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201. Tumor-Targeting Salmonella typhimurium A1-R Arrests a Chemo-Resistant Patient Soft-Tissue Sarcoma in Nude Mice

Author

Hiroshima, Yukihiko, primary, Zhao, Ming, additional, Zhang, Yong, additional, Zhang, Nan, additional, Maawy, Ali, additional, Murakami, Takashi, additional, Mii, Sumiyuki, additional, Uehara, Fuminari, additional, Yamamoto, Mako, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Mori, Ryutaro, additional, Matsuyama, Ryusei, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Ichikawa, Yasushi, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2015
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203. ALPPS

Author

Tanaka, Kuniya, primary and Endo, Itaru, additional

Published
2015
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204. Abstract 5272: The correlation between the change of future remnant liver volume and functional capacity in ALPPS (associating liver partition and portal vein ligation for staged hepatectomy), and establishment of ALPPS model in rats

Author

Kawaguchi, Daisuke, primary, Hiroshima, Yukihiko, additional, Murakami, Takashi, additional, Matsuo, Kenichi, additional, Kosugi, Chihiro, additional, Syuto, Kiyohiko, additional, Yamada, Akimitsu, additional, Endo, Itaru, additional, Koda, Keiji, additional, and Tanaka, Kuniya, additional

Published
2015
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205. Abstract 219: Fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore in combination with neoadjuvant chemotherapy inhibits metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Zhang, Yong, additional, Murakami, Takashi, additional, Momiyama, Masashi, additional, Mori, Ryutaro, additional, Matsuyama, Ryusei, additional, Katz, Matthew H., additional, Fleming, Jason B., additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, ichikawa, Yasushi, additional, Endo, Itaru, additional, Hoffman, Robert M., additional, and Bouvet, Michael, additional

Published
2015
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206. Abstract 5117: Fluorescence-guided surgery of liver metastasis in orthotopic nude-mouse models

Author

Murakami, Takashi, primary, Hiroshima, Yukihiko, additional, Miwa, Shinji, additional, Shuya, Yano, additional, Toneri, Makoto, additional, Yamamoto, Mako, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Hasegawa, Satoshi, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2015
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207. Abstract 5123: Curative fluorescence-guided surgery of pancreatic cancer in combination with UVC irradiation in orthotopic mouse models

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Zhang, Yong, additional, Sato, Sho, additional, Murakami, Takashi, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2015
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209. Abstract 1456: Efficacy of photo-immunotherapy in combination with surgical resection on a pancreatic cancer patient derived orthotopic xenograft (PDOX)

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Murakami, Takashi, additional, Magalhães, Nzola De, additional, Kawaguchi, Daisuke, additional, Matsuo, Kenichi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Hoffman, Robert M., additional, and Endo, Itaru, additional

Published
2015
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210. Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models

Author

Hiroshima, Yukihiko, primary, Zhang, Yong, additional, Zhao, Ming, additional, Zhang, Nan, additional, Murakami, Takashi, additional, Maawy, Ali, additional, Mii, Sumiyuki, additional, Uehara, Fuminari, additional, Yamamoto, Mako, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Mori, Ryutaro, additional, Matsuyama, Ryusei, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Ichikawa, Yasushi, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2015
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211. Fluorescence-guided surgery, but not bright-light surgery, prevents local recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) model resistant to neoadjuvant chemotherapy (NAC)

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Zhang, Yong, additional, Murakami, Takashi, additional, Momiyama, Masashi, additional, Mori, Ryutaro, additional, Matsuyama, Ryusei, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Ichikawa, Yasushi, additional, Endo, Itaru, additional, Hoffman, Robert M., additional, and Bouvet, Michael, additional

Published
2015
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212. Photoimmunotherapy Inhibits Tumor Recurrence After Surgical Resection on a Pancreatic Cancer Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Zhang, Yong, additional, Guzman, Miguel Garcia, additional, Heim, Roger, additional, Makings, Lew, additional, Luiken, George A., additional, Kobayashi, Hisataka, additional, Tanaka, Kuniya, additional, Endo, Itaru, additional, Hoffman, Robert M., additional, and Bouvet, Michael, additional

Published
2015
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213. Thrombomodulin improves rat survival after extensive hepatectomy

Author

Ota, Yohei, primary, Kumamoto, Takafumi, additional, Ishibe, Atsushi, additional, Watanabe, Kazuteru, additional, Mori, Ryutarou, additional, Taniguchi, Koichi, additional, Matsuyama, Ryusei, additional, Makino, Hirochika, additional, Ueda, Michio, additional, Kubota, Toru, additional, Akiyama, Hirotoshi, additional, Tanaka, Kuniya, additional, Ichikawa, Yasushi, additional, and Endo, Itaru, additional

Published
2015
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214. Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8+ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic-Cancer Orthotopic Mouse Model.

Author

Murakami, Takashi, Hiroshima, Yukihiko, Zhang, Yong, Zhao, Ming, Kiyuna, Tasuku, Hwang, Ho Kyoung, Miyake, Kentaro, Homma, Yuki, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Ichikawa, Yasushi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M.

Published
2018
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215. The Impact of Advanced Age on Hepatic Resection of Colorectal Liver Metastases

Author

Nojiri, Kazunori, Nagano, Yasuhiko, Matsuo, Kenichi, Tanaka, Kuniya, Togo, Shinji, and Shimada, Hiroshi

Subjects
education, social sciences, humanities, geographic locations, health care economics and organizations
Abstract

American College of Surgeons 91st Annual Clinical Congress

Published
2005

216. Remnant Liver Tumor Growth Activity During Treatment Associating Liver Partition and Portal Vein Occlusion for Staged Hepatectomy (ALPPS).

Author

Kikuchi, Yutaro, Hiroshima, Yukihiko, Matsuo, Kenichi, Murakami, Takashi, Kawaguchi, Daisuke, Endo, Itaru, Yamazaki, Kazuto, Ishida, Yasuo, and Tanaka, Kuniya

Subjects
TUMOR treatment, LIVER tumors, TUMOR growth, HEPATECTOMY, ARTERIAL occlusions, PORTAL vein diseases, CANCER invasiveness, PORTAL vein surgery, THERAPEUTIC embolization
Abstract

Background: We compared tumor growth activity during treatment associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS) with that in classical 2-stage hepatectomy.Methods: Short-term outcomes, serial changes in volume of the future liver remnant (FLR), and tumor growth activity during the treatment period were compared between 12 patients treated with ALPPS and 20 patients treated with 2-stage hepatectomy for colorectal liver metastases. This study was registered in UMIN Clinical Trials Registry (registration number, UMIN000018622).Results: The FLR hypertrophy ratio at 1 week after the first operation was greater in the ALPPS group (1.43 ± 0.24) than the 2-stage group (1.21 ± 0.28, P = 0.043). The mean kinetic growth rate (mKGR) of tumors in the ALPPS group (0.548 ± 7.29 mL/day) did not differ significantly from that in the 2-stage group (-3.53 ± 7.02 mL/day) in the first week after the initial procedure (P = 0.210). However, mKGR between 1 and 3 weeks after the first procedure (1.29 ± 2.34 mL/day) was significantly greater than that in first week after the procedure in the 2-stage group (P = 0.034).Conclusions: ALPPS induces a rapid FLR volume increase while avoiding remnant tumor progression. [ABSTRACT FROM AUTHOR]

Published
2017
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217. Neoadjuvant chemoradiotherapy of pancreatic cancer induces a favorable immunogenic tumor microenvironment associated with increased major histocompatibility complex class I-related chain A/B expression.

Author

Murakami, Takashi, Homma, Yuki, Matsuyama, Ryusei, Mori, Ryutaro, Miyake, Kentaro, Tanaka, Yusaku, Den, Kanechika, Nagashima, Yoji, Nakazawa, Masatoshi, Hiroshima, Yukihiko, Ueda, Michio, Tanaka, Kuniya, Hoffman, Robert M., Bouvet, Michael, and Endo, Itaru

Published
2017
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218. Immaturity of Bile Canalicular-Ductule Networks in the Future Liver Remnant While Associating Liver Partition and Portal Vein Occlusion for Staged Hepatectomy (ALPPS).

Author

Matsuo, Kenichi, Hiroshima, Yukihiko, Yamazaki, Kazuto, Kasahara, Kohei, Kikuchi, Yutaro, Kawaguchi, Daisuke, Murakami, Takashi, Ishida, Yasuo, and Tanaka, Kuniya

Abstract

Background: We studied histologic changes of bile canalicular-ductule networks in the future liver remnant (FLR) while associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS), since little is known about regeneration of these networks during the relatively short interval between procedures in ALPPS. Methods: Bile canalicular-ductule networks were examined in specimens from eight patients treated with ALPPS and six patients undergoing hepatectomy following portal vein embolization (PVE). Expression of multidrug resistance-1 (MDR1), a membrane transporter in bile canaliculi (BC), was analyzed immunohistochemistcally. Morphologic changes of BC and tight junctions (TJs) adjoining BC were also assessed electron microscopically. Results: Extrapolated kinetic growth of the FLR was greater during ALPPS (17.2 ± 6.8 mL/day) than after PVE (6.3 ± 3.4 mL/day; p = 0.005), and continuity of the MDR1-positive bile canalicular networks was less evident in ALPPS than PVE ( p < 0.001). Electron microscopically, no significant difference was evident in numbers of BC or BC lumen size between the two groups; however, development of microvilli in BC was poorer in the ALPPS group than in the PVE group ( p < 0.001). TJ/desmosome complexes were shorter in the ALPPS group (0.69 ± 0.52 μm) than in the PVE group (1.09 ± 0.50 μm; p < 0.001), and leaky TJs were seen more frequently in the ALPPS group (64.9 vs. 23.6%; p = 0.001). Conclusions: Regeneration of bile canalicular-ductule networks in the FLR was poorer in ALPPS than PVE, which may be associated with prolonged cholestasis following final hepatectomy in ALPPS. [ABSTRACT FROM AUTHOR]

Published
2017
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219. Modified ALPPS procedures: more safety through less invasive surgery.

Author

Tanaka, Kuniya

Subjects
*HEPATECTOMY, *SURGERY safety measures, *TUMOR treatment, *LIVER tumors, *CANCER-related mortality, *HISTOPATHOLOGY
Abstract

Purpose: Although associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been advocated for treating advanced liver tumors, increased morbidity and mortality remain serious problems. Many modified procedures have been devised to improve patient safety, but some confusion persists as to benefits and risks. Methods: Modifications to ALPPS as originally reported were reviewed to clarify their contributions to safety and their clinical relevance. Results: A variety of modifications are explained and considered. Modifications mainly aim to reduce adhesions, prevent tumor spread, avoid devascularization during liver splitting, and reduce surgical severity. Such changes aiming to increase safety and reduce invasiveness are needed to avoid high morbidity and mortality rates with this innovative procedure. However, these modified procedures still require more meaningful statistical comparisons of outcome. Conclusions: Prospective controlled studies are needed to confirm which modified procedures should be adopted in a standardized manner as an alternative to the original ALPPS. Further, we need to further explore mechanisms of liver regeneration, functional recovery, histopathologic changes of hepatocytes, and blood distribution during ALPPS simultaneously to developing and evaluating modifications of the procedure. [ABSTRACT FROM AUTHOR]

Published
2017
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220. The irony of highly-effective bacterial therapy of a patient-derived orthotopic xenograft (PDOX) model of Ewing's sarcoma, which was blocked by Ewing himself 80 years ago.

Author

Murakami, Takashi, Kiyuna, Tasuku, Kawaguchi, Kei, Igarashi, Kentaro, Singh, Arun S., Hiroshima, Yukihiko, Zhang, Yong, Zhao, Ming, Miyake, Kentaro, Nelson, Scott D., Dry, Sarah M., Li, Yunfeng, DeLong, Jonathan C., Lwin, Thinzar M., Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, Eilber, Fritz C., and Hoffman, Robert M.

Abstract

William B. Coley developed bacterial therapy of cancer more than 100 years ago and had clinical success. James Ewing, a very famous cancer pathologist for whom the Ewing sarcoma is named, was Coley's boss at Memorial Hospital in New York and terminated Coley's bacterial therapy of cancer. A tumor from a patient with soft-tissue Ewing's sarcoma, who failed doxorubicin (DOX) therapy, was previously implanted in nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the Ewing's sarcoma PDOX was treated with tumor-targetingS. typhimuriumA1-R expressing green fluorescent (GFP), alone and in combination with DOX.S. typhimuriumA1-R-GFP was detected in the tumors after intratumor (i.t.) or intravenous (i.v.) injection. The combination ofS. typhimuriumA1-R and DOX significantly reduced tumor weight (37.8 ± 15.6 mg) compared to the untreated control (73.8 ± 10.1 mg,P< 0.01).S. typhimuriumA1-R monotherapy-treated tumors tended to be smaller (50.9 ± 17.8 mg,P= 0.051). DOX monotherapy did not show efficacy (66.3 ± 26.4 mg,P= 0.82), as was the case with the patient. The PDOX model faithfully replicated the DOX resistance the Ewing's sarcoma had in the patient.S. typhimuriumA1-R converted the Ewing's sarcoma from DOX resistant to sensitive. One can only wonder how bacterial therapy and immunotherapy of cancer would have developed over the past 80 years if Ewing did not stop Coley. [ABSTRACT FROM PUBLISHER]

Published
2017
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221. Color-coded intravital imaging demonstrates a transforming growth factor-β (TGF-β) antagonist selectively targets stromal cells in a human pancreatic-cancer orthotopic mouse model.

Author

Murakami, Takashi, Hiroshima, Yukihiko, Miyake, Kentaro, Hwang, Ho Kyoung, Kiyuna, Tasuku, DeLong, Jonathan C., Lwin, Thinzar M., Matsuyama, Ryusei, Mori, Ryutaro, Kumamoto, Takafumi, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M.

Abstract

Pancreatic cancer is a recalcitrant malignancy, partly due to desmoplastic stroma which stimulates tumor growth, invasion, and metastasis, and inhibits chemotherapeutic drug delivery. Transforming growth factor-β (TGF-β) has an important role in the formation of stromal desmoplasia. The present study describes the ability of color-coded intravital imaging to demonstrate the efficacy of a TGF-β inhibitor to target stroma in an orthotopic mouse model of pancreatic cancer. The BxPC-3 human pancreatic adenocarcinoma cell line expressing green fluorescent protein (GFP), which also has a high TGF-β expression level, was used in an orthotopic model in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). Fourteen mice were randomized into a control group (n = 7, vehicle, i.p., weekly, for 3 weeks) and a treated group (n = 7, SB431542 [TGF-β receptor type I inhibitor] 0.3 mg, i.p., weekly, for 3 weeks). Stromal cells expressing RFP and cancer cells expressing GFP were observed weekly for 3 weeks by real-time color-coded intravital imaging. The RFP fluorescence area from the stromal cells, relative to the GFP fluorescence area of the cancer cells, was significantly decreased in the TGF-β-inhibitor-treatment group compared to the control group. The present study demonstrated color-coded imaging in an orthotopic pancreatic-cancer cell-line mouse model can readily detect the selective anti-stromal-cell targeting of a TGF-β inhibitor. [ABSTRACT FROM PUBLISHER]

Published
2017
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222. Establishment of a Patient-Derived Orthotopic Xenograft (PDOX) Model of HER-2-Positive Cervical Cancer Expressing the Clinical Metastatic Pattern

Author

Hiroshima, Yukihiko, primary, Zhang, Yong, additional, Zhang, Nan, additional, Maawy, Ali, additional, Mii, Sumiyuki, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Murakami, Takashi, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Ichikawa, Yasushi, additional, Bouvet, Michael, additional, Murata, Takuya, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2015
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226. The tumor-educated-macrophage increase of malignancy of human pancreatic cancer is prevented by zoledronic acid.

Author

Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Hassanein, Mohamed K, Menen, Rhiana, Momiyama, Masashi, Murakami, Takashi, Miwa, Shinji, Yamamoto, Mako, Uehara, Fuminari, Yano, Shuya, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, Hoffman, Robert M, Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Hassanein, Mohamed K, Menen, Rhiana, Momiyama, Masashi, Murakami, Takashi, Miwa, Shinji, Yamamoto, Mako, Uehara, Fuminari, Yano, Shuya, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M

Abstract

We previously defined macrophages harvested from the peritoneal cavity of nude mice with subcutaneous human pancreatic tumors as "tumor-educated-macrophages" (Edu) and macrophages harvested from mice without tumors as "naïve-macrophages" (Naïve), and demonstrated that Edu-macrophages promoted tumor growth and metastasis. In this study, Edu- and Naïve-macrophages were compared for their ability to enhance pancreatic cancer malignancy at the cellular level in vitro and in vivo. The inhibitory efficacy of Zoledronic acid (ZA) on Edu-macrophage-enhanced metastasis was also determined. XPA1 human pancreatic cancer cells in Gelfoam co-cultured with Edu-macrophages proliferated to a greater extent compared to XPA1 cells cultured with Naïve-macrophages (P = 0.014). XPA1 cells exposed to conditioned medium harvested from Edu culture significantly increased proliferation (P = 0.016) and had more migration stimulation capability (P<0.001) compared to cultured cancer cells treated with the conditioned medium from Naïve. The mitotic index of the XPA1 cells, expressing GFP in the nucleus and RFP in the cytoplasm, significantly increased in vivo in the presence of Edu- compared to Naïve-macrophages (P = 0.001). Zoledronic acid (ZA) killed both Edu and Naïve in vitro. Edu promoted tumor growth and metastasis in an orthotopic mouse model of the XPA1 human pancreatic cancer cell line. ZA reduced primary tumor growth (P = 0.006) and prevented metastasis (P = 0.025) promoted by Edu-macrophages. These results indicate that ZA inhibits enhanced primary tumor growth and metastasis of human pancreatic cancer induced by Edu-macrophages.

Published
2014

227. Efficacy of tumor-targeting Salmonella typhimurium A1-R in combination with anti-angiogenesis therapy on a pancreatic cancer patient-derived orthotopic xenograft (PDOX) and cell line mouse models.

Author

Hiroshima, Yukihiko, Hiroshima, Yukihiko, Zhang, Yong, Murakami, Takashi, Maawy, Ali, Miwa, Shinji, Yamamoto, Mako, Yano, Shuya, Sato, Sho, Momiyama, Masashi, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, Zhao, Ming, Hoffman, Robert M, Hiroshima, Yukihiko, Hiroshima, Yukihiko, Zhang, Yong, Murakami, Takashi, Maawy, Ali, Miwa, Shinji, Yamamoto, Mako, Yano, Shuya, Sato, Sho, Momiyama, Masashi, Mori, Ryutaro, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Bouvet, Michael, Endo, Itaru, Zhao, Ming, and Hoffman, Robert M

Abstract

The aim of the present study was to examine the efficacy of tumor-targeting Salmonella typhimurium A1-R treatment following anti-vascular endothelial growth factor (VEGF) therapy on VEGF-positive human pancreatic cancer. A pancreatic cancer patient-derived orthotopic xenograft (PDOX) that was VEGF-positive and an orthotopic VEGF-positive human pancreatic cancer cell line (MiaPaCa-2-GFP) as well as a VEGF-negative cell line (Panc-1) were tested. Nude mice with these tumors were treated with gemcitabine (GEM), bevacizumab (BEV), and S. typhimurium A1-R. BEV/GEM followed by S. typhimurium A1-R significantly reduced tumor weight compared to BEV/GEM treatment alone in the PDOX and MiaPaCa-2 models. Neither treatment was as effective in the VEGF-negative model as in the VEGF-positive models. These results demonstrate that S. typhimurium A1-R following anti-angiogenic therapy is effective on pancreatic cancer including the PDOX model, suggesting its clinical potential.

Published
2014

228. Fluorescence-guided surgery in combination with UVC irradiation cures metastatic human pancreatic cancer in orthotopic mouse models.

Author

Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Zhang, Yong, Sato, Sho, Murakami, Takashi, Yamamoto, Mako, Uehara, Fuminari, Miwa, Shinji, Yano, Shuya, Momiyama, Masashi, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, Hoffman, Robert M, Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Zhang, Yong, Sato, Sho, Murakami, Takashi, Yamamoto, Mako, Uehara, Fuminari, Miwa, Shinji, Yano, Shuya, Momiyama, Masashi, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M

Abstract

The aim of this study is to determine if ultraviolet light (UVC) irradiation in combination with fluorescence-guided surgery (FGS) can eradicate metastatic human pancreatic cancer in orthotopic nude-mouse models. Two weeks after orthotopic implantation of human MiaPaCa-2 pancreatic cancer cells, expressing green fluorescent protein (GFP), in nude mice, bright-light surgery (BLS) was performed on all tumor-bearing mice (n = 24). After BLS, mice were randomized into 3 treatment groups; BLS-only (n = 8) or FGS (n = 8) or FGS-UVC (n = 8). The residual tumors were resected using a hand-held portable imaging system under fluorescence navigation in mice treated with FGS and FGS-UVC. The surgical resection bed was irradiated with 2700 J/m2 UVC (254 nm) in the mice treated with FGS-UVC. The average residual tumor area after FGS (n = 16) was significantly smaller than after BLS only (n = 24) (0.135±0.137 mm2 and 3.338±2.929 mm2, respectively; p = 0.007). The BLS treated mice had significantly reduced survival compared to FGS- and FGS-UVC-treated mice for both relapse-free survival (RFS) (p<0.001 and p<0.001, respectively) and overall survival (OS) (p<0.001 and p<0.001, respectively). FGS-UVC-treated mice had increased RFS and OS compared to FGS-only treated mice (p = 0.008 and p = 0.025, respectively); with RFS lasting at least 150 days indicating the animals were cured. The results of the present study suggest that UVC irradiation in combination with FGS has clinical potential to increase survival.

Published
2014

229. Metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model is inhibited by neoadjuvant chemotherapy in combination with fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore.

Author

Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Zhang, Yong, Murakami, Takashi, Momiyama, Masashi, Mori, Ryutaro, Matsuyama, Ryusei, Katz, Matthew HG, Fleming, Jason B, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Endo, Itaru, Hoffman, Robert M, Bouvet, Michael, Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Zhang, Yong, Murakami, Takashi, Momiyama, Masashi, Mori, Ryutaro, Matsuyama, Ryusei, Katz, Matthew HG, Fleming, Jason B, Chishima, Takashi, Tanaka, Kuniya, Ichikawa, Yasushi, Endo, Itaru, Hoffman, Robert M, and Bouvet, Michael

Abstract

The aim of this study is to determine the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine (GEM) in combination with fluorescence-guided surgery (FGS) on a pancreatic cancer patient derived orthotopic xenograft (PDOX) model. A PDOX model was established from a CA19-9-positive, CEA-negative tumor from a patient who had undergone a pancreaticoduodenectomy for pancreatic adenocarcinoma. Mice were randomized to 4 groups: bright light surgery (BLS) only; BLS+NAC; FGS only; and FGS+NAC. An anti-CA19-9 or anti-CEA antibody conjugated to DyLight 650 was administered intravenously via the tail vein of mice with the pancreatic cancer PDOX 24 hours before surgery. The PDOX was brightly labeled with fluorophore-conjugated anti-CA19-9, but not with a fluorophore-conjugated anti-CEA antibody. FGS was performed using the fluorophore-conjugated anti-CA19-9 antibody. FGS had no benefit over BLS to prevent metastatic recurrence. NAC in combination with BLS did not convey an advantage over BLS to prevent metastatic recurrence. However, FGS+NAC significantly reduced the metastatic recurrence frequency to one of 8 mice, compared to FGS only after which metastasis recurred in 6 out of 8 mice, and BLS+NAC with metastatic recurrence in 7 out of 8 mice (p = 0.041). Thus NAC in combination with FGS can reduce or even eliminate metastatic recurrence of pancreatic cancer sensitive to NAC. The present study further emphasizes the power of the PDOX model which enables metastasis to occur and thereby identify the efficacy of NAC in combination with FGS on metastatic recurrence.

Published
2014

230. Successful fluorescence-guided surgery on human colon cancer patient-derived orthotopic xenograft mouse models using a fluorophore-conjugated anti-CEA antibody and a portable imaging system.

Author

Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Metildi, Cristina A, Zhang, Yong, Uehara, Fuminari, Miwa, Shinji, Yano, Shuya, Sato, Sho, Murakami, Takashi, Momiyama, Masashi, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, Hoffman, Robert M, Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Metildi, Cristina A, Zhang, Yong, Uehara, Fuminari, Miwa, Shinji, Yano, Shuya, Sato, Sho, Murakami, Takashi, Momiyama, Masashi, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M

Abstract

BackgroundFluorescence-guided surgery (FGS) can enable successful cancer surgery where bright-light surgery often cannot. There are three important issues for FGS going forward toward the clinic: (a) proper tumor labeling, (b) a simple portable imaging system for the operating room, and (c) patient-like mouse models in which to develop the technology. The present report addresses all three.Materials and methodsPatient colon tumors were initially established subcutaneously in nonobese diabetic (NOD)/severe combined immune deficiency (SCID) mice immediately after surgery. The tumors were then harvested from NOD/SCID mice and passed orthotopically in nude mice to make patient-derived orthotopic xenograft (PDOX) models. Eight weeks after orthotopic implantation, a monoclonal anti-carcinoembryonic antigen (CEA) antibody conjugated with AlexaFluor 488 (Molecular Probes Inc., Eugene, OR) was delivered to the PDOX models as a single intravenous dose 24 hours before laparotomy. A hand-held portable fluorescence imaging device was used.ResultsThe primary tumor was clearly visible at laparotomy with the portable fluorescence imaging system. Frozen section microscopy of the resected specimen demonstrated that the anti-CEA antibody selectively labeled cancer cells in the colon cancer PDOX. The tumor was completely resected under fluorescence navigation. Histologic evaluation of the resected specimen demonstrated that cancer cells were not present in the margins, indicating successful tumor resection. The FGS animals remained tumor free for over 6 months.ConclusionsThe results of the present report indicate that FGS using a fluorophore-conjugated anti-CEA antibody and portable imaging system improves efficacy of resection for CEA-positive colorectal cancer. These data provide the basis for clinical trials.

Published
2014

231. Hand-held high-resolution fluorescence imaging system for fluorescence-guided surgery of patient and cell-line pancreatic tumors growing orthotopically in nude mice.

Author

Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Sato, Sho, Murakami, Takashi, Uehara, Fuminari, Miwa, Shinji, Yano, Shuya, Momiyama, Masashi, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, Hoffman, Robert M, Hiroshima, Yukihiko, Hiroshima, Yukihiko, Maawy, Ali, Sato, Sho, Murakami, Takashi, Uehara, Fuminari, Miwa, Shinji, Yano, Shuya, Momiyama, Masashi, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, and Hoffman, Robert M

Abstract

BackgroundIn this study, we investigated the advantages of fluorescence-guided surgery (FGS) in mice of a portable hand-sized imaging system compared with a large fluorescence imaging system or a long-working-distance fluorescence microscope.MethodsMouse models of human pancreatic cancer for FGS included the following: (1) MiaPaCa-2-expressing green fluorescent protein, (2) BxPC3 labeled with Alexa Fluor 488-conjucated anti-carcinoembryonic antigen (CEA) antibody, and (3) patient-derived orthotopic xenograft (PDOX) labeled with Alexa Fluor 488-conjugated anti-carbohydrate antigen 19-9 antibody.ResultsEach device could clearly detect the primary MiaPaCa-2-green fluorescent protein tumor and any residual tumor after FGS. In the BxPC3 model labeled with Alexa Fluor 488-conjugated anti-CEA, each device could detect the primary tumor, but the MVX10 could not clearly detect the residual tumor remaining after FGS whereas the other devices could. In the PDOX model labeled with Alexa Fluor 488-conjugated anti-carbohydrate antigen 19-9, only the portable hand-held device could distinguish the residual tumor from the background, and complete resection of the residual tumor was achieved under fluorescence navigation.ConclusionsThe results described in the present report suggest that the hand-held mobile imaging system can be applied to the clinic for FGS because of its convenient size and high sensitivity which should help make FGS widely used.

Published
2014

232. Metastatic Recurrence in a Pancreatic Cancer Patient Derived Orthotopic Xenograft (PDOX) Nude Mouse Model Is Inhibited by Neoadjuvant Chemotherapy in Combination with Fluorescence-Guided Surgery with an Anti-CA 19-9-Conjugated Fluorophore

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Zhang, Yong, additional, Murakami, Takashi, additional, Momiyama, Masashi, additional, Mori, Ryutaro, additional, Matsuyama, Ryusei, additional, Katz, Matthew H. G., additional, Fleming, Jason B., additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Ichikawa, Yasushi, additional, Endo, Itaru, additional, Hoffman, Robert M., additional, and Bouvet, Michael, additional

Published
2014
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233. Abstract B01: A portable imaging system for fluorescence-guided surgery on a human colon cancer patient-derived orthotopic xenograft (PDOX™) nude mouse model

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Kaushal, Sharmeela, additional, Zhang, Yong, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Sato, Sho, additional, Murakami, Takashi, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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234. Abstract A40: Pancreatic cancer patient-derived orthotopic xenograft (PDOX™) is effectively targeted by Salmonella typhimurium A1-R

Author

Hiroshima, Yukihiko, primary, Zhao, Ming, additional, Maawy, Ali, additional, Zhang, Yong, additional, Katz, Matthew H.G., additional, Fleming, Jason B., additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Suetsugu, Atsushi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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235. Efficacy of tumor-targeting Salmonella typhimurium A1-R in combination with anti-angiogenesis therapy on a pancreatic cancer patient-derived orthotopic xenograft (PDOX) and cell line mouse models

Author

Hiroshima, Yukihiko, primary, Zhang, Yong, additional, Murakami, Takashi, additional, Maawy, Ali, additional, Miwa, Shinji, additional, Yamamoto, Mako, additional, Yano, Shuya, additional, Sato, Sho, additional, Momiyama, Masashi, additional, Mori, Ryutaro, additional, Matsuyama, Ryusei, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Ichikawa, Yasushi, additional, Bouvet, Michael, additional, Endo, Itaru, additional, Zhao, Ming, additional, and Hoffman, Robert M., additional

Published
2014
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236. Abstract 1204: Establishment of a patient-derived orthotopic xenograft (PDOX) model of patient cervical cancer

Author

Hiroshima, Yukihiko, primary, Zhang, Yong, additional, Maawy, Ali, additional, Sato, Sho, additional, Murakami, Takashi, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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237. Abstract CT318: FOLFOXIRI+B-mab showed powerful effect as preoperative chemotherapy for multiple liver metastases of colorectal cancer

Author

Ichikawa, Yasushi, primary, Goto, Ayumu, additional, Kobayashi, Noritoshi, additional, Tokuhisa, Motohiko, additional, Ishikawa, Takashi, additional, Ishibe, Atsushi, additional, Watanabe, Kazuteru, additional, Nojiri, Kazunori, additional, Kumamoto, Yoshibumi, additional, Takeda, kazuhisa, additional, Ota, Mitsuyoshi, additional, Akiyama, Hirotoshi, additional, Tanaka, Kuniya, additional, and Endo, Itaru, additional

Published
2014
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238. Abstract 3130: Zoledronic acid inhibits proliferation and metastasis of human pancreatic cancer in the patient-derived orthotopic xenograft (PDOX) model by targeting tumor-educated macrophages

Author

Hiroshima, Yukihiko, primary, Hassenein, Mohamed K., additional, Menen, Rhiana, additional, Katz, Matthew H.g., additional, Fleming, Jason B., additional, Sato, Sho, additional, Murakami, Takashi, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Maawy, Ali, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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239. Abstract 1230: Efficacy of Salmonella typhimurium A1-R and anti-VEGF therapy on a patient-derived orthotopic xenograft (PDOX) pancreatic cancer model

Author

Hiroshima, Yukihiko, primary, Zhao, Ming, additional, Katz, Matthew H.G., additional, Fleming, Jason B., additional, Sato, Sho, additional, Murakami, Takashi, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Zhang, Yong, additional, Maawy, Ali, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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240. Abstract 4375: UVC irradiation in combination with fluorescence-guided surgery cures metastatic human pancreatic cancer in orthotopic mouse models

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Sato, Sho, additional, Murakami, Takashi, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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241. Abstract 1229: The advantages of patient-derived orthotopic xenograft (PDOX) of metastatic cervical cancer for individualized therapy compared to the PDX model

Author

Hiroshima, Yukihiko, primary, Zhang, Yong, additional, Maawy, Ali, additional, Sato, Sho, additional, Murakami, Takashi, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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243. Abstract 3486: Efficacy of neoadjuvant chemotherapy in combination with fluorescence-guided surgery on a pancreatic cancer patient-derived orthotopic xenograft (PDOX)

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Zhang, Yong, additional, Sato, Sho, additional, Murakami, Takashi, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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245. The Tumor-Educated-Macrophage Increase of Malignancy of Human Pancreatic Cancer Is Prevented by Zoledronic Acid

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Hassanein, Mohamed K., additional, Menen, Rhiana, additional, Momiyama, Masashi, additional, Murakami, Takashi, additional, Miwa, Shinji, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Yano, Shuya, additional, Mori, Ryutaro, additional, Matsuyama, Ryusei, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Ichikawa, Yasushi, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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246. Fluorescence-Guided Surgery in Combination with UVC Irradiation Cures Metastatic Human Pancreatic Cancer in Orthotopic Mouse Models

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Zhang, Yong, additional, Sato, Sho, additional, Murakami, Takashi, additional, Yamamoto, Mako, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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248. Efficacy ofSalmonella typhimuriumA1-R Versus Chemotherapy on a Pancreatic Cancer Patient-Derived Orthotopic Xenograft (PDOX)

Author

Hiroshima, Yukihiko, primary, Zhao, Ming, additional, Maawy, Ali, additional, Zhang, Yong, additional, Katz, Matthew H.G., additional, Fleming, Jason B., additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Suetsugu, Atsushi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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249. Reversal of attachment to or invasion of major intrahepatic vessels by colorectal liver metastases according to prehepatectomy chemotherapy regimen

Author

Tanaka, Kuniya, primary, Nakagawa, Kazuya, additional, Yabushita, Yasuhiro, additional, Hiroshima, Yukihiko, additional, Matsuo, Kenichi, additional, Ota, Mitsuyoshi, additional, Ichikawa, Yasushi, additional, Taguri, Masataka, additional, Tanabe, Mikiko, additional, Koda, Keiji, additional, and Endo, Itaru, additional

Published
2014
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250. Hand-held high-resolution fluorescence imaging system for fluorescence-guided surgery of patient and cell-line pancreatic tumors growing orthotopically in nude mice

Author

Hiroshima, Yukihiko, primary, Maawy, Ali, additional, Sato, Sho, additional, Murakami, Takashi, additional, Uehara, Fuminari, additional, Miwa, Shinji, additional, Yano, Shuya, additional, Momiyama, Masashi, additional, Chishima, Takashi, additional, Tanaka, Kuniya, additional, Bouvet, Michael, additional, Endo, Itaru, additional, and Hoffman, Robert M., additional

Published
2014
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