SOX療法を施行した進行胃癌症例の治療成績(Outcomes of preoperative S-1 plus oxaliplatin(SOX) therapy for advanced gastric cancer)

    香川 俊輔, 黒田 新士, 菊地 覚次, 高田 暢夫, 垣内 慶彦, 武田 正, 野間 和広, 田辺 俊介, 寺石 文則, 近藤 喜太, 矢野 修也, 重安 邦俊, 西崎 正彦, 白川 靖博, 藤原 俊義

    日本胃癌学会総会記事   92回   288 - 288   2020.3

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  • Bone and Soft-Tissue Sarcoma: A New Target for Telomerase-Specific Oncolytic Virotherapy. Reviewed International journal

    Hiroshi Tazawa, Joe Hasei, Shuya Yano, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    Cancers   12 ( 2 )   2020.2

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    Adenovirus serotype 5 (Ad5) is widely and frequently used as a virus vector in cancer gene therapy and oncolytic virotherapy. Oncolytic virotherapy is a novel antitumor treatment for inducing lytic cell death in tumor cells without affecting normal cells. Based on the Ad5 genome, we have generated three types of telomerase-specific replication-competent oncolytic adenoviruses: OBP-301 (Telomelysin), green fluorescent protein (GFP)-expressing OBP-401 (TelomeScan), and tumor suppressor p53-armed OBP-702. These viruses drive the expression of the adenoviral E1A and E1B genes under the control of the hTERT (human telomerase reverse transcriptase-encoding gene) promoter, providing tumor-specific virus replication. This review focuses on the therapeutic potential of three hTERT promoter-driven oncolytic adenoviruses against bone and soft-tissue sarcoma cells with telomerase activity. OBP-301 induces the antitumor effect in monotherapy or combination therapy with chemotherapeutic drugs via induction of autophagy and apoptosis. OBP-401 enables visualization of sarcoma cells within normal tissues by serving as a tumor-specific labeling reagent for fluorescence-guided surgery via induction of GFP expression. OBP-702 exhibits a profound antitumor effect in OBP-301-resistant sarcoma cells via activation of the p53 signaling pathway. Taken together, telomerase-specific oncolytic adenoviruses are promising antitumor reagents that are expected to provide novel therapeutic options for the treatment of bone and soft-tissue sarcomas.

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  • Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody. Reviewed International journal

    Nobuhiko Kanaya, Shinji Kuroda, Yoshihiko Kakiuchi, Kento Kumon, Tomoko Tsumura, Masashi Hashimoto, Toshiaki Morihiro, Tetsushi Kubota, Katsuyuki Aoyama, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Hiroyuki Mizuguchi, Yasuo Urata, Toshiyoshi Fujiwara

    Molecular therapy : the journal of the American Society of Gene Therapy   28 ( 3 )   794 - 804   2020.1

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    The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.

    DOI: 10.1016/j.ymthe.2020.01.003

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  • Development of a Novel Oncolytic Adenovirus Expressing a Short-hairpin RNA Against Cullin 4A. International journal

    Keisaku Wakabayashi, Fuminori Sakurai, Ryosuke Ono, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi

    Anticancer research   40 ( 1 )   161 - 168   2020.1

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    BACKGROUND: Arming of an oncolytic adenovirus (OAd) by inserting expression cassettes of therapeutic transgenes into the OAd genome is a promising approach to enhance the therapeutic effects of an OAd. Ideally, this approach would simultaneously promote the replication of an OAd in tumor cells and transgene product-mediated antitumor effects by expressing therapeutic transgenes. We previously demonstrated that knockdown of cullin 4A (CUL4A), which is an E3 ubiquitin ligase, significantly promoted adenovirus replication by increasing the c-JUN protein level. In addition, previous studies reported that CUL4A was highly expressed in various types of tumor, and was involved in tumor growth and metastasis. MATERIALS AND METHODS: In this study, we developed a novel OAd expressing a short-hairpin RNA (shRNA) against CUL4A (OAd-shCUL4A). RESULTS: OAd-shCUL4 mediated higher levels of cytotoxic effects on various types of human tumor cell than a conventional OAd. Higher levels of OAd genome copy numbers were found in the tumor cells for OAd-shCUL4A, compared with a conventional OAd. CONCLUSION: OAd-shCUL4A showed efficient antitumor effects by both enhancing OAd replication and inhibiting tumor cell growth.

    DOI: 10.21873/anticanres.13937

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  • "伝わる"肝胆膵外科手術記録 iPadを用いた効率的で効果的なイラスト作成法

    楳田 祐三, 藤原 俊義

    日本消化器外科学会雑誌   53 ( 1 )   105 - 115   2020.1

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    手術記録は,診療情報にとどまらず,外科修練における研鑽,医療チーム内での手術情報の共有,そして紹介医へのfeed-backと,その意義は大きい.今回,iPadを用いた効率的で効果的なイラスト作成を中心に,我々が実践している"伝わる"肝胆膵外科手術記録の作成法を紹介する.従来の手描き法と異なり,iPad/Apple pencil/描画アプリを用いることで,自由な描き直し,レイヤー機能や多岐にわたる着色ツール,拡大・縮小機能による微細描画や着色時間の短縮,イラストパーツの貼付など,効率的で効果的なイラストの作成が可能となる.外科修練において,繰り返し手術イラストの作成に取り組むことは,観察力を養い,解剖構造の理解を深め,手術の本質を理解し修得するのに有用である.症例からの学びと反省,患者さん,そして紹介医の患者さんへの思い入れに報いるためにも,手術のみならず,外科医の想いが"伝わる"手術記録の作成に,外科医は一例入魂の精神で臨むことが望まれる.(著者抄録)

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01117&link_issn=&doc_id=20200131210016&doc_link_id=10.5833%2Fjjgs.2020.sr005&url=https%3A%2F%2Fdoi.org%2F10.5833%2Fjjgs.2020.sr005&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • Short-term and long-term comparisons of laparoscopy-assisted proximal gastrectomy with esophagogastrostomy by the double-flap technique and laparoscopy-assisted total gastrectomy for proximal gastric cancer. International journal

    Tomoko Tsumura, Shinji Kuroda, Masahiko Nishizaki, Satoru Kikuchi, Yoshihiko Kakiuchi, Nobuo Takata, Atene Ito, Megumi Watanabe, Kazuya Kuwada, Shunsuke Kagawa, Toshiyoshi Fujiwara

    PloS one   15 ( 11 )   e0242223   2020

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    BACKGROUND: Although proximal gastrectomy (PG) is a recognized surgical procedure for early proximal gastric cancer, total gastrectomy (TG) is sometimes selected due to concern about severe gastroesophageal reflux. Esophagogastrostomy by the double-flap technique (DFT) is an anti-reflux reconstruction after PG, and its short-term effectiveness has been reported. However, little is known about the long-term effects on nutritional status and quality of life (QOL). METHODS: Gastric cancer patients who underwent laparoscopy-assisted PG (LAPG) with DFT or laparoscopy-assisted TG (LATG) between April 2011 and March 2014 were retrospectively analyzed. Body weight (BW), body mass index (BMI), and prognostic nutritional index (PNI) were reviewed to assess nutritional status, and the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45 was used to assess QOL. RESULTS: A total of 36 patients (LATG: 17, LAPG: 19) were enrolled. Four of 17 LATG patients (24%) were diagnosed with Stage ≥II after surgery, and half received S-1 adjuvant chemotherapy. BW and PNI were better maintained in LAPG than in LATG patients until 1-year follow-up. Seven of 16 LATG patients (44%) were categorized as "underweight (BMI<18.5 kg/m2)" at 1-year follow-up, compared to three of 18 LAPG patients (17%; p = 0.0836). The PGSAS-45 showed no significant difference in all QOL categories except for decreased BW (p = 0.0132). Multivariate analysis showed that LATG was the only potential risk factor for severe BW loss (odds ratio: 3.03, p = 0.0722). CONCLUSIONS: LAPG with DFT was superior to LATG in postoperative nutritional maintenance, and can be the first option for early proximal gastric cancer.

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  • Efficacy of surgical management for recurrent intrahepatic cholangiocarcinoma: A multi-institutional study by the Okayama Study Group of HBP surgery. International journal

    Toru Kojima, Yuzo Umeda, Tomokazu Fuji, Takefumi Niguma, Daisuke Sato, Yoshikatsu Endo, Kenta Sui, Masaru Inagaki, Masahiro Oishi, Tetsuya Ota, Katsuyoshi Hioki, Tadakazu Matsuda, Hideki Aoki, Ryuji Hirai, Masashi Kimura, Takahito Yagi, Toshiyoshi Fujiwara

    PloS one   15 ( 9 )   e0238392   2020

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    BACKGROUND: The prognosis of intrahepatic cholangiocarcinoma (ICC) has been poor, because of the high recurrence rate even after curative surgery. This study aimed to evaluate the prognostic impact of surgical resection of recurrent ICC. PATIENTS AND METHODS: A total of 345 cases of ICC who underwent hepatectomy with curative intent in 17 institutions were retrospectively analyzed, focusing on recurrence patterns and treatment modalities for recurrent ICC. RESULTS: Median survival time and overall 5-year recurrence-free survival rate were 17.8 months and 28.5%, respectively. Recurrences (n = 223) were classified as early (recurrence at ≤1 year, n = 131) or late (recurrence at >1 year, n = 92). Median survival time was poorer for early recurrence (16.3 months) than for late recurrence (47.7 months, p<0.0001). Treatment modalities for recurrence comprised surgical resection (n = 28), non-surgical treatment (n = 134), and best supportive care (BSC) (n = 61). Median and overall 1-/5-year survival rates after recurrence were 39.5 months and 84.6%/36.3% for surgical resection, 14.3 months and 62.5%/2.9% for non-surgical treatment, and 3 months and 4.8%/0% for BSC, respectively (p<0.0001). Multivariate analysis identified early recurrence, simultaneous intra- and extrahepatic recurrence, and surgical resection of recurrence as significant prognostic factors. In subgroup analyses, surgical resection may have positive prognostic impacts on intra- and extrahepatic recurrences, and even on early recurrence. However, simultaneous intra- and extrahepatic recurrence may not see any survival benefit from surgical management. CONCLUSION: Surgical resection of recurrent ICC could improve survival after recurrence, especially for patients with intra- or extrahepatic recurrence as resectable oligo-metastases.

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  • Laparoscopic liver resection of segment seven: A case report and review of surgical techniques. International journal

    Kosei Takagi, Takashi Kuise, Yuzo Umeda, Ryuichi Yoshida, Fuminori Teraishi, Takahito Yagi, Toshiyoshi Fujiwara

    International journal of surgery case reports   73   168 - 171   2020

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    INTRODUCTION: Laparoscopic liver resection of segment seven (LLR-S7) is a technically challenging procedure due to its anatomical location and difficult accessibility. Herein, we present our experience with LLR-S7, and demonstrate a literature review regarding surgical techniques. PRESENTATION OF CASE: A 28-year-old female was diagnosed with rectosigmoid cancer and synchronous liver metastases at the segment three (S3) and S7, which were treated with laparoscopic procedure. After the completely mobilization of the right lobe, the Glissonean pedicle of S7 (G7) was intrahepatically transected. The right hepatic vein was exposed to identify the venous branch of S7 (V7). Finally the liver parenchyma between RHV and dissection line was divided. DISCUSSION: Various laparoscopic approaches for S7 have been reported including the Glissonian approach from the hilum, the intrahepatic Glissonean approach, the caudate lobe first approach, and the lateral approach from intercostal ports. To perform LLR-S7 safely, it is important to understand the advantage of each technique including the trocar placement and approaches to S7 by laparoscopy. CONCLUSION: We present our experience of LLR-S7 for the tumor located at the top of S7, successfully performed with the intrahepatic Glissonean approach. LLR-S7 can be performed safely with advanced laparoscopic techniques and sufficient knowledge on various approaches for S7.

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  • A novel modified hanging maneuver in laparoscopic left hemihepatectomy. International journal

    Kosei Takagi, Yuzo Umeda, Takashi Kuise, Ryuichi Yoshida, Kazuhiro Yoshida, Kazuya Yasui, Yuma Tani, Takahito Yagi, Toshiyoshi Fujiwara

    International journal of surgery case reports   76   251 - 253   2020

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    INTRODUCTION: The liver hanging maneuver is an essential technique for controlling bleeding in hepatectomy, however it is often difficult in laparoscopic major hepatectomy. The present study describes a novel modified hanging maneuver in laparoscopic left hemihepatectomy. PRESENTATION OF CASE: A 29-year-old female underwent laparoscopic left hemihepatectomy for mucinous cystic neoplasm. After mobilizing the left lobe, the liver parenchyma was dissected along the demarcation line. For the hanging technique, the upper edge of the hanging tape was placed on the lateral side of the left hepatic vein, and fixed with the Falciform ligament. The lower edge of the tape was extracted outside the abdomen. Accordingly the hanging tape can be controlled extraperitoneally during the liver parenchyma dissection. DISCUSSION: This technique includes several advantages including no need of assistance using forceps, easy control of the hanging tape extraperitoneally, outflow control, better exposure of surgical field, and helpful guide of the liver dissection line toward the root of the left hepatic vein. CONCLUSION: Our novel modified hanging maneuver is easy and reproducible to use in laparoscopic left hemihepatectomy. Moreover, this technique can be applied to other laparoscopic hepatectomy.

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  • 直腸癌腹腔鏡手術における縫合不全と回腸人工肛門合併症の因果関係についての検討 Reviewed

    重安 邦俊, 母里 淑子, 矢野 修也, 近藤 喜太, 寺石 文則, 香川 俊輔, 藤原 俊義

    日本内視鏡外科学会雑誌   24 ( 7 )   SF055 - 6   2019.12

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  • Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network. Reviewed International journal

    Ieda T, Tazawa H, Okabayashi H, Yano S, Shigeyasu K, Kuroda S, Ohara T, Noma K, Kishimoto H, Nishizaki M, Kagawa S, Shirakawa Y, Saitou T, Imamura T, Fujiwara T

    Scientific reports   9 ( 1 )   16378 - 16378   2019.11

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    Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remains unclear. Here, we show the spatiotemporal visualization of CRC cells undergoing EMT using a fluorescence-guided EMT imaging system in which the mesenchymal vimentin promoter drives red fluorescent protein (RFP) expression. An inflammatory microenvironment including TNF-α, IL-1β, and cytokine-secreting inflammatory macrophages induced RFP expression in association with the EMT phenotype in CRC cells. In vivo experiments further demonstrated the distribution of RFP-positive CRC cells in rectal and metastatic tumors. Our data suggest that the EMT imaging system described here is a powerful tool for monitoring EMT in inflammatory microenvironment-CRC networks.

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  • Comparison of the Effects of Epidural Analgesia and Patient-controlled Intravenous Analgesia on Postoperative Pain Relief and Recovery After Laparoscopic Gastrectomy for Gastric Cancer. International journal

    Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Takashi Matsusaki, Kazuya Kuwada, Yoshikazu Kimura, Shunsuke Kagawa, Hiroshi Morimatsu, Toshiyoshi Fujiwara

    Surgical laparoscopy, endoscopy & percutaneous techniques   29 ( 5 )   405 - 408   2019.10

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    PURPOSE: Epidural analgesia (EDA) is an imperative modality for postoperative pain relief after major open abdominal surgery. However, whether EDA has benefits in laparoscopic surgery has not been clear. In this study, the effects of EDA and patient-controlled intravenous analgesia (PCIA) after laparoscopic distal gastrectomy (LDG) were compared. METHODS: This was a retrospective study that included 82 patients undergoing LDG for gastric cancer. Patients received either EDA (n=67) or PCIA (n=15) for postoperative pain relief. Postoperative outcomes and analgesia-related adverse events were compared between the two modalities. RESULTS: EDA and PCIA patients showed no differences in the incidence of complications [9 (13%) vs. 2 (13%); P=0.99] and the length of postoperative hospital stay (9.6±4.5 d vs. 9.7±4.0 d; P=0.90), although the PCIA included poorer preoperative physical status (PS) patients. The number of additional doses of analgesics was higher in the EDA than in the PCIA (1.8±2.4 vs. 0.9±1.0; P=0.01), although postoperative pain scores were similar in the 2 groups. Though the time to first passage of flatus was shorter in the EDA (P<0.05), more EDA patients developed postoperative hypotension as an adverse event (P<0.01). The full mobilization day and the day of oral intake tolerance were not significantly different between the 2 groups after surgery. CONCLUSIONS: After LDG, EDA may not be indispensable, while PCIA may be the optimal modality for providing safe and effective postoperative analgesia and recovery.

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  • 鉄キレート剤による幹細胞性制御による新規食道癌治療法(Stemness control by iron chelator is a novel therapeutic strategy for esophageal cancer treatment) Reviewed

    鳴坂 徹, 大原 利章, 桂 佑貴, 野間 和広, 西脇 紀之, 河本 慧, 田澤 大, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   78回   P - 1077   2019.9

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  • がん関連線維芽細胞(CAFs)による腫瘍免疫抑制のメカニズムについて(Exploring the mechanism of cancer-associated fibroblasts(CAFs) induced immunosuppression in tumor microenvironment) Reviewed

    西脇 紀之, 野間 和広, 小林 照貴, 鳴坂 徹, 河本 慧, 大原 利章, 田澤 大, 藤原 俊義

    日本癌学会総会記事   78回   P - 3083   2019.9

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  • 骨肉腫に対する抗PD-1抗体と腫瘍融解アデノウイルスの複合免疫療法

    望月 雄介, 田澤 大, 出宮 光二, 久禮 美穂, 長谷井 嬢, 中田 英二, 国定 俊之, 浦田 泰生, 藤原 俊義, 尾崎 敏文

    日本整形外科学会雑誌   93 ( 8 )   S1672 - S1672   2019.9

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  • 骨肉腫に対するp53誘導性腫瘍融解ウイルス療法のアブスコパル効果

    出宮 光二, 田澤 大, 久禮 美穂, 望月 雄介, 長谷井 嬢, 中田 英二, 国定 俊之, 浦田 泰生, 藤原 俊義, 尾崎 敏文

    日本整形外科学会雑誌   93 ( 8 )   S1673 - S1673   2019.9

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  • 骨肉腫に対するテロメラーゼ特異的腫瘍融解ウイルスを用いた複合免疫療法(Combination immunotherapy with telomerase-specific oncolytic adenovirus for osteosarcoma)

    出宮 光二, 田澤 大, 望月 雄介, 久禮 美穂, 近藤 宏也, 長谷井 嬢, 国定 俊之, 浦田 泰生, 尾崎 敏文, 藤原 俊義

    日本癌学会総会記事   78回   J - 1001   2019.9

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  • 【肝内胆管癌のすべて】リンパ節郭清の意義

    稲垣 優, 楳田 祐三, 八木 孝仁, 藤原 俊義

    消化器外科   42 ( 10 )   1417 - 1426   2019.9

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  • 化学放射線療法は線維芽細胞の活性化を介して食道癌細胞の悪性度を向上させる(Chemoradiotherapy promotes malignancy of cancer cells via activating fibroblasts in esophageal squamous cell carcinomas) Reviewed

    河本 慧, 野間 和広, 小林 照貴, 西脇 紀之, 鳴坂 徹, 大原 利章, 田澤 大, 藤原 俊義

    日本癌学会総会記事   78回   E - 1038   2019.9

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  • Endoscopic Ultrasound-Guided Transgastric Drainage of an IntraAbdominal Abscess following Gastrectomy. International journal

    Satoru Kikuchi, Tetsushi Kubota, Shinji Kuroda, Masahiko Nishizaki, Shunsuke Kagawa, Hironari Kato, Hiroyuki Okada, Toshiyoshi Fujiwara

    Clinical endoscopy   52 ( 4 )   373 - 376   2019.7

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    Endoscopic ultrasound (EUS)-guided transgastric drainage has been performed as a less invasive procedure for pancreatic fistulas and intra-abdominal abscesses occurring after surgery in recent years. However, there are no reports of EUS-guided transgastric drainage of intra-abdominal abscesses following gastrectomy. This case report describes 2 patients who developed an intra-abdominal abscess following gastrectomy and underwent EUS-guided transgastric drainage. Both patients underwent laparoscopy-assisted distal gastrectomy with Billroth-I reconstruction for gastric cancer. The intra-abdominal abscesses were caused by postoperative pancreatic fistula that developed following gastrectomy. One patient underwent naso-cystic drainage and the other underwent only a needle puncture of the abscess cavity. EUS-guided drainage was performed safely and effectively, although 1 patient developed gastroduodenal anastomotic leakage related to this procedure. In summary, EUS-guided transgastric drainage is safe and technically feasible even in post-gastrectomy patients. However, it is necessary to be careful if this procedure is performed in the early period following gastrectomy.

    DOI: 10.5946/ce.2018.134

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  • 【大腸】ストーマ造設法と閉鎖法の工夫 回腸双孔式人工肛門の2大合併症である閉塞とhigh output stomaのリスク因子同定と回避のための工夫 Reviewed

    重安 邦俊, 矢野 修也, 母里 淑子, 近藤 喜太, 岸本 浩行, 寺石 文則, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本消化器外科学会総会   74回   WS10 - 6   2019.7

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  • Clinical Impact of Sarcopenia on Gastric Cancer. International journal

    Kazuya Kuwada, Shinji Kuroda, Satoru Kikuchi, Ryuichi Yoshida, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Anticancer research   39 ( 5 )   2241 - 2249   2019.5

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    Sarcopenia is a complex syndrome defined by progressive and generalized loss of skeletal muscle mass and strength. Although sarcopenia is mainly associated with aging, cancer is also one of its causes. Sarcopenia is now drawing attention as a poor prognostic factor in cancer. In patients with gastric cancer associated with eating disorders that often leads to loss of weight and muscle, sarcopenia is particularly important. Its definition and method of assessment, however, vary between studies, thus these need to be standardized. Nevertheless, emerging evidence suggests that sarcopenia contributes independently to postoperative complications and overall survival in gastric cancer. Interventions preventing sarcopenia with targeted nutrition and exercise are currently explored. This review aims to provide an understanding of sarcopenia, emphasizing its importance in the management of gastric cancer.

    DOI: 10.21873/anticanres.13340

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  • 岡山大学病院における大腸癌エキスパートパネル診療

    母里 淑子, 矢野 修也, 遠西 大輔, 田端 雅弘, 柳井 広之, 豊岡 伸一, 平沢 晃, 藤原 俊義

    日本外科学会定期学術集会抄録集   119回   PS - 1   2019.4

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  • PD-L1 expression combined with microsatellite instability/CD8+ tumor infiltrating lymphocytes as a useful prognostic biomarker in gastric cancer. Reviewed International journal

    Toshiaki Morihiro, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Tetsushi Kubota, Katsuyuki Aoyama, Takehiro Tanaka, Satoru Kikuchi, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara

    Scientific reports   9 ( 1 )   4633 - 4633   2019.3

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    While the importance of programmed death-ligand 1 (PD-L1), mutation burden caused by microsatellite instability (MSI), and CD8+ tumor infiltrating lymphocytes (TILs) has become evident, the significance of PD-L1 expression on prognosis still remains controversial. We evaluated the usefulness of combined markers of PD-L1 and MSI or CD8+ TILs as a prognostic biomarker in gastric cancer. A total of 283 patients with gastric cancer were reviewed retrospectively. PD-L1 expression on >5% tumor cells was defined as PD-L1-positive. PD-L1-positive rate was 15.5% (44/283). PD-L1 positivity was significantly correlated with invasive and advanced cancer and also significantly correlated with MSI, whereas no significance was observed with CD8+ TILs. Kaplan-Meier analysis showed that PD-L1 positivity significantly correlated with a poor prognosis (p = 0.0025). Multivariate analysis revealed that PD-L1 positivity was an independent poor prognostic factor (hazard ratio [HR]: 1.97, p = 0.0106) along with diffuse histological type and lymph node metastases. Combinations of PD-L1 and MSI (HR: 2.18) or CD8+ TILs (HR: 2.57) were stronger predictive factors for prognosis than PD-L1 alone. In conclusion, combined markers of PD-L1 and MSI or CD8+ TILs may be more useful prognostic biomarkers in gastric cancer, and better clarify the immune status of gastric cancer patients.

    DOI: 10.1038/s41598-019-41177-2

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  • Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer. Reviewed

    Takeda S, Shigeyasu K, Okugawa Y, Yoshida K, Mori Y, Yano S, Noma K, Umeda Y, Kondo Y, Kishimoto H, Teraishi F, Nagasaka T, Tazawa H, Kagawa S, Fujiwara T, Goel A

    Cancer letters   444   127 - 135   2019.3

  • 多発筋炎/皮膚筋炎でみつかった直腸癌の一例 Reviewed

    重安 邦俊, 母里 淑子, 三村 直毅, 小松 泰浩, 戸嶋 俊明, 矢野 修也, 近藤 喜太, 岸本 浩行, 寺石 文則, 香川 俊輔, 藤原 俊義

    日本臨床外科学会雑誌   80 ( 3 )   607 - 607   2019.3

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  • A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness. Reviewed International journal

    Yuki Katsura, Toshiaki Ohara, Kazuhiro Noma, Takayuki Ninomiya, Hajime Kashima, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Toru Narusaka, Yasuko Tomono, Boyi Xing, Yuehua Chen, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

    Cancers   11 ( 2 )   2019.2

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    Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

    DOI: 10.3390/cancers11020177

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  • Multicenter retrospective study to evaluate the efficacy and safety of the double-flap technique as antireflux esophagogastrostomy after proximal gastrectomy (rD-FLAP Study).

    Shinji Kuroda, Yasuhiro Choda, Shinya Otsuka, Satoshi Ueyama, Norimitsu Tanaka, Atsushi Muraoka, Shinji Hato, Toshikazu Kimura, Kohji Tanakaya, Satoru Kikuchi, Shunsuke Tanabe, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yasuhiro Shirakawa, Yasuaki Kamikawa, Toshiyoshi Fujiwara

    Annals of gastroenterological surgery   3 ( 1 )   96 - 103   2019.1

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    Aim: As a result of the difficulty in effective prevention of gastroesophageal reflux, no standard reconstruction procedure after proximal gastrectomy (PG) has yet been established. The double-flap technique (DFT), or Kamikawa procedure, is an antireflux reconstruction procedure in esophagogastrostomy. The efficacy of DFT has recently been reported in several studies. However, these were all single-center studies with a limited number of cases. Methods: We conducted a multicenter retrospective study in which patients who underwent DFT, irrespective of disease type and reconstruction approach, at each participating institution between 1996 and 2015 were registered. Primary endpoint was incidence of reflux esophagitis at 1-year after surgery, and secondary endpoint was incidence of anastomosis-related complications. Results: Of 546 patients who were eligible for this study, 464 patients who had endoscopic examination at 1-year follow up were evaluated for reflux esophagitis. Incidence of reflux esophagitis of all grades was 10.6% and that of grade B or higher was 6.0%. Male gender and anastomosis located in the mediastinum/intra-thorax were independent risk factors for grade B or higher reflux esophagitis (odds ratio [OR]: 4.21, 95% confidence interval [CI]: 1.44-10.9, P = 0.0109). Total incidence of anastomosis-related complications was 7.2%, including leakage in 1.5%, strictures in 5.5% and bleeding in 0.6% of cases. Laparoscopic reconstruction was the only independent risk factor for anastomosis-related complications (OR: 3.93, 95% CI: 1.93-7.80, P = 0.0003). Conclusion: Double-flap technique might be a feasible option after PG for effective prevention of reflux, although anastomotic stricture is a complication that must be well-prepared for.

    DOI: 10.1002/ags3.12216

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  • Photoimmunotherapy for cancer-associated fibroblasts targeting fibroblast activation protein in human esophageal squamous cell carcinoma. Reviewed International journal

    Shinichiro Watanabe, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Shinichi Urano, Ryoichi Katsube, Yuuri Hashimoto, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

    Cancer biology & therapy   20 ( 9 )   1234 - 1248   2019

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    Cancer-associated fibroblasts (CAFs) are strongly implicated in tumor progression, including in the processes of tumorigenesis, invasion, and metastasis. The targeting of CAFs using various therapeutic approaches is a novel treatment strategy; however, the efficacy of such therapies remains limited. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a novel targeted therapy employing a cell-specific mAb conjugated to a photosensitizer, has been introduced as a new type of phototherapy. In this study, we have developed a novel NIR-PIT technique to target CAFs, by focusing on fibroblast activation protein (FAP), and we evaluate the treatment efficacy in vitro and in vivo. Esophageal carcinoma cells exhibited enhanced activation of fibroblasts, with FAP over-expressed in the cytoplasm and on the cell surface. FAP-IR700-mediated PIT showed induced rapid cell death specifically for those cells in vitro and in vivo, without adverse effects. This novel therapy for CAFs, designed as local control phototherapy, was safe and showed a promising inhibitory effect on FAP+ CAFs. PIT targeting CAFs via the specific marker FAP may be a therapeutic option for CAFs in the tumor microenvironment in the future.

    DOI: 10.1080/15384047.2019.1617566

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  • Intraperitoneal cancer-immune microenvironment promotes peritoneal dissemination of gastric cancer. Reviewed International journal

    Shuichi Sakamoto, Shunsuke Kagawa, Kazuya Kuwada, Atene Ito, Hiroki Kajioka, Yoshihiko Kakiuchi, Megumi Watanabe, Tetsuya Kagawa, Ryuichi Yoshida, Satoru Kikuchi, Shinji Kuroda, Hiroshi Tazawa, Toshiyoshi Fujiwara

    Oncoimmunology   8 ( 12 )   e1671760   2019

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    A solid tumor consists of cancer and stromal cells, which comprise the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are usually abundant in the TME, contributing to tumor progression. In cases of peritoneal dissemination of gastric cancer (GC), the contribution of intraperitoneal TAMs remains unclear. Macrophages from peritoneal washings of GC patients were analyzed, and the link between intraperitoneal TAMs and GC cells was investigated to clarify the interaction between them in peritoneal dissemination. Macrophages were predominant among leukocytes constituting the microenvironment of the peritoneal cavity. The proportion of CD163-positive TAMs was significantly higher in stage IV than in stage I GC. Co-culture with TAMs potentiated migration and invasion of GC. IL-6 was the most increased in the medium of in vitro co-culture of macrophages and GC, and IL-6 elevation was also observed in the peritoneal washes with peritoneal dissemination. An elevated concentration of intraperitoneal IL-6 was correlated with a poor prognosis in clinical cases. In conclusion, intraperitoneal TAMs are involved in promoting peritoneal dissemination of GC via secreted IL-6. TAM-derived IL-6 could be a potential therapeutic target for peritoneal dissemination of GC.

    DOI: 10.1080/2162402X.2019.1671760

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  • The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer. Reviewed

    Kuwada K, Kagawa S, Yoshida R, Sakamoto S, Ito A, Watanabe M, Ieda T, Kuroda S, Kikuchi S, Tazawa H, Fujiwara T

    Journal of experimental & clinical cancer research : CR   37 ( 1 )   307   2018.12

  • Cancer-Associated Fibroblasts Affect Intratumoral CD8(+) and FoxP3(+) T Cells Via IL6 in the Tumor Microenvironment Reviewed

    Kato Takuya, Noma Kazuhiro, Ohara Toshiaki, Kashima Hajime, Katsura Yuki, Sato Hiroaki, Komoto Satoshi, Katsube Ryoichi, Ninomiya Takayuki, Tazawa Hiroshi, Shirakawa Yasuhiro, Fujiwara Toshiyoshi

    CLINICAL CANCER RESEARCH   24 ( 19 )   4820 - 4833   2018.10

  • Cancer-associated fibroblasts (CAFs) promote the lymph node metastasis of esophageal squamous cell carcinoma. Reviewed

    Kashima H, Noma K, Ohara T, Kato T, Katsura Y, Komoto S, Sato H, Katsube R, Ninomiya T, Tazawa H, Shirakawa Y, Fujiwara T

    International journal of cancer   144 ( 4 )   828 - 840   2018.10

  • Integrated fluorescent cytology with nano-biologics in peritoneally disseminated gastric cancer. Reviewed

    Watanabe M, Kagawa S, Kuwada K, Hashimoto Y, Shigeyasu K, Ishida M, Sakamoto S, Ito A, Kikuchi S, Kuroda S, Kishimoto H, Tomida S, Yoshida R, Tazawa H, Urata Y, Fujiwara T

    Cancer science   109 ( 10 )   3263 - 3271   2018.10

  • [The Elucidation of Tumor Immunosuppression Affected by Cancer-Associated Fibroblasts]. Reviewed

    Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hiroaki Sato, Satoshi Kohmoto, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    Gan to kagaku ryoho. Cancer & chemotherapy   45 ( 9 )   1279 - 1281   2018.9

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    Development of immunotherapy, especially checkpoint inhibitors, dramatically improved the prognosis of some malignancies. However, problems on the occurrence of severe adverse effects and limited responses to these checkpoint inhibitors remain. Recently, tumor infiltrating lymphocytes(TILs)are the predictive markers of immunotherapies based on clinical evidence. The proportion of cytotoxic T cells in the tumor has been reported to affect the antitumor effect. TILs in the tumor are thought to be controlled by the interaction between cancer and tumor microenvironment. As a cause of tumor immunosuppression, cancer-associated fibroblasts(CAFs)play the main role in the tumor microenvironment. We considered the strong involvement of tumor microenvironment, particularly the role of CAFs, and reported the interaction between CAFs and proliferation, invasion, angiogenesis, and resistance in the conventional therapy. The correlation between CAFs and tumor immunity and the immunosuppression promoted by CAFs were also evaluated. Their effects will be reported in our future studies.

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  • 炎症性微小環境-大腸がんクロストークにおけるEMTイメージング(Visualization of epithelial-mesenchymal transition in inflammatory microenvironment-colorectal cancer crosstalk) Reviewed

    田澤 大, 家田 偉史, 矢野 修也, 重安 邦俊, 黒田 新士, 大原 利章, 野間 和広, 岸本 浩行, 西崎 正彦, 香川 俊輔, 斎藤 卓, 今村 健志, 藤原 俊義

    日本癌学会総会記事   77回   1204 - 1204   2018.9

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  • 消化管がん治療の新展開 食道癌におけるがん細胞及びがん関連線維芽細胞に対するDual-targeting Photoimmunotherapy(Developments in gastrointestinal cancer treatments Dual-targeting Photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in tumor microenvironment) Reviewed

    佐藤 浩明, 野間 和広, 鳴坂 徹, 河本 慧, 大原 利章, 田澤 大, 藤原 俊義

    日本癌学会総会記事   77回   96 - 96   2018.9

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  • 癌関連線維芽細胞が放出するIL-6が腫瘍内に浸潤するCD8+ならびにFoxP3+T細胞に影響を与える(Cancer-associated fibroblasts affect the intra-tumoral infiltration of CD8+ and FoxP3+ T cells via IL-6)

    加藤 卓也, 野間 和広, 佐藤 浩明, 河本 慧, 大原 利章, 田澤 大, 白川 靖博, 藤原 俊義

    日本癌学会総会記事   77回   1860 - 1860   2018.9

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  • 骨肉腫に対する抗PD-1抗体とテロメラーゼ特異的ウイルス療法による新規治療戦略(Novel therapeutic strategy with anti-PD-1 antibody and telomerase-specific oncolytic virotherapy in osteosarcoma)

    望月 雄介, 田澤 大, 出宮 光二, 小松原 将, 杉生 和久, 長谷井 嬢, 国定 俊之, 浦田 泰生, 尾崎 敏文, 藤原 俊義

    日本癌学会総会記事   77回   1813 - 1813   2018.9

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  • HER増幅胃癌におけるアファチニブ耐性機序(Acquired resistant mechanism to afatinib in HER2 amplified gastric cancer cells)

    吉岡 貴裕, 枝園 和彦, 難波 圭, 冨田 秀太, 山本 寛斉, 宗 淳一, 藤原 俊義, 豊岡 伸一

    日本癌学会総会記事   77回   1449 - 1449   2018.9

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  • p53誘導性腫瘍融解ウイルス療法は骨肉腫に強力な免疫原性細胞死を誘導する(Oncolytic adenoviral therapy with p53 transactivation induces profound immunogenic cell death in osteosarcoma)

    出宮 光二, 田澤 大, 望月 雄介, 小松原 将, 杉生 和久, 長谷井 嬢, 国定 俊之, 浦田 泰生, 尾崎 敏文, 藤原 俊義

    日本癌学会総会記事   77回   2251 - 2251   2018.9

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  • 鉄キレート剤の幹細胞性制御による新規癌治療法(Stemness control by iron chelator is a novel strategy for cancer treatment) Reviewed

    大原 利章, 桂 佑貴, 野間 和広, 鳴坂 徹, 佐藤 浩明, 河本 慧, 加藤 卓也, 田澤 大, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   77回   2318 - 2318   2018.9

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  • 癌関連線維芽細胞が及ぼす腫瘍免疫逃避の解明 Reviewed

    加藤 卓也, 野間 和広, 桂 佑貴, 佐藤 浩明, 河本 慧, 二宮 卓之, 大原 利章, 田澤 大, 香川 俊輔, 白川 靖博, 藤原 俊義

    癌と化学療法   45 ( 9 )   1279 - 1281   2018.9

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    近年、免疫チェックポイント阻害薬をはじめがん免疫療法の発展により、飛躍的に予後の改善を認める癌腫が散見される。しかしながら、致命的な有害事象の発生や効果の得られる症例が限定的であることなど、克服すべき問題点も指摘されている。免疫チェックポイント阻害薬の治療効果予測因子として腫瘍浸潤リンパ球が注目されており、特に細胞傷害性T細胞の腫瘍内浸潤の程度が抗腫瘍効果に影響を与えていると報告されている。リンパ球の腫瘍浸潤においては、癌とがん微小環境の相互作用によって制御している可能性が指摘されている。そのなかで中心的な役割を担っている癌関連線維芽細胞(cancer-associated fibroblasts:CAFs)が注目されている。以前よりわれわれは、がん微小環境の強い関与を推測し、特にCAFsの作用に注目して癌の増殖・浸潤・血管新生・治療抵抗性について報告してきた。この度CAFsと腫瘍免疫に着目し、CAFsが寄与する腫瘍免疫抑制について検討している。今後、検討結果を随時報告する予定である。(著者抄録)

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  • ストーマ造設と管理における諸問題 回腸人工肛門狭窄のリスク因子の抽出と予防 Reviewed

    重安 邦俊, 母里 淑子, 戸嶋 俊明, 矢野 修也, 近藤 喜太, 岸本 浩行, 寺石 文則, 藤原 俊義

    日本大腸肛門病学会雑誌   71 ( 抄録号 )   A61 - A61   2018.9

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  • HER2-targeted gold nanoparticles potentially overcome resistance to trastuzumab in gastric cancer Reviewed International journal

    Kubota Tetsushi, Kuroda Shinji, Kanaya Nobuhiko, Morihiro Toshiaki, Aoyama Katsuyuki, Kakiuchi Yoshihiko, Kikuchi Satoru, Nishizaki Masahiko, Kagawa Shunsuke, Tazawa Hiroshi, Fujiwara Toshiyoshi

    NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE   14 ( 6 )   1919 - 1929   2018.8

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    An issue of concern is that no current HER2-targeted therapeutic agent is effective against Trastuzumab (Tmab)-resistant gastric cancer. Gold nanoparticles (AuNPs) are promising drug carriers with unique characteristics of a large surface area available for attachment of materials such as antibodies. Here, we created HER2-targeted AuNPs (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines. In vitro, T-AuNPs showed stronger cytotoxic effects than controls against MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy played an important role in T-AuNP cytotoxic mechanisms, which was considered to be driven by internalization of T-AuNPs. Finally, T-AuNPs displayed potent antitumor effects against NCI-N87 and MKN7 subcutaneous tumors in in vivo mouse models. In conclusion, HER2-targeted AuNPs with conjugated Tmab is a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.

    DOI: 10.1016/j.nano.2018.05.019

    Web of Science

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  • Heterogeneity of Epigenetic and Epithelial Mesenchymal Transition Marks in Hepatocellular Carcinoma with Keratin 19 Proficiency Reviewed

    Naosuke Yokomichi, Naoshi Nishida, Yuzo Umeda, Fumitaka Taniguchi, Kazuya Yasui, Toshiaki Toshima, Yoshiko Mori, Akihiro Nyuya, Takehiro Tanaka, Takeshi Yamada, Takahito Yagi, Toshiyoshi Fujiwara, Yoshiyuki Yamaguchi, Ajay Goel, Masatoshi Kudo, Takeshi Nagasaka

    Liver Cancer   2018.8

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  • 癌関連線維芽細胞が引き起こす腫瘍免疫抑制の解明 腫瘍浸潤リンパ球とIL-6と代謝の観点から Reviewed

    加藤 卓也, 野間 和広, 賀島 肇, 桂 佑貴, 佐藤 浩明, 河本 慧, 二宮 卓之, 大原 利章, 田澤 大, 白川 靖博, 稲垣 優, 岩垣 博巳, 藤原 俊義

    日本がん免疫学会総会プログラム・抄録集   22回   95 - 95   2018.7

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  • NCCNガイドラインにおける消化管神経内分泌腫瘍の内視鏡切除・手術適応の妥当性の検討 Reviewed

    重安 邦俊, 母里 淑子, 戸嶋 俊明, 矢野 修也, 近藤 喜太, 浅野 博昭, 岸本 浩行, 寺石 文則, 香川 俊輔, 藤原 俊義

    日本消化器外科学会総会   73回   496 - 496   2018.7

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  • The Outcome of Complex Hepato-Pancreato-Biliary Surgery for Elderly Patients: A Propensity Score Matching Analysis. Reviewed

    Takagi K, Umeda Y, Yoshida R, Nobuoka D, Kuise T, Fushimi T, Fujiwara T, Yagi T

    Digestive surgery   1 - 8   2018.6

  • 外科学の新知見(2)がんの早期診断に向けて がん特異的蛍光ウイルス製剤を用いた簡便な循環がん細胞(CTC)の遺伝子プロファイリング技術の開発 Reviewed

    重安 邦俊, 田澤 大, 橋本 悠里, 母里 淑子, 西崎 正彦, 岸本 浩行, 永坂 岳司, 黒田 新士, 香川 俊輔, 藤原 俊義

    日本外科学会定期学術集会抄録集   118回   282 - 282   2018.4

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  • Preoperative Controlling Nutritional Status Score Predicts Mortality after Hepatectomy for Hepatocellular Carcinoma. Reviewed

    Takagi K, Umeda Y, Yoshida R, Nobuoka D, Kuise T, Fushimi T, Fujiwara T, Yagi T

    Digestive surgery   2018.4

  • Factors Regulating Human Extravillous Trophoblast Invasion: Chemokine-peptidase and CD9-integrin Systems. Reviewed

    Fujiwara H, Matsumoto H, Sato Y, Horie A, Ono M, Nakamura M, Mizumoto Y, Kagami K, Fujiwara T, Hattori A, Maida Y, Daikoku T, Imakawa K, Araki Y

    Current pharmaceutical biotechnology   19 ( 10 )   764 - 770   2018

  • 多発筋炎/皮膚筋炎でみつかり腹腔鏡下に切除し得た直腸癌の一例 Reviewed

    重安 邦俊, 母里 淑子, 矢野 修也, 藤原 俊義

    日本内視鏡外科学会雑誌   22 ( 7 )   EP218 - 02   2017.12

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  • [Radical Thoracoscopic Esophagectomy for Elderly Patients with Advanced Esophageal Cancer].

    Yuki Matsumi, Yasuhiro Shirakawa, Shunsuke Tanabe, Satoshi Komoto, Naoaki Maeda, Takayuki Ninomiya, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Gan to kagaku ryoho. Cancer & chemotherapy   44 ( 12 )   1784 - 1786   2017.11

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    We report a case of an elderly patient with advanced esophageal cancer who underwent multidisciplinary treatment. An 86-year-old male consulted our hospital with complaints of pharynx discomfort and difficulty in swallowing. He was preoperatively diagnosed with esophageal cancer, T3N2M0, Stage III . We performed 2 courses of cisplatin plus 5-FU therapy as neoadjuvant chemotherapy. The primary tumor and metastatic lymph nodes reduced in size, and thoracoscopic esophagectomy in the prone position was performed. Pathological findings were esophageal cancer, pT3-Ad, INF b, ly2, v1, IM0, pPM0, pDM0, pRM1, pN3, pStage III . As the radical margin was positive, chemoradiotherapy was performed. We continued postoperative chemotherapy for approximately 1 year, and the patient has survived without relapse for 4 years from esophagectomy. Even in patients over 80 years old, long-term prognosis can be expected by performing radical surgery and chemoradiotherapy.

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  • 遅発性に肝転移・骨盤内リンパ節転移をきたした直腸神経内分泌腫瘍の1例 Reviewed

    重安 邦俊, 杭瀬 崇, 母里 淑子, 河合 毅, 矢野 修也, 戸嶋 俊明, 浅野 博昭, 近藤 喜太, 佃 和憲, 永坂 岳司, 八木 孝仁, 藤原 俊義

    日本大腸肛門病学会雑誌   70 ( 抄録号 )   A85 - A85   2017.9

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  • 抗体結合磁性ナノ粒子による温熱療法 癌播種病変への治療応用へ向けて

    香川 哲也, 岸本 浩行, 松三 雄騎, 田澤 大, 大原 利章, 永坂 岳司, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   76回   P - 2368   2017.9

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  • HER2陽性胃癌に対するアファチニブ・ネラチニブの抗腫瘍効果

    吉岡 貴裕, 枝園 和彦, 高橋 優太, 栗原 英祐, 難波 圭, 鳥越 英次郎, 佐藤 博紀, 山本 寛斉, 宗 淳一, 浅野 博昭, 佃 憲徳, 藤原 俊義, 豊岡 伸一

    日本癌学会総会記事   76回   P - 2336   2017.9

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  • がん免疫療法の一段の進化へむけて 腫瘍浸潤免疫細胞の代謝は抗腫瘍免疫応答を制御する

    鵜殿 平一郎, 榮川 伸吾, 國定 勇希, 上原 健敬, 渡邉 元嗣, 木村 裕司, 佐々木 朗, 尾崎 敏文, 豊岡 伸一, 藤原 俊義

    日本癌学会総会記事   76回   S10 - 5   2017.9

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  • Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction. Reviewed

    Yamakawa Y, Tazawa H, Hasei J, Osaki S, Omori T, Sugiu K, Komatsubara T, Uotani K, Fujiwara T, Yoshida A, Kunisada T, Urata Y, Kagawa S, Ozaki T, Fujiwara T

    Cancer science   108 ( 9 )   1870 - 1880   2017.9

  • Hyperthermia at the single-cell level for disseminated cancer disease with immuno-magnetic nanoparticles Reviewed

    Tetsuya Kagawa, Hiroyuki Kishimoto, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Takeshi Nagasaka, Satoshi Nohara, Ichiro Kato, Adarsh Sandhu, Hiromichi Aono, Toshiyoshi Fujiwara

    American Association for Cancer Research   77 ( 13 )   2017.7

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  • PVT1は癌遺伝子MYCを駆動するエンハンサーでありStage II、III大腸癌の予後予測マーカーになりうる Reviewed

    重安 邦俊, 小澤 毅士, 松山 貴俊, 河合 毅, 矢野 修也, 母里 淑子, 岸本 浩行, 永坂 岳司, Goel Ajay, 藤原 俊義

    日本消化器外科学会総会   72回   RS1 - 1   2017.7

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  • ePTFEを用いた新規カテーテル挿入補助デバイスの開発 Reviewed

    大原 利章, 櫻間 教文, 平松 聡, 野間 和広, 白川 靖博, 藤原 俊義

    日本外科学会定期学術集会抄録集   117回   SF - 7   2017.4

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  • p53活性化能を有するテロメラーゼ標的型ウイルス療法による腹腔内胃癌微小環境の浄化作用

    田澤 大, 堀 直人, 國府島 健, 谷本 光隆, 家田 偉史, 渡邉 めぐみ, 黒田 新士, 西崎 正彦, 浦田 泰生, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   75回   E - 2069   2016.10

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  • 鉄代謝は癌幹細胞の新規治療ターゲットとなり得る Reviewed

    大原 利章, 二宮 卓之, 桂 佑貴, 賀島 肇, 加藤 卓也, 野間 和広, 田澤 大, 藤原 俊義

    日本癌学会総会記事   75回   E - 1109   2016.10

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  • 癌関連線維芽細胞(CAFs)が及ぼす腫瘍免疫逃避の解明 CAFsと腫瘍浸潤リンパ球の検討 Reviewed

    加藤 卓也, 野間 和広, 賀島 肇, 桂 佑貴, 二宮 卓之, 大原 利章, 田澤 大, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本癌学会総会記事   75回   E - 1068   2016.10

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  • 外科における基礎的研究 セレンディピティーを求めて 鉄コントロールによる新規癌幹細胞治療 Reviewed

    二宮 卓之, 大原 利章, 桂 佑貴, 賀島 肇, 加藤 卓也, 野間 和広, 田辺 俊介, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本消化器外科学会総会   71回   WS7 - 2   2016.7

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  • 鉄コントロールによる新規がん幹細胞治療 Reviewed

    二宮 卓之, 大原 利章, 加藤 卓也, 賀島 肇, 野間 和広, 田澤 大, 田辺 俊介, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本外科学会定期学術集会抄録集   116回   PS - 8   2016.4

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  • p53 Replacement Therapy for Cancer. Reviewed

    Tazawa H, Kagawa S, Fujiwara T

    Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer   209   1 - 15   2016

  • [Therapeutic Potential of Targeting Cancer-Associated Fibroblasts in Esophageal Cancer]. Reviewed

    Kazuhiro Noma, Hajime Kashima, Takayuki Ninomiya, Ryoichi Katsube, Shinichiro Watanabe, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    Gan to kagaku ryoho. Cancer & chemotherapy   42 ( 10 )   1228 - 30   2015.10

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    Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer-associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular-targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future.

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  • 当科における食道憩室手術症例の検討 Reviewed

    賀島 肇, 白川 靖博, 前田 直見, 田辺 俊介, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    日本消化器外科学会総会   70回   P - 5   2015.7

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  • 上部消化管 超高齢者食道癌手術への取り組みと放射線併用ウイルス療法の可能性 Reviewed

    田辺 俊介, 白川 靖博, 賀島 肇, 国府島 健, 前田 直見, 大原 利章, 黒田 新士, 櫻間 教文, 野間 和広, 田澤 大, 香川 俊輔, 藤原 俊義

    日本外科学会定期学術集会抄録集   115回   OP - 2   2015.4

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  • その他 鉄コントロールによるがん幹細胞に対する新規治療 Reviewed

    二宮 卓之, 大原 利章, 浦野 真一, 勝部 亮一, 野間 和広, 田澤 大, 白川 靖博, 香川 俊輔, 藤原 俊義

    日本外科学会定期学術集会抄録集   115回   OP - 7   2015.4

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  • 大腸癌の遠隔転移(肝以外)の切除の限界とは 大腸癌肺転移に対するCTガイド下経皮的ラジオ波焼灼術(RFA)の短期・長期成績の検討

    稲田 涼, 永坂 岳司, 母里 淑子, 竹原 裕子, 竹原 清人, 佃 和憲, 平木 隆夫, 金澤 右, 藤原 俊義

    日本大腸肛門病学会雑誌   67 ( 9 )   634 - 634   2014.9

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  • 進行食道癌による食道狭窄に起因した経口摂取困難症例に対して、PEGを用いた術前栄養療法の有用性 Reviewed

    國府島 健, 白川 靖博, 前田 直見, 田邊 俊介, 大原 利章, 野間 和広, 櫻間 教文, 藤原 俊義

    日本消化器外科学会総会   69回   P - 3   2014.7

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  • ANTITUMOR EFFECT OF TELOMERASE-SPECIFIC ONCOLYTIC ADENOVIRUS ON HUMAN BONE AND SOFT TISSUE SARCOMA CELLS Reviewed

    Tazawa Hiroshi, Sasaki Tsuyoshi, Hasei Jo, Hashimoto Yuuri, Urata Yasuo, Ozaki Toshifumi, Fujiwara Toshiyoshi

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   261 - 262   2014.7

  • 当科における食道胃接合部癌の経験および治療戦略 Reviewed

    野間 和広, 白川 靖博, 国府島 健, 前田 直見, 大原 利章, 田辺 俊介, 西崎 正彦, 香川 俊輔, 藤原 俊義

    日本消化器外科学会総会   69回   O - 2   2014.7

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  • 食道癌手術における安全な吻合法 空腸を用いた食道再建及び吻合の工夫 全例に血管吻合が必要か? Reviewed

    白川 靖博, 國府島 健, 前田 直見, 大原 利章, 田辺 俊介, 櫻間 教文, 野間 和広, 藤原 俊義

    日本消化器外科学会総会   69回   VSY - 8   2014.7

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  • 食道切除・再建術におけるリスク評価と治療成績向上に向けた対策 食食道癌術前の呼吸機能管理目標設定とチーム介入の成果 Reviewed

    大原 利章, 白川 靖博, 國府島 健, 前田 直見, 田辺 俊介, 櫻間 教文, 野間 和広, 藤原 俊義

    日本消化器外科学会総会   69回   PD - 12   2014.7

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  • 鏡視下手術導入と多職種組織横断的周術期管理による高齢者食道癌手術への取り組み Reviewed

    田辺 俊介, 白川 靖博, 國府島 健, 前田 直見, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    日本食道学会学術集会プログラム・抄録集   68回   78 - 78   2014.7

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  • 食道がん手術患者の集中治療体験とその後の心理状態<第二報> Reviewed

    足羽 孝子, 伊藤 真理, 岩谷 美貴子, 國府島 健, 前田 直見, 大原 利章, 田辺 俊介, 野間 和広, 白川 靖博, 藤原 俊義

    日本食道学会学術集会プログラム・抄録集   68回   131 - 131   2014.7

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  • 消化器外科領域におけるマイクロサージェリー 空腸を用いた食道再建おけるマイクロサージェリーの適応とその工夫 Reviewed

    白川 靖博, 國府島 健, 前田 直見, 田辺 俊介, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    日本外科系連合学会誌   39 ( 3 )   506 - 506   2014.5

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  • 食道癌の狭窄による経口摂取困難症例に対するPEGを用いた術前管理の利点 Reviewed

    田辺 俊介, 白川 靖博, 國府島 健, 前田 直見, 勝部 亮一, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    Gastroenterological Endoscopy   56 ( Suppl.1 )   1220 - 1220   2014.4

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  • 食道癌周術期における外科医の負担軽減に対しチーム医療が果たした役割 Reviewed

    白川 靖博, 二宮 卓之, 前田 直見, 大原 利章, 田辺 俊助, 櫻間 教文, 野間 和広, 藤原 俊義

    日本外科学会雑誌   115 ( 臨増2 )   379 - 379   2014.3

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  • がん関連線維芽細胞(Cancer Associated Fibroblasts)を標的とした新規癌治療法の開発 Reviewed

    野間 和広, 白川 靖博, 二宮 卓之, 勝部 亮一, 前田 直見, 田辺 俊介, 大原 利章, 田澤 大, 香川 俊輔, 藤原 俊義

    日本外科学会雑誌   115 ( 臨増2 )   678 - 678   2014.3

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  • 肝臓癌における除鉄併用分子標的薬治療の可能性 Reviewed

    浦野 真一, 大原 利章, 白川 靖博, 勝部 亮一, 前田 直見, 田辺 俊介, 友野 靖子, 野間 和広, 藤原 俊義

    日本外科学会雑誌   115 ( 臨増2 )   489 - 489   2014.3

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  • 高度狭窄を伴う進行食道癌患者におけるPEGを用いた術前栄養管理の効果 術前後筋肉量変化に着目して Reviewed

    田辺 俊介, 白川 靖博, 前田 直見, 二宮 卓之, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    日本外科学会雑誌   115 ( 臨増2 )   464 - 464   2014.3

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  • 進行食道癌狭窄症例に対する術前栄養管理 経鼻胃管からPEGへの変遷 Reviewed

    田辺 俊介, 白川 靖博, 前田 直見, 二宮 卓之, 大原 利章, 櫻間 教文, 野間 和広, 長谷川 祐子, 平 健太郎, 名和 秀起, 岡田 恵子, 坂本 八千代, 藤原 俊義

    静脈経腸栄養   29 ( 1 )   552 - 552   2014.1

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  • 当科における進行食道癌における合理的胸腔鏡下手術の試み Reviewed

    野間 和広, 白川 靖博, 前田 直見, 二宮 卓之, 大原 利章, 田辺 俊介, 櫻間 教文, 西崎 正彦, 香川 俊輔, 藤原 俊義

    日本内視鏡外科学会雑誌   18 ( 7 )   549 - 549   2013.11

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  • 胸部食道癌に対する合理的縦隔郭清 腹臥位胸腔鏡下食道切除術における縦隔リンパ節郭清での助手による積極的術野展開とその定型化 Reviewed

    白川 靖博, 二宮 卓之, 前田 直見, 大原 利章, 田辺 俊介, 櫻間 教文, 野間 和広, 藤原 俊義

    日本内視鏡外科学会雑誌   18 ( 7 )   339 - 339   2013.11

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  • 80歳以上の超高齢者食道癌症例に対する胸腔鏡下手術の現況 Reviewed

    田辺 俊介, 白川 靖博, 前田 直見, 二宮 卓之, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    日本内視鏡外科学会雑誌   18 ( 7 )   502 - 502   2013.11

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  • [Current status of neoadjuvant chemotherapy for advanced esophageal cancer]. Reviewed

    Shunsuke Tanabe, Yasuhiro Shirakawa, Naoaki Maeda, Ryoichi Katsube, Toshiaki Ohara, Kazufumi Sakurama, Kazuhiro Noma, Toshiyoshi Fujiwara

    Gan to kagaku ryoho. Cancer & chemotherapy   40 ( 12 )   1612 - 4   2013.11

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    Since reported in the JCOG9907 trial, neoadjuvant chemotherapy prior to surgery has become the standard treatment for advanced (Stage II/III) esophageal cancers. However, more powerful neoadjuvant chemotherapy is required for the treatment of locally advanced cases or cases involving multiple lymph node metastases. At our institute, DCF therapy (docetaxel, cisplatin, and 5-fluorouracil) is administered selectively for the treatment of patients with far-advanced esophageal cancer. We treated 53 thoracic esophageal cancer patients who underwent surgery following neoadjuvant chemotherapy between January 2010 and December 2012. FP therapy (cisplatin and 5-fluorouracil) was administered to 43 patients, and DCF therapy to 7 patients who had far-advanced esophageal cancer. All patients treated with DCF therapy experienced grade 3 and 4 adverse events. With the exception of 1 patient, all patients who received DCF therapy could undergo curative surgery. DCF therapy could become an effective preoperative chemotherapy.

    PubMed

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  • 腹臥位胸腔鏡下食道亜全摘のための新しい解剖教材の開発 多視点3D解剖システム Reviewed

    前田 直見, 白川 靖博, 二宮 卓之, 大原 利章, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本内視鏡外科学会雑誌   18 ( 7 )   508 - 508   2013.11

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  • 食道胃接合部癌の手術 当科における食道胃接合部癌の治療経験 郭清範囲と再建法について Reviewed

    野間 和広, 白川 靖博, 前田 直見, 二宮 卓之, 大原 利章, 田辺 俊介, 櫻間 教文, 西崎 正彦, 香川 俊介, 藤原 俊義

    日本臨床外科学会雑誌   74 ( 増刊 )   467 - 467   2013.10

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  • Zenker憩室症の8例 Reviewed

    二宮 卓之, 田辺 俊介, 前田 直見, 大原 利章, 野間 和広, 白川 靖博, 藤原 俊義

    日本臨床外科学会雑誌   74 ( 増刊 )   842 - 842   2013.10

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  • 食道癌に対するESDの適応と限界 食道癌ESD後再発症例から考えるESDの適応と補助治療のあり方について Reviewed

    田辺 俊介, 白川 靖博, 前田 直見, 二宮 卓之, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    日本臨床外科学会雑誌   74 ( 増刊 )   369 - 369   2013.10

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  • 食道癌のサルベージ手術(適応と手技と成績と) 当科における食道癌サルベージ手術の検討 Reviewed

    前田 直見, 白川 靖博, 二宮 卓之, 大原 利章, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本臨床外科学会雑誌   74 ( 増刊 )   413 - 413   2013.10

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  • 吻合、再建の手術手技(食道) 当科における食道胃管吻合の変遷とその工夫 Reviewed

    白川 靖博, 二宮 卓之, 前田 直見, 大原 利章, 田辺 俊介, 櫻間 教文, 野間 和広, 藤原 俊義

    日本臨床外科学会雑誌   74 ( 増刊 )   360 - 360   2013.10

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  • 食道癌患者のより良い周術期医療のために歯科はどのような貢献ができるのか? 周術期管理センター(PERIO) Reviewed

    山中 玲子, 曽我 賢彦, 前田 直見, 田辺 俊介, 大原 利章, 野間 和広, 白川 靖博, 森田 学, 佐藤 健治, 森松 博史, 藤原 俊義

    日本臨床外科学会雑誌   74 ( 増刊 )   478 - 478   2013.10

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  • 鉄欠乏状態は肝細胞癌におけるソラフェニブの感受性を改善しうる(Iron depletion status has a possibility to improve the sensitivity of sorafenib in HCC) Reviewed

    浦野 真一, 大原 利章, 勝部 亮一, 渡邉 伸一郎, 野間 和広, 友野 靖子, 田澤 大, 能祖 一裕, 白川 靖博, 貞森 裕, 藤原 俊義

    日本癌学会総会記事   72回   345 - 345   2013.10

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  • 透視を用いず位置確認が可能な内視鏡的バルーン拡張術の工夫 Reviewed

    田辺 俊介, 白川 靖博, 前田 直見, 勝部 亮一, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    Gastroenterological Endoscopy   55 ( Suppl.2 )   2890 - 2890   2013.9

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  • 蛍光標識による血中遊離癌細胞のLiquid Biopsy技術のバイオマーカー解析への応用 Reviewed

    重安 邦俊, 橋本 悠里, 竹原 清人, 宇野 太, 永坂 岳司, 田澤 大, 香川 俊輔, 浦田 泰生, 藤原 俊義

    日本癌治療学会誌   48 ( 3 )   2759 - 2759   2013.9

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  • Selectively Replicating Oncolytic Adenoviruses Combined with Chemotherapy, Radiotherapy, or Molecular Targeted Therapy for Treatment of Human Cancers Reviewed

    Shinji Kuroda, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Gene Therapy of Cancer: Translational Approaches from Preclinical Studies to Clinical Implementation: Third Edition   171 - 183   2013.8

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    Oncolytic adenovirotherapy presents a novel approach for cancer therapy. Oncolytic adenoviruses are modified to replicate and induce oncolytic cell death in cancer cells but not in normal somatic cells. The first oncolytic adenovirus to be developed was ONYX-015, an E1B-55. kDa gene-deleted oncolytic adenovirus
    after which many inventive oncolytic adenoviruses have followed. H101, an oncolytic adenovirus with very similar gene constructs as ONYX-015, was approved in China as the world's first adenovirus cancer treatment in humans in 2005. Many clinical trials have revealed that oncolytic adenoviruses produce synergistic antitumor effects in combination with conventional chemotherapeutic agents, radiation, and some molecular targeted agents, although monotherapy with oncolytic adenoviruses shows limited effects. In this chapter, we discuss the developments of oncolytic adenoviruses, focusing on their synergistic effects when combined with other treatment modalities. Then we discuss the problems that must be overcome for adenoviruses to become more attractive as cancer treatment agents and to expand their clinical applications. © 2014 Elsevier Inc. All rights reserved.

    DOI: 10.1016/B978-0-12-394295-1.00012-3

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  • 当科における腹臥位胸腔鏡下食道切除術定型化の工夫 Reviewed

    青山 克幸, 白川 靖博, 勝部 亮一, 前田 直見, 大原 利章, 田辺 俊介, 櫻間 教文, 野間 和広, 藤原 俊義

    日本消化器外科学会総会   68回   O - 6   2013.7

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  • 胃が使用できない食道癌症例における空腸による食道再建術の工夫 血管吻合は全例に必要か? Reviewed

    渡邊 伸一郎, 白川 靖博, 勝部 亮一, 前田 直見, 大原 利章, 田辺 俊介, 櫻間 教文, 野間 和広, 藤原 俊義

    日本消化器外科学会総会   68回   RV - 5   2013.7

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  • 当科における低侵襲再建術の試み 用手補助的腹腔鏡下胃管作製の60例の検討 Reviewed

    前田 直見, 白川 靖博, 勝部 亮一, 大原 利章, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本消化器外科学会総会   68回   RV - 3   2013.7

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  • 胸部食道癌のよりよい周術期管理を目指して PERIOと鏡視下手術の融合 Reviewed

    白川 靖博, 勝部 亮一, 前田 直見, 大原 利章, 田辺 俊介, 櫻間 教文, 野間 和広, 藤原 俊義

    日本消化器外科学会総会   68回   O - 1   2013.7

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  • 食道胃接合部癌の外科治療戦略 当科における食道胃接合部癌の治療経験 下縦隔リンパ節転移症例の検討 Reviewed

    野間 和広, 白川 靖博, 前田 直見, 勝部 亮一, 大原 利章, 田辺 俊介, 櫻間 教文, 西崎 正彦, 香川 俊輔, 藤原 俊義

    日本消化器外科学会総会   68回   PD - 5   2013.7

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  • 患者負担軽減のためのPEGを用いた食道癌術前補助栄養療法の現状について Reviewed

    勝部 亮一, 白川 靖博, 前田 直見, 大原 利章, 田辺 俊介, 櫻間 教文, 野間 和宏, 藤原 俊義

    日本消化器外科学会総会   68回   RS - 1   2013.7

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  • Accumulation of Epigenetic Alteration Could Predict Malignant Formation in Intraductal Papillary Mucinous Neoplasm (IPMN) Reviewed

    Yoshida Kazuhiro, Nagasaka Takeshi, Umeda Yuzo, Yokomichi Naosuke, Mori Yoshiko, Kubota Nobuhito, Morikawa Tatsuya, Takehara Yuko, Takehara Kiyoto, Shigeyasu Kunitoshi, Nyuya Akihiro, Shiwaku Rikiya, Suno Manabu, Nishida Naoshi, Fujiwara Toshiyoshi, Goel Ajay

    GASTROENTEROLOGY   144 ( 5 )   S98   2013.5

  • Fecal DNA Methylation Assay for the Identification of a Multiple Gastrointestinal Cancers Including Pancreatic Caner Reviewed

    Morikawa Tatsuya, Nagasaka Takeshi, Yoshida Kazuhiro, Mori Yoshiko, Kubota Nobuhito, Takehara Yuko, Yokomichi Naosuke, Nishida Naoshi, Takehara Kiyoto, Shigeyasu Kunitoshi, Nyuya Akihiro, Shiwaku Rikiya, Suno Manabu, Fujiwara Toshiyoshi, Goel Ajay

    GASTROENTEROLOGY   144 ( 5 )   S601 - S602   2013.5

  • Genetic and Epigenetic Alterations in the Netrin-1 Receptors, UNC5c and DCC, Constitutes a Previously Unrecognized Pathway in Gastric Cancer Progression Reviewed

    Kubota Nobuhito, Nagasaka Takeshi, Toda Keisuke, Mori Yoshiko, Morikawa Tatsuya, Umeda Yuzo, Yokomichi Naosuke, Yoshida Kazuhiro, Takehara Yuko, Takehara Kiyoto, Nyuya Akihiro, Shiwaku Rikiya, Shigeyasu Kunitoshi, Suno Manabu, Nishida Naoshi, Fujiwara Toshiyoshi, Goel Ajay

    GASTROENTEROLOGY   144 ( 5 )   S527   2013.5

  • Cytokeratin 19 Staining Is a Novel, Predictive Biomarker for Extra-Hepatic Metastasis in Hepatocellular Carcinoma Reviewed

    Yokomichi Naosuke, Nagasaka Takeshi, Nishida Naoshi, Umeda Yuzo, Mori Yoshiko, Morikawa Tatsuya, Kubota Nobuhito, Yoshida Kazuhiro, Takehara Yuko, Takehara Kiyoto, Shigeyasu Kunitoshi, Nyuya Akihiro, Shiwaku Rikiya, Suno Manabu, Fujiwara Toshiyoshi, Goel Ajay

    GASTROENTEROLOGY   144 ( 5 )   S719 - S720   2013.5

  • MGMT Methylation As a Novel Biomarker for the Identification of Stage III Colorectal Cancers At High-Risk of Disease Recurrence Following Curative Surgery Reviewed

    Mori Yoshiko, Nagasaka Takeshi, Tazawa Hiroshi, Umeda Yuzo, Morikawa Tatsuya, Kubota Nobuhito, Yoshida Kazuhiro, Takehara Yuko, Yokomichi Naosuke, Takehara Kiyoto, Shigeyasu Kunitoshi, Nyuya Akihiro, Shiwaku Rikiya, Suno Manabu, Nishida Naoshi, Fujiwara Toshiyoshi, Goel Ajay

    GASTROENTEROLOGY   144 ( 5 )   S85   2013.5

  • 食道癌手術の周術期管理におけるチーム医療 当院での胸部食道癌周術期管理におけるPERIO導入についての検討 Reviewed

    白川 靖博, 勝部 亮一, 前田 直見, 大原 利章, 田辺 俊介, 櫻間 教文, 野間 和広, 藤原 俊義

    日本外科系連合学会誌   38 ( 3 )   605 - 605   2013.5

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  • 病期診断に難渋した早期食道癌の一例 術前PET-CT偽陽性症例の検討 Reviewed

    山辻 知樹, 平林 葉子, 高岡 宗徳, 深澤 拓也, 繁光 薫, 林 次郎, 浦上 淳, 吉田 和弘, 中島 一毅, 森田 一郎, 大原 利章, 田辺 俊介, 櫻間 教文, 野間 和広, 白川 靖博, 藤原 俊義, 河本 博文, 猶本 良夫

    Gastroenterological Endoscopy   55 ( Suppl.1 )   1160 - 1160   2013.4

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  • Gene therapy for cancer treatment Reviewed

    Shunsuke Kagawa, Toshiyoshi Fujiwara

    Gene Therapy: Technologies and Applications   70 - 83   2013.3

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    DOI: 10.2217/EBO.12.279

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  • 血清鉄コントロールを用いた新たな肝細胞癌治療戦略 Reviewed

    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 ( 臨増2 )   634 - 634   2013.3

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  • パラチノースを主糖質源とした流動食MHN-01を用いた食道癌周術期管理の意義 Reviewed

    山辻 知樹, 田村 卓也, 小池 良和, 平林 葉子, 高岡 宗徳, 深澤 拓也, 林 次郎, 繁光 薫, 浦上 淳, 吉田 和弘, 大原 利章, 田辺 俊介, 藤原 康宏, 櫻間 教文, 野間 和広, 白川 靖博, 羽井佐 実, 中島 一毅, 森田 一郎, 藤原 俊義, 猶本 良夫

    日本外科学会雑誌   114 ( 臨増2 )   919 - 919   2013.3

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  • 消化器癌における血中遊離癌細胞の検出と臨床応用 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 Reviewed

    重安 邦俊, 橋本 悠里, 宇野 太, 永坂 岳司, 田澤 大, 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 ( 臨増2 )   338 - 338   2013.3

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  • 超高齢者に対する外科治療の問題点 消化管外科、術式の選択 当科における80歳以上の超高齢者食道癌症例に対する外科治療の変遷 Reviewed

    田辺 俊介, 白川 靖博, 青山 克幸, 前田 直見, 大原 利章, 櫻間 教文, 野間 和広, 西崎 正彦, 香川 俊輔, 藤原 俊義

    日本外科学会雑誌   114 ( 臨増2 )   317 - 317   2013.3

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  • 腹臥位胸腔鏡下食道亜全摘術においてEndoCAMeleonがもたらした新たな視野展開 Reviewed

    野間 和広, 白川 靖博, 青山 克幸, 前田 直見, 大原 利章, 田辺 俊介, 櫻間 教文, 西崎 正彦, 香川 俊輔, 藤原 俊義

    日本外科学会雑誌   114 ( 臨増2 )   451 - 451   2013.3

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  • 血清鉄コントロールによる食道癌細胞の浸潤・転移能制御の可能性 Reviewed

    浦野 真一, 野間 和広, 大原 利章, 西谷 正史, 前田 直見, 渡邉 伸一郎, 田辺 俊介, 櫻間 教文, 友野 靖子, 白川 靖博, 藤原 俊義

    日本外科学会雑誌   114 ( 臨増2 )   747 - 747   2013.3

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  • 高リスクGIST症例の検討 無作為化比較試験SSGXVIII/AIOの報告をうけて Reviewed

    宇野 太, 永坂 岳司, 香川 俊輔, 西崎 正彦, 岸本 浩行, 黒田 新士, 石田 道拡, 青山 克幸, 稲田 涼, 前田 直見, 大原 利章, 近藤 喜太, 田辺 俊介, 野間 和広, 白川 靖博, 藤原 俊義

    日本外科学会雑誌   114 ( 臨増2 )   891 - 891   2013.3

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  • 内視鏡外科におけるチーム医療の在り方 食道癌鏡視下手術の周術期におけるチーム医療の関わり Reviewed

    白川 靖博, 青山 克幸, 前田 直見, 田辺 俊介, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    日本内視鏡外科学会雑誌   17 ( 7 )   313 - 313   2012.12

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  • Non-recurrent inferior laryngeal nerveを伴う胸部食道癌に対して胸腔鏡下食道亜全摘を施行した1例 Reviewed

    前田 直見, 白川 靖博, 大原 利章, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本内視鏡外科学会雑誌   17 ( 7 )   696 - 696   2012.12

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  • 我々の目指すチーム内視鏡外科 当科における腹臥位胸腔鏡下食道亜全摘における術者助手のコラボレーション Reviewed

    野間 和広, 白川 靖博, 青山 克幸, 前田 直見, 大原 利章, 田辺 俊介, 香川 俊輔, 藤原 俊義

    日本内視鏡外科学会雑誌   17 ( 7 )   604 - 604   2012.12

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  • 当科における食道胃接合部癌に対する再建法の工夫 胸腔内観音開き法吻合の経験 Reviewed

    野間 和広, 白川 靖博, 青山 克幸, 前田 直見, 大原 利章, 田辺 俊介, 西崎 正彦, 香川 俊輔, 藤原 俊義

    日本臨床外科学会雑誌   73 ( 増刊 )   525 - 525   2012.10

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  • 出血性ショックをきたした回腸静脈瘤破裂に対しバルーン下逆行性経静脈的塞栓術(BRTO)が奏功した1例

    濱田 侑紀, 竹原 裕子, 竹原 清人, 大原 利章, 近藤 喜太, 永坂 岳司, 香川 俊輔, 藤原 俊義

    日本臨床外科学会雑誌   73 ( 増刊 )   1084 - 1084   2012.10

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  • チームで乗り切る食道癌手術(当院での周術期管理センター:PERIOの取り組み) Reviewed

    白川 靖博, 青山 克幸, 前田 直見, 田辺 俊介, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    日本臨床外科学会雑誌   73 ( 増刊 )   481 - 481   2012.10

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  • 低肺機能合併の胸部食道癌症例に対する腹臥位胸腔鏡下食道切除の経験 Reviewed

    前田 直見, 白川 靖博, 青山 克幸, 大原 利章, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本臨床外科学会雑誌   73 ( 増刊 )   706 - 706   2012.10

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  • Zenker憩室に合併した頸部食道表在癌の1例 Reviewed

    大原 利章, 白川 靖博, 青山 克幸, 前田 直見, 田辺 俊介, 櫻間 教文, 野間 和広, 藤原 俊義

    日本臨床外科学会雑誌   73 ( 増刊 )   945 - 945   2012.10

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  • 食道癌手術における再建法の安全性とQOL 胃が使用できない食道癌症例におけるQOL向上を目指した腸管による食道再建法 Reviewed

    田辺 俊介, 白川 靖博, 青山 克幸, 前田 直見, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    日本臨床外科学会雑誌   73 ( 増刊 )   383 - 383   2012.10

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  • 頭頸部表在癌のESDにおける工夫 Reviewed

    田辺 俊介, 白川 靖博, 前田 直見, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    耳鼻咽喉科展望   55 ( 4 )   262 - 263   2012.8

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  • 腫瘍特異的制限増殖型アデノウイルスを用いた血液循環腫瘍細胞の遺伝子解析技術の開発(Development of genetic analysis of circulating tumor cells using a telomerase-specific replication-competent adenovirus) Reviewed

    重安 邦俊, 橋本 悠里, 宇野 太, 永坂 岳司, 田澤 大, 香川 俊輔, 水口 裕之, 浦田 泰生, 藤原 俊義

    日本癌学会総会記事   71回   50 - 50   2012.8

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  • 癌関連線維芽細胞が食道癌の増殖に寄与する(Cancer-associated fibroblasts contribute to progression of esophageal cancer) Reviewed

    渡邉 伸一郎, 野間 和広, 浦野 真一, 大原 利章, 橋本 悠里, 田澤 大, 藤原 俊義

    日本癌学会総会記事   71回   143 - 143   2012.8

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  • 鉄コントロールによる新しい食道癌治療法の開発 Reviewed

    大原 利章, 白川 靖博, 青山 克幸, 前田 直見, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本食道学会学術集会プログラム・抄録集   66回   196 - 196   2012.6

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  • 大学病院の特殊な疾患群に対する胃瘻造設の現況 Reviewed

    田辺 俊介, 白川 靖博, 前田 直見, 大原 利章, 櫻間 教文, 野間 和広, 藤原 俊義

    Gastroenterological Endoscopy   54 ( Suppl.1 )   1201 - 1201   2012.4

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  • 当科における中下咽頭表在癌に対するESDの工夫 Reviewed

    白川 靖博, 前田 直見, 大原 利章, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    Gastroenterological Endoscopy   54 ( Suppl.1 )   1154 - 1154   2012.4

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  • 当科での胸部食道癌手術の低侵襲化の推移とその成果 Reviewed

    白川 靖博, 前田 直見, 大原 利章, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本外科学会雑誌   113 ( 臨増2 )   736 - 736   2012.3

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  • 高齢者食道癌症例に対する手術術式と周術期管理 Reviewed

    田辺 俊介, 白川 靖博, 前田 直見, 大原 利章, 野間 和広, 櫻間 教文, 藤原 俊義

    日本外科学会雑誌   113 ( 臨増2 )   362 - 362   2012.3

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  • ロボット支援下幽門側胃切除術の安全な導入 Reviewed

    西崎 正彦, 香川 俊輔, 宇野 太, 岸本 浩行, 近藤 喜太, 田邊 俊介, 大原 利章, 野間 和広, 永坂 岳志, 白川 靖博, 藤原 俊義

    日本外科学会雑誌   113 ( 臨増2 )   490 - 490   2012.3

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  • 当科における高齢者食道癌手術症例の術式選択の工夫 Reviewed

    田辺 俊介, 白川 靖博, 前田 直見, 大原 利章, 野間 和広, 櫻間 教文, 藤原 俊義

    日本臨床外科学会雑誌   72 ( 増刊 )   533 - 533   2011.10

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  • 当科における胃管再建作成および吻合における工夫 Reviewed

    野間 和広, 白川 康博, 前田 直見, 大原 利章, 田辺 俊介, 永坂 岳司, 香川 俊輔, 藤原 俊義

    日本臨床外科学会雑誌   72 ( 増刊 )   517 - 517   2011.10

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  • 当科における食道胃接合部の食道癌についての検討 Reviewed

    白川 靖博, 前田 直見, 大原 利章, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本臨床外科学会雑誌   72 ( 増刊 )   501 - 501   2011.10

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  • 当科における食道癌頭頸部癌重複症例の検討 Reviewed

    前田 直見, 白川 靖博, 田辺 俊介, 大原 利章, 野間 和広, 櫻間 教文, 藤原 俊義

    日本臨床外科学会雑誌   72 ( 増刊 )   557 - 557   2011.10

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  • 当科におけるT4食道癌に対する治療戦略についての検討 Reviewed

    大原 利章, 白川 靖博, 前田 直見, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本臨床外科学会雑誌   72 ( 増刊 )   531 - 531   2011.10

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  • 当科における食道及び中下咽頭表在癌に対するESDの工夫 Reviewed

    白川 靖博, 前田 直見, 大原 利章, 田辺 俊介, 野間 和広, 櫻間 教文, 藤原 俊義

    日本臨床外科学会雑誌   72 ( 増刊 )   593 - 593   2011.10

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  • 鉄欠乏状態は食道がんにおいてNカドヘリンを低下させることでEMTを抑制する(Iron deficiency suppress EMT through downregulation of N-cadherin in esophageal cancer) Reviewed

    西谷 正史, 野間 和広, 大原 利章, 長谷井 嬢, 佐々木 剛, 渡邊 伸一郎, 大西 哲平, 吉田 亮介, 橋本 悠里, 田澤 大, 宇野 太, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   70回   467 - 468   2011.9

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  • 体内鉄コントロールによるN-cadheinの発現低下が癌細胞の浸潤・転移能にどのような影響を与えるかについての検討 Reviewed

    西谷 正史, 野間 和広, 大原 利章, 友野 靖子, 田邊 俊介, 白川 靖博, 藤原 俊義

    日本外科学会雑誌   112 ( 臨増1-2 )   595 - 595   2011.5

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  • 食道癌転移診断におけるPET-CT偽陽性症例の検討 Reviewed

    山辻 知樹, 関 亮太, 木下 真一郎, 深澤 拓也, 林 次郎, 繁光 薫, 吉田 和弘, 森田 一郎, 山田 英司, 西谷 正史, 大原 利章, 田邊 俊介, 藤原 康宏, 櫻間 教文, 野間 和広, 高岡 宗徳, 白川 靖博, 松岡 順治, 羽井佐 実, 藤原 俊義, 猶本 良夫

    日本外科学会雑誌   112 ( 臨増1-2 )   837 - 837   2011.5

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  • 体内鉄コントロールを利用したBevacizumabの新規治療法 Reviewed

    大原 利章, 野間 和広, 友野 靖子, 西谷 正史, 田辺 俊介, 田澤 大, 白川 靖博, 藤原 俊義

    日本外科学会雑誌   112 ( 臨増1-2 )   771 - 771   2011.5

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  • Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas Reviewed

    Tsuyoshi Sasaki, Hiroshi Tazawa, Jo Hasei, Toshiyuki Kunisada, Aki Yoshida, Yuuri Hashimoto, Shuya Yano, Ryosuke Yoshida, Futoshi Uno, Shunsuke Kagawa, Yuki Morimoto, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CLINICAL CANCER RESEARCH   17 ( 7 )   1828 - 1838   2011.4

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    Purpose: Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells.
    Experimental Design: The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bone (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1, and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1, and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified OBP-301 (termed OBP-405) was used to confirm an antitumor effect on OBP-301-resistant sarcomas.
    Results: OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR-expressing OUMS27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression and not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells.
    Conclusions: A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas. Clin Cancer Res; 17(7); 1828-38. (C) 2011 AACR.

    DOI: 10.1158/1078-0432.CCR-10-2066

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  • MicroRNAs as potential target gene in cancer gene therapy of gastrointestinal tumors Reviewed

    Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    EXPERT OPINION ON BIOLOGICAL THERAPY   11 ( 2 )   145 - 155   2011.2

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    Language:English   Publisher:INFORMA HEALTHCARE  

    Introduction: MicroRNA (miRNA) is a small non-coding RNA, which negatively regulates the expression of many target genes, thereby contributing to the modulation of diverse cell fates. Recent advances in molecular biology have revealed the potential role of miRNAs in tumor initiation, progression and metastasis. Aberrant regulation of miRNAs has been frequently reported in a variety of cancers, including gastrointestinal tumors, suggesting that cancer-related miRNAs are promising as novel biomarkers for tumor diagnosis and are potential target genes for cancer gene therapy against gastrointestinal tumors.
    Areas covered: The review focuses on the role of specific miRNAs (miR-192/194/215 and miR-7) in the differentiation of gastrointestinal epithelium and on the role of tumor-suppressive (miR-34, miR-143, miR-145) and oncogenic miRNAs (miR-21, miR-17-92 cluster) in gastrointestinal tumors. Furthermore, the potential role of miRNAs as novel biomarkers and target genes for cancer gene therapy against gastrointestinal tumors are discussed. We will also outline the potential clinical application of miRNAs for tumor diagnosis and cancer gene therapy against gastrointestinal tumors.
    Expert opinion: Exploration of tumor-related miRNAs would provide important opportunities for the development of novel cancer gene therapies aimed at normalizing the critical miRNAs that are deregulated in gastrointestinal tumors.

    DOI: 10.1517/14712598.2011.542749

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  • Telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery. Reviewed

    Kuroda S, Fujiwara T, Shirakawa Y, Yamasaki Y, Yano S, Uno F, Tazawa H, Hashimoto Y, Watanabe Y, Noma K, Urata Y, Kagawa S, Fujiwara T

    Cancer research   70 ( 22 )   9339 - 9348   2010.11

  • In vivo biological purging for lymph node metastasis of human colorectal cancer by telomerase-specific oncolytic virotherapy. Reviewed

    Kojima T, Watanabe Y, Hashimoto Y, Kuroda S, Yamasaki Y, Yano S, Ouchi M, Tazawa H, Uno F, Kagawa S, Kyo S, Mizuguchi H, Urata Y, Tanaka N, Fujiwara T

    Annals of surgery   251 ( 6 )   1079 - 1086   2010.6

  • 当科における食道憩室切除症例の検討 Reviewed

    山辻 知樹, 山田 英司, 西谷 正史, 大原 利章, 田辺 俊介, 藤原 康宏, 野間 和広, 櫻間 一史, 高岡 宗徳, 白川 靖博, 貞森 裕, 小林 直哉, 藤原 俊義, 八木 孝仁, 羽井佐 実, 松岡 順治, 猶本 良夫

    日本外科学会雑誌   111 ( 臨増2 )   582 - 582   2010.3

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  • 食道癌縦隔再発に対するラジオ波焼灼術

    浅海 信也, 猶本 良夫, 櫻間 一史, 野間 和広, 白川 靖博, 山辻 知樹, 藤原 俊義, 松原 長秀, 羽井佐 実, 岩垣 博巳, 田中 紀章, 花崎 元彦, 多賀 直行, 中塚 秀輝, 森田 潔, 郷原 英夫, 三村 秀文, 金澤 右

    岡山医学会雑誌   116 ( 3 )   318 - 318   2005.1

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Books

  • 希少がん:がん診療の新たな課題

    日本臨床社  2021 

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  • よくわかるがん免疫療法ガイドブック

    金原出版  2020 

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  • いま、本格化する遺伝子治療(実験医学 増刊)

    羊土社  2020 

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  • 消化器外科専門医の心得

    一般社団法人 日本消化器外科学会  2020 

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  • 分子細胞治療フロンティア2020

    飯田橋パピルス  2020 

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  • 入門 腫瘍内科学(改訂第3版)

    南江堂  2020 

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  • 別冊・医学の歩み 遺伝子治療の新局面

    医歯薬出版株式会社  2019 

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  • 消化管吻合法バイブル

    医学書院  2018 

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  • 次世代がん治療

    エヌ・ティー・エス  2017 

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  • Current Strategies in Cancer Gene Therapy

    Springer International Publishing  2016 

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  • Advances inMedicine and Biology. Vol.110

    Nova Publishers, Inc.  2016 

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  • 今,着実に実り始めた遺伝子治療 - 最新研究と今後の展開

    株式会社メディカルドゥ  2016 

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  • 新人ナースのための消化器外科 術前術後ケアQ&A102

    メディカ出版  2016 

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  • 次世代のがん治療薬・診断のための研究開発~免疫療法・遺伝子治療・がん幹細胞~

    技術情報協会  2016 

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  • 消化器外科学レビュー2015-’16

    総合医学社  2015 

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  • LECS−イラストと写真で見る内視鏡医と外科医のコラボレーション手術

    メジカルビュー社  2015 

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  • 消化器病診療(第2版)

    医学書院  2014 

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  • 分子細胞治療フロンティア2015

    株式会社パピルス  2014 

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  • 肝移植後グラフト機能不全/アルコール性肝不全の肝移植適応<第10回伊豆肝臓カンファレンス記録>

    株式会社アークメディア  2014 

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  • Gene Therapy: Technologies & Applications

    Future Medicine Ltd  2013 

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  • OGS NOW

    メジカルビュー社  2013 

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  • Gene Therapy of Cancer, 3rd Edition

    Academic Press  2013 

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  • Hemodynamics: Monitoring, Theory and Applications

    Nova science publishers, Inc.  2013 

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  • OGS NOW

    メジカルビュー社  2013 

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  • Tumor Suppressor Genes: Functions, Regulation and Health Effects

    Nova science publishers, Inc.  2013 

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  • 消化器外科学レビュー2012

    総合医学社  2012 

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  • 示唆に富む肝移植症例の総合討論 / 第7回 伊豆肝臓カンファレンス記録

    アークメディア  2012 

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  • Liver Transplantation

    INTEC  2012 

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  • In Vivo Vellular Imaging Using Fluorescent Proteins

    Human Press, c/o Springer Science+Business Media  2012 

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  • 新臨床腫瘍学 改訂第3版

    南江堂  2012 

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  • Telomeres and Telomerase in Cancer

    Humana Press  2009 

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  • 別冊・医学の歩み 呼吸器疾患 -State of arts

    医歯薬出版株式会社,東京  2007 

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  • 呼吸器commondiseaseの診療:肺癌のすべて

    文光堂  2006 

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  • 新しい診断と治療のABC(最新医学 別冊)

    最新医学社  2005 

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  • 先端医療シリーズ20・癌 肺癌の最新医療

    先端医学社,東京  2003 

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  • プラクティカル内科シリーズ:肺癌 改訂第2版

    南江堂,東京  2003 

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  • 肺癌診療ガイド特集 肺癌の新しい検査と治療

    リノ・メディカル株式会社,東京  2002 

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  • 平成11年度-平成12年度 科学研究費補助金(基盤研究C2)研究成果報告書

    2002 

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  • 厚生科学研究研究費補助金 ヒトゲノム・再生医療等研究事業 平成13年度総括研究報告書

    2002 

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  • TECHNICAL TERM 緩和医療

    先端医学社,東京  2002 

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  • 先端医療シリーズ10・呼吸器疾患-最新医療と21世紀への展望-

    先端医療技術研究所  2001 

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  • 新臨床医のための分子医学シリーズ 遺伝子治療の新展開:ベクター開発と臨床応用の最前線

    羊土社  2001 

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  • p53研究の新たな挑戦

    羊土社  2001 

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  • 実験医学増刊 癌治療の先端に迫る!

    羊土社  2001 

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  • がん治療におけるアポトーシスの応用

    医薬ジャーナル社  2001 

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MISC

  • 消化器系遺伝性腫瘍のスクリーニングとサーベイランスのための早期介入プログラムの構築

    重安邦俊, 武田正, 矢野修也, 二川摩周, 山本英喜, 近藤喜太, 寺石文則, 香川俊輔, 平沢晃, 藤原俊義

    日本外科学会定期学術集会(Web)   121st   2021

  • RNA editing activated by chemoradiation therapy artificially generates neoantigen in colorectal cancer

    小松泰浩, 重安邦俊, 重安邦俊, 武田正, 高橋一剛, 畑七々子, 吉田一博, 矢野修也, 矢野修也, 大原利章, 野間和広, 楳田祐三, 黒田新士, 黒田新士, 近藤喜太, 寺石文則, 寺石文則, 田澤大, 香川俊輔, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020

  • 希少MSI-H大腸癌患者由来組織片を用いたマウスモデル(PDX)による擬似クローン化の試み

    矢野修也, 矢野修也, 重安邦俊, 三村直毅, 岸本浩行, 母里淑子, 黒田新士, 近藤喜太, 寺石文則, 香川俊輔, 平沢晃, 藤原俊義

    日本遺伝性腫瘍学会学術集会プログラム・抄録集   26th   2020

  • ペムブロリズマブ使用中に下垂体機能低下症を来たしステロイド投与が著効した高頻度マイクロサテライト不安定性大腸癌の1例

    重安邦俊, 岸本浩行, 母里淑子, 武田正, 矢野修也, 黒田新士, 近藤喜太, 寺石文則, 香川俊輔, 平沢晃, 藤原俊義

    日本遺伝性腫瘍学会学術集会プログラム・抄録集   26th   2020

  • Reversible EMT-MET biosensor-mediated imaging visualizes inducible resistance to chemotherapy with hybrid E/M phase

    三村直毅, 矢野修也, 矢野修也, 田澤大, 家田偉史, 岡林大樹, 重安邦俊, 重安邦俊, 武田正, 吉田一博, 寺石文則, 寺石文則, 楳田祐三, 香川俊輔, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020

  • Perspective and prospective of RNA editing in colorectal cancer microenvironme

    武田正, 重安邦俊, 重安邦俊, 小松泰浩, 高橋一剛, 畑七々子, 吉田一博, 矢野修也, 矢野修也, 近藤喜太, 寺石文則, 寺石文則, 楳田祐三, 田澤大, 香川俊輔, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020

  • Development of novel photoimmunotherapy targeting cancer associated fibroblasts.

    小林照貴, 野間和広, 河崎健人, 赤井正明, 西脇紀之, 大原利章, 田澤大, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020

  • 癌微小環境が引き起こす腫瘍免疫抑制の解明“Drug repositioning′′による免疫応答賦活化の可能性

    西脇紀之, 野間和広, 赤井正明, 小林照貴, 鳴坂徹, 河本慧, 加藤卓也, 前田直見, 田辺俊介, 大原利章, 田澤大, 白川靖博, 藤原俊義

    日本外科学会定期学術集会(Web)   120th   2020

  • 新世代の外科医の苦悩と挑戦

    西脇紀之, 野間和広, 赤井正明, 小林照貴, 鳴坂徹, 河本慧, 大原利章, 田澤大, 藤原俊義

    日本外科学会定期学術集会(Web)   120th   2020

  • Fibroblast activation protein-α(FAP)を標的とした癌関連線維芽細胞(CAFs)に対する光免疫療法~Sunrise of targeting tumor microenvironment therapy~

    小林照貴, 野間和広, 赤井正明, 西脇紀之, 鳴坂徹, 河本慧, 前田直見, 大原利章, 田辺俊介, 田澤大, 白川靖博, 藤原俊義

    日本外科学会定期学術集会(Web)   120th   2020

  • Interplay between gastric cancer subtypes and cancer-associated fibroblasts

    李云成, 田澤大, 野間和広, 大原利章, 黒田新士, 黒田新士, 菊地覚次, 菊地覚次, 香川俊輔, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020

  • Overcoming cancer-associated fibroblasts induced immunosuppression by blocking IL-6-Exploring for Drug Repositioning-

    西脇紀之, 野間和広, 大原利章, 小林照貴, 菊地覚次, 菊地覚次, 田澤大, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020

  • 小腸腺癌2症例の治療経験

    母里淑子, 近藤喜太, 重安邦俊, 小松泰造, 三村直毅, 戸嶋俊明, 矢野修也, 岸本浩行, 寺石文則, 香川俊輔, 藤原俊義

    日本大腸肛門病学会雑誌(Web)   72 ( 5 )   2019

  • Fluorescence-guided novel therapeutic strategy for therapy-refractory tumor cells identified by cell cycle imaging

    矢野修也, 矢野修也, 田澤大, 重安邦俊, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   78th   2019

  • StageIV大腸癌における腫瘍占拠部位別の予後の検討

    寺石文則, 寺石文則, 公文剣斗, 戸嶋俊明, 重安邦俊, 矢野修也, 母里淑子, 近藤喜太, 浅野博昭, 岸本浩行, 稲田涼, 尾崎和秀, 志摩泰生, 西岡豊, 藤原俊義

    日本大腸肛門病学会雑誌(Web)   72 ( 5 )   2019

  • T1大腸癌手術症例の病理組織学的特徴と予後の検討

    寺石文則, 戸嶋俊明, 重安邦俊, 母里淑子, 矢野修也, 近藤喜太, 岸本浩行, 藤原俊義

    日本大腸肛門病学会雑誌(Web)   72 ( 5 )   2019

  • RNA編集とマイクロサテライト不安定性の関連および免疫療法に与える影響について

    重安邦俊, 武田正, 小松泰浩, 母里淑子, 矢野修也, 近藤喜太, 寺石文則, 香川俊輔, 藤原俊義

    日本家族性腫瘍学会学術集会プログラム・抄録集   25th   2019

  • 同時性肝転移を有する大腸癌症例における原発巣切除の意義

    寺石文則, 藤本卓也, 重安邦俊, 矢野修也, 母里淑子, 近藤喜太, 香川俊輔, 尾崎和秀, 藤原俊義

    大腸癌研究会プログラム・抄録集   91st   2019

  • Multiple gastrointestinal stromal tumors of the small intestine in a patient with neurofibromatosis type 1: a case report

    母里淑子, 重安邦俊, 吉岡貴裕, 永坂岳司, 原賀順子, 香川俊輔, 寺石文則, 豊岡伸一, 平沢晃, 藤原俊義

    家族性腫瘍(Web)   19 ( 2 )   2019

  • 周術期管理チーム介入によるリスク評価が高齢者大腸癌患者の術後アウトカムに与える影響

    寺石文則, 重安邦俊, 矢野修也, 母里淑子, 近藤喜太, 藤原俊義, 藤原俊義

    日本消化器外科学会雑誌(Web)   52 ( Supplement2 )   2019

  • 【膵癌に挑む】 膵癌に対するウイルス療法の実用化に向けて

    國府島 健, 田澤 大, 杭瀬 崇, 吉田 龍一, 楳田 祐三, 藤原 俊義

    消化器外科   41 ( 6 )   931 - 938   2018.5

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  • 腫瘍融解ウイルス併用放射線療法による食道癌治療成績向上への取り組み

    田辺 俊介, 白川 靖博, 前田 直見, 二宮 卓之, 黒田 新士, 野間 和広, 楳田 祐三, 田澤 大, 香川 俊輔, 藤原 俊義

    日本外科学会定期学術集会抄録集   118回   944 - 944   2018.4

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  • Molecular radiosensitization of p53-armed telomerase-dependent oncolytic adenovirus against human soft-tissue sarcoma

    Tadashi Komatsubara, Hiroshi Tazawa, Yusuke Mochizuki, Kazuhisa Sugiu, Toshinori Omori, Yasuaki Yamakawa, Syuhei Osaki, Joe Hasei, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER SCIENCE   109   454 - 454   2018.1

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  • 大腸癌におけるAZIN1RNA編集の意義

    重安邦俊, 重安邦俊, GOEL A., 藤原俊義

    肝臓   59 ( Supplement 2 )   2018

  • Bevacizumab+mFOLFOX6療法が有効であった肝内胆管癌の一例

    母里淑子, 永坂岳司, 楳田祐三, 重安邦俊, 吉田一博, 岸本浩行, 香川俊輔, 藤原俊義

    日本臨床腫瘍学会学術集会(CD-ROM)   16th   2018

  • 大腸癌における新規oncogenic small nucleolar RNA(oncSNOR)の探求

    吉田一博, 重安邦俊, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬崇, 安井和也, 香川俊輔, 白川靖博, 八木孝仁, GOEL Ajay, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   29th   2018

  • 消化管外瘻を伴う炎症性腸疾患に対する腹腔鏡下手術の安全性

    戸嶋俊明, 近藤善太, 小松泰浩, 三村直毅, 重安邦俊, 矢野修也, 母里淑子, 寺石文則, 岸本浩行, 香川俊輔, 藤原俊義

    日本大腸肛門病学会雑誌(Web)   71 ( 9 )   2018

  • StageIV大腸癌の原発巣切除後に長期予後が期待できる症例とは

    寺石文則, 戸嶋俊明, 重安邦俊, 矢野修也, 母里淑子, 近藤喜太, 岸本浩行, 尾崎和秀, 藤原俊義

    日本大腸肛門病学会雑誌(Web)   71 ( 9 )   2018

  • 回腸人工肛門狭窄のリスク因子の抽出と予防

    重安邦俊, 母里淑子, 戸嶋俊明, 矢野修也, 近藤喜太, 岸本浩行, 寺石文則, 藤原俊義

    日本大腸肛門病学会雑誌(Web)   71 ( 9 )   2018

  • 鉄キレート剤の幹細胞性制御による新規癌治療法の確立

    大原利章, 大原利章, 桂佑貴, 野間和広, 鳴坂徹, 二宮卓之, 友野靖子, 田澤大, 香川俊輔, 白川靖博, 松川昭博, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   29th   2018

  • 食道癌におけるがん細胞及びがん関連線維芽細胞に対するDual-targeting Photoimmunotherapy

    佐藤浩明, 野間和宏, 鳴坂徹, 河本慧, 大原利章, 田澤大, 白川靖博, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   29th   2018

  • 骨肉腫に対するp53誘導性腫瘍融解ウイルス療法による免疫原性細胞死の誘導効果

    出宮光二, 田澤大, 田澤大, 望月雄介, 小松原将, 長谷井嬢, 中田英二, 国定俊之, 浦田泰生, 藤原俊義, 尾崎敏文

    日本整形外科学会雑誌   92 ( 8 )   2018

  • 軟部肉腫に対するp53発現腫瘍融解アデノウイルスによるアポトーシス抑制遺伝子発現の制御を介した放射線感受性増感作用の検討

    小松原将, 出宮光二, 望月雄介, 長谷井嬢, 吉田晶, 中田英二, 国定俊之, 浦田泰生, 田澤大, 藤原俊義, 尾崎敏文

    日本整形外科学会雑誌   92 ( 8 )   2018

  • Iron depletion is a novel therapeutic strategy to target cancer stem cells. International journal

    Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Ryoichi Katsube, Hajime Kashima, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Ling Chen, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

    Oncotarget   8 ( 58 )   98405 - 98416   2017.11

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    Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.

    DOI: 10.18632/oncotarget.21846

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  • Novel therapeutic strategy for human epidermal growth factor receptor 2-positive gastric cancer

    Nobuhiko Kanaya, Shinji Kuroda, Tetsushi Kubota, Toshiaki Morihiro, Satoru Kikuchi, Masahiko Nishizaki, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Japanese Journal of Cancer and Chemotherapy   44 ( 10 )   883 - 885   2017.10

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    Trastuzumab (Tmab), a humanized monoclonal antibody that selectively targets human epidermal growth factor receptor 2 (HER2), is currently used in the clinical setting for the treatment of both breast and gastric cancer. While Tmab has shown improvements in patient prognoses, acquired resistance to this agent remains an issue. While some novel HER2-targeted agents have been approved for clinical use in breast cancer, no such agent has shown treatment efficacy for gastric malignancies with Tmab-resistance. Nanotechnology, which has progressed rapidly, has been applied to medical fields in recent years. Gold nanopartides, which are characterized by their in vivo stability and ease of surface modification, have been reported to show efficacy as the carriers of therapeutic agents, such as drugs, antibodies, peptides, and nucleic acids. In this work, we developed Tmab-conjugated gold nanopartides and demonstrate their efficacy for the treatment of HER2-positive, Tmab-resistant gastric cancer cell lines. Our findings demonstrate that Tmab-conjugated gold nanopartides have the potential to be a novel HER2-targeted therapeutic agent.

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  • Preoperative Controlling Nutritional Status (CONUT) Score for Assessment of Prognosis Following Hepatectomy for Hepatocellular Carcinoma

    Kosei Takagi, Takahito Yagi, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Hiroyuki Araki, Toshiyoshi Fujiwara

    WORLD JOURNAL OF SURGERY   41 ( 9 )   2353 - 2360   2017.9

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    Immune-nutritional status has been recently reported as a prognostic factor in hepatocellular carcinoma (HCC). The controlling nutritional status (CONUT) score has been established as a useful tool to evaluate immune-nutritional status. This study aimed to investigate the efficacy of the CONUT score as a prognostic factor in patients undergoing hepatectomy for HCC.
    A total of 295 patients who underwent curative hepatectomy for HCC between January 2007 and December 2014 were retrospectively analyzed. Patients were divided into two groups according to the CONUT score. The impact of the CONUT score on clinicopathological, surgical, and long-term outcomes was evaluated. Subsequently, the impact of prognostic factors, including the CONUT score, associated with outcomes was assessed using multivariate analyses.
    Of 295 patients, 118 (40%) belonged to the high CONUT group (CONUT score 3). The high CONUT group had a significantly lower 5-year recurrence-free survival rate than the low CONUT group (27.9 vs. 41.4%, p = 0.011) and a significantly lower 5-year overall survival rate (61.9 vs. 74.9%, p = 0.006). In multivariate analyses of prognostic factors, the CONUT score was an independent predictor of recurrence-free survival (hazard ratio = 1.64, p = 0.006) and overall survival (hazard ratio = 2.50, p = 0.001).
    The CONUT score is a valuable preoperative predictor of survival in patients undergoing hepatectomy for HCC.

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  • IS POOR OUTCOME OF LIVING DONOR LIVER TRANSPLANTATION FOR PRIMARY SCLEROSING CHOLANGITIS THE NATURE OF THE DISEASE ITSELF OR INSUFFICIENT IMMUNOSUPPRESSION?

    Takahito Yagi, Daisuke Nobuoka, Yuzo Umeda, Ryuichi Yoshida, Takashi Kuise, Kosei Takagi, Kenjiro Kumano, Toshiyoshi Fujiwara

    TRANSPLANT INTERNATIONAL   30   288 - 289   2017.9

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  • SURGICAL OUTCOMES OF LIVING DONOR LIVER SURGERY: TECHNICAL KNACK FOR ZERO MORBIDITY

    Takashi Kuise, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Kenjiro Kumano, Takeshi Koujima, Kosei Takagi, Toshiyoshi Fujiwara, Takahito Yagi

    TRANSPLANT INTERNATIONAL   30   128 - 129   2017.9

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  • PREDICTION OF SALVAGE LIVER TRANSPLANTATION FOR HCC RECURRENCE: WHEN AND WHICH PATIENT SHOULD WE DECIDE TRANSPLANT?

    Yuzo Umeda, Takahito Yagi, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kenjiro Kumano, Takeshi Koujima, Kosei Takagi, Takeshi Nagasaka, Toshiyoshi Fujiwara

    TRANSPLANT INTERNATIONAL   30   180 - 180   2017.9

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  • ANALYSIS OF PROGNOSTIC FACTORS OF PEDIATRIC LIVING DONOR LIVER TRANSPLANTATION: A SINGLE CENTER EXPERIENCE OF MORTALITY ZERO TRANSPLANTATION FOR CHOLESTATIC DISEASE

    Takahito Yagi, Kosei Takagi, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kenjiro Kumano, Mari Yoshida, Toshiyoshi Fujiwara

    TRANSPLANT INTERNATIONAL   30   158 - 159   2017.9

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  • SNORA21 - An Oncogenic Small Nucleolar RNA, with a Prognostic Biomarker Potential in Human Colorectal Cancer

    Kazuhiro Yoshida, Shusuke Toden, Wenhao Weng, Kunitoshi Shigeyasu, Jinsei Miyoshi, Jacob Turner, Takeshi Nagasaka, Yanlei Ma, Tetsuji Takayama, Toshiyoshi Fujiwara, Ajay Goel

    EBIOMEDICINE   22   68 - 77   2017.8

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    Background: Emerging evidence indicates that small nucleolar RNAs (snoRNAs) play a central role in oncogenesis. Herein, we systematically evaluated expression profiles of snoRNAs in colorectal cancer (CRC) and investigated their clinical and functional role in this malignancy.
    Methods: We compared expression levels of snoRNAs between cancer and normal tissues using publicly available datasets and identified the most differentially expressed and commonly upregulated snoRNAs in CRC. These results were examined in 489 colorectal tissues to assess their clinical significance, followed by a series of in vitro and in vivo experiments to evaluate the functional role of candidate snoRNAs.
    Results: Usingmultiple RNA profiling datasets, we identified consistent overexpression of SNORA21 in CRC. In the clinical validation cohorts, the expression level of SNORA21was upregulated in colorectal adenomas and cancers. Furthermore, elevated SNORA21 emerged as an independent factor for predicting poor survival. Both in vitro and in vivo experiments revealed that CRISPR/Cas9-mediated inhibition of SNORA21 expression resulted in decreased cell proliferation and invasion through modulation of multiple cancer related pathways.
    Conclusions: Wesystematically identified SNORA21 as a key oncogenic snoRNA in CRC, which plays an important role in cancer progression, and might serve as an important prognostic biomarker in CRC. (C) 2017 The Authors. Published by Elsevier B.V.

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  • Training system for laparoscopy-assisted distal gastrectomy

    Shinji Kuroda, Satoru Kikuchi, Naoto Hori, Shuichi Sakamoto, Tetsuya Kagawa, Megumi Watanabe, Tetsushi Kubota, Kazuya Kuwada, Michihiro Ishida, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    SURGERY TODAY   47 ( 7 )   802 - 809   2017.7

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    Purpose Laparoscopy-assisted distal gastrectomy (LADG) is likely to become a standard procedure for gastric cancer, which highlights the importance of establishing a training system in which even inexperienced surgeons can perform this procedure safely. This study assesses our training system for LADG based on short-term surgical outcomes.
    Methods We evaluated retrospectively the short-term outcomes of 100 consecutive LADGs with curative D1/D1+ lymph node dissection. Our training system was assessed based on the learning curve of trainees, and factors related to achieving good-quality operations were analyzed statistically.
    Results Overall, postoperative complications developed in 10 patients (10%), and included one case of anastomotic leakage (1%) and one case of pancreatic fistula (1%). The learning curve of the trainees plateaued after 10 operator cases in terms of operation time. The importance of the trainer's position was also confirmed by the result that the operation time was significantly longer when trainees with &lt;= 10 operator cases performed LADG with a trainer as scopist vs. a trainer as the first assistant. Univariate and multivariate analyses revealed that &gt; 10 operator cases were the most important factor for achieving good-quality operations.
    Conclusion These results show that our current LADG procedure and training system are appropriate and effective.

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  • Training system for laparoscopy-assisted distal gastrectomy

    Shinji Kuroda, Satoru Kikuchi, Naoto Hori, Shuichi Sakamoto, Tetsuya Kagawa, Megumi Watanabe, Tetsushi Kubota, Kazuya Kuwada, Michihiro Ishida, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    SURGERY TODAY   47 ( 7 )   802 - 809   2017.7

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    Purpose Laparoscopy-assisted distal gastrectomy (LADG) is likely to become a standard procedure for gastric cancer, which highlights the importance of establishing a training system in which even inexperienced surgeons can perform this procedure safely. This study assesses our training system for LADG based on short-term surgical outcomes.
    Methods We evaluated retrospectively the short-term outcomes of 100 consecutive LADGs with curative D1/D1+ lymph node dissection. Our training system was assessed based on the learning curve of trainees, and factors related to achieving good-quality operations were analyzed statistically.
    Results Overall, postoperative complications developed in 10 patients (10%), and included one case of anastomotic leakage (1%) and one case of pancreatic fistula (1%). The learning curve of the trainees plateaued after 10 operator cases in terms of operation time. The importance of the trainer's position was also confirmed by the result that the operation time was significantly longer when trainees with &lt;= 10 operator cases performed LADG with a trainer as scopist vs. a trainer as the first assistant. Univariate and multivariate analyses revealed that &gt; 10 operator cases were the most important factor for achieving good-quality operations.
    Conclusion These results show that our current LADG procedure and training system are appropriate and effective.

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  • Circular RNA ciRS-7-A Promising Prognostic Biomarker and a Potential Therapeutic Target in Colorectal Cancer

    Wenhao Weng, Qing Wei, Shusuke Toden, Kazuhiro Yoshida, Takeshi Nagasaka, Toshiyoshi Fujiwara, Sanjun Cai, Huanlong Qin, Yanlei Ma, Ajay Goel

    CLINICAL CANCER RESEARCH   23 ( 14 )   3918 - 3928   2017.7

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    Purpose: Colorectal cancer is one of themost common malignancies worldwide. Recently, a novel circular RNA, ciRS-7, was proposed to be a potential miR-7 sponge. As miR-7, a putative tumor-suppressor, regulates the expression of several important drivers of colorectal cancer, we analyzed the clinical significance of ciRS-7 in colorectal cancer patients.
    Experimental Design: Initially, we evaluated the expression levels of ciRS-7 in a training cohort comprising of 153 primary colorectal cancer tissues and 44 matched normal mucosae. We subsequently confirmed its clinical relevance in an independent validation cohort (n = 165), and evaluated the effect of ciRS-7 on miR-7, and its target genes EGFR and RAF1. Functional analyses were performed in cell lines and an animal model to support clinical findings.
    Results: Our data revealed that ciRS-7 was significantly upregulated in colorectal cancer tissues compared with matched normal mucosae (P = 0.0018), and its overexpression was associated with poor patient survival (P = 0.0224 and 0.0061 in the training and validation cohorts, respectively). Multivariate survival analysis revealed that ciRS-7 emerged as an independent risk factor for overall survival (P = 0.0656 and 0.0324 in the training and validation cohorts, respectively). Overexpression of ciRS-7 in HCT116 and HT29 cells led to the blocking of miR-7 and resulted in a more aggressive oncogenic phenotype, and ciRS-7 overexpression permitted the inhibition of miR-7 and subsequent activation of EGFR and RAF1 oncogenes.
    Conclusions: CiRS-7 is a promising prognostic biomarker in colorectal cancer patients and may serve as a therapeutic target for reducing EGFR-RAF1 activity in colorectal cancer patients. (C) 2017 AACR.

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  • Primary pancreatic-type acinar cell carcinoma of the jejunum with tumor thrombus extending into the mesenteric venous system: a case report and literature review

    Kosei Takagi, Takahito Yagi, Takehiro Tanaka, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Toshiyoshi Fujiwara

    BMC SURGERY   17 ( 1 )   237 - 243   2017.6

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    Background: Although ectopic pancreatic tissue is common in the upper gastrointestinal tract, the incidence of ectopic pancreatic tissue in the jejunum is low, and malignant transformation in ectopic pancreatic tissue is rare. Furthermore, pancreatic-type acinar cell carcinoma (ACC) developing in the jejunum and ACC accompanied by tumor thrombus are extremely rare.
    Case presentation: A 78-year-old-woman presented with melena. Abdominal computed tomography images and endoscopic examination revealed a submucosal jejunal mass with tumor thrombus extending into a jejunal vein. The patient underwent a curative resection combined with a partial jejunectomy and partial pancreatectomy. Histopathological examination of the resected tissue showed tumor cells with a homogeneous acinar architecture identical to pancreatic-type ACC and tumor thrombus. Postoperatively, she was followed for 10 months and had no recurrence.
    Conclusion: We present an extremely rare case of pancreatic-type ACC in the jejunum with extensive tumor thrombus invading into the mesenteric venous system. This type of cancer has not been reported previously but should be considered in the differential diagnosis of a jejunal mass.

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  • Management of early gastric cancer that meet the indication for radical lymph node dissection following endoscopic resection: a retrospective cohort analysis

    Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Tetsuya Kagawa, Hiromitsu Kanzaki, Yoshiro Kawahara, Shunsuke Kagawa, Takehiro Tanaka, Hiroyuki Okada, Toshiyoshi Fujiwara

    BMC SURGERY   17 ( 1 )   687 - 694   2017.6

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    Background: Endoscopic resection (ER) has been widely accepted as the standard treatment for early gastric cancer (EGC). However, in patients considered to have undergone non-curative ER due to their potential risk of lymph node metastasis (LNM), additional gastrectomy is recommended. The aim of the present study was to identify EGC patients after non-curative ER at high risk of LNM.
    Methods: A total of 150 patients who had undergone ER for EGC were diagnosed as non-curative ER due to their potential risk of LNM. Clinicopathological data and clinical outcomes were examined retrospectively.
    Results: Additional gastrectomy with lymph node dissection was performed in 73 patients, and the remaining 77 patients were followed-up without additional gastrectomy. In patients who underwent additional gastrectomy, 8 patients had local residual tumor, and 8 patients had LNM, which were limited in the peritumoral nodes. Only lymphatic invasion (p = 0.012) was a statistically significant factor for LNM. The 5-year overall survival and recurrence-free survival were not significantly different between patients with and without additional gastrectomy.
    Conclusion: Additional gastrectomy with lymph node dissection is recommended for patients who were diagnosed as non-curative ER with lymphatic invasion, and minimizing the extent of lymph node dissection may be allowed for these patients.

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  • Radiographic sarcopenia predicts postoperative infectious complications in patients undergoing pancreaticoduodenectomy

    Kosei Takagi, Ryuichi Yoshida, Takahito Yagi, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Toshiyoshi Fujiwara

    BMC SURGERY   17 ( 1 )   453 - 466   2017.5

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    Background: Recently, skeletal muscle depletion (sarcopenia) has been reported to influence postoperative outcomes after certain procedures. This study investigated the impact of sarcopenia on postoperative outcomes following pancreaticoduodenectomy (PD).
    Methods: We performed a retrospective study of consecutive patients (n = 219) who underwent PD at our institution between January 2007 and May 2013. Sarcopenia was evaluated using preoperative computed tomography. We evaluated postoperative outcomes and the influence of sarcopenia on short-term outcomes, especially infectious complications. Subsequently, multivariate analysis was used to assess the impact of prognostic factors (including sarcopenia) on postoperative infections.
    Results: The mortality, major complication, and infectious complication rates for all patients were 1.4%, 16.4%, and 47.0%, respectively. Fifty-five patients met the criteria for sarcopenia. Sarcopenia was significantly associated with a higher incidence of in-hospital mortality (P = 0.004) and infectious complications (P &lt; 0.001). In multivariate analyses, sarcopenia (odds ratio = 3.43; P &lt; 0.001), preoperative biliary drainage (odds ratio = 2.20; P = 0.014), blood loss (odds ratio = 1.92; P = 0.048), and soft pancreatic texture (odds ratio = 3.71; P &lt; 0.001) were independent predictors of postoperative infections.
    Conclusions: Sarcopenia is an independent preoperative predictor of infectious complications after PD. Clinical assessment combined with sarcopenia may be helpful for understanding the risk of postoperative outcomes and determining perioperative management strategies.

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  • Nonexposure laparoscopic and endoscopic cooperative surgery (closed laparoscopic and endoscopic cooperative surgery) for gastric submucosal tumor

    Satoru Kikuchi, Masahiko Nishizaki, Shinji Kuroda, Shunsuke Tanabe, Kazuhiro Noma, Shunsuke Kagawa, Yasuhiro Shirakawa, Hiroshi Kato, Hiroyuki Okada, Toshiyoshi Fujiwara

    GASTRIC CANCER   20 ( 3 )   553 - 557   2017.5

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    Laparoscopic and endoscopic cooperative surgery (LECS) is increasingly applied for gastric submucosal tumors (SMTs) such as gastrointestinal stromal tumors. However, the conventional LECS procedure has the potential risk that gastric contents and even tumor cells could spread into the abdominal cavity because the gastric wall has to be opened during the resection. To avoid this problem, we have developed a modified LECS procedure named "closed LECS." Ten patients underwent closed LECS for the resection of gastric SMTs. Closed LECS consists of the following steps: endoscopic submucosal layer dissection around the tumor, laparoscopic marking of a resection line on the serosal surface along submucosal dissection line, seromuscular suturing with the marked lesion inverted into the inside of the stomach, endoscopic circumferential seromuscular dissection, and peroral retrieval. In three of the initial five cases, the closed LECS procedure was not completed as planned because of the tumor size and endoscopic inappropriate seromuscular dissection. After modification of the procedure, the entire procedure was successful in all five cases. The mean resected tumor diameter was 24.1 +/- 7.6 mm. The mean operation time was 253 +/- 45 min. One patient experienced an intra-abdominal abscess potentially related to delayed perforation as a postoperative complication. The closed LECS procedure for gastric SMTs can theoretically be applied without contamination and tumor cell dissemination into the abdominal cavity.

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  • Nonexposure laparoscopic and endoscopic cooperative surgery (closed laparoscopic and endoscopic cooperative surgery) for gastric submucosal tumor

    Satoru Kikuchi, Masahiko Nishizaki, Shinji Kuroda, Shunsuke Tanabe, Kazuhiro Noma, Shunsuke Kagawa, Yasuhiro Shirakawa, Hiroshi Kato, Hiroyuki Okada, Toshiyoshi Fujiwara

    GASTRIC CANCER   20 ( 3 )   553 - 557   2017.5

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    Laparoscopic and endoscopic cooperative surgery (LECS) is increasingly applied for gastric submucosal tumors (SMTs) such as gastrointestinal stromal tumors. However, the conventional LECS procedure has the potential risk that gastric contents and even tumor cells could spread into the abdominal cavity because the gastric wall has to be opened during the resection. To avoid this problem, we have developed a modified LECS procedure named "closed LECS." Ten patients underwent closed LECS for the resection of gastric SMTs. Closed LECS consists of the following steps: endoscopic submucosal layer dissection around the tumor, laparoscopic marking of a resection line on the serosal surface along submucosal dissection line, seromuscular suturing with the marked lesion inverted into the inside of the stomach, endoscopic circumferential seromuscular dissection, and peroral retrieval. In three of the initial five cases, the closed LECS procedure was not completed as planned because of the tumor size and endoscopic inappropriate seromuscular dissection. After modification of the procedure, the entire procedure was successful in all five cases. The mean resected tumor diameter was 24.1 +/- 7.6 mm. The mean operation time was 253 +/- 45 min. One patient experienced an intra-abdominal abscess potentially related to delayed perforation as a postoperative complication. The closed LECS procedure for gastric SMTs can theoretically be applied without contamination and tumor cell dissemination into the abdominal cavity.

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  • Outcome of Radiation Monotherapy for High-risk Patients with Stage I Esophageal Cancer

    Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Shunsuke Tanabe, Shinji Kuroda, Shunsuke Kagawa, Kuniaki Katsui, Norihisa Katayama, Susumu Kanazawa, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   71 ( 2 )   127 - 133   2017.4

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    Currently, chemoradiation is the most widely used nonsurgical treatment for esophageal cancer. However, some patients, particularly the very elderly or those with severe vital organ dysfunction, face difficulty with the chemotherapy component. We therefore examined the outcome of radiation therapy (RT) alone for patients with esophageal cancer at our facility. Between January 2005 and December 2014, 84 patients underwent RT at our hospital, and 78 of these patients received concomitant chemotherapy. The remaining 6 patients underwent RT alone; these patients were considered to be high-risk and to have no lymph node metastasis (stage I). Five of them received irradiation up to a curative dose: 4 showed a complete response (CR) and 1 showed a partial response (PR). Of the patients exhibiting CR, 3 are currently living recurrence-free, whereas 1 patient underwent endoscopic submucosal dissection (ESD) as salvage therapy for local recurrence, with no subsequent recurrence. High-risk stage I esophageal cancer patients can be treated radically with RT alone under certain conditions. In the future, to broaden the indications for RT monotherapy to include some degree of advanced cancers, a novel concurrent therapy should be identified.

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  • Outcome of Radiation Monotherapy for High-risk Patients with Stage I Esophageal Cancer

    Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Shunsuke Tanabe, Shinji Kuroda, Shunsuke Kagawa, Kuniaki Katsui, Norihisa Katayama, Susumu Kanazawa, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   71 ( 2 )   127 - 133   2017.4

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    Currently, chemoradiation is the most widely used nonsurgical treatment for esophageal cancer. However, some patients, particularly the very elderly or those with severe vital organ dysfunction, face difficulty with the chemotherapy component. We therefore examined the outcome of radiation therapy (RT) alone for patients with esophageal cancer at our facility. Between January 2005 and December 2014, 84 patients underwent RT at our hospital, and 78 of these patients received concomitant chemotherapy. The remaining 6 patients underwent RT alone; these patients were considered to be high-risk and to have no lymph node metastasis (stage I). Five of them received irradiation up to a curative dose: 4 showed a complete response (CR) and 1 showed a partial response (PR). Of the patients exhibiting CR, 3 are currently living recurrence-free, whereas 1 patient underwent endoscopic submucosal dissection (ESD) as salvage therapy for local recurrence, with no subsequent recurrence. High-risk stage I esophageal cancer patients can be treated radically with RT alone under certain conditions. In the future, to broaden the indications for RT monotherapy to include some degree of advanced cancers, a novel concurrent therapy should be identified.

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  • Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers

    Takayuki Iwamoto, Toyomasa Katagiri, Naoki Niikura, Yuichiro Miyoshi, Mariko Kochi, Tomohiro Nogami, Tadahiko Shien, Takayuki Motoki, Naruto Taira, Masako Omori, Yutaka Tokuda, Toshiyoshi Fujiwara, Hiroyoshi Doihara, Balazs Gyorffy, Junji Matsuoka

    ONCOTARGET   8 ( 16 )   26122 - 26128   2017.4

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    Background: The purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers.
    Results: Thirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P &lt; 0.001). PostKi67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P &lt; 0.001 and 0.041, respectively).
    Materials and Methods: Core needle biopsy specimens of primary breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre-and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed.
    Conclusions: IHC based post-Ki67 levels may have distinct predictive power compared with the naive IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.

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  • Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers

    Takayuki Iwamoto, Toyomasa Katagiri, Naoki Niikura, Yuichiro Miyoshi, Mariko Kochi, Tomohiro Nogami, Tadahiko Shien, Takayuki Motoki, Naruto Taira, Masako Omori, Yutaka Tokuda, Toshiyoshi Fujiwara, Hiroyoshi Doihara, Balazs Gyorffy, Junji Matsuoka

    ONCOTARGET   8 ( 16 )   26122 - 26128   2017.4

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    Background: The purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers.
    Results: Thirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P &lt; 0.001). PostKi67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P &lt; 0.001 and 0.041, respectively).
    Materials and Methods: Core needle biopsy specimens of primary breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre-and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed.
    Conclusions: IHC based post-Ki67 levels may have distinct predictive power compared with the naive IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.

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  • High-metastatic triple-negative breast-cancer variants selected in vivo become chemoresistant in vitro

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL   53 ( 4 )   285 - 287   2017.4

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    DOI: 10.1007/s11626-016-0117-y

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  • Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    JOURNAL OF CELLULAR BIOCHEMISTRY   118 ( 3 )   559 - 569   2017.3

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    We previously developed and characterized a highly invasive and metastatic triple-negative breast cancer (TNBC) variant by serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Eventually, a highly invasive and metastatic variant of human TNBC was isolated after lymph node metastases was harvested and orthotopically re-implanted into the mammary gland of nude mice for two cycles. The variant thereby isolated is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present report, we observed that high-metastatic MDA-MB-231H-RFP cells produced significantly larger subcutaneous tumors compared with parental MDA-MB-231 cells in nude mice. Extensive lymphatic trafficking by high-metastatic MDA-MB-231 cells was also observed. High-metastatic MDA-MB-231 developed larger recurrent tumors 2 weeks after tumor resection compared with tumors that were not resected in orthotopic models. Surgical resection of the MDA-MB-231 high-metastatic variant primary tumor in orthotopic models also resulted in rapid and enhanced lymphatic trafficking of residual cancer cells and extensive lymph node and lung metastasis that did not occur in the non-surgical mice. These results suggest that surgical resection of high metastatic TNBC can greatly increase the malignancy of residual cancer. J. Cell. Biochem. 118: 559-569, 2017. (c) 2016 Wiley Periodicals, Inc.

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  • Early Chimerism After Liver Transplantation Reflects the Clinical Course of Recurrent Hepatitis C

    Masashi Utsumi, Akinobu Takaki, Yuzo Umeda, Kazuko Koike, Stephanie C. Napier, Nobukazu Watanabe, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Takahiro Oto, Motoo Araki, Kazuhide Yamamoto, Toshiyoshi Fujiwara, Takahito Yagi

    ANNALS OF TRANSPLANTATION   22   156 - 165   2017.3

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    Background: Human leukocyte antigen (HLA) mismatch is a characteristic feature of post-orthotopic liver transplantation (OLT) hepatitis C. To investigate the importance of donor HLA-restricted immune cells in post-OLT hepatitis C recurrence, we analyzed the frequency of donor chimerism and the clinical course of post-OLT hepatitis C.
    Material/Methods: We analyzed peripheral blood chimerism in 11 HCV-reinfected patients with post-HLA mismatched OLT. Patients were divided into 2 groups: the OLT chronic hepatitis C (CHC) group (n=8), exhibiting active hepatitis C recurrence; and the OLT-persistently normal ALT (PNALT) group (n=3), without active hepatitis. Chimerism was analyzed by flow cytometry using donor-specific anti-HLA antibodies in peripheral blood mononuclear cells from 1-100 days after OLT. Kidney (n=7) and lung (n=7) transplant recipients were also analyzed for comparison. As immune cells from the donor liver might contribute to post-OLT chimerism, the characteristics of perfusates from donor livers (n=10) were analyzed and defined.
    Results: Donor-derived cells were frequently observed in liver and lung transplant recipients. The frequency of donor-derived cells from the B cell subset was significantly higher in peripheral blood from OLT-CHC group than in that of the OLT-PNALT group. B cells, however, were not the predominant subset in the perfusates, indicating that inflow of donor-derived cells alone did not cause the chimerism.
    Conclusions: Chimerism of B cells is frequent in liver transplant patients with early recurrence of hepatitis C. We propose that monitoring of early chimerism could facilitate early detection of chronic hepatitis C recurrence, although we need more cases to investigate.

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  • Early Chimerism After Liver Transplantation Reflects the Clinical Course of Recurrent Hepatitis C

    Masashi Utsumi, Akinobu Takaki, Yuzo Umeda, Kazuko Koike, Stephanie C. Napier, Nobukazu Watanabe, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Takahiro Oto, Motoo Araki, Kazuhide Yamamoto, Toshiyoshi Fujiwara, Takahito Yagi

    ANNALS OF TRANSPLANTATION   22   156 - 165   2017.3

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    Background: Human leukocyte antigen (HLA) mismatch is a characteristic feature of post-orthotopic liver transplantation (OLT) hepatitis C. To investigate the importance of donor HLA-restricted immune cells in post-OLT hepatitis C recurrence, we analyzed the frequency of donor chimerism and the clinical course of post-OLT hepatitis C.
    Material/Methods: We analyzed peripheral blood chimerism in 11 HCV-reinfected patients with post-HLA mismatched OLT. Patients were divided into 2 groups: the OLT chronic hepatitis C (CHC) group (n=8), exhibiting active hepatitis C recurrence; and the OLT-persistently normal ALT (PNALT) group (n=3), without active hepatitis. Chimerism was analyzed by flow cytometry using donor-specific anti-HLA antibodies in peripheral blood mononuclear cells from 1-100 days after OLT. Kidney (n=7) and lung (n=7) transplant recipients were also analyzed for comparison. As immune cells from the donor liver might contribute to post-OLT chimerism, the characteristics of perfusates from donor livers (n=10) were analyzed and defined.
    Results: Donor-derived cells were frequently observed in liver and lung transplant recipients. The frequency of donor-derived cells from the B cell subset was significantly higher in peripheral blood from OLT-CHC group than in that of the OLT-PNALT group. B cells, however, were not the predominant subset in the perfusates, indicating that inflow of donor-derived cells alone did not cause the chimerism.
    Conclusions: Chimerism of B cells is frequent in liver transplant patients with early recurrence of hepatitis C. We propose that monitoring of early chimerism could facilitate early detection of chronic hepatitis C recurrence, although we need more cases to investigate.

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  • A Novel "Shrug Technique" for Totally Implantable Venous Access Devices via the External Jugular Vein: A Consecutive Series of 254 Patients

    Tetsuya Kagawa, Satoshi Ueyama, Tatsunori Kobayashi, Hiroki Okabayashi, Shinji Kuroda, Toshiyoshi Fujiwara

    JOURNAL OF SURGICAL ONCOLOGY   115 ( 3 )   291 - 295   2017.3

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    Background: The external jugular vein (EJV) approach for totally implantable venous access devices (TIVADs) is safe. However, the success rate is unsatisfactory because of the difficulty in catheterization due to the acute angle between the EJV and the subclavian vein (SCV). A novel "shrug technique" to overcome this difficulty was developed, and its efficacy was assessed in a consecutive case series.
    Methods: TIVAD placement was performed via the EJV cut-down approach. "Shrug technique," a simple way to straighten the EJV-SVC angle by shrugging the patient's shoulder, was applied to facilitate the passage of the guidewire and sheath-introducer when there was acute angulation between the EJV and SCV.
    Results: A total of 254 patients underwent TIVAD implantation by the EJV cut-down approach. The " shrug technique" was applied in 51 cases (20%), and catheterization was successful in all cases. Thus, TIVAD implantation was successfully completed in all 254 cases (100%) in a single operative setting. The median operating time was 38 [IQR 30-45] min. Eleven complications (4%) were observed, but none of them were EJV-specific.
    Conclusion: The " shrug technique" is simple but very useful to achieve a higher success rate and safer insertion of TIVADs from the EJV. (C) 2016 Wiley Periodicals, Inc.

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  • A Novel "Shrug Technique" for Totally Implantable Venous Access Devices via the External Jugular Vein: A Consecutive Series of 254 Patients

    Tetsuya Kagawa, Satoshi Ueyama, Tatsunori Kobayashi, Hiroki Okabayashi, Shinji Kuroda, Toshiyoshi Fujiwara

    JOURNAL OF SURGICAL ONCOLOGY   115 ( 3 )   291 - 295   2017.3

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    Background: The external jugular vein (EJV) approach for totally implantable venous access devices (TIVADs) is safe. However, the success rate is unsatisfactory because of the difficulty in catheterization due to the acute angle between the EJV and the subclavian vein (SCV). A novel "shrug technique" to overcome this difficulty was developed, and its efficacy was assessed in a consecutive case series.
    Methods: TIVAD placement was performed via the EJV cut-down approach. "Shrug technique," a simple way to straighten the EJV-SVC angle by shrugging the patient's shoulder, was applied to facilitate the passage of the guidewire and sheath-introducer when there was acute angulation between the EJV and SCV.
    Results: A total of 254 patients underwent TIVAD implantation by the EJV cut-down approach. The " shrug technique" was applied in 51 cases (20%), and catheterization was successful in all cases. Thus, TIVAD implantation was successfully completed in all 254 cases (100%) in a single operative setting. The median operating time was 38 [IQR 30-45] min. Eleven complications (4%) were observed, but none of them were EJV-specific.
    Conclusion: The " shrug technique" is simple but very useful to achieve a higher success rate and safer insertion of TIVADs from the EJV. (C) 2016 Wiley Periodicals, Inc.

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  • OBP-401-GFP telomerase-dependent adenovirus illuminates and kills high-metastatic more effectively than low-metastatic triple-negative breast cancer in vitro

    S. Yano, K. Takehara, H. Kishimoto, H. Tazawa, Y. Urata, S. Kagawa, M. Bouvet, T. Fujiwara, R. M. Hoffman

    CANCER GENE THERAPY   24 ( 2 )   45 - 47   2017.2

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    We previously described the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. The isolated variant is highly invasive in the mammary gland and Metastasized to lymph nodes in 10 of 12 mice compared with 2 of 12 of the parental cell line. OBP-401 is a telomerase-dependent cancer-specific, green fluorescent protein (GFP)-expressing adenovirus. OBP-401 was used to infect parental MDA-MB-231P cells and high-metastatic MDA-MB-231H and MDA-MB-231HLN isolated from a lymph node metastasis and MDA-MB-231HLM isolated from a lung metastasis. Time-course imaging showed that OBP-401 labeled MDA-MB-231HP, MDA-MB-231HLN, and MDA-MB-231HLM cells more brightly than MDA-MB-231 parental cells. OBP-401 killed MDA-MB-231H, MDA-MB-231HLN, and MDA-MB-231HLM cells more efficiently than MDA-MB-231P parental cells. These results indicate that OBP-401 could infect, label and then kill high-metastatic MDA-MB-231 more efficiently than low-metastatic MDA-MB-231.

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  • Comparison of in vitro invasiveness of high- and low-metastatic triple-negative human breast cancer visualized by color-coded imaging

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL   53 ( 2 )   96 - 98   2017.2

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    DOI: 10.1007/s11626-016-0092-3

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  • Syndrome of Inappropriate Antidiuretic Hormone Secretion Following Liver Transplantation

    Kosei Takagi, Takahito Yagi, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Nobuyuki Watanabe, Takashi Kuise, Tomokazu Fuji, Hiroyuki Araki, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   71 ( 1 )   85 - 89   2017.2

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    Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an extremely rare cause of hyponatremia post-liver transplantation. A 15-year-old Japanese girl with recurrent cholangitis after Kasai surgery for biliary atresia underwent successful living donor liver transplantation. Peritonitis due to gastrointestinal perforation occurred. Hyponatremia gradually developed but improved after hypertonic sodium treatment. One month later, severe hyponatremia rapidly recurred. We considered the hyponatremia's cause as SIADH. We suspected that tacrolimus was the disease's cause, so we used cyclosporine instead, plus hypertonic sodium plus water intake restriction, which improved the hyponatremia. Symptomatic hyponatremia manifested by SIADH is a rare, serious complication post-liver transplantation.

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  • Comparison of Tumor Recurrence After Resection of Highly- and Poorly-Metastatic Triple-negative Breast Cancer in Orthotopic Nude-Mouse Models

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Michael Bouvet, Robert M. Hoffman

    ANTICANCER RESEARCH   37 ( 1 )   57 - 60   2017.1

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    Background: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2, is a recalcitrant disease in need of effective therapy. We previously isolated highly-metastatic variants of the human TNBC cell line MDA-MB-231 using serial orthotopic implantation in nude mice. Materials and Methods: In the present report, we compared local and metastatic recurrence in lymph nodes in orthotopic nude-mouse models after bright-light surgery (BLS) of tumors from highly-metastatic variants or poorly-metastatic parental MDA-MB-231-RFP cells. Orthotopic tumors from parental MDA-MB-231 or highly-metastatic MDA-MB-231 were resected under bright light similar to an operating room. Results: After resection of primary tumors, local recurrence from highly-metastatic MDA-MB-231 cells grew more rapidly than did parental MDA-MB-231 cells. Lymph-node metastasis from highly-metastatic MDA-MB-231 cells occurred after primary tumor resection much more extensively than after parental MDAMB- 231 tumors were resected. Conclusion: The results of the present report suggest that conventional surgery under bright light was unable to control highly-metastatic compared with poorly-metastatic MDA-MB-231 TNBC.

    DOI: 10.21873/anticanres.11288

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  • Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study

    Nobuaki Suzuki, Shoichi Hazama, Haruo Iguchi, Kazuhiro Uesugi, Hiroaki Tanaka, Kosei Hirakawa, Atsushi Aruga, Takashi Hatori, Hidenobu Ishizaki, Yuzo Umeda, Toshiyoshi Fujiwara, Tetsuya Ikemoto, Mitsuo Shimada, Kazuhiko Yoshimatsu, Ryoichi Shimizu, Hiroto Hayashi, Koichiro Sakata, Hiroko Takenouchi, Hiroto Matsui, Yoshitaro Shindo, Michihisa Iida, Yasunobu Koki, Hideki Arima, Hiroyuki Furukawa, Tomio Ueno, Shigefumi Yoshino, Yusuke Nakamura, Masaaki Oka, Hiroaki Nagano

    CANCER SCIENCE   108 ( 1 )   73 - 80   2017.1

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    We previously conducted a phase I clinical trial combining the HLA-A*2402-restricted KIF20A-derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single-armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naive PC patients were enrolled to evaluate primarily the 1-year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide-specific immune responses. All enrolled patients received therapy without the HLA-A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1-year survival rates between the HLA-A*2402-matched and -unmatched groups were not significantly different. In the HLA-A*2402 matched group, patients showing peptide-specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA-A*2402-matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide-specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.

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  • Comparison of Tumor Recurrence After Resection of Highly- and Poorly-Metastatic Triple-negative Breast Cancer in Orthotopic Nude-Mouse Models

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Michael Bouvet, Robert M. Hoffman

    ANTICANCER RESEARCH   37 ( 1 )   57 - 60   2017.1

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    Background: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2, is a recalcitrant disease in need of effective therapy. We previously isolated highly-metastatic variants of the human TNBC cell line MDA-MB-231 using serial orthotopic implantation in nude mice. Materials and Methods: In the present report, we compared local and metastatic recurrence in lymph nodes in orthotopic nude-mouse models after bright-light surgery (BLS) of tumors from highly-metastatic variants or poorly-metastatic parental MDA-MB-231-RFP cells. Orthotopic tumors from parental MDA-MB-231 or highly-metastatic MDA-MB-231 were resected under bright light similar to an operating room. Results: After resection of primary tumors, local recurrence from highly-metastatic MDA-MB-231 cells grew more rapidly than did parental MDA-MB-231 cells. Lymph-node metastasis from highly-metastatic MDA-MB-231 cells occurred after primary tumor resection much more extensively than after parental MDAMB- 231 tumors were resected. Conclusion: The results of the present report suggest that conventional surgery under bright light was unable to control highly-metastatic compared with poorly-metastatic MDA-MB-231 TNBC.

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  • Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer

    Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Masashi Tachibana, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi

    MOLECULAR CANCER THERAPEUTICS   16 ( 1 )   251 - 259   2017.1

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    Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter- driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad. Based on these findings, we herein developed a novel TRAD expressing shorthairpin RNA against Dicer (shDicer; TRAD-shDicer). After infection, TRAD-shDicer efficiently induced the knockdown of Dicer. TRAD-shDicer showed significantly higher replication efficiency and tumor cell lysis activity compared with the conventional TRAD in tumor cells. The Dicer expression levels and viabilities of normal cells were not altered by infection with TRAD-shDicer. These results indicate that TRAD-shDicer is a potent antitumor reagent by virtue of its enhanced oncolytic activity. (C) 2016 AACR.

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  • Enhanced Oncolytic Activities of the Telomerase-Specific Replication-Competent Adenovirus Expressing Short-Hairpin RNA against Dicer

    Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Masashi Tachibana, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi

    MOLECULAR CANCER THERAPEUTICS   16 ( 1 )   251 - 259   2017.1

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    Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter- driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad. Based on these findings, we herein developed a novel TRAD expressing shorthairpin RNA against Dicer (shDicer; TRAD-shDicer). After infection, TRAD-shDicer efficiently induced the knockdown of Dicer. TRAD-shDicer showed significantly higher replication efficiency and tumor cell lysis activity compared with the conventional TRAD in tumor cells. The Dicer expression levels and viabilities of normal cells were not altered by infection with TRAD-shDicer. These results indicate that TRAD-shDicer is a potent antitumor reagent by virtue of its enhanced oncolytic activity. (C) 2016 AACR.

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  • Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study

    Nobuaki Suzuki, Shoichi Hazama, Haruo Iguchi, Kazuhiro Uesugi, Hiroaki Tanaka, Kosei Hirakawa, Atsushi Aruga, Takashi Hatori, Hidenobu Ishizaki, Yuzo Umeda, Toshiyoshi Fujiwara, Tetsuya Ikemoto, Mitsuo Shimada, Kazuhiko Yoshimatsu, Ryoichi Shimizu, Hiroto Hayashi, Koichiro Sakata, Hiroko Takenouchi, Hiroto Matsui, Yoshitaro Shindo, Michihisa Iida, Yasunobu Koki, Hideki Arima, Hiroyuki Furukawa, Tomio Ueno, Shigefumi Yoshino, Yusuke Nakamura, Masaaki Oka, Hiroaki Nagano

    CANCER SCIENCE   108 ( 1 )   73 - 80   2017.1

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    We previously conducted a phase I clinical trial combining the HLA-A*2402-restricted KIF20A-derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single-armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naive PC patients were enrolled to evaluate primarily the 1-year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide-specific immune responses. All enrolled patients received therapy without the HLA-A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1-year survival rates between the HLA-A*2402-matched and -unmatched groups were not significantly different. In the HLA-A*2402 matched group, patients showing peptide-specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA-A*2402-matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide-specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.

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  • Sarcopenia predicts postoperative infection in patients undergoing hepato-biliary-pancreatic surgery

    Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Toshiyoshi Fujiwara

    International Journal of Surgery Open   6   12 - 18   2017

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    Background Operative mortality and morbidity rates after hepato-biliary-pancreatic (BILI) surgery remain high. This study evaluated clinical characteristics and surgical outcomes of patients who underwent BILI surgery and investigated predictors of outcomes by focusing on sarcopenia. Materials and methods A prospective observational study was performed for consecutive patients who underwent BILI surgery at our institution between June 2013 and May 2014. Sarcopenia was evaluated using computed tomography. Surgical outcomes and the influence of sarcopenia on outcomes were evaluated. Subsequently, the impact of prognostic factors, including sarcopenia, associated with postoperative infections was assessed using multivariate analyses. Results Total mortality, major complications, and infectious disease rates for all 157 patients were 0%, 9.6%, and 21.7%, respectively. Thirty-eight patients met the criteria for sarcopenia. The sarcopenic group had a significantly higher incidence of infectious complications compared to the non-sarcopenic group (36.8% vs. 17.2%
    P = 0.015). During multivariate analyses of prognostic factors, sarcopenia (hazard ratio = 2.44
    P = 0.043) and diabetes mellitus (hazard ratio = 3.07
    P = 0.01) were detected as independent predictors of postoperative infections. Conclusions Sarcopenia is an independent preoperative predictor of infection after BILI surgery. Earlier diagnosis and therapeutic intervention for patients with sarcopenia could be useful in the development of comprehensive approaches for perioperative care.

    DOI: 10.1016/j.ijso.2016.12.002

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  • Primary pancreatic-type acinar cell carcinoma of the jejunum with tumor thrombus extending into the mesenteric venous system: a case report and literature review

    Takagi K, Yagi T, Tanaka T, Umeda Y, Yoshida R, Nobuoka D, Kuise T, Fujiwara T

    BMC Surg   17 ( 75 )   doi: 10.1186/s12893-017-0273-3   2017

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  • Management of early gastric cancer that meet the indication for radical lymph node dissection following endoscopic resection: a retrospective cohort analysis

    Kikuchi S, Kuroda S, Nishizaki M, Kagawa T, Kanzaki H, Kawahara Y, Kagawa S, Tanaka T, Okada H, Fujiwara T

    BMC Surg   17 ( 1 )   doi: 10.1186/s12893-017-0268-0   2017

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  • GFP labeling kinetics of triple-negative human breast cancer by a killer-reporter adenovirus in 3D Gelfoam® histoculture

    Yano S, Takehara K, Miwa S, Kishimoto H, Tazawa H, Urata Y, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM

    In Vitro Cell Dev Biol Anim   53 ( 6 )   479 - 482   2017

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  • 胃癌術後再発病変に対する複数回の放射線療法が奏功し長期生存が得られた1例

    堀 直人, 香川俊輔, 菊地覚次, 黒田新士, 渡邉めぐみ, 坂本修一, 香川哲也, 桒田和也, 久保田哲史, 岸本浩行, 西﨑正彦, 片山敬久, 藤原俊義

    癌と化学療法   44 ( 2 )   165 - 167   2017

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  • Multiple Salvage Radiotherapies for Metachronous Lymph Node Metastasis from Gastric Cancer Contributed to Long-Term Management of Disease

    Naoto Hori, Shunsuke Kagawa, Satoru Kikuchi, Shinji Kuroda, Megumi Watanabe, Shuichi Sakamoto, Tetsuya Kagawa, Kazuya Kuwada, Tetsushi Kubota, Hiroyuki Kishimoto, Masahiko Nishizaki, Norihisa Katayama, Toshiyoshi Fujiwara

    Japanese Journal of Cancer and Chemotherapy, Gan to kagaku ryoho. Cancer & chemotherapy   44 ( 2 )   165 - 167   2017

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  • GFP labeling kinetics of triple-negative human breast cancer by a killer-reporter adenovirus in 3D Gelfoam? histoculture

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert, M. Hoffman

    In Vitro Cellular and Developmental Biology - Plant, In Vitro Cellular and Developmental Biology - Animal   1 - 4   2017

  • Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    CELL CYCLE   16 ( 5 )   406 - 414   2017

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    We previously demonstrated that quiescent cancer cells in a tumor are resistant to conventional chemotherapy as visualized with a fluorescence ubiquitination cell cycle indicator (FUCCI). We also showed that proliferating cancer cells exist in a tumor only near nascent vessels or on the tumor surface as visualized with FUCCI and green fluorescent protein (GFP)-expressing tumor vessels. In the present study, we show the relationship between cell-cycle phase and chemotherapy-induced tumor angiogenesis using in vivo FUCCI real-time imaging of the cell cycle and nestin-driven GFP to detect nascent blood vessels. We observed that chemotherapy-treated tumors, consisting of mostly of quiescent cancer cells after treatment, had much more and deeper tumor vessels than untreated tumors. These newly-vascularized cancer cells regrew rapidly after chemotherapy. In contrast, formerly quiescent cancer cells decoyed to S/G(2) phase by a telomerase-dependent adenovirus did not induce tumor angiogenesis. The present results further demonstrate the importance of the cancer-cell position in the cell cycle in order that chemotherapy be effective and not have the opposite effect of stimulating tumor angiogenesis and progression.

    DOI: 10.1080/15384101.2016.1220461

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  • 40年経過した食道アカラシア術後の食道拡張・下部食道狭窄症に対して胸腔鏡下食道亜全摘が著効した1例

    桂 佑貴, 白川靖博, 田邊俊介, 前田直見, 野間和広, 藤原俊義

    岡山医学会雑誌   129 ( 1 )   41 - 44   2017

  • 食道胃接合部癌に対する下部食道噴門側胃切除術-腹臥位胸腔鏡・腹腔鏡アプローチによる完全鏡視下手術-

    野間和広, 白川靖博, 田辺俊介, 黒田新士, 西﨑正彦, 藤原俊義

    手術   71 ( 5 )   767 - 772   2017

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  • Radiographic sarcopenia predicts postoperative infectious complications in patients undergoing pancreaticoduodenectomy

    Takagi K, Yoshida R, Yagi T, Umeda Y, Nobuoka D, Kuise T, Fujiwara T

    BMC Surg   17 ( 64 )   DOI: 10.1186/s12893-017-0261-7   2017

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  • A case of long-term survival after surgical resection for solitary adrenal recurrence of esophageal squamous carcinoma

    Kanaya N, Noma K, Okada T, Maeda N, Tanabe S, Sakurama K, Shirakawa Y, Fujiwara T

    Surg Case Rep   3 ( 61 )   doi: 10.1186/s40792-017-0337-8   2017

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  • Comparison of outcomes between symptomatic and asymptomatic patients with colorectal cancer: a propensity score-matched analysis of surgical invasiveness, medical costs and oncological outcomes

    Inada R, Nagasaka T, Watanabe A, Yagi T, Mori Y, Kondo Y, Kishimoto H, Umeda Y, Fujiwara T

    BMJ Open Gastroenterol   4 ( 1 )   doi: 10.1136/bmjgast-2017-000146   2017

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  • Impact of Autophagy in Oncolytic Adenoviral Therapy for Cancer

    Tazawa H, Kuroda S, Hasei J, Kagawa S, Fujiwara T

    Int J Mol Sci   18 ( 7 )   doi:10.3390/ijms18071479   2017

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  • Eradication of melanoma in vitro and in vivo via targeting with a Killer-Red-containing telomerase-dependent adenovirus

    Kiyoto Takehara, Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Nobuhiro Narii, Hiroyuki Mizuguchi, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert, M. Hoffman

    Cell Cycle   1 - 7   2017

  • A novel intestinal rotation method for digestive reconstruction after combined pancreaticoduodenectomy and extended right hemicolectomy: A case report and surgical technique

    Kosei Takagi, Takahito Yagi, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kenjiro Kumano, Takeshi Kojima, Takuro Fushimi, Toshiyoshi Fujiwara

    International Journal of Surgery Case Reports   39   51 - 55   2017

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    Introduction Pancreaticoduodenectomy (PD) combined with extended right hemicolectomy (RH) is a challenging procedure for locally advanced malignancies. However, information concerning the reconstruction method of the digestive system is limited. Here, we present a case and surgical technique of a novel intestinal rotation method for digestive reconstruction after PD combined with RH. Presentation of case A 62-year-old man with locally advanced pancreatic cancer received conversion surgery combined with PD and RH after preoperative chemotherapy. With respect to the reconstruction of the digestive system, the entire intestinal mesentery was rotated 180° forward counterclockwise around the axis of the superior mesenteric artery, and then the reconstruction, according to Child's method, was performed. The patient recovered without problems in gastroenterological functions after the operation. Discussion With respect to the reconstruction of the digestive system in patients undergoing combined PD and RH, practitioners should pay close attention to twisting of the intestinal mesentery when bringing up the proximal jejunum for pancreatojejunostomy and hepatojejunostomy and the distal ileum for ileocolic anastomosis. This intestinal rotation method enables a smooth and uneventful reconstruction of the digestive system. Conclusion This is the first detailed description of an intestinal rotation method for digestive reconstruction after combined PD and extended RH. The intestinal rotation method can be an alternative and helpful technical option for digestive reconstruction in patients with combined PD and RH.

    DOI: 10.1016/j.ijscr.2017.07.063

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  • Role of zoledronic acid in oncolytic virotherapy

    Yasuaki Yamakawa, Hiroshi Tazawa, Joe Hasei, Shuhei Osaki, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Kouji Uotani, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    Cancer Science, Japanese Journal of Cancer Research, Gann, The Japanese Journal of Cancer Research   149 - 160   2017

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  • Visualized Evaluation of Blood Flow to the Gastric Conduit and Complications in Esophageal Reconstruction

    Kazuhiro Noma, Yasuhiro Shirakawa, Nobuhiko Kanaya, Tsuyoshi Okada, Naoaki Maeda, Takayuki Ninomiya, Shunsuke Tanabe, Kazufumi Sakurama, Toshiyoshi Fujiwara

    Journal of the American College of Surgeons, Surgery Gynecology and Obstetrics   858 - 867   2017

  • Preoperative Controlling Nutritional Status (CONUT) Score for Assessment of Prognosis Following Hepatectomy for Hepatocellular Carcinoma

    Kosei Takagi, Takahito Yagi, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Hiroyuki Araki, Toshiyoshi Fujiwara

    World Journal of Surgery, Bulletin de la Societe internationale de chirurgie   1 - 8   2017

  • Therapeutic Cell-Cycle-Decoy Efficacy of a Telomerase-Dependent Adenovirus in an Orthotopic Model of Chemotherapy-Resistant Human Stomach Carcinomatosis Peritonitis Visualized With FUCCI Imaging

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert, M. Hoffman

    Journal of Cellular Biochemistry, Journal of Supramolecular and Cellular Biochemistry, Journal of supramolecular structure   476 - 479   2017

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  • Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer

    Shindo Y, Hazama S, Suzuki N, Iguchi H, Uesugi K, Tanaka H, Aruga A, Hatori T, Ishizaki H, Umeda Y, Fujiwara T, Ikemoto T, Shimada M, Yoshimatsu K, Takenouchi H, Matsui H, Kanekiyo S, Iida M, Koki Y, Arima H, Furukawa H, Ueno T, Yoshino S, Fujita T, Kawakami Y, Nakamura Y, Oka M, Nagano H

    J Exp Clin Cancer Res   36 ( 1 )   doi: 10.1186/s13046-017-0509-1   2017

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  • OBP-401-GFP telomerase-dependent adenovirus illuminates and kills high-metastatic more effectively than low-metastatic triple-negative breast cancer in vitro.

    Yano S, Takehara K, Kishimoto H, Tazawa H, Urata Y, Kagawa S, Bouvet M, Fujiwara T, Hoffman R.M

    Cancer Gene Therapy   20 ( 2 )   45 - 47   2017

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  • Living donor liver transplantation for acute liver failure

    Kazuhiro Yoshida, Yuzo Umeda, Akinobu Takaki, Takeshi Nagasaka, Ryuichi Yoshida, Daisuke Nobuoka, Takashi Kuise, Kosei Takagi, Tetsuya Yasunaka, Hiroyuki Okada, Takahito Yagi, Toshiyoshi Fujiwara

    Acta Medica Okayama, Acta. Medica Okayama, Acta medicinae Okayama, Acta medica Okayama   71 ( 5 )   381 - 390   2017

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  • 遅発性に肝転移・骨盤内リンパ節転移をきたした直腸神経内分泌腫瘍の1例

    重安邦俊, 杭瀬崇, 母里淑子, 河合毅, 矢野修也, 戸嶋俊明, 浅野博昭, 近藤喜太, 佃和憲, 永坂岳司, 八木孝仁, 藤原俊義

    日本大腸肛門病学会雑誌(Web)   70   2017

  • 癌関連線維芽細胞はIL-6を分泌しリンパ球の遊走を制御することで腫瘍免疫抑制を誘導する

    加藤卓也, 野間和広, 賀島肇, 桂佑貴, 佐藤浩明, 二宮卓之, 大原利章, 藤原俊義

    日本がん転移学会学術集会・総会プログラム抄録集   26th   2017

  • 癌関連線維芽細胞は食道癌のリンパ節転移を促進するか~臨床検体の解析と同所移植モデルを用いた検証~

    賀島肇, 野間和広, 佐藤浩明, 桂佑貴, 加藤卓也, 大原利章, 田澤大, 白川靖博, 藤原俊義

    日本がん転移学会学術集会・総会プログラム抄録集   26th   2017

  • In Vivo Selection of Intermediately- and Highly-Malignant Variants of Triple-negative Breast Cancer in Orthotopic Nude Mouse Models

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    ANTICANCER RESEARCH   36 ( 12 )   6273 - 6277   2016.12

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    Aim: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2 (HER2), is a recalcitrant disease in need of effective therapy. We previously isolated very-highly metastatic variants of the TNBC cell line MDA-MB-231 using serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Materials and Methods: MDA-MB-231 cells expressing red fluorescent protein (MDA-MB-231-RFP) (1x10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation into the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for three or seven cycles in order to isolate intermediately, or highly-metastatic variants, respectively. Results: The degree of malignancy of isolated variants of MDA-MB-231 depends on the extent of orthotopic transplantation. Serial transplantation resulted in MDA-MB-231-RFP which significantly produced larger tumors compared with the parental MDA-MB-231-RFP. Serial orthotopic implantation for three cycles resulted in intermediately-metastatic variants of MDA-MB-231-RFP. MDA-MB-231-RFP serially orthotopically transplanted seven times significantly metastasized more to lymph nodes compared with parental MDA-MB-231-RFP cells and the intermediately-metastatic variant. The highly-metastatic variant MDA-MB-231-RFP cells significantly metastasized to the lung to a greater extent compared with parental MDA-MB-231-RFP and intermediate variants of MDA-MB-231-RFP. Conclusion: These results suggest that the number of serial orthotopic transplantations of MDA-MB-231-RFP correlates positively with tumor aggressiveness, and the intermediately- and highly-metastatic variants can serve as models of metastatic progression of TNBC.

    DOI: 10.21873/anticanres.11222

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  • A successful case of deceased donor liver transplantation for a patient with intrahepatic arterioportal fistula

    Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Nobuyuki Watanabe, Takashi Kuise, Kenta Sui, Akira Hirose, Makiko Tsuboi, Mitsunari Ogasawara, Shinji Iwasaki, Toshiji Saibara, Toshiyoshi Fujiwara

    HEPATOLOGY RESEARCH   46 ( 13 )   1409 - 1415   2016.12

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    Intrahepatic arterioportal fistula (IAPF) is a rare cause of portal hypertension that is often difficult to treat with interventional radiology or surgery. Liver transplantation for IAPF is extremely rare. We report a case of bilateral diffuse IAPF with severe portal hypertension requiring deceased donor liver transplantation (DDLT). A 51-year-old woman with no past medical history was admitted to another hospital complaining of abdominal distension and marasmus. A computed tomography scan and digital subtraction angiography indicated a massive pleural effusion, ascites, and a very large IAPF. Several attempts of interventional embolization of the feeding artery failed to ameliorate arterioportal shunt flow. As ruptures of the esophageal varices became more frequent, hepatic encephalopathy worsened. After repeated, uncontrollable attacks of hepatic coma, the patient was referred to our facility for further treatment. Surgical approaches to IAPF other than liver transplantation were challenging because of diffuse collateralization; therefore, we placed the patient on the national waiting list for DDLT. Although her Model for End-Stage Liver Disease score was relatively low, she received a DDLT 2 months after the waiting period. The postoperative course was uneventful, and the patient was discharged 44 days after her transplant. Liver transplantation may be a valid treatment option for uncontrollable IAPF with severe portal hypertension.

    DOI: 10.1111/hepr.12701

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  • A successful case of deceased donor liver transplantation for a patient with intrahepatic arterioportal fistula

    Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Nobuyuki Watanabe, Takashi Kuise, Kenta Sui, Akira Hirose, Makiko Tsuboi, Mitsunari Ogasawara, Shinji Iwasaki, Toshiji Saibara, Toshiyoshi Fujiwara

    HEPATOLOGY RESEARCH   46 ( 13 )   1409 - 1415   2016.12

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    Intrahepatic arterioportal fistula (IAPF) is a rare cause of portal hypertension that is often difficult to treat with interventional radiology or surgery. Liver transplantation for IAPF is extremely rare. We report a case of bilateral diffuse IAPF with severe portal hypertension requiring deceased donor liver transplantation (DDLT). A 51-year-old woman with no past medical history was admitted to another hospital complaining of abdominal distension and marasmus. A computed tomography scan and digital subtraction angiography indicated a massive pleural effusion, ascites, and a very large IAPF. Several attempts of interventional embolization of the feeding artery failed to ameliorate arterioportal shunt flow. As ruptures of the esophageal varices became more frequent, hepatic encephalopathy worsened. After repeated, uncontrollable attacks of hepatic coma, the patient was referred to our facility for further treatment. Surgical approaches to IAPF other than liver transplantation were challenging because of diffuse collateralization; therefore, we placed the patient on the national waiting list for DDLT. Although her Model for End-Stage Liver Disease score was relatively low, she received a DDLT 2 months after the waiting period. The postoperative course was uneventful, and the patient was discharged 44 days after her transplant. Liver transplantation may be a valid treatment option for uncontrollable IAPF with severe portal hypertension.

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  • Tumor-targeting adenovirus OBP-401 inhibits primary and metastatic tumor growth of triple-negative breast cancer in orthotopic nude-mouse models

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    ONCOTARGET   7 ( 51 )   85273 - 85282   2016.12

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    Our laboratory previously developed a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of the human MDA-MB-231 cell line in nude mice. The isolated variant was highly-invasive in the mammary gland and lymphatic channels and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present study, the tumor-selective telomerase dependent OBP-401 adenovirus was injected intratumorally (i. t.) (1 x 10(8) PFU) when the high-metastatic MDA-MB-231 primary tumor expressing red fluorescent protein (MDA-MB-231-RFP) reached approximately 500 mm3 (diameter; 10 mm). The mockinfected orthotopic primary tumor grew rapidly. After i. t. OBP-401 injection, the growth of the orthotopic tumors was arrested. Six weeks after implantation, the fluorescent area and fluorescence intensity showed no increase from the beginning of treatment. OBP-401 was then injected into high-metastatic MDA-MB-231-RFP primary orthotopic tumor growing in mice which already had developed metastasis within lymphatic ducts. All 7 of 7 control mice subsequently developed lymph node metastasis. In contrast, none of 7 mice which received OBP-401 had lymph node metastasis. Seven of 7 control mice also had gross lung metastasis. In contrast, none of the 7 mice which received OBP-401 had gross lung metastasis. Confocal laser microscopy imaging demonstrated that all control mice had diffuse lung metastases. In contrast, all 7 mice which received OBP-401 only had a few metastatic cells in the lung. OBP-401 treatment significantly extended survival of the treated mice.

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  • Tumor-targeting adenovirus OBP-401 inhibits primary and metastatic tumor growth of triple-negative breast cancer in orthotopic nude-mouse models

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    ONCOTARGET   7 ( 51 )   85273 - 85282   2016.12

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    Language:English   Publisher:IMPACT JOURNALS LLC  

    Our laboratory previously developed a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of the human MDA-MB-231 cell line in nude mice. The isolated variant was highly-invasive in the mammary gland and lymphatic channels and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present study, the tumor-selective telomerase dependent OBP-401 adenovirus was injected intratumorally (i. t.) (1 x 10(8) PFU) when the high-metastatic MDA-MB-231 primary tumor expressing red fluorescent protein (MDA-MB-231-RFP) reached approximately 500 mm3 (diameter; 10 mm). The mockinfected orthotopic primary tumor grew rapidly. After i. t. OBP-401 injection, the growth of the orthotopic tumors was arrested. Six weeks after implantation, the fluorescent area and fluorescence intensity showed no increase from the beginning of treatment. OBP-401 was then injected into high-metastatic MDA-MB-231-RFP primary orthotopic tumor growing in mice which already had developed metastasis within lymphatic ducts. All 7 of 7 control mice subsequently developed lymph node metastasis. In contrast, none of 7 mice which received OBP-401 had lymph node metastasis. Seven of 7 control mice also had gross lung metastasis. In contrast, none of the 7 mice which received OBP-401 had gross lung metastasis. Confocal laser microscopy imaging demonstrated that all control mice had diffuse lung metastases. In contrast, all 7 mice which received OBP-401 only had a few metastatic cells in the lung. OBP-401 treatment significantly extended survival of the treated mice.

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  • Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    ONCOTARGET   7 ( 46 )   75635 - 75647   2016.11

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    We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative highinvasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model.

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  • Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    ONCOTARGET   7 ( 46 )   75635 - 75647   2016.11

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    We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative highinvasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model.

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  • Tumor-specific delivery of biologics by a novel T-cell line HOZOT

    Teppei Onishi, Hiroshi Tazawa, Yuuri Hashimoto, Makoto Takeuchi, Takeshi Otani, Shuji Nakamura, Fuminori Sakurai, Hiroyuki Mizuguchi, Hiroyuki Kishimoto, Yuzo Umeda, Yasuhiro Shirakawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Scientific Reports   6 ( 38060 )   doi: 10.1038/srep38060   2016.11

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    "Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35-loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice. This unique cell-in-cell property provides a platform for selective delivery of biologics into human cancer cells, which has important implications for the treatment of human cancers.

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  • Tumor-specific delivery of biologics by a novel T-cell line HOZOT

    Teppei Onishi, Hiroshi Tazawa, Yuuri Hashimoto, Makoto Takeuchi, Takeshi Otani, Shuji Nakamura, Fuminori Sakurai, Hiroyuki Mizuguchi, Hiroyuki Kishimoto, Yuzo Umeda, Yasuhiro Shirakawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Scientific Reports   6   2016.11

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    "Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35-loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice. This unique cell-in-cell property provides a platform for selective delivery of biologics into human cancer cells, which has important implications for the treatment of human cancers.

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  • Real-time in-vivo image-guided cell-cycle perturbation to increase tumor chemosensitivity

    Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Yoshihiko Kadowaki, Nobuhiro Ishido, Takahiro Okamoto, Yasuo Urata, Kiyoto Takehara, Robert M. Hoffman, Toshiyoshi Fujiwara

    MOLECULAR CANCER RESEARCH   14   2016.11

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    DOI: 10.1158/1557-3125.CELLCYCLE16-PR14

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  • Iron depletion-induced downregulation of N-cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer

    Seishi Nishitani, Kazuhiro Noma, Toshiaki Ohara, Yasuko Tomono, Shinichiro Watanabe, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    INTERNATIONAL JOURNAL OF ONCOLOGY   49 ( 4 )   1351 - 1359   2016.10

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    Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, iron depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased iron conditions were made using an iron-depletion diet in mice and the iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased iron conditions. In vitro study showed that decreased iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin.

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  • Sarcopenia and American Society of Anesthesiologists Physical Status in the Assessment of Outcomes of Hepatocellular Carcinoma Patients Undergoing Hepatectomy

    Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Nobuyuki Watanabe, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   70 ( 5 )   363 - 370   2016.10

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    Sarcopenia following liver surgery has been reported as a predictor of poor prognosis. Here we investigated predictors of outcomes in patients with hepatocellular carcinoma (HCC) and attempted to establish a new comprehensive preoperative assessment protocol. We retrospectively analyzed the cases of 254 patients who underwent curative hepatectomy for HCC with Child-Pugh classification A at our hospital between January 2007 and December 2013. Sarcopenia was evaluated by computed tomography measurement. The influence of sarcopenia on outcomes was evaluated. We used multivariate analyses to assess the impact of prognostic factors associated with outcomes, including sarcopenia. Of the 254 patients, 118 (46.5) met the criteria for sarcopenia, and 32 had an American Society of Anesthesiologists (ASA) physical status &gt;= 3. The sarcopenic group had a significantly lower 5-year overall survival rate than the non-sarcopenic group (58.2 vs. 82.4, p=0.0002). In multivariate analyses of prognostic factors, sarcopenia was an independent predictor of poor survival (hazard ratio [HR]= 2.28, p= 0.002) and poor ASA status (HR= 3.17, p= 0.001). Sarcopenia and poor ASA status are independent preoperative predictors for poor outcomes after hepatectomy. The preoperative identification of sarcopenia and ASA status might enable the development of comprehensive approaches to assess surgical eligibility.

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  • Sarcopenia and American Society of Anesthesiologists Physical Status in the Assessment of Outcomes of Hepatocellular Carcinoma Patients Undergoing Hepatectomy

    Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Nobuyuki Watanabe, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   70 ( 5 )   363 - 370   2016.10

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    Sarcopenia following liver surgery has been reported as a predictor of poor prognosis. Here we investigated predictors of outcomes in patients with hepatocellular carcinoma (HCC) and attempted to establish a new comprehensive preoperative assessment protocol. We retrospectively analyzed the cases of 254 patients who underwent curative hepatectomy for HCC with Child-Pugh classification A at our hospital between January 2007 and December 2013. Sarcopenia was evaluated by computed tomography measurement. The influence of sarcopenia on outcomes was evaluated. We used multivariate analyses to assess the impact of prognostic factors associated with outcomes, including sarcopenia. Of the 254 patients, 118 (46.5) met the criteria for sarcopenia, and 32 had an American Society of Anesthesiologists (ASA) physical status &gt;= 3. The sarcopenic group had a significantly lower 5-year overall survival rate than the non-sarcopenic group (58.2 vs. 82.4, p=0.0002). In multivariate analyses of prognostic factors, sarcopenia was an independent predictor of poor survival (hazard ratio [HR]= 2.28, p= 0.002) and poor ASA status (HR= 3.17, p= 0.001). Sarcopenia and poor ASA status are independent preoperative predictors for poor outcomes after hepatectomy. The preoperative identification of sarcopenia and ASA status might enable the development of comprehensive approaches to assess surgical eligibility.

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  • A Phase II Clinical Trial of the Efficacy and Safety of Short-term (3 days) Enoxaparin for the Prevention of Venous Thromboembolism after Gastric Cancer Surgery

    Shinji Kuroda, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Shiro Hinotsu, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   70 ( 5 )   401 - 404   2016.10

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    Although intermittent pneumatic compression (IPC) has become common as perioperative prophylaxis for venous thromboembolism (VTE) consisting of pulmonary thromboembolism (PE) and deep vein thrombosis (DVT), the prophylactic effect against VTE, especially lethal PE, is not yet satisfactory. Therefore, pharmacologic prophylaxis, such as with enoxaparin, is desirable. While the efficacy and safety of enoxaparin have been proven in several clinical trials, concern about bleeding with long-term (at least 7 days) use have potentially decreased its widespread adoption. We have launched a phase II study to evaluate the efficacy and safety of short-term (3 days) enoxaparin, in which a total of 70 gastric cancer patients undergoing gastrectomy will be recruited, and the primary endpoint is the incidence of DVT. This study could contribute to making pharmacologic prophylaxis for VTE more common.

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  • Iron depletion-induced downregulation of N-cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer

    Seishi Nishitani, Kazuhiro Noma, Toshiaki Ohara, Yasuko Tomono, Shinichiro Watanabe, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    INTERNATIONAL JOURNAL OF ONCOLOGY   49 ( 4 )   1351 - 1359   2016.10

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    Language:English   Publisher:SPANDIDOS PUBL LTD  

    Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, iron depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased iron conditions were made using an iron-depletion diet in mice and the iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased iron conditions. In vitro study showed that decreased iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin.

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  • Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam (R)-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    PLOS ONE   11 ( 9 )   doi: 10.1371/journal.pone.0162991   2016.9

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    Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam (R) histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam (R) grew into tumor-like structures with G(0)/G(1) cancer cells in the center and S/G(2) cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam (R) histoculture with OBP-301, cisplatinum (CDDP), or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam (R). In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN45 cells in tumors on Gelfoam (R) to cycle from G(0)/G(1) phase to S/G(2) phase and reduced their viability. CDDP-or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam 1. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam (R) histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301.

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  • Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam (R)-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    PLOS ONE   11 ( 9 )   2016.9

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    Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam (R) histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam (R) grew into tumor-like structures with G(0)/G(1) cancer cells in the center and S/G(2) cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam (R) histoculture with OBP-301, cisplatinum (CDDP), or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam (R). In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN45 cells in tumors on Gelfoam (R) to cycle from G(0)/G(1) phase to S/G(2) phase and reduced their viability. CDDP-or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam 1. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam (R) histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301.

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  • Double-Flap Technique as an Antireflux Procedure in Esophagogastrostomy after Proximal Gastrectomy

    Shinji Kuroda, Masahiko Nishizaki, Satoru Kikuchi, Kazuhiro Noma, Shunsuke Tanabe, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS   223 ( 2 )   E7 - E13   2016.8

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    DOI: 10.1016/j.jamcollsurg.2016.04.041

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  • Double-Flap Technique as an Antireflux Procedure in Esophagogastrostomy after Proximal Gastrectomy

    Shinji Kuroda, Masahiko Nishizaki, Satoru Kikuchi, Kazuhiro Noma, Shunsuke Tanabe, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS   223 ( 2 )   E7 - E13   2016.8

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  • In Vivo Isolation of a Highly-aggressive Variant of Triple-negative Human Breast Cancer MDA-MB-231 Using Serial Orthotopic Transplantation

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    ANTICANCER RESEARCH   36 ( 8 )   3817 - 3820   2016.8

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    Aim: We describe the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. Materials and Methods: MDA-MB-231 cells expressing red fluorescent protein (RFP) (1x10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation in the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically reimplanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for two cycles and then isolated. Results: The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. Conclusion: The availability of a highly invasive variant of TNBC targeting lymph nodes will be very useful for drug discovery of TNBC, a recalcitrant cancer and for mechanistic studies of its aggressiveness.

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  • Study about the Efficacy of Metformin to Immune Function in Cancer Patients

    Mototsugu Watanabe, Hiromasa Yamamoto, Shingo Eikawa, Kazuhiko Shien, Tadahiko Shien, Junichi Soh, Katsuyuki Hotta, Jun Wada, Shiro Hinotsu, Toshiyoshi Fujiwara, Katsuyuki Kiura, Hiroyoshi Doihara, Shinichiro Miyoshi, Heiichiro Udono, Shinichi Toyooka

    ACTA MEDICA OKAYAMA   70 ( 4 )   327 - 330   2016.8

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    A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8(+) T cells, which produce multiple cytokines.

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  • In Vivo Isolation of a Highly-aggressive Variant of Triple-negative Human Breast Cancer MDA-MB-231 Using Serial Orthotopic Transplantation

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    ANTICANCER RESEARCH   36 ( 8 )   3817 - 3820   2016.8

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    Aim: We describe the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. Materials and Methods: MDA-MB-231 cells expressing red fluorescent protein (RFP) (1x10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation in the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically reimplanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for two cycles and then isolated. Results: The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. Conclusion: The availability of a highly invasive variant of TNBC targeting lymph nodes will be very useful for drug discovery of TNBC, a recalcitrant cancer and for mechanistic studies of its aggressiveness.

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  • Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms

    Kazuhiro Yoshida, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Keisuke Kimura, Fumitaka Taniguchi, Tomokazu Fuji, Kunitoshi Shigeyasu, Yoshiko Mori, Hiroyuki Yanai, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara

    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY   142 ( 7 )   1557 - 1569   2016.7

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    Although limited understanding exists for the presence of specific genetic mutations and aberrantly methylated genes in pancreatobiliary intraductal papillary mucinous neoplasms (IPMNs), the fundamental understanding of the dynamics of methylation expansion across CpG dinucleotides in specific gene promoters during carcinogenesis remains unexplored. Expansion of DNA methylation in some gene promoter regions, such as EFEMP1, one of the fibulin family, with tumor progression has been reported in several malignancies. We hypothesized that DNA hypermethylation in EFEMP1 promoter would expand with the tumor grade of IPMN.
    A sample of 65 IPMNs and 30 normal pancreatic tissues was analyzed. IPMNs were divided into the following three subsets according to pathological findings: 31 with low-grade dysplasia (low grade), 11 with high-grade dysplasia (high grade), and 23 with associated invasive carcinoma (invasive Ca). Mutations in the KRAS or GNAS genes were analyzed by Sanger sequencing, and methylation status of two discrete regions within the EFEMP1 promoter, namely region 1 and region 2, was analyzed by bisulfite sequencing and fluorescent high-sensitive assay for bisulfite DNA (Hi-SA). Expression status of EFEMP1 was investigated by immunohistochemistry (IHC).
    KRAS mutations were detected in 39, 55, and 70 % of low-grade, high-grade, and invasive Ca, respectively. GNAS mutations were observed in 32, 55, and 22 % of low-grade, high-grade, and invasive Ca, respectively. The methylation of individual regions (region 1 or 2) in the EFEMP1 promoter was observed in 84, 91, and 87 % of low-grade, high-grade, and invasive Ca, respectively. However, simultaneous methylation of both regions (extensive methylation) was exclusively detected in 35 % of invasive Ca (p = 0.001) and five of eight IPMNs (63 %) with extensive methylation, whereas 20 of 57 (35.1 %) tumors of unmethylation or partial methylation of the EFEMP1 promoter region showed weak staining EFEMP1 in extracellular matrix (p = 0.422). In addition, extensive EFEMP1 methylation was particularly present in malignant tumors without GNAS mutations and associated with disease-free survival of patients with IPMNs (p &lt; 0.0001).
    Extensive methylation of the EFEMP1 gene promoter can discriminate invasive from benign IPMNs with superior accuracy owing to their stepwise accumulation of tumor progression.

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  • Prognostic correlation of tumor-infiltrating lymphocytes (TILs) and cancer associated fibroblasts (CAFs) in patients with human esophageal carcinoma

    Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hajime Kashima, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-4160

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  • PD-L1 expression as a predictive factor for recurrence pattern and prognosis in curatively resected gastric cancer

    Toshiaki Morihiro, Shinji Kuroda, Tetsushi Kubota, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-2649

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  • A novel live imaging system for inflammation-induced epithelial-mesenchymal transition in colorectal cancers

    Takeshi Ieda, Hiroshi Tazawa, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-1613

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  • Iron control is a novel therapeutic target of cancer stem cells

    Toshiaki Ohara, Takayuki Ninomiya, Kazuhiro Noma, Hajime Kashima, Yuki Katsura, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-2510

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  • Functional analysis of tumor associated macrophage utilizing virus-guided fluorescent imaging of pancreatic cancer cells in the peritoneal cavity

    Kazuya Kuwada, Shunsuke Kagawa, Megumi Watanabe, Shuichi Sakamoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Tetuya Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-4156

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  • Novel HER2-targeted gold nanoparticles; integration of antibody therapy and nanotechnology

    Tetsushi Kubota, Shinji Kuroda, Toshiaki Morihiro, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-4747

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  • Correlation of FAP(fibroblast activation protein)-expressing cancer associated fibroblasts (CAFs) and tumor metastasis in esophageal carcinoma

    Hajime Kashima, Kazuhiro Noma, Yuki Katsura, Takuya Kato, Ryoichi Katsube, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-1560

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  • Genome-wide enhancer analysis identifies PVT1 as an oncogenic enhancer of MYC

    Kunitoshi Shigeyasu, Shusuke Toden, Takeshi Nagasaka, Toshiyoshi Fujiwara, C. Richard Boland, Ajay Goel

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-952

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  • Virally enhanced p53 reactivation impairs KRAS-driven pancreatic cancer invasion

    Takeshi Koujima, Hiroshi Tazawa, Takeshi Leda, Kazuya Kuwada, Terutaka Tanimoto, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-3748

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  • Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas

    Shuhei Osaki, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Tsuyoshi Sasaki, Toshiyuki Kunisada, Aki Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    SCIENTIFIC REPORTS   6   2016.6

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    Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.

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  • Surgical Outcome of Patients Undergoing Pancreaticoduodenectomy: Analysis of a 17-Year Experience at a Single Center

    Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Nobuyuki Watanabe, Kenta Sui, Tomokazu Fuji, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   70 ( 3 )   197 - 203   2016.6

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    The operative mortality and morbidity of pancreaticoduodenectomy (PD) remain high. We analyzed PD patients' clinical characteristics and surgical outcomes and discuss how PD clinical outcomes could be improved. We retrospectively reviewed the cases of 400 patients who underwent a PD between January 1998 and April 2014 at Okayama University Hospital, a very-high-volume center. We identified and compared the clinical outcomes between two time periods (period 1: 1998-2006 vs. period 2: 2007-2014). The total postoperative mortality and major complication rates were 0.75 and 15.8, respectively, and the median postoperative length of stay (LOS) was 32 days. Subsequently, patients who underwent a PD during period 2 had a significantly shorter LOS than those who underwent a PD during period 1 (29 days vs. 38.5 days, p&lt;0.001). The incidence of mortality and major complications did not differ between the two periods. In our multivariate analysis, period 1 was an independent factor associated with a long LOS (p&lt;0.001). The improvement of the surgical procedure and perioperative care might be related to the shorter LOS in period 2 and to the consistently maintained low mortality rate after PD. The development of multimodal strategies to accelerate postoperative recovery may further improve PD's clinical outcomes.

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  • Recurrence after Endoscopic Curative Resection of Mucosal Gastric Cancer Associated with an Adjacent Neoplastic Precursor Lesion

    Satoru Kikuchi, Shunsuke Kagawa, Toshiaki Ohara, Tetsushi Kubota, Kazuya Kuwada, Tetsuya Kagawa, Shinji Kuroda, Yasuhiro Shirakawa, Masahiko Nishizaki, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   70 ( 3 )   213 - 216   2016.6

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    A 69-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) at the lesser curvature in the angle of stomach. Histological examination revealed tub1, pM, ly0, v0, pLM(-), pVM(-), and the resection was considered curative. The scar after ESD was followed by esophagogastroduodenoscopy (EGD) and biopsy. Twenty months later, EGD showed an ulcerative lesion in the vicinity of the ESD scar, and histological examination of the biopsy specimen showed adenocarcinoma. A distal gastrectomy with lymph node dissection was then performed. Postoperative pathology showed tub1, pM, pN0, ly0, v0, and Stage 1A. Skip lesions were seen in the specimen resected by ESD, and the histological review confirmed so-called "dysplasia-like atypia" (DLA) between the lesions. It has been reported recently that in DLA, the dysplasia-like change involves only the bases of the pits, without upper pit or surface epithelium involvement, and it is said that the rate of DLA is higher in gastric cancer patients. We speculated that a precancerous lesion close to the resected cancer developed into a local recurrence.

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  • Recurrence after Endoscopic Curative Resection of Mucosal Gastric Cancer Associated with an Adjacent Neoplastic Precursor Lesion

    Satoru Kikuchi, Shunsuke Kagawa, Toshiaki Ohara, Tetsushi Kubota, Kazuya Kuwada, Tetsuya Kagawa, Shinji Kuroda, Yasuhiro Shirakawa, Masahiko Nishizaki, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   70 ( 3 )   213 - 216   2016.6

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    A 69-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) at the lesser curvature in the angle of stomach. Histological examination revealed tub1, pM, ly0, v0, pLM(-), pVM(-), and the resection was considered curative. The scar after ESD was followed by esophagogastroduodenoscopy (EGD) and biopsy. Twenty months later, EGD showed an ulcerative lesion in the vicinity of the ESD scar, and histological examination of the biopsy specimen showed adenocarcinoma. A distal gastrectomy with lymph node dissection was then performed. Postoperative pathology showed tub1, pM, pN0, ly0, v0, and Stage 1A. Skip lesions were seen in the specimen resected by ESD, and the histological review confirmed so-called "dysplasia-like atypia" (DLA) between the lesions. It has been reported recently that in DLA, the dysplasia-like change involves only the bases of the pits, without upper pit or surface epithelium involvement, and it is said that the rate of DLA is higher in gastric cancer patients. We speculated that a precancerous lesion close to the resected cancer developed into a local recurrence.

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  • Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas

    Shuhei Osaki, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Tsuyoshi Sasaki, Toshiyuki Kunisada, Aki Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    SCIENTIFIC REPORTS   6 ( 28953 )   doi: 10.1038/srep28953   2016.6

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    Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.

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  • Eradication of osteosarcoma by fluorescence-guided surgery with tumor labeling by a killer-reporter adenovirus

    Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Yasuo Urata, Hiroshi Tazawa, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    JOURNAL OF ORTHOPAEDIC RESEARCH   34 ( 5 )   836 - 844   2016.5

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    In a previous study, we developed fluorescence-guided surgery (FGS) for osteosarcoma using an orthotopic model with 143B human osteosarcoma cells expressing red fluorescent protein (RFP) implanted into the intramedullary cavity of the tibia in nude mice. The FGS-treated mice had a significantly higher disease-free survival (DFS) rate than the bright-light surgery (BLS). However, although FGS significantly reduced the recurrence of the primary tumor, it did not reduce lung metastasis. In the present study, we utilized the OBP-401 telomerase-dependent killer-reporter adenovirus, carrying green fluorescent protein (GFP), to label human osteosarcoma in situ in orthotopic mouse models. OBP-401-illuminated human osteosarcoma cell lines, 143B and MNNG/HOS cells in vitro and in vivo. OBP-401 tumor illumination enabled effective FGS of the 143B-derived orthotopic mouse model of human osteosarcoma model as well as FGS eradication of residual cancer cells after BLS. OBP-401-assisted FGS significantly inhibited local recurrence and lung metastasis after surgery, thereby prolonging DFS and overall survival (OS), achieving a very important improvement of therapeutic outcomes over our previously reported FGS study. These therapeutic benefits of FGS were demonstrated using a clinically-viable methodology of direct labeling of human osteosarcoma in situ with the OBP-401 killer-reporter adenovirus in contrast with previous reports, which used genetically engineered labeled cells or antibody-based fluorescent labels for FGS. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:836-844, 2016.

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  • Diminished Gastric Resection Preserves Better Quality of Life in Patients with Early Gastric Cancer

    Hiroshi Isozaki, Sasau Matsumoto, Shigeki Murakami, Takehiro Takama, Tatuo Sho, Kiyohiro Ishihara, Kunihiko Sakai, Masanori Takeda, Koji Nakada, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   70 ( 2 )   119 - 130   2016.4

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    Using the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45, we compared the surgical outcomes and the quality of life (QOL) between patients undergoing limited gastrectomies and those undergoing conventional gastrectomies. In Oomoto Hospital between January 2004 and December 2013, a total of 124 patients who met the eligibility criteria were enrolled. Using the main outcome measures of PGSAS-45, we compared 4 types of limited gastrectomy procedures (1/2 distal gastrectomy [1/2DG] in 21 patients; pylorus-preserving gastrectomy [PPG] in 15 patients; segmental gastrectomy [SG] in 26 patients; and local resection [LR] in 13 patients) with conventional gastrectomy (total gastrectomy [TG] in 24 patients and 2/3 or more distal gastrectomy [WDG] in 25 patients). The TG group showed the worst QOL in almost all items of the main outcome measures. The 1/2DG, PPG, and SG groups showed better QOL than the WDG group in many of the main outcome measures, including the body weight ratio, total symptom score, ingested amount of food per meal, and the dissatisfaction for daily life subscale. The LR group showed a better intake of food than the 1/2DG, PPG, and SG groups. The body weight ratio of the LR group was better than that of the SG group. Diminished gastric resection preserved better QOL in patients with early gastric cancer.

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  • Adenoviral targeting of malignant melanoma for fluorescence-guided surgery prevents recurrence in orthotopic nude-mouse models

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    ONCOTARGET   7 ( 14 )   18558 - 18572   2016.4

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    Malignant melanoma requires precise resection in order to avoid metastatic recurrence. We report here that the telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401 could label malignant melanoma with GFP in situ in orthotopic mouse models. OBP-401-based fluorescence-guided surgery (FGS) resulted in the complete resection of malignant melanoma in the orthotopic models, where conventional bright-light surgery (BLS) could not. High-dose administration of OBP-401 enabled FGS without residual cancer cells or recurrence, due to its dual effect of cancer-cell labeling with GFP and killing.

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  • Diminished Gastric Resection Preserves Better Quality of Life in Patients with Early Gastric Cancer

    Hiroshi Isozaki, Sasau Matsumoto, Shigeki Murakami, Takehiro Takama, Tatuo Sho, Kiyohiro Ishihara, Kunihiko Sakai, Masanori Takeda, Koji Nakada, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   70 ( 2 )   119 - 130   2016.4

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    Using the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45, we compared the surgical outcomes and the quality of life (QOL) between patients undergoing limited gastrectomies and those undergoing conventional gastrectomies. In Oomoto Hospital between January 2004 and December 2013, a total of 124 patients who met the eligibility criteria were enrolled. Using the main outcome measures of PGSAS-45, we compared 4 types of limited gastrectomy procedures (1/2 distal gastrectomy [1/2DG] in 21 patients; pylorus-preserving gastrectomy [PPG] in 15 patients; segmental gastrectomy [SG] in 26 patients; and local resection [LR] in 13 patients) with conventional gastrectomy (total gastrectomy [TG] in 24 patients and 2/3 or more distal gastrectomy [WDG] in 25 patients). The TG group showed the worst QOL in almost all items of the main outcome measures. The 1/2DG, PPG, and SG groups showed better QOL than the WDG group in many of the main outcome measures, including the body weight ratio, total symptom score, ingested amount of food per meal, and the dissatisfaction for daily life subscale. The LR group showed a better intake of food than the 1/2DG, PPG, and SG groups. The body weight ratio of the LR group was better than that of the SG group. Diminished gastric resection preserved better QOL in patients with early gastric cancer.

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  • Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

    Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Yasuhiro Shirakawa, Hiroshi Tazawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

    MOLECULAR CANCER THERAPEUTICS   15 ( 3 )   402 - 411   2016.3

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    Peritoneal dissemination is the most frequent metastasis in gastric cancer and is associated with poor prognosis. The lack of particular target antigens in gastric cancer other than HER2 has hampered the development of treatments for peritoneal dissemination of gastric cancer. Wehypothesized that HER2-extracellular domain (HER2-ECD) gene transduction combined with trastuzumab-based photoimmunotherapy (PIT) might provide excellent and selective antitumor effects for peritoneal dissemination of gastric cancer. In vitro, adenovirus/HER2-ECD (Ad/HER2-ECD) efficiently transduced HER2-ECD into HER2-negative gastric cancer cells. Trastuzumab-IR700 (Tra-IR700)-mediated PIT induced selective cell death of HER2-ECD-transduced tumor cells. Ad/HER2-ECD also induced homogenous expression of HER2 in heterogeneous gastric cancer cells, resulting in uniform sensitivity of the cells to Tra-IR700-mediated PIT. Anti-HER2 PIT integrated with adenoviral HER2-ECD gene transfer was applied in mice bearing peritoneal dissemination of HER2-negative gastric cancer. Intraperitoneal administration of Ad/HER2-ECD and Tra-IR700 with PIT inhibited peritoneal metastasis and prolonged the survival of mice bearing MKN45. Furthermore, minimal side effects allowed the integrated therapy to be used repeatedly, providing better control of peritoneal dissemination. In conclusion, the novel therapy of molecular-targeted PIT integrated with gene transfer technology is a promising approach for the treatment of peritoneal dissemination in gastric cancer. (C) 2016 AACR.

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  • Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

    Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Yasuhiro Shirakawa, Hiroshi Tazawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

    MOLECULAR CANCER THERAPEUTICS   15 ( 3 )   402 - 411   2016.3

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    Peritoneal dissemination is the most frequent metastasis in gastric cancer and is associated with poor prognosis. The lack of particular target antigens in gastric cancer other than HER2 has hampered the development of treatments for peritoneal dissemination of gastric cancer. Wehypothesized that HER2-extracellular domain (HER2-ECD) gene transduction combined with trastuzumab-based photoimmunotherapy (PIT) might provide excellent and selective antitumor effects for peritoneal dissemination of gastric cancer. In vitro, adenovirus/HER2-ECD (Ad/HER2-ECD) efficiently transduced HER2-ECD into HER2-negative gastric cancer cells. Trastuzumab-IR700 (Tra-IR700)-mediated PIT induced selective cell death of HER2-ECD-transduced tumor cells. Ad/HER2-ECD also induced homogenous expression of HER2 in heterogeneous gastric cancer cells, resulting in uniform sensitivity of the cells to Tra-IR700-mediated PIT. Anti-HER2 PIT integrated with adenoviral HER2-ECD gene transfer was applied in mice bearing peritoneal dissemination of HER2-negative gastric cancer. Intraperitoneal administration of Ad/HER2-ECD and Tra-IR700 with PIT inhibited peritoneal metastasis and prolonged the survival of mice bearing MKN45. Furthermore, minimal side effects allowed the integrated therapy to be used repeatedly, providing better control of peritoneal dissemination. In conclusion, the novel therapy of molecular-targeted PIT integrated with gene transfer technology is a promising approach for the treatment of peritoneal dissemination in gastric cancer. (C) 2016 AACR.

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  • Improved Resection and Outcome of Colon-Cancer Liver Metastasis with Fluorescence-Guided Surgery Using In Situ GFP Labeling with a Telomerase-Dependent Adenovirus in an Orthotopic Mouse Model

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Yukihiko Hiroshima, Takashi Murakami, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    PLOS ONE   11 ( 2 )   doi: 10.1371/journal.pone.0148760.   2016.2

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    Fluorescence-guided surgery (FGS) of cancer is an area of intense development. In the present report, we demonstrate that the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 could label colon-cancer liver metastasis in situ in an orthotopic mouse model enabling successful FGS. OBP-401-GFP-labeled liver metastasis resulted in complete resection with FGS, in contrast, conventional bright-light surgery (BLS) did not result in complete resection of the metastasis. OBP-401-FGS reduced the recurrence rate and prolonged over-all survival compared with BLS. In conclusion, adenovirus OBP-401 is a powerful tool to label liver metastasis in situ with GFP which enables its complete resection, not possible with conventional BLS.

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  • Improved Resection and Outcome of Colon-Cancer Liver Metastasis with Fluorescence-Guided Surgery Using In Situ GFP Labeling with a Telomerase-Dependent Adenovirus in an Orthotopic Mouse Model

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Yukihiko Hiroshima, Takashi Murakami, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    PLOS ONE   11 ( 2 )   2016.2

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    Fluorescence-guided surgery (FGS) of cancer is an area of intense development. In the present report, we demonstrate that the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 could label colon-cancer liver metastasis in situ in an orthotopic mouse model enabling successful FGS. OBP-401-GFP-labeled liver metastasis resulted in complete resection with FGS, in contrast, conventional bright-light surgery (BLS) did not result in complete resection of the metastasis. OBP-401-FGS reduced the recurrence rate and prolonged over-all survival compared with BLS. In conclusion, adenovirus OBP-401 is a powerful tool to label liver metastasis in situ with GFP which enables its complete resection, not possible with conventional BLS.

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  • Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

    Kiyoto Takehara, Hiroshi Tazawa, Naohiro Okada, Yuuri Hashimoto, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Yasuhiro Shirakawa, Nobuhiro Narii, Hiroyuki Mizuguchi, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    MOLECULAR CANCER THERAPEUTICS   15 ( 1 )   199 - 208   2016.1

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    Photodynamic therapy (PDT) is a minimally invasive antitumor therapy that eradicates tumor cells through a photosensitizer-mediated cytotoxic effect upon light irradiation. However, systemic administration of photosensitizer often makes it difficult to avoid a photosensitive adverse effect. The red fluorescent protein KillerRed generates reactive oxygen species (ROS) upon green light irradiation. Here, we show the therapeutic potential of a novel tumor-specific replicating photodynamic viral agent (TelomeKiller) constructed using the human telomerase reverse transcriptase (hTERT) promoter. We investigated the light-induced antitumor effect of TelomeKiller in several types of human cancer cell lines. Relative cell viability was investigated using an XTT assay. The in vivo antitumor effect was assessed using subcutaneous xenografted tumor and lymph node metastasis models. KillerRed accumulation resulted in ROS generation and apoptosis in light-irradiated cancer cells. Intratumoral injection of TelomeKiller efficiently delivered the KillerRed protein throughout the tumors and exhibited a long-lasting antitumor effect with repeated administration and light irradiation in mice. Moreover, intratumorally injected TelomeKiller could spread into the regional lymph node area and eliminate micrometastasis with limited-field laser irradiation. Our results suggest that KillerRed has great potential as a novel photosensitizer if delivered with a tumor-specific virus-mediated delivery system. TelomeKiller-based PDT is a promising antitumor strategy to efficiently eradicate tumor cells. (C) 2015 AACR.

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  • Anti-high mobility group box 1 monoclonal antibody improves ischemia/reperfusion injury and mode of liver regeneration after partial hepatectomy

    Masahiro Sugihara, Hiroshi Sadamori, Masahiro Nishibori, Yasuharu Sato, Hiroshi Tazawa, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Kyotaro Ohno, Takeshi Nagasaka, Tadashi Yoshino, Hideo Kohka Takahashi, Takahito Yagi, Toshiyoshi Fujiwara

    AMERICAN JOURNAL OF SURGERY   211 ( 1 )   179 - 188   2016.1

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    BACKGROUND: The purpose of this study is to determine the effects of anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) on ischemia/reperfusion injury (IRI) and the mode of liver regeneration.
    METHODS: Rats underwent 70% hepatectomy with IRI caused by clamping the hepatoduodenal ligament for 20 minutes, followed by the administration of anti-HMGB1 mAb immediately before declamping the hepatoduodenal ligament. Five animals were used for each time point. We then evaluated IRI, regeneration parameters and the status of HMGB1 in remnant livers.
    RESULTS: The anti-HMGB1 mAb significantly ameliorated the degree of IRI in the remnant livers in association with the downregulation of HMGB1 protein. The ratio of Ki67-positive hepatocytes at 48 hours after 70% hepatectomy was significantly improved. Mean hepatocyte size was significantly reduced and cyclin-dependent kinase inhibitor 1 expression was significantly attenuated.
    CONCLUSIONS: Anti-HMGB1 mAb ameliorated IRI and improved the mode of liver regeneration after IRI followed by 70% hepatectomy in rats. (C) 2016 Elsevier Inc. All rights reserved.

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  • Anti-high mobility group box 1 monoclonal antibody improves ischemia/reperfusion injury and mode of liver regeneration after partial hepatectomy

    Masahiro Sugihara, Hiroshi Sadamori, Masahiro Nishibori, Yasuharu Sato, Hiroshi Tazawa, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Kyotaro Ohno, Takeshi Nagasaka, Tadashi Yoshino, Hideo Kohka Takahashi, Takahito Yagi, Toshiyoshi Fujiwara

    AMERICAN JOURNAL OF SURGERY   211 ( 1 )   179 - 188   2016.1

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    BACKGROUND: The purpose of this study is to determine the effects of anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) on ischemia/reperfusion injury (IRI) and the mode of liver regeneration.
    METHODS: Rats underwent 70% hepatectomy with IRI caused by clamping the hepatoduodenal ligament for 20 minutes, followed by the administration of anti-HMGB1 mAb immediately before declamping the hepatoduodenal ligament. Five animals were used for each time point. We then evaluated IRI, regeneration parameters and the status of HMGB1 in remnant livers.
    RESULTS: The anti-HMGB1 mAb significantly ameliorated the degree of IRI in the remnant livers in association with the downregulation of HMGB1 protein. The ratio of Ki67-positive hepatocytes at 48 hours after 70% hepatectomy was significantly improved. Mean hepatocyte size was significantly reduced and cyclin-dependent kinase inhibitor 1 expression was significantly attenuated.
    CONCLUSIONS: Anti-HMGB1 mAb ameliorated IRI and improved the mode of liver regeneration after IRI followed by 70% hepatectomy in rats. (C) 2016 Elsevier Inc. All rights reserved.

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  • Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

    Yano S, Takehara K, Tazawa H, Kishimoto H, Urata Y, Kagawa S, Fujiwara T, Hoffman RM

    Cell Cycle   DOI: 10.1080/15384101.2016.1220461   2016

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  • Adenoviral targeting of malignant melanoma for fluorescenceguided surgery prevents recurrence in orthotopic nude-mouse models

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Oncotarget   7 ( 14 )   18558 - 18572   2016

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    Malignant melanoma requires precise resection in order to avoid metastatic recurrence. We report here that the telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401 could label malignant melanoma with GFP in situ in orthotopic mouse models. OBP-401-based fluorescence-guided surgery (FGS) resulted in the complete resection of malignant melanoma in the orthotopic models, where conventional bright-light surgery (BLS) could not. High-dose administration of OBP-401 enabled FGS without residual cancer cells or recurrence, due to its dual effect of cancer-cell labeling with GFP and killing.

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  • Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms

    Kazuhiro Yoshida, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Keisuke Kimura, Fumitaka Taniguchi, Tomokazu Fuji, Kunitoshi Shigeyasu, Yoshiko Mori, Hiroyuki Yanai, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara

    Journal of Cancer Research and Clinical Oncology, Zeitschrift fur Krebsforschung und Klinische Onkologie, Zeitschrift fur Krebsforschung   1 - 13   2016

  • Surgical outcome of patients undergoing pancreaticoduodenectomy

    Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Nobuyuki Watanabe, Kenta Sui, Tomokazu Fuji, Toshiyoshi Fujiwara

    Acta Medica Okayama, Acta. Medica Okayama, Acta medicinae Okayama, Acta medica Okayama   70 ( 3 )   197 - 204   2016

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  • A case of right-sided Bochdalek hernia incidentally diagnosed in a gastric cancer patient

    Kikuchi S, Nishizaki M, Kuroda S, Kagawa S, Fujiwara T

    BMC Surg   16 ( 34 )   doi: 10.1186/s12893-016-0145-2   2016

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  • Iron depletion enhances the effect of sorafenib in hepatocarcinoma

    Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Kazuhiro Nouso, Akihiro Matsukawa, Kazuhide Yamamoto, Toshiyoshi Fujiwara

    CANCER BIOLOGY & THERAPY   17 ( 6 )   648 - 656   2016

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    Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that iron depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed iron depletion therapy including iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of iron depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar (R)) and/or deferasirox (EXJADE (R)) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both iron depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by iron depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.

    DOI: 10.1080/15384047.2016.1177677

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  • Iron depletion enhances the effect of sorafenib in hepatocarcinoma

    Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Kazuhiro Nouso, Akihiro Matsukawa, Kazuhide Yamamoto, Toshiyoshi Fujiwara

    CANCER BIOLOGY & THERAPY   17 ( 6 )   648 - 656   2016

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    Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that iron depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed iron depletion therapy including iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of iron depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar (R)) and/or deferasirox (EXJADE (R)) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both iron depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by iron depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.

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  • Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

    Shuya Yano, Kiyoto Takehara, Ming Zhao, Yuying Tan, Qinghong Han, Shukuan Li, Michael Bouvet, Toshiyoshi Fujiwara, Robert, M. Hoffman

    Cell Cycle   1 - 9   2016

  • Efficient detection of human circulating tumor cells without significant production of false-positive cells by a novel conditionally replicating adenovirus

    Sakurai F, Narii N, Tomita K, Togo S, Takahashi K, Machitani M, Tachibana M, Ouchi M, Katagiri N, Urata Y, Fujiwara T, Mizuguchi H

    Mol. Ther. Methods Clin. Dev   3 ( 16001 )   2016

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  • 肝移植医療を地域と大学が一体としてまとめ上げた実績とさらなる発展

    八木孝仁, 篠浦 先, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬 崇, 渡辺信之, 高木弘誠, 須井健太, 藤原俊義, 高木章乃夫, 吉田真理, 保田裕子, 森松博史

    肝胆膵   72 ( 3 )   481 - 487   2016

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  • 回盲部潰瘍穿孔, 食道潰瘍穿孔をきたした腸管Behçet病の1手術例

    九十九悠太, 河本和幸, 高木弘誠, 陳 開, 松葉優里, 長久吉雄, 岡部道雄, 白川靖博, 伊藤 雅, 藤原俊義

    岡山医学会雑誌   128 ( 1 )   27 - 32   2016

  • Therapeutic efficacy in vivo of a telomerase-dependent adenovirus in an orthotopic model of chemotherapy-resistant human stomach carcinomatosis peritonitis visualized with cell cycle color coding FUCCI imaging

    Yano S, Takehara K, Tazawa H, Kishimoto H, Urata Y, Kagawa S, Fujiwara T, Hoffman RM

    Journal of Cellular Biochemistry   doi: 10.1002/jcb.25593   2016

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  • Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

    Kenjiro Kumano, Hitomi Nishinakamura, Toshiyuki Mera, Takeshi Itoh, Hiroyuki Takahashi, Toshiyoshi Fujiwara, Shohta Kodama

    ISLETS   8 ( 5 )   145 - 155   2016

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    Although current immunosuppression protocols improve the efficacy of clinical allogenic islet transplantation, T cell-mediated allorejection remains unresolved, and major histocompatibility complexes (MHCs) play a crucial role in this process. Papain, a cysteine protease, has the unique ability to cleave the extracellular domain of the MHC class I structure. We hypothesized that pretreatment of donor islets with papain would diminish the expression of MHC class I on islets, reducing allograft immunogenicity and contributing to prolongation of islet allograft survival. BALB/c islets pretreated with papain were transplanted into C57BL/6J mice as an acute allorejection model. Treatment with 1mg/mL papain significantly prolonged islet allograft survival. In vitro, to determine the inhibitory effect on T cell-mediated alloreactions, we performed lymphocyte proliferation assays and mixed lymphocyte reactions. Host T cell activation against allogenic islet cells was remarkably suppressed by pretreatment of donor islet cells with 10mg/mL papain. Flow cytometric analysis was also performed to investigate the effect of papain treatment on the expression of MHC class I on islets. One or 10mg/mL papain treatment reduced MHC class I expression on the islet cell surface. Pretreatment of donor islets with papain suppresses MHC class I-mediated allograft rejection in mice and contributes to prolongation of islet allograft survival without administration of systemic immunosuppressants. These results suggest that pretreatment of human donor islets with papain may reduce the immunogenicity of the donor islets and minimize the dosage of systemic immunosuppressants required in a clinical setting.

    DOI: 10.1080/19382014.2016.1223579

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  • Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models

    Yano S, Takehara K, Tazawa H, Kishimoto H, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM

    Journal of Cellular Biochemistry   doi: 10.1002/jcb.25735   2016

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  • 胃癌術後肝転移再発に対してThird-LineのCPT-11が奏効し長期生存を得た1 例

    菊地覚次, 西﨑正彦, 黒田新士, 香川俊輔, 藤原俊義

    癌と化学療法   43 ( 12 )   2219 - 2221   2016

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  • Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

    Shuya Yano, Kiyoto Takehara, Ming Zhao, Yuying Tan, Qinghong Han, Shukuan Li, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    CELL CYCLE   15 ( 13 )   1715 - 1723   2016

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    We previously reported real-time monitoring of cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G(0)/G(1) phase. Longitudinal real-time FUCCI imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, and had little effect on the quiescent cancer cells. Resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Thus cytotoxic chemotherapy which targets cells in S/G(2)/M, is mostly ineffective on solid tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon tumor intrinsic chemoresistance (TIC). We previously demonstrated that tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent cancer cells in tumors to cycle from G(0)/G(1) to S/G(2)/M demonstrated by FUCCI imaging. We have also previously shown that when cancer cells were treated with recombinant methioninase (rMETase), the cancer cells were selectively trapped in S/G(2), shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed cancer cells in S/G(2) phase, followed by cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy to kill the decoyed and trapped cancer cells completely prevented or regressed tumor growth. These results demonstrate the effectiveness of the praradigm of decoy, trap and shoot chemotherapy.

    DOI: 10.1080/15384101.2016.1181240

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  • Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma

    Daisuke Uchida, Akinobu Takaki, Hisashi Ishikawa, Yasuko Tomono, Hironari Kato, Koichiro Tsutsumi, Naofumi Tamaki, Takayuki Maruyama, Takaaki Tomofuji, Ryuichiro Tsuzaki, Tetsuya Yasunaka, Kazuko Koike, Hiroshi Matsushita, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Kazuhiro Nouso, Ryuichi Yoshida, Yuzo Umeda, Susumu Shinoura, Takahito Yagi, Toshiyoshi Fujiwara, Manabu Morita, Masaki Fukushima, Kazuhide Yamamoto, Hiroyuki Okada

    FREE RADICAL RESEARCH   50 ( 7 )   732 - 743   2016

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    Background: Pancreatico-biliary malignancies exhibit similar characteristics, including obesity-related features and poor prognosis, and require new treatment strategies. Oxidative stress is known to induce DNA damage and carcinogenesis, and its reduction is viewed as being favorable. However, it also has anti-infection and anti-cancer functions that need to be maintained. To reveal the effect of oxidative stress on cancer progression, we evaluated oxidative stress and anti-oxidative balance in pancreatic cancer (PC) and cholangiocarcinoma (CC) patients, as well as the effect of add-on antioxidant treatment to chemotherapy in a mouse cholangiocarcinoma model.
    Methods: We recruited 84 CC and 80 PC patients who were admitted to our hospital. Serum levels of reactive oxygen metabolites (ROM) and the anti-oxidative OXY-adsorbent test were determined and the balance of these tests was defined as an oxidative index. A diabetic mouse-based cholangiocarcinoma model was utilized to evaluate the effects of add-on antioxidant therapy on cholangiocarcinoma chemotherapy.
    Results: Serum ROM was higher and anti-oxidant OXY was lower in CC patients with poor outcomes. These parameters were not significantly different in PC patients. In mice, vitamin E administration induced antioxidant hemeoxygenase (HO)-1 protein expression in cancer tissue, while the number of stem-like cells increased. L-carnitine administration improved intestinal microbiome and biliary acid balance, upregulated the hepatic mitochondrial membrane uptake related gene Cpt1 in non-cancerous tissue, and did not alter stem-like cell numbers.
    Conclusion: Oxidative stress balance was dysregulated in cholangiocarcinoma with poor outcome. The mitochondrial function-supporting agent L-carnitine is a good candidate to control oxidative stress conditions.

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  • Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma

    Daisuke Uchida, Akinobu Takaki, Hisashi Ishikawa, Yasuko Tomono, Hironari Kato, Koichiro Tsutsumi, Naofumi Tamaki, Takayuki Maruyama, Takaaki Tomofuji, Ryuichiro Tsuzaki, Tetsuya Yasunaka, Kazuko Koike, Hiroshi Matsushita, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Kazuhiro Nouso, Ryuichi Yoshida, Yuzo Umeda, Susumu Shinoura, Takahito Yagi, Toshiyoshi Fujiwara, Manabu Morita, Masaki Fukushima, Kazuhide Yamamoto, Hiroyuki Okada

    FREE RADICAL RESEARCH   50 ( 7 )   732 - 743   2016

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    Background: Pancreatico-biliary malignancies exhibit similar characteristics, including obesity-related features and poor prognosis, and require new treatment strategies. Oxidative stress is known to induce DNA damage and carcinogenesis, and its reduction is viewed as being favorable. However, it also has anti-infection and anti-cancer functions that need to be maintained. To reveal the effect of oxidative stress on cancer progression, we evaluated oxidative stress and anti-oxidative balance in pancreatic cancer (PC) and cholangiocarcinoma (CC) patients, as well as the effect of add-on antioxidant treatment to chemotherapy in a mouse cholangiocarcinoma model.
    Methods: We recruited 84 CC and 80 PC patients who were admitted to our hospital. Serum levels of reactive oxygen metabolites (ROM) and the anti-oxidative OXY-adsorbent test were determined and the balance of these tests was defined as an oxidative index. A diabetic mouse-based cholangiocarcinoma model was utilized to evaluate the effects of add-on antioxidant therapy on cholangiocarcinoma chemotherapy.
    Results: Serum ROM was higher and anti-oxidant OXY was lower in CC patients with poor outcomes. These parameters were not significantly different in PC patients. In mice, vitamin E administration induced antioxidant hemeoxygenase (HO)-1 protein expression in cancer tissue, while the number of stem-like cells increased. L-carnitine administration improved intestinal microbiome and biliary acid balance, upregulated the hepatic mitochondrial membrane uptake related gene Cpt1 in non-cancerous tissue, and did not alter stem-like cell numbers.
    Conclusion: Oxidative stress balance was dysregulated in cholangiocarcinoma with poor outcome. The mitochondrial function-supporting agent L-carnitine is a good candidate to control oxidative stress conditions.

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  • An extended retroperitoneal emphysema with diversion colitis after colonoscopy

    Tetsuya Kagawa, Shin Nakatani, Hiroyuki Kishimoto, Yoshitaka Kondo, Toshiko Mori, Takeshi Nagasaka, Toshiyoshi Fujiwara

    Japanese Journal of Gastroenterological Surgery   49 ( 8 )   804 - 811   2016

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    A 68-year-old man with a history of intersphincteric resection and transverse colostomy for rectal cancer underwent diagnostic colonoscopy as a post-operative follow up. Colonoscopy revealed diversion colitis of the sigmoid colon. Two hours after the examination, the patient complained of mild abdominal pain. Blumberg sign was negative and no remarkable changes were observed, but abdominal pain did not improve for 6 hours. A CT scan showed retropneumoperitoneum, pneumomediastinum, subcutaneous emphysema and pneumatosis intestinalis of the sigmoid colon without any evidence of perforation. We diagnosed retroperitoneal emphysema with diversion colitis after colonoscopy and the patient was admitted to our hospital. We decided on a conservative treatment method because of the lack of peritonitis and good general condition. The clinical course was uneventful and he was discharged 11 days after the initial observation. Retroperitoneal emphysema is a very rare complication that occurs after colonoscopy. We report our case with a literature review of 25 cases of retroperitoneal emphysema after colonoscopy in Japan.

    DOI: 10.5833/jjgs.2015.0141

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  • 腸骨広範囲切除術後に発生した腹壁瘢痕ヘルニアに対しメッシュ修復術を行った一例

    佃 和憲, 浅野博昭, 万代康弘, 藤原俊義

    岡山医学会雑誌   128 ( 2 )   117 - 120   2016

  • 癌関連線維芽細胞が食道癌の浸潤と転移に及ぼす影響の検証

    賀島肇, 野間和広, 桂佑貴, 加藤卓也, 大原利章, 田澤大, 白川靖博, 香川俊輔, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   27th   2016

  • A Case-matched Comparative Study of Laparoscopic and Open Total Proctocolectomy for Ulcerative Colitis

    Ryo Inada, Takeshi Nagasaka, Yoshitaka Kondo, Ayako Watanabe, Toshiaki Toshima, Nobuhito Kubota, Satoru Kikuchi, Michihiro Ishida, Shinji Kuroda, Yoshiko Mori, Hiroyuki Kishimoto, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   69 ( 5 )   267 - 273   2015.10

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    The aim of this single-institution, retrospective, observational case-control study was to evaluate the safety and feasibility of laparoscopic proctocolectomy (PC) for ulcerative colitis (VC), by comparing it with a case-control series of open PC. Twenty UC patients who underwent laparoscopic PC were retrospectively compared with the open PC group of 12 patients matched for age, sex, and urgency of the operation. In the laparoscopic PC group, the operative time was significantly longer, but the amount of blood loss was significantly smaller. The open PC patients underwent an intraoperative blood transfusion significantly more often, and the serum C-reactive protein level on the first postoperative day was significantly higher in the open PC group. In the laparoscopic PC group, the rate of severe postoperative morbidities, grades 3 and 4 on the Clavien-Dindo classification, was significantly lower, and the median length of hospital stay was significantly shorter. Laparoscopic PC for patients with UC showed superior perioperative outcomes to open PC, except for longer operative time.

    DOI: 10.18926/AMO/53672

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  • Neoadjuvant Chemotherapy with or without Concurrent Hormone Therapy in Estrogen Receptor-Positive Breast Cancer: NACED-Randomized Multicenter Phase II Trial

    Kumi Sugiu, Takayuki Iwamoto, Catherine M. Kelly, Naoki Watanabe, Takayuki Motoki, Mitsuya Itoh, Shoichiro Ohtani, Kenji Higaki, Takako Imada, Takeshi Yuasa, Masako Omori, Hiroshi Sonobe, Toshiyoshi Fujiwara, Junji Matsuoka

    ACTA MEDICA OKAYAMA   69 ( 5 )   291 - 299   2015.10

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    Although in the neoadjuvant setting for estrogen receptor (ER)-positive breast cancers, chemotherapy or hormone therapy alone does not result in satisfactory tumor response, it is unknown whether concurrent chemo-endocrine therapy is superior to chemotherapy alone in clinical outcomes. We conducted a randomized phase II trial to test the responses of ER-positive patients to concurrent administration of chemo-endocrine therapy in the neoadjuvant setting. Women with stage ER-positive, invasive breast cancer (n=28) received paclitaxel followed by fluorouracil, epirubicin, cyclophosphamide (T-FEC) and were randomized to receive concurrent chemo-endocrine therapy consisting of goserelin administered subcutaneously for premenopausal women or an aromatase inhibitor for post-menopausal women. The primary endpoint was the pathological complete response (pCR) rate after neoadjuvant therapy. Twenty-eight patients were randomized. There were no significant differences in pCR rate between the concurrent group (12.5%; 2/16) and the chemotherapy alone group (8.3%; 1112). Tumor size after therapy was significantly reduced in the concurrent therapy group (p=0.035), but not in the chemotherapy-alone group (p=0.622). Neoadjuvant chemotherapy with concurrent hormone therapy provided no significant improvement in pCR rate in ER-positive breast cancers. These preliminary results should be followed up by further studies.

    DOI: 10.18926/AMO/53675

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  • HER2-targeted gold nanoparticles produce potent antitumor effects on human gastric cancer cells

    Tetsushi Kubota, Shinji Kuroda, Katsuyuki Aoyama, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-5520

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  • Differentiated gastric cancer cells have a potential to induce cancer-associated fibroblasts

    Yuncheng Li, Hiroshi Tazawa, Nishizaki Masahiko, Yuuri Hashimoto, Naoto Hori, Ryoichi Katsube, Shinji Kuroda, Kazuhiro Noma, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-2368

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  • Preclinical study of telomerase-specific p53 tumor suppressor gene overexpression in human scirrhous gastric cancer cells with different p53 status

    Naoto Hori, Hiroshi Tazawa, Masahiko Nishizaki, Satoru Kikuchi, Shuya Yano, Michihiro Ishida, Megumi Watanabe, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-5338

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  • A novel photoimmunotherapy targeting cancer-associated fibroblasts (CAFs) overcomes therapeutic resistance in human esophageal cancer

    Ryoichi Katsube, Kazuhiro Noma, Shinichiro Watanabe, Shinichi Urano, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-401

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  • Phase I/II trial of endoscopic intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, with radiation in elderly esophageal cancer patients

    Shunsuke Tanabe, Hiroshi Tazawa, Shunsuke Kagawa, Kazuhiro Noma, Kiyoto Takehara, Takeshi Koujima, Hajime Kashima, Takuya Kato, Shinji Kuroda, Satoru Kikuchi, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-CT123

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  • A novel tumor-specific oncolytic biological therapy against invasive pancreatic cancer

    Takeshi Koujima, Hiroshi Tazawa, Naoto Hori, Shuta Tamura, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-3535

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  • Companion diagnostics-based telomerase-specific oncolytic virotherapy: preclinical evaluation in human colorectal cancer cell lines differentially affected in the RAS/RAF/MEK signaling pathway

    Shuta Tamura, Hiroshi Tazawa, Naoto Hori, Takeshi Koujima, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-3531

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  • Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells: a preliminary clinical study as a potential clinical biomarker

    Megumi Watanabe, Shunsuke Kagawa, Kazuya Kuwata, Michihiro Ishida, Yuuri Hashimoto, Naoto Hori, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-3412

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  • Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability

    Keisuke Toda, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Takashi Kawai, Tomokazu Fuji, Fumitaka Taniguchi, Kazuya Yasui, Nobuhito Kubota, Yuko Takehara, Hiroshi Tazawa, Shunsuke Kagawa, Dong-Sheng Sun, Naoshi Nishida, Ajay Goel, Toshiyoshi Fujiwara

    CLINICAL EPIGENETICS   7   doi:10.1186/s13148-015-0096-y   2015.7

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    Background: The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis.
    Results: In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers.
    Conclusions: Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis.

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  • Enhancement of Programmed Death Ligand 2 on Hepatitis C Virus Infected Hepatocytes by Calcineurin Inhibitors

    Kazuko Koike, Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Tetsuya Yasunaka, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Sato, Daisuke Nobuoka, Masashi Utsumi, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    TRANSPLANTATION   99 ( 7 )   1447 - 1454   2015.7

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    Background. Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2. Methods. The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines. Results. The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity. Conclusions. The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

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  • Experimental Curative Fluorescence-guided Surgery of Highly Invasive Glioblastoma Multiforme Selectively Labeled With a Killer-reporter Adenovirus

    Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Makoto Toneri, Yukihiko Hiroshima, Mako Yamamoto, Michael Bouvet, Yasuo Urata, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    MOLECULAR THERAPY   23 ( 7 )   1182 - 1188   2015.7

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    Fluorescence-guided surgery (FGS) of cancer is an area of intense current interest. However, although benefits have been demonstrated with FGS, curative strategies need to be developed. Glioblastoma multiforme (GBM) is one of the most invasive of cancers and is not totally resectable using standard bright-light surgery (BLS) or current FGS strategies. We report here a curative strategy for FGS of GBM. In this study, telomerase-dependent adenovirus OBP-401 infection brightly and selectively labeled GBM with green fluorescent protein (GFP) for FGS in orthotopic nude mouse models. OBP-401-based FGS enabled curative resection of GBM without recurrence for at least 150 days, compared to less than 30 days with BLS.

    DOI: 10.1038/mt.2015.63

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  • Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery

    S. Yano, Y. Hiroshima, A. Maawy, H. Kishimoto, A. Suetsugu, S. Miwa, M. Toneri, M. Yamamoto, M. H. G. Katz, J. B. Fleming, Y. Urata, H. Tazawa, S. Kagawa, M. Bouvet, T. Fujiwara, R. M. Hoffman

    CANCER GENE THERAPY   22 ( 7 )   344 - 350   2015.7

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    Precise fluorescence-guided surgery (FGS) for pancreatic canter has the potential to greatly improve the outcome in this recalcitrant disease. To achieve this goal, we have used genetic reporters to-color code cancer and stroma cells in a patient-derived orthotopic xenograft (PDOX) model. The telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 was used to label the cancer cells of a pancreatic cancer PDOX. The PDOX was previously grown in a red fluorescent protein (RFP) transgenic Mouse that stably labeled the PDOX stroma cells bright red. The color-coded PDOX Model enabled FGS to to completely resect the pancreatic tumors including stroma. Dual-colored FGS significantly prevented local recurrence; which bright-light surgery or single-color FGS could not. FGS, with color-coded canter and stroma cells has important potential for improving the outcome of recalcitrant-cancer surgery.

    DOI: 10.1038/cgt.2015.26

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  • Prone-Position Thoracoscopic Ligation of the Thoracic Duct for Chyle Leak Following Radical Neck Dissection in a Patient with a Right Aortic Arch

    Yasuhiro Shirakawa, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Naoaki Maeda, Shunsuke Tanabe, Shunsuke Kagawa, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   69 ( 3 )   173 - 176   2015.6

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    A chyle leak can occur as a complication after neck or chest surgery. Such a leak prolongs the hospital stay and is sometimes life-threatening. The treatment options are conservative management, interventional radiologic embolization, and surgery. Thoracoscopic ligation of the thoracic duct has emerged as a promising and definitive treatment The case of a 65-year-old Japanese male patient with a rare congenital right aortic arch (type IIIB1 of Edward's classification) and a severe chyle leak that occurred after a total pharyngolaryngo-esophagectomy (TPLE) is described. The chyle leak was successfully managed by thoracoscopic ligation of the thoracic duct via a left-side approach with the patient in the prone position.

    DOI: 10.18926/AMO/53524

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  • Heterogeneous cell-cycle behavior in response to UVB irradiation by a population of single cancer cells visualized by time-lapse FUCCI imaging

    Shinji Miwa, Shuya Yano, Hiroaki Kimura, Mako Yamamoto, Makoto Toneri, Takashi Murakami, Katsuhiro Hayashi, Norio Yamamoto, Toshiyoshi Fujiwara, Hiroyuki Tsuchiya, Robert M. Hoffman

    CELL CYCLE   14 ( 12 )   1932 - 1937   2015.6

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    The present study analyzed the heterogeneous cell-cycle dependence and fate of single cancer cells in a population treated with UVB using a fluorescence ubiquitination-based cell-cycle (FUCCI) imaging system. HeLa cells expressing FUCCI were irradiated by 100 or 200 J/m(2) UVB. Modulation of the cell-cycle and apoptosis were observed by time-lapse confocal microscopy imaging every 30min for 72h. Correlation between cell survival and factors including cell-cycle phase at the time of the irradiation of UVB, mitosis and the G(1)/S transition were analyzed using the Kaplan-Meier method along with the log rank test. Time-lapse FUCCI imaging of HeLa cells demonstrated that UVB irradiation induced cell-cycle arrest in S/G(2)/M phase in the majority of the cells. The cells irradiated by 100 or 200 J/m(2) UVB during G(0)/G(1) phase had a higher survival rate than the cells irradiated during S/G(2)/M phase. A minority of cells could escape S/G(2)/M arrest and undergo mitosis which significantly correlated with decreased survival of the cells. In contrast, G(1)/S transition significantly correlated with increased survival of the cells after UVB irradiation. UVB at 200 J/m(2) resulted in a greater number of apoptotic cells.

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  • Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer

    Kunitoshi Shigeyasu, Takeshi Nagasaka, Yoshiko Mori, Naosuke Yokomichi, Takashi Kawai, Tomokazu Fuji, Keisuke Kimura, Yuzo Umeda, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

    PLOS ONE   10 ( 6 )   e0130409   2015.6

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    Background
    To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown.
    Methods
    This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox's proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1methylation status in relation to overall survival (OS).
    Results
    By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis.
    Conclusions
    CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer.

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  • Targeting tumors with a killer-reporter adenovirus for curative fluorescence-guided surgery of soft-tissue sarcoma

    Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Fuminari Uehara, Hiroshi Tazawa, Makoto Toneri, Yukihiko Hiroshima, Mako Yamamoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    ONCOTARGET   6 ( 15 )   13133 - 13148   2015.5

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    Fluorescence-guided surgery (FGS) of cancer is an area of intense interest. However, FGS of cancer has not yet been shown to be curative due to residual microscopic disease. Human fibrosarcoma HT1080 expressing red fluorescent protein (RFP) was implanted orthotopically in the quadriceps femoris muscle of nude mice. The tumor-bearing mice were injected with high and low-dose telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401, which labeled the tumor with GFP. Fluorescence-guided surgery (FGS) or bright light surgery (BLS) was then performed. OBP-401 could label soft-tissue sarcoma (STS) with GFP in situ, concordant with RFP. OBP-401-based FGS resulted in superior resection of STS in the orthotopic model of soft-tissue sarcoma, compared to BLS. High-dose administration of OBP-401 enabled FGS without residual sarcoma cells or local or metastatic recurrence, due to its dual effect of cancer-cell labeling with GFP and killing. High-dose OBP-401 based-FGS improved disease free survival (p = 0.00049) as well as preserved muscle function compared with BLS. High-dose OBP-401-based FGS could cure STS, a presently incurable disease. Since the parent virus of OBP-401, OBP-301, has been previously proven safe in a Phase I clinical trial, it is expected the OBP-401-FGS technology described in the present report should be translatable to the clinic in the near future.

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  • Effect of methionine-depletion via methioninase-treatment on cancer cells in S/G2 phase and chemosensitivity.

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

    JOURNAL OF CLINICAL ONCOLOGY   33 ( 15 )   2015.5

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  • Aggressive Multimodality Treatment for Advanced Rectal Cancer

    Ryo Inada, Takeshi Nagasaka, Toshiaki Toshima, Yoshiko Mori, Yoshitaka Kondo, Hiroyuki Kishimoto, Takao Hiraki, Taihei Oshiro, Yukihide Kanemitsu, Toshiyoshi Fujiwara

    ACTA MEDICA OKAYAMA   69 ( 2 )   113 - 118   2015.4

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    A case of advanced rectal cancer treated by aggressive local and systemic treatment who has survived more than 7 years from initial recurrence is presented. A 55-year-old woman was diagnosed with advanced lower rectal cancer and underwent a low anterior resection with complete removal of all regional lymph nodes and total mesorectal excision. The tumor was diagnosed as a moderately differentiated adenocarcinoma, pStage IIIB (T3, N2a, M0). Twenty-six months after the initial surgery, local recurrence in the pelvis was detected by computed tomography, and total pelvic exenteration with distal sacrectomy (TPES) was performed after systemic chemotherapy with a molecular-targeted drug. Six months after the TPES, multiple lung metastases were detected. Consequently, the patient underwent radiofrequency ablation (RFA) and chemotherapy. The disease has since been controlled for 38 months. As volume control is essential for cancer treatment, it may be important to combine appropriate local therapy with systemic therapy to metastatic or recurrent sites in order to achieve much longer disease control.

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  • Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnostics

    Kunitoshi Shigeyasu, Hiroshi Tazawa, Yuuri Hashimoto, Yoshiko Mori, Masahiko Nishizaki, Hiroyuki Kishimoto, Takeshi Nagasaka, Shinji Kuroda, Yasuo Urata, Ajay Goel, Shunsuke Kagawa, Toshiyoshi Fujiwara

    GUT   64 ( 4 )   627 - 635   2015.4

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    Background Molecular-based companion diagnostic tests are being used with increasing frequency to predict their clinical response to various drugs, particularly for molecularly targeted drugs. However, invasive procedures are typically required to obtain tissues for this analysis. Circulating tumour cells (CTCs) are novel biomarkers that can be used for the prediction of disease progression and are also important surrogate sources of cancer cells. Because current CTC detection strategies mainly depend on epithelial cell-surface markers, the presence of heterogeneous populations of CTCs with epithelial and/or mesenchymal characteristics may pose obstacles to the detection of CTCs.
    Methods We developed a new approach to capture live CTCs among millions of peripheral blood leukocytes using a green fluorescent protein (GFP)-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401, TelomeScan).
    Results Our biological capturing system can image epithelial and mesenchymal tumour cells with telomerase activities as GFP-positive cells. After sorting, direct sequencing or mutation-specific PCR can precisely detect different mutations in KRAS, BRAF and KIT genes in epithelial, mesenchymal or epithelial-mesenchymal transition-induced CTCs, and in clinical blood samples from patients with colorectal cancer.
    Conclusions This fluorescence virus-guided viable CTC capturing method provides a non-invasive alternative to tissue biopsy or surgical resection of primary tumours for companion diagnostics.

    DOI: 10.1136/gutjnl-2014-306957

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  • Correlation of Computed Tomography Imaging Features and Pathological Features of 41 Patients with Pancreatic Neuroendocrine Tumors

    Masashi Utsumi, Yuzo Umeda, Kosei Takagi, Kuise Takashi, Daisuke Nobuoka, Ryuichi Yoshida, Susumu Shinoura, Hiroshi Sadamori, Takahito Yagi, Toshiyoshi Fujiwara

    HEPATO-GASTROENTEROLOGY   62 ( 138 )   441 - 446   2015.3

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    Background:/Aims: Pancreatic neuroendocrine tumors (PNET) are relatively rare. Here, we present clinical and pathological characteristics of PNETs to show a relationship between computed tomography (CT) imaging and the 2010 World Health Organization (WHO) classification. Methodology: We retrospectively reviewed the records of 41 PNET patients who were treated between 2002 and 2012. All tumors were classified as neuroendocrine tumor (NET) grade 1 (121), NET grade 2 (G2), or neuroendocrine carcinoma (NEC) grade 3 (G3) on the basis of the 2010 WHO classification system. Results: Twenty-five tumors were classified as G1, 11 as G2, and five as G3. Mean sizes of the G1, G2 and G3 tumors were 1.84 +/- 0.54, 4.90 +/- 0.84, and 5.62 +/- 1.18 cm, respectively, (P &lt; 0.01). A PNET is typically hypervascular and exhibits contrast enhancement on enhanced CT. Higher percentage of G1 tumors demonstrated typical imaging and showed a significantly greater distinct mass compared with G2 and G3 tumors. Conclusions: Although PNET has many imaging features that appear on CT, G2 and G3 tumors often show atypical imaging features, particularly with large sizes and/or ill-defined features, when compared with G1 tumors. If a PNET has atypical imaging features, possibility of malignancy should be considered.

    DOI: 10.5754/hge14388

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  • Cancer cells mimic in vivo spatial-temporal cell-cycle phase distribution and chemosensitivity in 3-dimensional Gelfoam (R) histoculture but not 2-dimensional culture as visualized with real-time FUCCI imaging

    Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminaru Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    CELL CYCLE   14 ( 6 )   808 - 819   2015.3

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    The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We previously reported monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor, intravitally in live mice, using a fluorescence ubiquitination-based cell-cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G(0)/G(1) phase. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after cessation of chemotherapy. These results suggested why most drugs currently in clinical use, which target cancer cells in S/G(2)/M, are mostly ineffective on solid tumors. In the present report, we used FUCCI imaging and Gelfoam (R) collagen-sponge-gel histoculture, to demonstrate in real time, that the cell-cycle phase distribution of cancer cells in Gelfoam (R) and in vivo tumors is highly similar, whereby only the surface cells proliferate and interior cells are quiescent in G(0)/G(1). This is in contrast to 2D culture where most cancer cells cycle. Similarly, the cancer cells responded similarly to toxic chemotherapy in Gelfoam (R) culture as in vivo, and very differently than cancer cells in 2D culture which were much more chemosensitive. Gelfoam (R) culture of FUCCI-expressing cancer cells offers the opportunity to image the cell cycle of cancer cells continuously and to screen for novel effective therapies to target quiescent cells, which are the majority in a tumor and which would have a strong probability to be effective in vivo.

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  • ARID1A expression in gastric adenocarcinoma: Clinicopathological significance and correlation with DNA mismatch repair status

    Ryo Inada, Shigeki Sekine, Hirokazu Taniguchi, Hitoshi Tsuda, Hitoshi Katai, Toshiyoshi Fujiwara, Ryoji Kushima

    WORLD JOURNAL OF GASTROENTEROLOGY   21 ( 7 )   2159 - 2168   2015.2

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    AIM: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.
    METHODS: We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables.
    RESULTS: The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6 +/- 9.2 vs 60.4 +/- 11.7, P &lt; 0.001), a female sex (55.3% vs 31.3%, P = 0.004), an antral location (44.7% vs 25.7%, P = 0.021), and a differentiated histology (57.9% vs 39.7%, P = 0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P = 0.022) and lymph node metastasis (83.5% vs 73.7%, P = 0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P &lt; 0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR = 1.36, 95% CI: 1.01-1.84; P = 0.040).
    CONCLUSION: Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas.

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  • Cell-cycle fate-monitoring distinguishes individual chemosensitive and chemoresistant cancer cells in drug-treated heterogeneous populations demonstrated by real-time FUCCI imaging

    Shinji Miwa, Shuya Yano, Hiroaki Kimura, Mako Yamamoto, Makoto Toneri, Yasunori Matsumoto, Fuminari Uehara, Yukihiko Hiroshima, Takashi Murakami, Katsuhiro Hayashi, Norio Yamamoto, Michael Bouvet, Toshiyoshi Fujiwara, Hiroyuki Tsuchiya, Robert M. Hoffman

    CELL CYCLE   14 ( 4 )   621 - 629   2015.2

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    Essentially every population of cancer cells within a tumor is heterogeneous, especially with regard to chemosensitivity and resistance. In the present study, we utilized the fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging system to investigate the correlation between cell-cycle behavior and apoptosis after treatment of cancer cells with chemotherapeutic drugs. HeLa cells expressing FUCCI were treated with doxorubicin (DOX) (5M) or cisplatinum (CDDP) (5M) for 3h. Cell-cycle progression and apoptosis were monitored by time-lapse FUCCI imaging for 72h. Time-lapse FUCCI imaging demonstrated that both DOX and CDDP could induce cell cycle arrest in S/G(2)/M in almost all the cells, but a subpopulation of the cells could escape the block and undergo mitosis. The subpopulation which went through mitosis subsequently underwent apoptosis, while the cells arrested in S/G(2)/M survived. The present results demonstrate that chemoresistant cells can be readily identified in a heterogeneous population of cancer cells by S/G(2)/M arrest, which can serve in future studies as a visible target for novel agents that kill cell-cycle-arrested cells.

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  • Prone-position thoracoscopic resection of posterior mediastinal lymph node metastasis from rectal cancer

    Yasuhiro Shirakawa, Kazuhiro Noma, Takeshi Koujima, Naoaki Maeda, Shunsuke Tanabe, Toshiaki Ohara, Toshiyoshi Fujiwara

    WORLD JOURNAL OF SURGICAL ONCOLOGY   13 ( 45 )   doi:10.1186/s12957-015-0466-0   2015.2

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    Mediastinal lymph node metastasis from colorectal cancer is rare, and barely any reports have described resection of this pathology. We report herein a successful thoracoscopic resection of mediastinal lymph node metastasis in a prone position. A 65-year-old man presented with posterior mediastinal lymph node metastasis after resection of the primary rectal cancer and metachronous hepatic metastasis. Metastatic lymph nodes were resected completely using thoracoscopic surgery in the prone position, which provided advantages of minimal invasiveness, good surgical field, and reduced ergonomic burden on the surgeon. Thoracoscopic resection in the prone position was thought to have the potential to become the standard procedure of posterior mediastinal tumors.

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  • Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells

    Kyoko Shimoyama, Shunsuke Kagawa, Michihiro Ishida, Shinichiro Watanabe, Kazuhiro Noma, Kiyoto Takehara, Hiroshi Tazawa, Yuuri Hashimoto, Shunsuke Tanabe, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara

    BREAST CANCER RESEARCH AND TREATMENT   149 ( 3 )   597 - 605   2015.2

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    The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20-25 % of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.

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  • The rare BRAF VK600-601E mutation as a possible indicator of poor prognosis in rectal carcinoma - a report of a case

    Yoshiko Mori, Takeshi Nagasaka, Hideyuki Mishima, Yuzo Umeda, Ryo Inada, Hiroyuki Kishimoto, Ajay Goel, Toshiyoshi Fujiwara

    BMC MEDICAL GENETICS   16 ( 1 )   10.1186/s12881-015-0144-7   2015.1

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    Background: The BRAF V600E mutation is reportedly associated with inferior survival among colon cancer patients. Here we report a patient with rectal cancer who carried the novel BRAF mutation VK600-601E, which has analogous molecular functions to those of the conventional BRAF mutation V600E, and may have potential as a prognostic marker for colorectal cancer (CRC).
    Case presentation: The present 65-year-old male patient was diagnosed with recurrent rectal adenocarcinoma (stage II by AJCC TNM staging 7th edition) 14 months after surgery and was treated with modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin), radiation, and FOLFIRI (fluorouracil, leucovorin, and irinotecan). The tumor progressed before further treatment could be initiated, resulting in death after 15 months. This survival period was similar to the median overall survival among patients with metastatic CRC and BRAF mutations who were treated with the FOLFIRI regimen with or without cetuximab.
    Conclusions: Thus, the BRAF VK600-601E mutation may lead to an aggressive clinical course in CRC patients suffering from rapid progression and potential resistance to multiple therapeutic modalities.

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  • Operative technique of antethoracic esophageal reconstruction with pedicled jejunal flap

    Yasuhiro Shirakawa, Kazuhiro Noma, Takeshi Koujima, Naoaki Maeda, Shunsuke Tanabe, Toshiaki Ohara, Kazufumi Sakurama, Toshiyoshi Fujiwara

    ESOPHAGUS   12 ( 1 )   57 - 64   2015.1

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    Esophageal reconstruction using intestine is often performed for esophageal cancer patients in cases where the stomach cannot be used. We have previously performed reconstruction using ileocolon with supercharge and drainage as our first choice in those cases. However, a less invasive, simpler, and safer reconstructive technique using jejunum without vascular anastomosis has recently become popular at our facility. This study describes the technique of esophageal reconstruction with jejunum, compares the surgical outcomes to those of standard reconstruction using ileocolon, and discusses the clinical significance of this new concept.
    Subjects comprised 53 patients (52 males, 1 female) who underwent esophageal reconstruction using jejunum between January 2008 and July 2013. Patient characteristics, technical details, and outcomes were compared with those of 51 subjects who had undergone esophageal reconstruction using ileocolon. When making the pedicled jejunal flap, the first jejunal vascular arcade was preserved, which in most cases allowed it to be pulled up to the cervical region by processing and transection up to the second jejunal vascular branch.
    The vascular anastomosis techniques were used in 80.4 % (41/51) of esophageal reconstructions using colon, compared with only 24.5 % (13/53) of reconstructions using jejunum. No difference in the frequency of postoperative adverse effects was seen between groups, but the frequency of diarrhea was significantly lower with reconstruction using jejunum.
    Esophageal reconstruction using jejunum with the blood vessel processing technique results in both simpler and safer pulling up. Thus the need to perform supercharge and superdrainage is reduced.

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  • Enlarging lymphoepithelial cyst of the pancreas during 12 months of observation: report of a case

    Daisuke Satoh, Hiroshi Sadamori, Takahito Yagi, Toshiyoshi Fujiwara

    SURGERY TODAY   45 ( 1 )   101 - 104   2015.1

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    Pancreatic lymphoepithelial cysts (LECs) are rare benign pancreatic cystic lesions, the etiology of which is unknown. We report a case of a pancreatic LEC, discovered incidentally in a 63-year-old man during a follow-up clinic visit for an abdominal aneurysm. Computed tomography showed a multilocular cyst, 60-mm diameter in the body of the pancreas. This cyst increased from 6.0 to 6.5 cm during 12 months of observation. Part of the cyst was also visualized on positron emission tomography imaging. Since a pancreatic cystic neoplasm could not be ruled out, we performed distal pancreatectomy and postoperative pathological examination confirmed that the lesion was an LEC of the pancreas. Despite the conclusive postoperative findings, resection is unavoidable when a true pancreatic neoplasm cannot be excluded.

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  • Multidisciplinary cancer therapy with telomerase-specific oncolytic adenovirus

    Toshiyoshi Fujiwara, Shunsuke Kagawa, Hiroshi Tazawa

    Current Cancer Therapy Reviews   11 ( 3 )   178 - 187   2015

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    A multidisciplinary approach of combining surgery, chemotherapy and radiotherapy has remained the accepted standard management for various types of human cancer. However, many new treatment options have recently become available, including molecular targeted therapies, immunotherapies and oncolytic virotherapies. Replication-selective tu-mor-specific viruses have been designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. We constructed an attenuated adenovirus 5 vector, telomelysin (OBP-301), in which the telomerase-specific promoter drives expression of viral replication-inducible E1 genes. Although telomelysin alone exhibited substantial antitumor effects both in animal models and in clinical trials, telomelysin has the potential to be the first-in-class oncolytic virus for combination therapy based on our current understanding of the molecular mechanisms. Telomelysin sensitizes human cancer cells to ionizing radiation by inhibiting the radiation-induced DNA repair machinery, and also eliminates radio-resistant quiescent cancer stem-like cells by promoting cell cycle entry. A clinical trial of intratumoral administration of telomelysin with radiotherapy in esophageal cancer patients is currently underway. This article reviews recent highlights in the rapidly evolving field of multidisciplinary therapy with telomelysin.

    DOI: 10.2174/1573394712666160128201822

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  • 腹腔鏡下に切除した腹腔内デスモイド腫瘍の1例

    八木朝彦, 稲田涼, 永坂岳司, 渡邉彩子, 松本聖, 戸嶋俊明, 母里淑子, 近藤喜太, 岸本浩行, 藤原俊義

    日本外科系連合学会誌   40 ( 1 )   111 - 115   2015

  • 術前診断に難渋した原発性小腸癌の1例

    松本聖, 稲田涼, 近藤喜太, 渡邉彩子, 八木朝彦, 戸嶋俊明, 母里淑子, 岸本浩行, 永坂岳司, 藤原俊義

    日本外科系連合学会誌   40 ( 1 )   61 - 65   2015

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  • 遺伝子組換えアデノウイルスを用いたCirculating Tumor Cell検出系の開発と臨床応用

    櫻井文教, 水口裕之, 藤原俊義

    大和証券ヘルス財団研究業績集38号   108 - 112   2015

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  • Precise navigation surgery of tumours in the lung in mouse models enabled by in situ fluorescence labelling with a killer-reporter adenovirus

    Shuya Yano, Yong Zhang, Shinji Miwa, Hiroyuki Kishimoto, Yasuo Urata, Michael Bouvet, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    BMJ Open Respiratory Research   2 ( 1 )   1 - 6   2015

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    Background: Current methods of image-guided surgery of tumours of the lung mostly rely on CT. A sensitive procedure of selective tumour fluorescence labelling would allow simple and high-resolution visualisation of the tumour for precise surgical navigation. Methods: Human lung cancer cell lines H460 and A549 were genetically transformed to express red fluorescent protein (RFP). Tumours were grown subcutaneously for each cell line and harvested and minced for surgical orthotopic implantation on the left lung of nude mice. Tumour growth was measured by fluorescence imaging. After the tumours reached 5 mm in diameter, they were injected under fluorescence guidance with the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus, OBP-401. Viral labelling of the lung tumours with GFP precisely colocalised with tumour RFP expression. Three days after administration of OBP-401, fluorescence-guided surgery (FGS) was performed. Results: FGS of tumours in the lung was enabled by labelling with a telomerase-dependent adenovirus containing the GFP gene. Tumours in the lung were selectively and brightly labelled. FGS enabled complete lung tumour resection with no residual fluorescent tumour. Conclusions: FGS of tumours in the lung is feasible and more effective than bright-light surgery.

    DOI: 10.1136/bmjresp-2015-000096

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  • Eradication of osteosarcoma by fluorescence-guided surgery with tumor labeling by a killer-reporter adenovirus

    Yano S, Miwa S, Kishimoto H, Urata Y, Tazawa H, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM

    J Orthop Res   doi: 10.1002/jor.23073. [Epub ahead of print]   2015

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  • Strategic approach to concurrent aberrant left gastric vein and aberrant left hepatic artery in laparoscopic distal gastrectomy for early gastric cancer: A case report

    Kuwada K, Kuroda S, Kikuchi S, Hori N, Kubota T, Nishizaki M, Kagawa S, Fujiwara T

    Asian J Endosc Surg   8 ( 4 )   454 - 456   2015

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  • 6.血液凝固と線溶現象:b)血栓症の予防,診断および治療

    黒田新士, 藤原俊義

    外科   77 ( 12 )   1385 - 1390   2015

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  • Relative Prognostic and Predictive Value of Gene Signature and Histologic Grade in Estrogen Receptor–Positive, HER2-Negative Breast Cancer

    Iwamoto T, Kelly C, Mizoo T, Nogami T, Motoki T, Shien T, Taira N, Hayashi N, Niikura N, Fujiwara T, Doihara H, Matsuoka J

    Clin Breast Cancer   doi: 10.1016/j.clbc.2015.10.004.   2015

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  • Serum Oxidative/anti-oxidative Stress Balance Is Dysregulated in Potentially Pulmonary Hypertensive Patients with Liver Cirrhosis: A Case Control Study

    Masako Terao, Akinobu Takaki, Takayuki Maruyama, Hiroki Oe, Tetsuya Yasunaka, Naofumi Tamaki, Kazufumi Nakamura, Takaaki Tomofuji, Takahito Yagi, Hiroshi Sadamori, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Kazuhiro Nouso, Daisuke Ekuni, Kazuko Koike, Fusao Ikeda, Hidenori Shiraha, Manabu Morita, Hiroshi Ito, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    INTERNAL MEDICINE   54 ( 22 )   2815 - 2826   2015

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    Objective Hepatopulmonary syndrome (HPS) is characterized by vascular dilatation and hyperdynamic circulation, while portopulmonary hypertension (POPH) is characterized by vasoconstriction with fibrous obliteration of the vascular bed. Vasoactive molecules such as nitric oxide (NO) are candidate factors for cirrhotic complications associated with these diseases. However, oxidative stress balance is not well characterized in HPS and POPH. The present objective is to investigate the oxidative stress and anti-oxidative stress balance and NO pathway balance in patients with potential HPS and POPH.
    Methods We recruited patients with decompensated cirrhosis (n = 69) admitted to our hospital as liver transplantation candidates. Patients exhibiting partial pressure of oxygen lower than 80 mmHg and alveolararterial oxygen gradient (AaDO(2)) &gt;= 15 mmHg were categorized as potentially having HPS (23 of 69 patients). Patients exhibiting a tricuspid regurgitation pressure gradient &gt;= 25 mmHg were categorized as potentially having POPH (29 of 61 patients). Serum reactive oxygen metabolites were measured and anti-oxidative OXY-adsorbent test (OXY) were performed, and the balance of these tests was defined as the oxidative index. The correlation between these values and the clinical characteristics of the patients were assessed in a cross-sectional study.
    Results Potential HPS patients exhibited no correlation with oxidative stress markers. Potential POPH patients exhibited lower OXY (p = 0.037) and higher oxidative index values (p = 0.001). Additionally, the vascular NO synthase enzyme inhibiting protein, asymmetric dimethylarginine, was higher in potential POPH patients (p = 0.049). The potential POPH patients exhibited elevated AaDO(2), suggesting the presence of pulmonary shunting.
    Conclusion Potential POPH patients exhibited elevated oxidative stress with decreased anti-oxidative function accompanied by inhibited NO production. Anti-oxidants represent a candidate treatment for potential POPH patients.

    DOI: 10.2169/internalmedicine.54.4889

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  • Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

    Takehara K, Tazawa H, Okada N, Hashimoto Y, Kikuchi S, Kuroda S, Kishimoto H, Shirakawa Y, Narii N, Mizuguchi H, Urata Y, Kagawa S, Fujiwara T

    Mol Cancer Ther   DOI: 10.1158/1535-7163   DOI: 10.1158/1535-7163   2015

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  • 食道癌におけるFAP(fibroblast activation protein)陽性癌関連線維芽細胞の発現と癌転移の関係

    賀島肇, 野間和広, 加藤卓也, 勝部亮一, 二宮卓之, 大原利章, 田澤大, 白川靖博, 香川俊輔, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   26th   2015

  • 鉄制御を用いた新しい癌の浸潤・転移抑制治療法の開発

    大原利章, 大原利章, 二宮卓之, 野間和広, 賀島肇, 加藤卓也, 勝部亮一, 白川靖博, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   26th   2015

  • 癌関連線維芽細胞を標的とした新規食道癌治療法の開発

    勝部亮一, 野間和広, 賀島肇, 加藤卓也, 二宮卓之, 大原利章, 田澤大, 白川靖博, 香川俊輔, 小林久隆, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   26th   2015

  • Tumor-targeting Salmonella typhimurium A1-R decoys quiescent cancer cells to cycle as visualized by FUCCI imaging and become sensitive to chemotherapy

    Shuya Yano, Yong Zhang, Ming Zhao, Yukihiko Hiroshima, Shinji Miwa, Fuminari Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    CELL CYCLE   13 ( 24 )   3958 - 3963   2014.12

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    Quiescent cancer cells are resistant to cytotoxic agents which target only proliferating cancer cells. Time-lapse imaging demonstrated that tumor-targeting Salmonella typhimurium A1-R (A1-R) decoyed cancer cells in monolayer culture and in tumor spheres to cycle from G(0)/G(1) to S/G(2)/M, as demonstrated by fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging. A1-R infection of FUCCI-expressing subcutaneous tumors growing in nude mice also decoyed quiescent cancer cells, which were the majority of the cells in the tumors, to cycle from G(0)/G(1) to S/G(2)/M, thereby making them sensitive to cytotoxic agents. The combination of A1-R and cisplatinum or paclitaxel reduced tumor size compared with A1-R monotherapy or cisplatinum or paclitaxel alone. The results of this study demonstrate that A1-R can decoy quiescent cancer cells to cycle to S/G(2)/M and sensitize them to cytotoxic chemotherapy. These results suggest a new paradigm of bacterial-decoy chemotherapy of cancer.

    DOI: 10.4161/15384101.2014.964115

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  • Establishment of a Non-Invasive Semi-Quantitative Bioluminescent Imaging Method for Monitoring of an Orthotopic Esophageal Cancer Mouse Model

    Shinji Kuroda, Tetsushi Kubota, Katsuyuki Aoyama, Satoru Kikuchi, Hiroshi Tazawa, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    PLOS ONE   9 ( 12 )   e114562   2014.12

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    Orthotopic models of various types of tumors are widely used in anti-tumor therapeutic experiments in preclinical studies. However, there are few ways to appropriately monitor therapeutic effect in orthotopic tumor models, especially for tumors invisible from the outside. In this study we aimed to establish a non-invasive semi-quantitative bioluminescent imaging method of monitoring an orthotopic esophageal cancer mouse model. We confirmed that the TE8 esophageal cancer cell line implanted orthotopically into the abdominal esophagus of nu/nu mice (n=5) developed not only a main tumor at the implanted site, but also local lymph node metastases and peritoneal disseminations within 6 weeks after inoculation. We established a TE8 cell line that stably expressed the firefly luciferase gene (TE8-Luc). We showed that TE8-Luc cells implanted subcutaneously into nu/nu mice (n=5) grew over time until 5 weeks after inoculation. Tumor volume was strongly correlated with luminescent intensity emitted from the tumor, which was quantified using the IVIS imaging system. We then showed that TE8-Luc cells implanted orthotopically into the mouse abdominal esophagus (n=8) also formed a tumor and that the luminescent intensity of such a tumor, as detected by IVIS, increased over time until 7 weeks after inoculation and was therefore likely to reflect tumor progression. We therefore propose that this orthotopic esophageal cancer model, monitored using the non-invasive semi-quantitative IVIS imaging system, will be useful for in vivo therapeutic experiments against esophageal cancer. This experimental setting is expected to contribute to the development of novel therapeutic technologies for esophageal cancer in preclinical studies.

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  • Risk Factors of Morbidity and Predictors of Long-term Survival after Hepatopancreatoduodenectomy for Biliary Cancer

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

    HEPATO-GASTROENTEROLOGY   61 ( 136 )   2167 - 2172   2014.11

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    Background/Aims: Hepatopancreatoduodenectomy (HPD) is performed to achieve radical resection of malignant biliary tumors. We reviewed clinical outcomes to evaluate the utility of HPD in terms of morbidity and mortality. Methodology: A retrospective analysis was conducted on 17 patients underwent HPD between August 1991 and May 2013; 9 bile duct cancel; 5 advanced gallbladder and 3pancreatic tumor with liver metastasis. Results: The morbidity and mortality rates were 88.3% and 0%, respectively. Univariate analysis showed that a body mass index of &gt;= 22 and preoperative total bilirubin level &gt;= 0.8 mg/dl were significantly associated with severe complications. One, 3- and 5-year survival rate were 73.3%, 60.0% and 30.0%. In 14 patients with biliary carcinoma, univariate analysis showed that a histological grade of G1 was significantly associated with survival. Patients without pancreatic invasion or portal vein invasion tended to survive longer than patients with these types of invasion, although the difference was not significant. Conclusions: HPD can be performed with no mortality and provides a survival benefit for some patients with biliary carcinoma undergoing curative resection. In patients with grade G1 biliary carcinoma without pancreatic or portal vein invasion in particular, this aggressive surgery might offer a chance of long-term survival.

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  • Hepatitis C Virus-specific T-cell Response Correlates with Hepatitis Activity and Donor IL28B Genotype Early after Liver Transplantation

    Ryuichiro Tsuzaki, Akinobu Takaki, Takahito Yagi, Fusao Ikeda, Kazuko Koike, Yoshiaki Iwasaki, Hidenori Shiraha, Yasuhiro Miyake, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Eiichi Nakayama, Toshiyoshi Fujiwara, Kazuhide Yamamoto

    ACTA MEDICA OKAYAMA   68 ( 5 )   291 - 302   2014.10

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    It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-gamma) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At &gt; 3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.

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  • Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case

    Kunitoshi Shigeyasu, Kohji Tanakaya, Takeshi Nagasaka, Hideki Aoki, Toshiyoshi Fujiwara, Kokichi Sugano, Hideki Ishikawa, Teruhiko Yoshida, Yoshihiro Moriya, Yoichi Furukawa, Ajay Goel, Hitoshi Takeuchi

    SURGERY TODAY   44 ( 10 )   1975 - 1981   2014.10

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    Lynch syndrome is an autosomal dominant disease associated with a high incidence of colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, bile duct and brain tumors. The syndrome can also include sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel. The lifetime risk for bile duct cancer in patients with Lynch syndrome is approximately 2 %. The present report describes a case of Lynch syndrome with metachronous bile duct cancer diagnosed at an early stage. The patient was a 73-year-old Japanese male who underwent a successful left lobectomy of the liver, and there was no sign of recurrence for 2 years postoperative. However, this patient harbored a germline mutation in MLH1, which prompted diagnostic examinations for noncolorectal tumors when a periodic surveillance blood examination showed abnormal values of hepatobiliary enzymes. Although most patients with bile duct cancer are diagnosed at an advanced stage, the bile duct cancer was diagnosed at an early stage in the present patient due to the observation of the gene mutation and the preceding liver tumor. This case illustrates the importance of continuous surveillance for extracolonic tumors, including bile duct cancer, in patients with Lynch syndrome.

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  • Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case

    Kunitoshi Shigeyasu, Kohji Tanakaya, Takeshi Nagasaka, Hideki Aoki, Toshiyoshi Fujiwara, Kokichi Sugano, Hideki Ishikawa, Teruhiko Yoshida, Yoshihiro Moriya, Yoichi Furukawa, Ajay Goel, Hitoshi Takeuchi

    SURGERY TODAY   44 ( 10 )   1975 - 1981   2014.10

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    Lynch syndrome is an autosomal dominant disease associated with a high incidence of colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, bile duct and brain tumors. The syndrome can also include sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel. The lifetime risk for bile duct cancer in patients with Lynch syndrome is approximately 2 %. The present report describes a case of Lynch syndrome with metachronous bile duct cancer diagnosed at an early stage. The patient was a 73-year-old Japanese male who underwent a successful left lobectomy of the liver, and there was no sign of recurrence for 2 years postoperative. However, this patient harbored a germline mutation in MLH1, which prompted diagnostic examinations for noncolorectal tumors when a periodic surveillance blood examination showed abnormal values of hepatobiliary enzymes. Although most patients with bile duct cancer are diagnosed at an advanced stage, the bile duct cancer was diagnosed at an early stage in the present patient due to the observation of the gene mutation and the preceding liver tumor. This case illustrates the importance of continuous surveillance for extracolonic tumors, including bile duct cancer, in patients with Lynch syndrome.

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  • Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells as a potential clinical biomarker

    Megumi Watanabe, Shunsuke Kagawa, Michihiro Ishida, Naoto Hori, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Hiroshi Tazawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014.10

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    DOI: 10.1158/1538-7445.AM2014-4726

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  • Novel combination therapy of adenoviral gene transfer of HER2-extracellular domain and trastuzumab-based photoimmunotherapy for HER2 negative cancer cells

    Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Hiroshi Tazawa, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014.10

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  • Combination strategy of endoscopic resection and telomerase-targeting oncolytic virus for eradicating lymph node metastasis of submucosal invasive colorectal cancer

    Naoto Hori, Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Yuuri Hashimoto, Shinji Kuroda, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014.10

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    DOI: 10.1158/1538-7445.AM2014-4025

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  • Development of systemically-deliverable telomerase-specific oncolytic adenovirus

    Katsuyuki Aoyama, Shinji Kuroda, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014.10

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  • Selective methioninase-induced trap of cancer cells in S/G(2) phase visualized by FUCCI imaging confers chemosensitivity

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

    ONCOTARGET   5 ( 18 )   8729 - 8736   2014.9

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    A major impediment to the response of tumors to chemotherapy is that the large majority of cancer cells within a tumor are quiescent in G(0)/G(1), where cancer cells are resistant to chemotherapy. To attempt to solve this problem of quiescent cells in a tumor, c