論文 - 井山　諭

Intravenous Infusion of Autologous Mesenchymal Stem Cells Expanded in Auto Serum for Chronic Spinal Cord Injury Patients: A Case Series.

Ryosuke Hirota, Masanori Sasaki, Satoshi Iyama, Kota Kurihara, Ryunosuke Fukushi, Hisashi Obara, Tsutomu Oshigiri, Tomonori Morita, Masahito Nakazaki, Takahiro Namioka, Ai Namioka, Rie Onodera, Yuko Kataoka-Sasaki, Shinichi Oka, Mitsuhiro Takemura, Ryo Ukai, Takahiro Yokoyama, Yuichi Sasaki, Tatsuro Yamashita, Masato Kobayashi, Yusuke Okuma, Reiko Kondo, Ryo Aichi, Satoko Ohmatsu, Noritaka Kawashima, Yoichi M Ito, Masayoshi Kobune, Kohichi Takada, Sumio Ishiai, Toru Ogata, Atsushi Teramoto, Toshihiko Yamashita, Jeffery D Kocsis, Osamu Honmou

Journal of clinical medicine   13 ( 20 )  2024年10月  [国際誌]

　概要を見る

Objective: The safety, feasibility, and potential functional improvement following the intravenous infusion of mesenchymal stem cells (MSCs) were investigated in patients with chronic severe spinal cord injury (SCI). Methods: The intravenous infusion of autologous MSCs cultured in auto-serum under Good Manufacturing Practices (GMP) was administered to seven patients with chronic SCI (ranging from 1.3 years to 27 years after the onset of SCI). In addition to evaluating feasibility and safety, neurological function was evaluated using the American Spinal Injury Association Impairment Scale (AIS), International Standards for Neurological Classification of Spinal Cord Injury (ISCSCI-92), and Spinal Cord Independence Measure III (SCIM-III). Results: No serious adverse events occurred. Neither CNS tumors, abnormal cell growth, nor neurological deterioration occurred in any patients. While this initial case series was not blinded, significant functional improvements and increased quality of life (QOL) were observed at 90 and 180 days post-MSC infusion compared to pre-infusion status. One patient who had an AIS grade C improved to grade D within six months after MSC infusion. Conclusions: This case series suggests that the intravenous infusion of autologous MSCs is a safe and feasible therapeutic approach for chronic SCI patients. Furthermore, our data showed significant functional improvements and better QOL after MSC infusion in patients with chronic SCI. A blind large-scale study will be necessary to fully evaluate this possibility.

DOI PubMed

Intravenous Infusion of Autologous Mesenchymal Stem Cells Expanded in Auto Serum for Chronic Spinal Cord Injury Patients: A Case Series

Ryosuke Hirota, Masanori Sasaki, Satoshi Iyama, Kota Kurihara, Ryunosuke Fukushi, Hisashi Obara, Tsutomu Oshigiri, Tomonori Morita, Masahito Nakazaki, Takahiro Namioka, Ai Namioka, Rie Onodera, Yuko Kataoka-Sasaki, Shinichi Oka, Mitsuhiro Takemura, Ryo Ukai, Takahiro Yokoyama, Yuichi Sasaki, Tatsuro Yamashita, Masato Kobayashi, Yusuke Okuma, Reiko Kondo, Ryo Aichi, Satoko Ohmatsu, Noritaka Kawashima, Yoichi M. Ito, Masayoshi Kobune, Kohichi Takada, Sumio Ishiai, Toru Ogata, Atsushi Teramoto, Toshihiko Yamashita, Jeffery D. Kocsis, Osamu Honmou

Journal of Clinical Medicine   13 ( 20 )  2024年10月

　概要を見る

Objective: The safety, feasibility, and potential functional improvement following the intravenous infusion of mesenchymal stem cells (MSCs) were investigated in patients with chronic severe spinal cord injury (SCI). Methods: The intravenous infusion of autologous MSCs cultured in auto-serum under Good Manufacturing Practices (GMP) was administered to seven patients with chronic SCI (ranging from 1.3 years to 27 years after the onset of SCI). In addition to evaluating feasibility and safety, neurological function was evaluated using the American Spinal Injury Association Impairment Scale (AIS), International Standards for Neurological Classification of Spinal Cord Injury (ISCSCI-92), and Spinal Cord Independence Measure III (SCIM-III). Results: No serious adverse events occurred. Neither CNS tumors, abnormal cell growth, nor neurological deterioration occurred in any patients. While this initial case series was not blinded, significant functional improvements and increased quality of life (QOL) were observed at 90 and 180 days post-MSC infusion compared to pre-infusion status. One patient who had an AIS grade C improved to grade D within six months after MSC infusion. Conclusions: This case series suggests that the intravenous infusion of autologous MSCs is a safe and feasible therapeutic approach for chronic SCI patients. Furthermore, our data showed significant functional improvements and better QOL after MSC infusion in patients with chronic SCI. A blind large-scale study will be necessary to fully evaluate this possibility.

DOI

Novel method for assessing sinusoidal obstruction syndrome using four‐dimensional computed tomography

Saori Shimoyama‐Ibuki, Satoshi Iyama, Yoshiya Ohashi, Kento Ono, Yusuke Sugama, Chisa Fujita, Akari Goto, Hiroto Horiguchi, Akihito Fujimi, Takeo Tanaka, Kohichi Takada, Koh‐Ichi Sakata, Masayoshi Kobune

eJHaem ( Wiley )   2024年07月

　概要を見る

Abstract Introduction To diagnose sinusoidal obstruction syndrome/veno‐occlusive disease (SOS/VOD), transabdominal ultrasonography is usually used to detect hemodynamic changes, but we tried to detect the changes using four‐dimensional computed tomography (4D‐CT). A 42‐year‐old Japanese woman was diagnosed with late‐onset SOS/VOD with transabdominal ultrasonography and was also assessed using 4D‐CT. Method We analyzed the portal vein (PV) contrast effect every 1.5 seconds and plotted the values of the contrast effect. With this graph, we analyzed three hemodynamic parameters. Result We found that these parameters correlated with the patient's status and indicated stasis due to sinusoid constriction. Conclusion 4D‐CT may become a helpful tool to diagnose and follow up with SOS/VOD.

DOI

Intravenous infusion of auto-serum-expanded autologous mesenchymal stem cells into chronic severe brain injury patients

Tomohiro Yamaki, Shinichi Oka, Satoshi Iyama, Masanori Sasaki, Rie Onodera, Yuko Kataoka-Sasaki, Takahiro Namioka, Ai Namioka, Masahito Nakazaki, Mitsuhiro Takemura, Ryo Ukai, Takahiro Yokoyama, Yuichi Sasaki, Tatsuro Yamashita, Masato Kobayashi, Misako Yamaguchi, Marina Fukino, Taro Takazawa, Megumi Hayasaka, Takamitsu Owaku, Mika Funakura, Shinji Onodera, Yoichi M. Ito, Masayoshi Kobune, Junji Kato, Sumio Ishiai, Jeffery D. Kocsis, Masaru Odaki, Yasuo Iwadate, Shigeki Kobayashi, Osamu Honmou

Interdisciplinary Neurosurgery: Advanced Techniques and Case Management   36  2024年06月

　概要を見る

Objective: This study explores safety, feasibility, and potential improvement in functional status after intravenous infusion of mesenchymal stem cells (MSCs) in chronic severe brain injury (BI) patients. Methods: An intravenous infusion of autologous MSCs in autoserum cultured under Good Manufacturing Practice was delivered to four chronic patients with BI. In addition to assessing feasibility and safety, neurological function was evaluated using the National Institutes of Health Stroke Scale, Fugl-Meyer Assessment, Barthel Index, and cognitive-related behavioral assessment. Imaging studies with 18F-FDG-PETCT and 11C-methionine-PETCT (METPET) were carried out to evaluate brain metabolic activity. Results: No serious adverse events were recorded. None of the patients developed CNS tumors, abnormal cell growth, or neurological deterioration. While this initial case series was not blinded, gradual functional improvement was observed after MSC infusion. Serial 11C-METPETs displayed a statistically significant increase in methionine uptake, primarily in the thalamus and pons. Conclusion: We emphasize that this study was unblinded and did not exclude placebo effects, the contribution of endogenous recovery, or observer bias; however, our observations support feasibility and safety. No adverse events were observed. The data suggests improved quality of life after infused MSCs; however, a blinded, larger-scale study will be necessary to fully address this possibility.

DOI

Anti‐CD38 antibody isatuximab monotherapy for Japanese individuals with relapsed/refractory multiple myeloma: An update of the phase 1/2 ISLANDs study

Kazutaka Sunami, Shin‐ichi Fuchida, Kenshi Suzuki, Masaki Ri, Morio Matsumoto, Chihiro Shimazaki, Hideki Asaoku, Hirohiko Shibayama, Kenichi Ishizawa, Hiroyuki Takamatsu, Takashi Ikeda, Dai Maruyama, Kazunori Imada, Michihiro Uchiyama, Toru Kiguchi, Satoshi Iyama, Hirokazu Murakami, Reiko Onishi, Keisuke Tada, Shinsuke Iida

Hematological Oncology ( Wiley )  41 ( 3 ) 442 - 452  2022年12月

　概要を見る

Abstract The primary analysis of the phase 1/2 ISLANDs study in Japanese individuals with relapsed/refractory multiple myeloma (RRMM) showed that isatuximab monotherapy was well tolerated and effective, even in participants with high‐risk cytogenetic abnormalities. Here, we report a prespecified second analysis conducted 20 months after the first dosing of the last participant (ClinicalTrials.gov identifier: NCT02812706). The primary objectives were to evaluate the safety and tolerability of isatuximab in phase 1 and to evaluate the efficacy of isatuximab, including assessment of overall response rate (ORR) at the recommended dose (RD), in phase 2. In phase 1, three participants received isatuximab 10 mg/kg every week (QW) for 4 weeks/cycle followed by every 2 weeks (Q2W) and five participants received 20 mg/kg QW/Q2W. Since no dose‐limiting toxicities occurred in phase 1, 20 mg/kg QW/Q2W was identified as the RD for the phase 2 study (n = 28). At the time of data cut‐off, three participants (one in phase 1 and two in phase 2) continued to receive isatuximab; disease progression and treatment‐related adverse events were the most common reasons for treatment discontinuation. The overall safety profile was consistent with the primary analysis. One death, not related to isatuximab treatment, was reported since the first analysis. The ORR and clinical benefit rate remained unchanged from the primary analysis at 36.4% (95% confidence interval [CI]: 20.4%–54.9%) and 54.5% (95% CI: 36.4%–71.9%), respectively. The median progression‐free survival (PFS) was 5.6 months, longer than the median PFS reported in the primary analysis (4.7 months), whereas median overall survival was not reached. Overall, isatuximab 20 mg/kg QW/Q2W had an acceptable safety and tolerability profile and showed promising antitumor activity in Japanese individuals with RRMM.

DOI

Humanized <scp>anti‐IL</scp> ‐26 monoclonal antibody as a novel targeted therapy for chronic graft‐versus‐host disease

Ryo Hatano, Takumi Itoh, Haruna Otsuka, Harumi Saeki, Ayako Yamamoto, Dan Song, Yuki Shirakawa, Satoshi Iyama, Tsutomu Sato, Noriaki Iwao, Norihiro Harada, Thomas M. Aune, Nam H. Dang, Yutaro Kaneko, Taketo Yamada, Chikao Morimoto, Kei Ohnuma

American Journal of Transplantation ( Wiley )   2022年08月

DOI

血液疾患患者におけるCOVID-19感染症4例の報告(Four cases of COVID-19 patients with hematological malignancy)

小野 賢人, 堀口 拓人, 下山 紗央莉, 藤田 千紗, 後藤 亜香利, 池田 博, 井山 諭, 村瀬 和幸, 高田 弘一, 藤谷 好弘, 高橋 聡, 黒沼 幸治, 小船 雅義

日本血液学会学術集会 ( (一社)日本血液学会 )  83回   OS3 - 4  2021年09月

未分化大細胞リンパ腫の加療中に発症したCOVID-19関連肺炎

小野 賢人, 堀口 拓人, 下山 紗央莉, 藤田 千紗, 後藤 亜香利, 池田 博, 井山 諭, 藤谷 好弘, 高橋 聡, 黒沼 幸治, 小船 雅義

臨床血液 ( (一社)日本血液学会-東京事務局 )  62 ( 7 ) 852 - 852  2021年07月

Six-transmembrane epithelial antigen of the prostate 1 accelerates cell proliferation by targeting c-Myc in liver cancer cells

Kazutaka Iijima, Hajime Nakamura, Kohichi Takada, Naotaka Hayasaka, Tomohiro Kubo, Yui Umeyama, Satoshi Iyama, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Oncology Letters ( Spandidos Publications )  22 ( 1 )  2021年05月

DOI

Intravenous infusion of auto serum-expanded autologous mesenchymal stem cells in spinal cord injury patients: 13 case series.

Osamu Honmou, Toshihiko Yamashita, Tomonori Morita, Tsutomu Oshigiri, Ryosuke Hirota, Satoshi Iyama, Junji Kato, Yuichi Sasaki, Sumio Ishiai, Yoichi M Ito, Ai Namioka, Takahiro Namioka, Masahito Nakazaki, Yuko Kataoka-Sasaki, Rie Onodera, Shinichi Oka, Masanori Sasaki, Stephen G Waxman, Jeffery D Kocsis

Clinical neurology and neurosurgery   203   106565 - 106565  2021年04月  [国際誌]

　概要を見る

BACKGROUND: Although spinal cord injury (SCI) is a major cause of disability, current therapeutic options remain limited. Recent progress in cellular therapy with mesenchymal stem cells (MSCs) has provided improved function in animal models of SCI. We investigated the safety and feasibility of intravenous infusion of MSCs for SCI patients and assessed functional status after MSC infusion. METHODS: In this phase 2 study of intravenous infusion of autologous MSCs cultured in auto-serum, a single infusion of MSCs under Good Manufacturing Practice (GMP) production was delivered in 13 SCI patients. In addition to assessing feasibility and safety, neurological function was assessed using the American Spinal Injury Association Impairment Scale (ASIA), International Standards for Neurological and Functional Classification of Spinal Cord (ISCSCI-92). Ability of daily living was assessed using Spinal Cord Independence Measure (SCIM-III). The study protocol was based on advice provided by the Pharmaceuticals and Medical Devices Agency in Japan. The trial was registered with the Japan Medical Association (JMA-IIA00154). RESULTS: No serious adverse events were associated with MSC injection. There was neurologic improvement based on ASIA grade in 12 of the 13 patients at six months post-MSC infusion. Five of six patients classified as ASIA A prior to MSC infusion improved to ASIA B (3/6) or ASIA C (2/6), two ASIA B patients improved to ASIA C (1/2) or ASIA D (1/2), five ASIA C patients improved and reached a functional status of ASIA D (5/5). Notably, improvement from ASIA C to ASIA D was observed one day following MSC infusion for all five patients. Assessment of both ISCSCI-92, SCIM-III also demonstrated functional improvements at six months after MSC infusion, compared to the scores prior to MSC infusion in all patients. CONCLUSION: While we emphasize that this study was unblinded, and does not exclude placebo effects or a contribution of endogenous recovery or observer bias, our observations provide evidence supporting the feasibility, safety and functional improvements of infused MSCs into patients with SCI.

DOI PubMed

Possible clinical outcomes using early enteral nutrition in individuals with allogeneic hematopoietic stem cell transplantation: A single-center retrospective study

Satoshi Iyama, Hiroomi Tatsumi, Tsukasa Shiraishi, Masahiro Yoshida, Ayumi Tatekoshi, Akihito Endo, Taichiro Ishige, Yuh Shiwa, Soushi Ibata, Akari Goto, Kana Nagashima, Hiroto Horiguchi, Chisa Fujita, Hiroshi Ikeda, Kohichi Takada, Takayuki Nobuoka, Yusuke Kamihara, Shohei Kikuchi, Tsutomu Sato, Hirofumi Ohnishi, Shin-ichi Yokota, Masayoshi Kobune

Nutrition ( Elsevier BV )  83   111093 - 111093  2021年03月  [査読有り]

担当区分：   筆頭著者  , 責任著者

DOI

Successful mycophenolate mofetil treatment of a patient with severe steroid‐refractory hepatitis evoked by nivolumab plus ipilimumab treatment for relapsed bladder cancer

Ginji Omori, Kohichi Takada, Kazuyuki Murase, Naotaka Hayasaka, Hajime Nakamura, Satoshi Iyama, Hiroyuki Ohnuma, Koji Miyanishi, Fumimasa Fukuta, Toshiaki Tanaka, Naoya Masumori, Junji Kato

Clinical Case Reports ( Wiley )  9 ( 2 ) 654 - 659  2021年02月

DOI

Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study

Kazutaka Sunami, Kenshi Suzuki, Masaki Ri, Morio Matsumoto, Chihiro Shimazaki, Hideki Asaoku, Hirohiko Shibayama, Kenichi Ishizawa, Hiroyuki Takamatsu, Takashi Ikeda, Dai Maruyama, Hitomi Kaneko, Michihiro Uchiyama, Toru Kiguchi, Satoshi Iyama, Hirokazu Murakami, Keishiro Takahashi, Keisuke Tada, Sandrine Macé, Hélène Guillemin‐Paveau, Shinsuke Iida

Cancer Science ( Wiley )  111 ( 12 ) 4526 - 4539  2020年12月  [査読有り]  [国際誌]

　概要を見る

Isatuximab, an anti-CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open-label, single-arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose-limiting toxicities occurred; the recommended dose for the single-arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high-risk cytogenetic abnormalities had comparable results. In phase 2, the median progression-free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high-risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.

DOI PubMed

Successful Treatment by Surgery and Lenvatinib of a Patient with Adrenal Metastasis of Papillary Thyroid Cancer

Hajime Nakamura, Kohichi Takada, Kazuyuki Murase, Hiroki Sakamoto, Naotaka Hayasaka, Kazuma Ishikawa, Yuki Ikeda, Makoto Yoshida, Satoshi Iyama, Ko Kobayashi, Tetsuya Shindo, Shintaro Sugita, Koji Miyanishi, Masayoshi Kobune, Naoya Masumori, Junji Kato

Case Reports in Oncological Medicine ( Hindawi Limited )  2020   1 - 4  2020年11月

　概要を見る

Papillary thyroid cancer (PTC) is considered an indolent cancer, but some PTC patients do present with distant metastases and treatment strategies for such patients are not well established. Recently, lenvatinib, an inhibitor of multiple tyrosine kinases, has been introduced to treat patients with advanced PTC but carries a risk of serious adverse events such as hemorrhage. Here, we report a PTC patient with a left adrenal metastasis and lenvatinib-induced hemorrhage who underwent successful surgical resection and was subsequently treated with a lower dose of lenvatinib. The patient has now been in a stable state with no adverse events for nearly two years. This case highlights the importance of surgical resection of metastatic PTC and subsequent lenvatinib therapy, even when the tumor is at an advanced stage.

DOI

Prospective evaluation of alternative donor from unrelated donor and cord blood in adult acute leukemia and myelodysplastic syndrome

Seitaro Terakura, Tetsuya Nishida, Masashi Sawa, Tomonori Kato, Kotaro Miyao, Yukiyasu Ozawa, Tatsunori Goto, Akio Kohno, Kazutaka Ozeki, Yasushi Onishi, Noriko Fukuhara, Nobuharu Fujii, Hisayuki Yokoyama, Masanobu Kasai, Hiroatsu Iida, Nobuhiro Kanemura, Tomoyuki Endo, Hiroatsu Ago, Makoto Onizuka, Satoshi Iyama, Yuichiro Nawa, Mika Nakamae, Yasuyuki Nagata, Shingo Kurahashi, Yasuo Tomiya, Atsumi Yanagisawa, Ritsuro Suzuki, Yachiyo Kuwatsuka, Yoshiko Atsuta, Koichi Miyamura, Makoto Murata

Bone Marrow Transplantation ( Springer Science and Business Media LLC )  55 ( 7 ) 1399 - 1409  2020年07月  [査読有り]

DOI

Acquired amegakaryocytic thrombocytopenic purpura possibly induced by anti-PD-1 antibody

Satoshi Iyama, K. Takada, M. Yoshida, D. Takahashi, M. Kobune

Annals of Hematology ( Springer Science and Business Media LLC )  99 ( 7 ) 1669 - 1670  2020年07月  [査読有り]

担当区分：   筆頭著者  , 責任著者

DOI

Successful brentuximab vedotin monotherapy against late relapse of classical Hodgkin lymphoma 6 years after first remission

Kana Nagashima, Shohei Kikuchi, Satoshi Iyama, Chisa Fujita, Akari Goto, Hiroto Horiguchi, Masayoshi Kobune

Clinical Case Reports ( Wiley-Blackwell Publishing Ltd )  8 ( 3 ) 466 - 468  2020年03月

　概要を見る

Brentuximab vedotin monotherapy for late-relapse CHL is a promising therapeutic with sustained CR benefit and avoiding potential toxicities caused by aPBSCT/HDT.

DOI

Blastic plasmacytoid dendritic cell neoplasm(BPDCN)の2例

執行 延明, 西田 彩華, 菅野 莉英, 藤岡 茉生, 大橋 隆宏, 堀本 浩平, 加藤 潤史, 肥田 時征, 宇原 久, 村瀬 和幸, 井山 諭, 須釜 佑介, 前田 和男

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 )  130 ( 3 ) 418 - 418  2020年03月

Exceptionally rapid response to pembrolizumab in a SMARCA4‐deficient thoracic sarcoma overexpressing PD‐L1: A case report

Kohichi Takada, Shintaro Sugita, Kazuyuki Murase, Tomoki Kikuchi, Ginji Oomori, Ryo Ito, Naotaka Hayasaka, Koji Miyanishi, Satoshi Iyama, Hiroshi Ikeda, Masayoshi Kobune, Makoto Emori, Junji Kato, Tadashi Hasegawa

Thoracic Cancer ( Wiley )  10 ( 12 ) 2312 - 2315  2019年12月

DOI

DPP8 is a novel therapeutic target for multiple myeloma

Tsutomu Sato, Ayumi Tatekoshi, Kohichi Takada, Satoshi Iyama, Yusuke Kamihara, Paras Jawaid, Mati Ur Rehman, Kyo Noguchi, Takashi Kondo, Sayaka Kajikawa, Kotaro Arita, Akinori Wada, Jun Murakami, Miho Arai, Ichiro Yasuda, Nam H. Dang, Ryo Hatano, Noriaki Iwao, Kei Ohnuma, Chikao Morimoto

Scientific Reports ( Springer Science and Business Media LLC )  9 ( 1 )  2019年12月  [査読有り]

　概要を見る

Dipeptidyl peptidases (DPPs) are proteolytic enzymes that are ideal therapeutic targets in human diseases. Indeed, DPP4 inhibitors are widely used in clinical practice as anti-diabetic agents. In this paper, we show that DPP4 inhibitors also induced cell death in multiple human myeloma cells. Among five DPP4 inhibitors, only two of them, vildagliptin and saxagliptin, exhibited apparent cytotoxic effects on myeloma cell lines, without any difference in suppression of DPP4 activity. As these two DPP4 inhibitors are known to have off-target effects against DPP8/9, we employed the specific DPP8/9 inhibitor 1G244. 1G244 demonstrated anti-myeloma effects on several cell lines and CD138+ cells from patients as well as in murine xenograft model. Through siRNA silencing approach, we further confirmed that DPP8 but not DPP9 is a key molecule in inducing cell death induced by DPP8/9 inhibition. In fact, the expression of DPP8 in CD38+ cells from myeloma patients was higher than that of healthy volunteers. DPP8/9 inhibition induced apoptosis, as evidenced by activated form of PARP, caspases-3 and was suppressed by the pan-caspase inhibitor Z-VAD-FMK. Taken together, these results indicate that DPP8 is a novel therapeutic target for myeloma treatment.

DOI

Pneumothorax as an Adverse Event in Patients with Lung Metastasis of Soft Tissue Sarcoma under Eribulin Treatment

Kohichi Takada, Kazuyuki Murase, Hajime Nakamura, Naotaka Hayasaka, Yohei Arihara, Satoshi Iyama, Hiroshi Ikeda, Makoto Emori, Shintaro Sugita, Katsuyuki Nakamura, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Internal Medicine ( Japanese Society of Internal Medicine )  58 ( 20 ) 3009 - 3012  2019年10月

DOI

Six-transmembrane epithelial antigen of the prostate 1 protects against increased oxidative stress via a nuclear erythroid 2-related factor pathway in colorectal cancer

Hajime Nakamura, Kohichi Takada, Yohei Arihara, Naotaka Hayasaka, Kazuyuki Murase, Satoshi Iyama, Masayoshi Kobune, Koji Miyanishi, Junji Kato

Cancer Gene Therapy ( Springer Science and Business Media LLC )  26 ( 9-10 ) 313 - 322  2019年09月

DOI

EPO-R+ myelodysplastic cells with ring sideroblasts produce high erythroferrone levels to reduce hepcidin expression in hepatic cells

Shogo Miura, Masayoshi Kobune, Hiroto Horiguchi, Shohei Kikuchi, Satoshi Iyama, Kazuyuki Murase, Akari Goto, Hiroshi Ikeda, Kohichi Takada, Koji Miyanishi, Junji Kato

Blood Cells, Molecules, and Diseases ( Elsevier BV )  78   1 - 8  2019年09月

DOI

Blastic plasmacytoid dendritic cell neoplasm(BPDCN)の1例

執行 延明, 西田 彩華, 菅野 莉英, 藤岡 茉生, 大橋 隆宏, 堀本 浩平, 加藤 潤史, 肥田 時征, 宇原 久, 井山 諭, 前田 和男, 須釜 佑介

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 )  129 ( 9 ) 1910 - 1910  2019年08月

Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells.

Naotaka Hayasaka, Kohichi Takada, Hajime Nakamura, Yohei Arihara, Yutaka Kawano, Takahiro Osuga, Kazuyuki Murase, Shohei Kikuchi, Satoshi Iyama, Makoto Emori, Shintaro Sugita, Tadashi Hasegawa, Akira Takasawa, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Scientific reports   9 ( 1 ) 5759 - 5759  2019年04月  [査読有り]  [国際誌]

　概要を見る

An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth in vivo as well as in vitro. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.

DOI PubMed

miR-7977 inhibits the Hippo-YAP signaling pathway in bone marrow mesenchymal stromal cells.

Masahiro Yoshida, Hiroto Horiguchi, Shohei Kikuchi, Satoshi Iyama, Hiroshi Ikeda, Akari Goto, Yutaka Kawano, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Junji Kato, Masayoshi Kobune

PloS one   14 ( 3 ) e0213220  2019年  [査読有り]  [国際誌]

　概要を見る

We and others have demonstrated that various abnormalities of the bone marrow (BM) mesenchymal stromal cells (MSCs) such as aberrant cytokine expression, abnormal hedgehog signaling, and impaired miRNA biogenesis are observed in patients with acute myeloid leukemia (AML). However, underlying mechanisms to induce the dysfunction of BM MSCs have not yet been clarified. We previously showed that AML cells release abundant exosomal miR-7977, which, in turn, enters BM mesenchymal stromal cells (MSCs). However, the precise function of miR-7977 is not known. In this study, we performed transduction of a miR-7977 mimic into MSCs, compared transcriptomes between control-transduced (n = 3) and miR-7977-transduced MSCs (n = 3), and conducted pathway analysis. The array data revealed that the expression of 0.05% of genes was reduced 2-fold and the expression of 0.01% of genes was increased 2-fold. Interestingly, approximately half of these genes possessed a miR-7977 target site, while the other genes did not, suggesting that miR-7977 regulates the gene expression level directly and indirectly. Gene set enrichment analysis showed that the gene sets of Yes-associated protein 1 (YAP1) _up were significantly enriched (p<0.001, q<0.25), suggesting that miR-7977 modulates the Hippo-YAP signaling pathway. Visualization of pathway and network showed that miR-7977 significantly reduced the expression of Hippo core kinase, STK4. miR-7977 inactivated the Hippo-YAP signaling pathway as proven by GFP-tagged YAP nuclear trans localization and TEAD reporter assay. The miR-7977-transduced MSC cell line, HTS-5, showed elevated saturation density and enhanced entry into the cell cycle. These results suggest that miR-7977 is a critical factor that regulates the Hippo-YAP signaling pathway in BM-MSCs and may be involved in the upregulation of leukemia-supporting stroma growth.

DOI PubMed

Denosumab prevents bone loss in newly diagnosed malignant lymphoma patients undergoing corticosteroid-containing chemotherapy: A prospective, non-randomized study

Ayumi Tatekoshi, Tsutomu Sato, Satoshi Iyama, Kohichi Takada, Kazuyuki Murase, Masahiro Yoshida, Soushi Ibata, Akari Hashimoto, Yusuke Kamihara, Hiroto Horiguchi, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Sapporo Medical journal ( Sapporo Medical University )  87 ( 1-6 ) 35 - 47  2018年12月

　概要を見る

Background: Malignant lymphoma patients have a high risk of bone mineral density (BMD) loss caused by corticosteroid-containing chemotherapy. Bisphosphonates have been used to prevent bone loss: however, little is known about effects of denosumab, a fully humanized monoclonal antibody inhibiting osteoclast-mediated bone resorption. Methods: This clinical trial was conducted in newly diagnosed lymphoma patients undergoing corticosteroidcontaining chemotherapy. BMD was evaluated at baseline, and patients with a lumbar spine T-score of < -1 were subcutaneously administered once with 60 mg of denosumab ("Denosumab" group). Patients with a T-score > -1 were allocated to the "No treatment" group. BMD was reevaluated at 24 weeks after enrollment. Bone turnover markers (BTMs) were collected at 0,2, and 24 weeks. Results: Forty-three patients were enrolled (19 in the "Denosumab" group and 24 in the "No treatment" group). Patients in the "No treatment" group had decreased T-scores for the lumbar spine or femoral neck (P < 0.0001 or P = 0.0029, respectively) at 24 weeks after enrollment, whereas both T-scores were stable in the "Denosumab" group. Of the 18 patients in the "Denosumab" group, 12 had a T-score change from baseline (AT-score) of > 0, whereas the remaining six patients had a AT-score < 0. These six patients had severely low T-scores at enrollment. Osteoclastic BTMs were strongly suppressed during the 24 weeks in the "Denosumab" group. The probability of major osteoporotic fracture or hip fracture in the "No treatment?' group increased during the 24 weeks (P = 0.0195 or P = 0.0289, respectively), whereas pretreatment with denosumab prevented increased risks of both types of fractures. Conclusions: Our data suggests that BMD screening at diagnosis of lymphoma should be considered so that the bone health of lymphoma survivors can be improved with denosumab.

DOI

Long-term prognosis of human herpesvirus 6 reactivation following allogeneic hematopoietic stem cell transplantation.

Kotoe Iesato, Tsukasa Hori, Yuko Yoto, Masaki Yamamoto, Natsuko Inazawa, Kenichi Kamo, Hiroshi Ikeda, Satoshi Iyama, Naoki Hatakeyama, Akihiro Iguchi, Junichi Sugita, Ryoji Kobayashi, Nobuhiro Suzuki, Hiroyuki Tsutsumi

Pediatrics international : official journal of the Japan Pediatric Society   60 ( 6 ) 547 - 552  2018年06月  [査読有り]  [国際誌]

　概要を見る

BACKGROUND: Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently have HHV-6 reactivation typically during the early phase following HSCT. The long-term clinical complications and prognosis, however, remain unclear. METHODS: Between September 2010 and October 2012, whole blood samples from 105 patients collected weekly from prior to 6 weeks after HSCT underwent multiplex polymerase chain reaction (PCR) to screen for viral DNA, followed by real-time PCR for quantitative estimation. In 48 patients, only HHV-6 was detected in at least one sample. In 30 patients, no viral DNA was detected. Long-term clinical records were reviewed in March 2016. All 48 HHV-6-positive patients, and 24 patients in whom no viral DNA detected, were followed up. RESULTS: Median maximum HHV-6 DNA load in the blood of the HHV-6 reactivation group (n = 48) was 11 800 copies/μg peripheral blood leukocyte DNA (range, 52-310 000 000). Hemophagocytic syndrome (HPS) was diagnosed in two subjects with HHV-6 reactivation. Acute graft-versus-host disease (GVHD) developed more frequently in patients with HHV-6 reactivation than in patients without viral reactivation (P = 0.002), but there was no difference in incidence of chronic GVHD. There was no difference in engraftment of neutrophils and platelets between groups. There was also no difference in overall survival between groups. Onset of HPS, however, was associated with lower overall survival (P = 0.009). CONCLUSIONS: Human herpesvirus 6 reactivation was associated with acute GVHD, but not with chronic GVHD, engraftment or overall survival. Onset of HPS, however, predicts lower overall survival.

DOI PubMed

High expression of nucleoporin 133 mRNA in bone marrow CD138+ cells is a poor prognostic factor in multiple myeloma

Soushi Ibata, Masayoshi Kobune, Shohei Kikuchi, Masahiro Yoshida, Shogo Miura, Hiroto Horiguchi, Kazuyuki Murase, Satoshi Iyama, Kohichi Takada, Koji Miyanishi, Junji Kato

Oncotarget ( Impact Journals LLC )  9 ( 38 ) 25127 - 25135  2018年05月  [査読有り]

　概要を見る

Recent advances in plasma cell biology and molecularly-targeted therapy enable us to employ various types of drugs including immunomodulatory drugs, proteasome inhibitors, and immunotherapy. However, the optimal therapeutic strategies to introduce these drugs for heterogeneous patients with multiple myeloma (MM) have not yet been clarified. In the present study, we attempted to identify a new factor indicating poor prognosis in CD138+ myeloma cells using accumulated Gene Expression Omnibus (GEO) datasets from studies of MM and to assess the relationship between gene expression and survival using MAQC-II Project Myeloma (GSE24080). Five GEO datasets (GSE5900, GSE58133, GSE68871, GSE57317 and GSE16791) which were analyzed by the same microarray platform (GLP570) were combined into one MM database including various types of MM. However, we found that gene expression levels were quite heterogeneous. Hence, we focused on the differentially-expressed genes (DEGs) between newlydiagnosed MM and relapsed/refractory MM and found that the expression levels of more than 20 genes changed two-fold or more. Additionally, pathway analysis indicated that six pathways including Hippo signaling were significantly enriched. Then, we applied all DEGs and genes associated with core enrichment for GSE24080 to evaluate their involvement in disease prognosis. We found that nucleoporin 133 (NUP133) is an independent poor prognostic factor by Cox proportional hazard analysis. These results suggested that high expression of NUP133 could be useful when choosing the appropriate MM therapy and may be a new target of MM therapy.

DOI

ART療法中に多発血栓症を併発した悪性リンパ腫患者の一例

池田 博, 吉田 正宏, 舘越 鮎美, 菊地 尚平, 村瀬 和幸, 高田 弘一, 井山 諭, 小船 雅義, 村上 則子, 宮越 郁子, 又村 了輔, 國本 雄介, 加藤 淳二

日本エイズ学会誌 ( (一社)日本エイズ学会 )  19 ( 4 ) 501 - 501  2017年11月

Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma

Yohei Arihara, Kohichi Takada, Yusuke Kamihara, Naotaka Hayasaka, Hajime Nakamura, Kazuyuki Murase, Hiroshi Ikeda, Satoshi Iyama, Tsutomu Sato, Koji Miyanishi, Masayoshi Kobune, Junji Kato

ONCOTARGET ( IMPACT JOURNALS LLC )  8 ( 39 ) 65889 - 65899  2017年09月  [査読有り]

　概要を見る

Reactive oxygen species (ROS) are normal byproducts of a wide variety of cellular processes. ROS have dual functional roles in cancer cell pathophysiology. At low to moderate levels, ROS act as signaling transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS induce cell death. In multiple myeloma (MM), ROS overproduction is the trigger for apoptosis induced by several anticancer compounds, including proteasome inhibitors. However, no drugs for which oxidative stress is the main mechanism of action are currently used for treatment of MM in clinical situations. In this study, we demonstrate that the p53-activating small molecule CP-31398 (CP) effectively inhibits the growth of MM cell lines and primary MM isolates from patients. CP also suppresses the growth of MM xenografts in mice. Mechanistically, CP was found to induce intrinsic apoptosis in MM cells via increasing ROS production. Interestingly, CP-induced apoptosis occurs regardless of the p53 status, suggesting that CP has additional mechanisms of action. Our findings thus indicate that CP could be an attractive candidate for treatment of MM patients harboring p53 abnormalities; this satisfies an unmet clinical need, as such individuals currently have a poor prognosis.

DOI PubMed

[A Case of Chronic Myelogenous Leukemia That Developed Fibrous Pericarditis Owing to Nilotinib Use].

Miura S, Murase K, Sakurada A, Takada K, Iyama S, Sato T, Sato Y, Miyanishi K, Kobune M, Muranaka A, Tachibana K, Kato J

Gan to kagaku ryoho. Cancer & chemotherapy   44 ( 6 ) 529 - 531  2017年06月  [査読有り]  [国内誌]

　概要を見る

A 64-year-old man was diagnosed with chronic-phase chronic myelogenous leukemia(CML)in May 2009. He was treated with imatinib and achieved complete cytogenetic response(CCyR)in 2 months. After 4 months of treatment, he developed interstitial pneumonia and became intolerant to imatinib. He was then switched to nilotinib from October of the same year. In June 2013, he was diagnosed with drug-induced pericarditis resulting from nilotinib use, and thus, nilotinib was discontinued. Subsequently, he was followed up without specific treatment for CML. In January 2014, he was admitted to the Dept. of Cardiovascular, Renal and Metabolic Medicine at our hospital because of heart failure. After examinations of cardiac function, he was diagnosed with constrictive pericarditis. Therefore, pericardiolysis was performed by the Dept. of Cardiovascular Surgery at our hospital. Pathologic findings showed hyaline-like fibrous tissue proliferation in the pericardium, which was diagnosed as fibrous pericarditis induced by nilotinib. We report a case of chronic myelogenous leukemia that developed fibrous pericarditis owing to nilotinib use.

PubMed

低分子化合物CP-31398は多発性骨髄腫に対して活性酸素種依存的なアポトーシスを誘導する

在原 洋平, 高田 弘一, 神原 悠輔, 河野 豊, 早坂 尚貴, 中村 元, 菊地 尚平, 村瀬 和幸, 井山 諭, 池田 博, 佐藤 勉, 宮西 浩嗣, 小船 雅義, 加藤 淳二

International Journal of Myeloma ( 日本骨髄腫学会 )  7 ( 1 ) 76 - 76  2017年04月  [査読有り]

A Multicenter Retrospective Study of Mogamulizumab Efficacy in Adult T-Cell Leukemia/Lymphoma

Satoshi Iyama, Tsutomu Sato, Hirofumi Ohnishi, Yuji Kanisawa, Shuichi Ohta, Takeshi Kondo, Akio Mori, Yutaka Tsutsumi, Hiroyuki Kuroda, Yasutaka Kakinoki, Satoshi Yamamoto, Tohru Takahashi, Motohiro Shindo, Yoshihiro Torimoto, Kazuya Sato, Hiroshi Iwasaki, Yoshihito Haseyama, Kyuhei Kohda, Yasuhiro Nagamachi, Yasuo Hirayama, Hajime Sakai, Yasuji Hirata, Takashi Fukuhara, Hiroshi Ikeda, Masayoshi Kobune, Junji Kato, Mitsutoshi Kurosawa

CLINICAL LYMPHOMA MYELOMA & LEUKEMIA ( CIG MEDIA GROUP, LP )  17 ( 1 ) 23 - 30  2017年01月  [査読有り]

担当区分：   筆頭著者  , 責任著者

　概要を見る

Mogamulizumab recently became available for the treatment of adult T-cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab for ATL treatment in patients in Japan and found that mogamulizumab is an effective therapeutic strategy in ATL. Some concern exists that the use of mogamulizumab in patients undergoing hematopoietic stem cell transplantation patients might cause severe graft-versus-host disease. Determining the optimum number of mogamulizumab administrations should be a priority for future studies. Background: Mogamulizumab, a defucosylated humanized monoclonal antibody targeting C-C chemokine receptor 4, recently became available for the treatment of adult T-cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab in ATL treatment in patients on Hokkaido Island, Japan. Materials and Methods: A total of 125 patients with ATL treated from January 2010 to December 2014 in 20 hospitals affiliated with the Hokkaido Hematology Study Group were enrolled in the present retrospective study. Results: Of the 125 ATL patients, 62 (46.6%) presented with the acute type, 51 (38.3%) with the lymphoma type, and 12 (9.0%) with the chronic type; the latter group included 7 unfavorable chronic cases. The median age at diagnosis was 68 years (range, 35-86 years). The median survival for those with acute, lymphoma, and unfavorable chronic types was 302, 279, and 921 days, respectively. Advanced age, high lactate dehydrogenase level, poor performance status (3-4), and the existence of B symptoms were unfavorable prognostic factors for overall survival (OS). Survival rate calculated from the day of diagnosis was significantly higher in patients treated with mogamulizumab. The OS of individuals receiving hematopoietic stem cell transplantation (HSCT) was superior to that of the non-HSCT group. The median interval between the last mogamulizumab dose and allogeneic HSCT was 38 days (range, 21-53 days). Of the 22 HSCT recipients who were not treated with mogamulizumab, overall acute graft-versus-host disease (aGVHD) and grade III-IV aGVHD occurred in 12 (54.5%) and 3 (13.6%) patients, respectively. However, overall aGVHD and grade III-IV aGVHD developed in 8 (88.9%) and 3 (33.3%) of the 9 HSCT recipients treated with mogamulizumab, respectively. Conclusion: Mogamulizumab improves OS in patients with ATL, although its use in HSCT patients might trigger severe GVHD. Determining the optimal pre-HSCT mogamulizumab treatment regimen is thus a priority. (C) 2016 Elsevier Inc. All rights reserved.

DOI PubMed

A phase II trial of small-dose bortezomib, lenalidomide and dexamethasone (sVRD) as consolidation/maintenance therapy in patients with multiple myeloma

Soushi Ibata, Tsutomu Sato, Hiroyuki Kuroda, Yasuhiro Nagamachi, Satoshi Iyama, Akihito Fujimi, Yusuke Kamihara, Yuichi Konuma, Masahiro Yoshida, Ayumi Tatekoshi, Akari Hashimoto, Hiroto Horiguchi, Kaoru Ono, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Masayoshi Kobune, Yasuo Hirayama, Junji Kato

CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER )  78 ( 5 ) 1041 - 1049  2016年11月  [査読有り]

　概要を見る

Consolidation/maintenance therapy induces deep remission in patients with multiple myeloma (MM); however, the most suitable regimen has been under investigation. The combination therapy with bortezomib, lenalidomide and dexamethasone (VRD) is a powerful regimen for relapsed/refractory as well as newly diagnosed MM as an induction therapy. However, severe adverse events (AEs) may become a problem when VRD is introduced without dose reduction as a consolidation/maintenance therapy. In this single-arm phase II study, we evaluated the efficacy of small-dose VRD regimen (sVRD) in the consolidation/maintenance setting. Sixteen patients who had partial response (PR) or better after any induction therapy were enrolled. Patients received at least six 28-day cycles of subcutaneous bortezomib (1.3 mg/m(2) on days 1 and 15), lenalidomide (10 mg on days 1-21) and dexamethasone (40 mg on days 1, 8, 15 and 22). The overall response rate and the complete response (CR) rate were 100 and 43.8 %, respectively. In particular, one patient with CR and two patients with very good PR at enrollment achieved stringent CR during 6 courses of sVRD. With a median follow-up time of 29.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached, while the PFS and OS rates at 2.5 years were 66.6 and 77.3 %, respectively. Univariate analysis demonstrated that disease progression as a reason for discontinuation of sVRD had a negative impact on OS. There were no grade 3 or 4 hematologic or nonhematologic AEs. Our sVRD regimen as a consolidation/maintenance therapy was highly effective and well tolerable.

DOI PubMed

Phase I/IIa Study of Low Dose Subcutaneous Interleukin-2 (IL-2) for Treatment of Refractory Chronic Graft Versus Host Disease

Takeru Asano, Ken-Ichi Matsuoka, Satoshi Iyama, Kazuteru Ohashi, Yoshihiro Inamoto, Chikako Ohwada, Makoto Murata, Atsushi Satake, Chikamasa Yoshida, Koichi Nakase, Yasuo Mori, Mitsune Tanimoto

ACTA MEDICA OKAYAMA ( OKAYAMA UNIV MED SCHOOL )  70 ( 5 ) 429 - 433  2016年10月  [査読有り]

　概要を見る

Chronic graft versus host disease (cGVHD) remains a major problem for long survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, corticosteroid therapy is effective for cGVHD as the first line therapy. However, prolonged therapy with corticosteroids causes various severe adverse events. To develop the new therapeutic strategy of cGVHD, we have launched a multicenter phase I/IIa clinical trial of low dose subcutaneous interleukin-2 (IL-2) for treatment of steroid refractory cGVHD, which is constituted of 2 sequential phases (induction phase and maitanance phase). This study will provide the new therapeutic option for patients with refractory cGVHD after allogeneic HSCT.

The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/β-catenin signaling in human multiple myeloma.

Kamihara Y, Takada K, Sato T, Kawano Y, Murase K, Arihara Y, Kikuchi S, Hayasaka N, Usami M, Iyama S, Miyanishi K, Sato Y, Kobune M, Kato J

Oncotarget   7 ( 39 ) 64330 - 64341  2016年09月  [査読有り]  [国際誌]

　概要を見る

Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/β-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling.

DOI PubMed

Relationship Between Increased Fucosylation and Metastatic Potential in Colorectal Cancer.

Osuga T, Takimoto R, Ono M, Hirakawa M, Yoshida M, Okagawa Y, Uemura N, Arihara Y, Sato Y, Tamura F, Sato T, Iyama S, Miyanishi K, Takada K, Hayashi T, Kobune M, Kato J

Journal of the National Cancer Institute   108 ( 9 )  2016年09月  [査読有り]  [国際誌]

　概要を見る

BACKGROUND: Fucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-ß-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC. METHODS: In this study, we first examined the expression of fucosylated proteins in 50 cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided. RESULTS: We found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P ≤ .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 ± 3.09; SN38-treated group [SN38], 3.53 ± 1.47; liposome-carrying, SN38-treated group [F0], 3.1 ± 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 ± 0.89; F50 vs NT, P = .003; F50 vs SN38, P = .02, F50 vs F0, P = .04), as well as prolonging survival of mouse xenograft models (log-rank test, P < .001). CONCLUSIONS: Thus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.

DOI PubMed

Relationship Between Increased Fucosylation and Metastatic Potential in Colorectal Cancer

Takahiro Osuga, Rishu Takimoto, Michihiro Ono, Masahiro Hirakawa, Makoto Yoshida, Yutaka Okagawa, Naoki Uemura, Yohei Arihara, Yasushi Sato, Fumito Tamura, Tsutomu Sato, Satoshi Iyama, Koji Miyanishi, Kohichi Takada, Tsuyoshi Hayashi, Masayoshi Kobune, Junji Kato

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE ( OXFORD UNIV PRESS INC )  108 ( 8 )  2016年08月  [査読有り]

　概要を見る

Background: Fucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-beta-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC. Methods: In this study, we first examined the expression of fucosylated proteins in 50 cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided. Results: We found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P <= .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 +/- 3.09; SN38-treated group [SN38], 3.53 +/- 1.47; liposome-carrying, SN38-treated group [F0], 3.1 +/- 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 +/- 0.89; F50 vs NT, P = .003; F50 vs SN38, P = .02, F50 vs F0, P = .04), as well as prolonging survival of mouse xenograft models (log-rank test, P < .001). Conclusions: Thus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.

DOI PubMed

[Treatment Outcomes of Adult-Onset Ewing Sarcoma: A Single-Center Retrospective Study of Five Cases].

Murase K, Takada K, Kamihara Y, Usami M, Yoshida M, Tatekoshi A, Hashimoto A, Arihara Y, Hayasaka N, Miura S, Iyama S, Sato T, Sato Y, Miyanishi K, Kobune M, Emori M, Kaya M, Yamashita T, Sugita S, Hasegawa T, Kato J

Gan to kagaku ryoho. Cancer & chemotherapy   43 ( 8 ) 1015 - 8  2016年08月  [査読有り]  [国内誌]

　概要を見る

UNLABELLED: We report the treatment outcomes of 5 cases of adult-onset Ewing sarcoma(ES)managed between 2011 and 2014. We examined prognostic factors including the primary lesion, tumor size, metastatic status, and serum LDH levels. RESULTS: The locations of the primary lesions included the limbs in 1 case and the trunk in 4; the cases in the trunk had a worse prognosis than that in the limbs. Tumor size was greater than 8 cm in only 1 patient, who also displayed evidence of metastases at presentation and high LDH levels. All the patients received chemotherapy consisting of alternating vincristine, doxorubicin, and cyclophosphamide(VDC)and etoposide and ifosfamide(IE). Surgery was selected for the treatment of 4 patients, and radiotherapy was administered to 1 patient for local treatment of the tumor. A median follow-up duration of 31.6 months revealed the 2-year overall survival rate and progression-free survival rate to be 80.0%. CONCLUSIONS: The prognosis of patients with adult-onset ES is poor; however, combined modality therapy, including VDC-IE, was demonstrated to improve the outcome of patients in the present study. Nevertheless, the patient with tumor size exceeding 8 cm, metastasis, and high LDH levels, relapsed 1 year after treatment, as reported previously. Further investigation is required to clarify the factors affecting prognosis in adults, and to develop effective therapies for patients with a poor prognosis.

PubMed

Targeting Notch-1 positive acute leukemia cells by novel fucose-bound liposomes carrying daunorubicin

Michihiro Ono, Rishu Takimoto, Takahiro Osuga, Yutaka Okagawa, Masahiro Hirakawa, Makoto Yoshida, Yohei Arihara, Naoki Uemura, Naoki Hayasaka, Shogo Miura, Teppei Matsuno, Fumito Tamura, Yasushi Sato, Tsutomu Sato, Satoshi Iyama, Koji Miyanishi, Kohichi Takada, Masayoshi Kobune, Junji Kato

ONCOTARGET ( IMPACT JOURNALS LLC )  7 ( 25 ) 38586 - 38597  2016年06月  [査読有り]

　概要を見る

Complete remission by induction therapy in acute myelogenous leukemia (AML) can be achieved due to improvements in supportive and optimized therapy. However, more than 20% of patients will still need to undergo salvage therapy, and most will have a poor prognosis. Determining the specificity of drugs to leukemia cells is important since this will maximize the dose of chemotherapeutic agents that can be administered to AML patients. In turn, this would be expected to lead to reduced drug toxicity and its increased efficacy. We targeted Notch-1 positive AML cells utilizing fucose-bound liposomes, since activation of Notch-1 is required for O-fucosylation. Herein, we report that intravenously injected, L-fucose-bound liposomes containing daunorubicin can be successfully delivered to AML cells that express fucosylated antigens. This resulted in efficient tumor growth inhibition in tumor-bearing mice and decreased proliferation of AML patient-derived leukemia cells. Thus, biological targeting by fucose-bound liposomes that takes advantage of the intrinsic characteristics of AML cells could be a promising new strategy for Notch-1 positive-AML treatment.

DOI PubMed

Efficacy of upfront high-dose chemotherapy plus rituximab followed by autologous peripheral blood stem cell transplantation for untreated high-intermediate-, and high-risk diffuse large B-cell lymphoma: a multicenter prospective phase II study (JSCT-NHL04)

Tohru Murayama, Takahiro Fukuda, Hirokazu Okumura, Kazutaka Sunami, Aiko Sawazaki, Yoshinobu Maeda, Hisashi Tsurumi, Naokuni Uike, Tomonori Hidaka, Yoshifusa Takatsuka, Tetsuya Eto, Hiroyuki Tsuda, Tomoaki Fujisaki, Toshihiro Miyamoto, Naoko Tsuneyoshi, Satoshi Iyama, Koji Nagafuji, Mine Harada

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER JAPAN KK )  103 ( 6 ) 676 - 685  2016年06月  [査読有り]

　概要を見る

To evaluate the efficacy and feasibility of upfront high-dose chemotherapy (HDCT) and rituximab (R) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) in patients with newly diagnosed high-intermediate(HI)-, and high(H)-risk diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter prospective phase II trial. In 15-60-year-old patients with H- or HI-risk DLBCL, after three courses of (R-)CHOP14, high-dose etoposide was given prior to peripheral blood stem cell harvesting. After an additional three courses of (R-)CHOP14, auto-PBSCT was performed following HDCT. The primary endpoint of the study is progression-free survival (PFS) at 2 years after registration in eligible patients. The expected PFS and the threshold PFS were estimated to be 70 and 50 %, respectively. Among 40 eligible patients registered, 30 patients completed treatment. With a median observation period in surviving eligible patients of 63 months, the 2- and 4-year PFS after registration were 79.9 and 72.0 %, respectively. The 2- and 4-year overall survival (OS) were 92.5 and 84.6 %, respectively. In 30 patients who completed treatment, the 4-year PFS and OS after auto-PBSCT were 79.2 and 85.9 %, respectively. In conclusion, the results of our study suggest that upfront HDCT and auto-PBSCT combined with rituximab is highly effective as an initial treatment for HI-, and H-risk DLBCL.

DOI PubMed

Isoform D of vascular endothelial growth factor in systemic capillary leak syndrome: a case report.

Ibata S, Sato T, Takada K, Tatekoshi A, Hashimoto A, Kamihara Y, Jomen W, Horiguchi H, Ono K, Murase K, Iyama S, Miyanishi K, Sato Y, Takimoto R, Kobune M, Kato J

Journal of medical case reports   10   125 - 125  2016年05月  [査読有り]  [国際誌]

　概要を見る

BACKGROUND: Systemic capillary leak syndrome is a rare condition characterized by episodic attacks of hypovolemia due to systemic capillary hyperpermeability, which results in profound hypotension and edema. Although the implication of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 has been suggested, the pathogenesis of systemic capillary leak syndrome remains unclear. In this report, we describe a case of systemic capillary leak syndrome in which serum isoform D of vascular endothelial growth factor was elevated. To the best of our knowledge, this is the first reported case of systemic capillary leak syndrome in which isoform D of vascular endothelial growth factor is suggested as the plausible biomarker. CASE PRESENTATION: A 41-year-old Japanese man was transferred to our emergency department. He was hypotensive, tachycardic, and edematous over the trunk and all four limbs. He received aggressive intravenous fluid therapy and underwent fasciotomy of the right forearm to prevent muscle necrosis. A diagnosis of systemic capillary leak syndrome was suspected. The presence of serum monoclonal immunoglobulin G and κ light chain supported this diagnosis. Prevention of hypotensive crises was unsuccessfully attempted with theophylline, intravenous immunoglobulin, high-dose dexamethasone, bortezomib, melphalan, and prednisolone; however, the patient's attacks dramatically disappeared after the introduction of thalidomide. The serum of the patient was stored soon after the onset of hypotensive crisis and analyzed to profile possible mediators responsible for the capillary leak. The concentration of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 were all within normal ranges. Meanwhile, we found that isoform D of vascular endothelial growth factor was elevated, which was normalized after the introduction of thalidomide. CONCLUSIONS: In our patient, isoform D of vascular endothelial growth factor (instead of vascular endothelial growth factor) may have been a causative factor of hypotensive crises, since isoform D contributes to vascular endothelial growth factor receptor-2 signaling, which is the major mediator of the permeability-enhancing effects of vascular endothelial growth factor. We suggest the measurement of isoform D of vascular endothelial growth factor in patients with systemic capillary leak syndrome in whose serum vascular endothelial growth factor is not elevated.

DOI PubMed

Extracellular vesicle miR-7977 is involved in hematopoietic dysfunction of mesenchymal stromal cells via poly(rC) binding protein 1 reduction in myeloid neoplasms

Hiroto Horiguchi, Masayoshi Kobune, Shohei Kikuchi, Masahiro Yoshida, Masaki Murata, Kazuyuki Murase, Satoshi Iyama, Kohichi Takada, Tsutomu Sato, Kaoru Ono, Akari Hashimoto, Ayumi Tatekoshi, Yusuke Kamihara, Yutaka Kawano, Koji Miyanishi, Norimasa Sawada, Junji Kato

HAEMATOLOGICA ( FERRATA STORTI FOUNDATION )  101 ( 4 ) 437 - 447  2016年04月  [査読有り]

　概要を見る

The failure of normal hematopoiesis is observed in myeloid neoplasms. However, the precise mechanisms governing the replacement of normal hematopoietic stem cells in their niche by myeloid neoplasm stem cells have not yet been clarified. Primary acute myeloid leukemia and myelodysplastic syndrome cells induced aberrant expression of multiple hematopoietic factors including Jagged-1, stem cell factor and angiopoietin-1 in mesenchymal stem cells even in non-contact conditions, and this abnormality was reverted by extracellular vesicle inhibition. Importantly, the transfer of myeloid neoplasm-derived extracellular vesicles reduced the hematopoietic supportive capacity of mesenchymal stem cells. Analysis of extracellular vesicle microRNA indicated that several species, including miR-7977 from acute myeloid leukemia cells, were higher than those from normal CD34(+) cells. Remarkably, the copy number of miR-7977 in bone marrow interstitial fluid was elevated not only in acute myeloid leukemia, but also in myelodysplastic syndrome, as compared with lymphoma without bone marrow localization. The transfection of the miR-7977 mimic reduced the expression of the posttranscriptional regulator, poly(rC) binding protein 1, in mesenchymal stem cells. Moreover, the miR-7977 mimic induced aberrant reduction of hematopoietic growth factors in mesenchymal stem cells, resulting in decreased hematopoietic-supporting capacity of bone marrow CD34(+) cells. Furthermore, the reduction of hematopoietic growth factors including Jagged-1, stem cell factor and angiopoietin-1 were reverted by target protection of poly(rC) binding protein 1, suggesting that poly(rC) binding protein 1 could be involved in the stabilization of several growth factors. Thus, miR-7977 in extracellular vesicles may be a critical factor that induces failure of normal hematopoiesis via poly(rC) binding protein 1 suppression.

DOI PubMed

Narrow-Band Ultraviolet B Phototherapy Ameliorates Acute Graft-Versus-Host Disease of the Intestine by Expansion of Regulatory T Cells

Akari Hashimoto, Tsutomu Sato, Satoshi Iyama, Masahiro Yoshida, Soushi Ibata, Ayumi Tatekoshi, Yusuke Kamihara, Hiroto Horiguchi, Kazuyuki Murase, Yutaka Kawano, Kohichi Takada, Koji Miyanishi, Masayoshi Kobune, Shingo Ichimiya, Junji Kato

PLOS ONE ( PUBLIC LIBRARY SCIENCE )  11 ( 3 ) e0152823  2016年03月  [査読有り]

　概要を見る

Narrowband ultraviolet B (NB-UVB) has been widely used in dermatological phototherapy. As for the application of NB-UVB phototherapy to graft-versus-host disease (GVHD), we previously reported that it was highly efficacious for cutaneous lesions of acute GVHD (aGVHD) and that expansion of regulatory T (Treg) cells induced by NB-UVB might be one of the mechanisms. In order to examine whether NB-UVB irradiation through expansion of Treg cells is effective for the treatment of not only cutaneous aGVHD but also aGVHD of inner organs such as the intestine or liver, we conducted experiments in which a murine lethal aGVHD model, characterized by severe involvement of the intestine, was irradiated with NB-UVB. We found that NB-UVB irradiation improved the clinical score and survival rate. The pathological score of aGVHD was improved in all affected organs: intestine, liver, and skin. In the serum of mice irradiated with NB-UVB, the levels of Treg cells-associated cytokines such as transforming growth factor beta (TGF beta) and interleukin-10 (IL-10) were elevated. The numbers of infiltrating Treg cells in inflamed tissue of the intestine and those in spleen were increased in mice treated with NB-UVB. This is the first report demonstrating that NB-UVB phototherapy has the ability to ameliorate intestinal aGVHD through the expansion of Treg cells.

DOI PubMed

RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential in gastric cancer cells

Fumito Tamura, Yasushi Sato, Masahiro Hirakawa, Makoto Yoshida, Michihiro Ono, Takahiro Osuga, Yutaka Okagawa, Naoki Uemura, Yohei Arihara, Kazuyuki Murase, Yutaka Kawano, Satoshi Iyama, Kohichi Takada, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Junji Kato

GASTRIC CANCER ( SPRINGER )  19 ( 1 ) 85 - 97  2016年01月  [査読有り]

　概要を見る

ST6GalNAc I is a sialyltransferase controlling the expression of sialyl-Tn antigen (STn), which is overexpressed in several epithelial cancers, including gastric cancer, and is highly correlated with cancer metastasis. However, the functional contribution of ST6GalNAc I to development or progression of gastric cancer remains unclear. In this study, we investigated the effects of suppression of ST6GalNAc I on gastric cancer in vitro and in vivo. Gastric cancer cell lines were transfected with ST6GalNAc I siRNA and were examined by cell proliferation, migration, and invasion assays. We also evaluated the effect of ST6GalNAc I siRNA treatment in a peritoneal dissemination mouse model. The differences in mRNA levels of selected signaling molecules were analyzed by polymerase chain reaction (PCR) arrays associated with tumor metastasis in MKN45 cells. The signal transducer and activator of transcription 5b (STAT5b) signaling pathways that reportedly regulate the insulin-like growth factor-1 (IGF-1) were analyzed by Western blot. ST6GalNAc I siRNA inhibited gastric cancer cell growth, migration, and invasion in vitro. Furthermore, intraperitoneal administration of ST6GalNAc I siRNA- liposome significantly inhibited peritoneal dissemination and prolonged the survival of xenograft model mice with peritoneal dissemination of gastric cancer. PCR array confirmed that suppression of ST6GalNAc I caused a significant reduction in expression of IGF-1 mRNA. Decreased IGF-1 expression in MKN45 cells treated with ST6GalNAc I siRNA was accompanied by reduced phosphorylation of STAT5b. ST6GalNAc I may regulate the gene expression of IGF-1 through STAT5b activation in gastric cancer cells and may be a potential target for treatment of metastasizing gastric cancer.

DOI PubMed

[Neurolymphomatosis of the sciatic nerve diagnosed by FDG-PET/CT].

Usami M, Murase K, Takada K, Iijima K, Yoshida M, Tatekoshi A, Hashimoto A, Iyama S, Sato T, Kobune M, Takimoto R, Kaya M, Yamashita T, Morita R, Hasegawa T, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology   57 ( 1 ) 52 - 55  2016年01月  [査読有り]

DOI PubMed J-GLOBAL

[RS3PE syndrome associated with senile Epstein-Barr virus-positive diffuse large B cell lymphoma of a patient with colon cancer].

Shimoyama S, Kuroda H, Yoshida M, Usami M, Sakamoto H, Yamada M, Fujii S, Maeda M, Fujita M, Nakano T, Kanari Y, Iyama S, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology ( The Japanese Society of Hematology )  56 ( 11 ) 2329 - 2335  2015年11月  [査読有り]

　概要を見る

症例は75歳，女性。2014年1月に両側手背・肘・肩・膝の関節痛のため前医へ受診した。RS3PE症候群の診断で低用量プレドニゾロンによる治療を受け関節痛は改善したが，同年4月に右頸部リンパ節腫脹を自覚し当科へ紹介となった。加齢性EBV陽性びまん性大細胞型B細胞リンパ腫（EBV陽性DLBCL）の診断が得られ，下部消化管内視鏡で早期大腸がんを認めた。なお，リンパ腫と大腸がんはともにvascular endothelial growth factor (VEGF)染色が陽性であった。R-CHOP療法2コース後に完全寛解が得られ，RS3PE症候群の再燃は認めなかった。本症例はRS3PE症候群の発症機序にEBV関連DLBCLから産生されたVEGFの関与が示唆された。

DOI PubMed CiNii

Identification of anti-thrombopoietin receptor antibody in prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation treated successfully with eltrombopag

Akihito Fujimi, Yusuke Kamihara, Akari Hashimoto, Yuji Kanisawa, Chisa Nakajima, Naotaka Hayasaka, Shota Yamada, Toshinori Okuda, Shinya Minami, Kaoru Ono, Satoshi Iyama, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER JAPAN KK )  102 ( 4 ) 471 - 476  2015年10月  [査読有り]

　概要を見る

A 55-year-old female with stage IVA follicular lymphoma in third complete remission underwent allogeneic peripheral blood stem cell transplantation. Neutrophil engraftment was achieved on day +18; however, platelet counts remained below 10 x 10(3)/A mu L, necessitating transfusions twice a week for more than 3 months. Bone marrow showed a decreased number of megakaryocytes with hypolobulated nuclei. No graft versus host disease, viral infection, or disease relapse was observed. Furthermore, severe thrombocytopenia below 5.0 x 10(3)/A mu L refractory to transfusion appeared on day +240 after influenza virus infection. Treatments with intravenous immunoglobulin, romiplostim, and rituximab were administered without any recovery. Subsequently, eltrombopag was initiated on day +443, after which platelet counts rose gradually and continued to rise above 20 x 10(3)/A mu L after 10 weeks of administration. The serum thrombopoietin (TPO) level was markedly elevated, and anti-TPO receptor (TPOR) antibody was detected in the patient's serum. Anti-TPOR antibody may play an important role in some cases of prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation with unknown etiology, and eltrombopag could be a novel therapeutic option for such cases.

DOI PubMed

Effect of duloxetine in Japanese patients with chemotherapy-induced peripheral neuropathy: a pilot randomized trial

Yasuo Hirayama, Kunihiko Ishitani, Yasushi Sato, Satoshi Iyama, Kohichi Takada, Kazuyuki Murase, Hiroyuki Kuroda, Yasuhiro Nagamachi, Yuichi Konuma, Akihito Fujimi, Tamotsu Sagawa, Kaoru Ono, Hiroto Horiguchi, Takeshi Terui, Kazuhiko Koike, Toshiro Kusakabe, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY ( SPRINGER JAPAN KK )  20 ( 5 ) 866 - 871  2015年10月  [査読有り]

　概要を見る

Chemotherapy-induced peripheral neuropathy (CIPN) is difficult to manage. A phase III trial conducted in the United States demonstrated that duloxetine was effective for CIPN caused by taxane and platinum-based chemotherapy. No randomized trial of duloxetine for CIPN has been conducted in Japan. In this open-label, randomized, crossover study, eligible patients were randomized to Group A or Group B. Group A received duloxetine 20 mg/day orally for the first week and 40 mg/day for the next 3 weeks. Group B received vitamin B12 (VB12) 1.5 mg/day orally for 4 weeks. After a 2- to 4-week washout period, treatment was crossed over for another 4 weeks. The severity of numbness and pain was assessed using a visual analog scale (VAS). Thirty-four patients were enrolled. Obvious decreases in the mean VAS scores for numbness and pain were observed for the periods of duloxetine administration. Significant differences were observed between the duloxetine-first (Group A) and the VB12-first (Group B) groups with respect to numbness (p = 0.03) and pain (p = 0.04) at 4 weeks after administration. Fatigue was observed in six of the 34 participants (17.6 %). Our data suggests that duloxetine has a beneficial effect on CIPN caused by oxaliplatin, paclitaxel, vincristine, or bortezomib in Japanese patients.

DOI PubMed

Therapy-related myelodysplastic syndrome as a late adverse event of definitive chemoradiotherapy for esophageal and oropharyngeal cancer

Yusuke Kamihara, Yasushi Sato, Kohichi Takada, Yutaka Okagawa, Satoshi Iyama, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Junji Kato

Journal of Japanese Society of Gastroenterology ( Japanese Society of Gastroenterology )  112 ( 9 ) 1664 - 1673  2015年09月  [査読有り]

　概要を見る

The risks of myelodysplastic syndrome (MDS) and acute leukemia are increased in patients previously treated for other malignancies. Therapy-related MDS (t-MDS) occurs after exposure to certain cytotoxic agents or radiation used for cancer treatment. We report a case of t-MDS following curative chemoradiotherapy (CRT) for esophageal and oropharyngeal cancer. An 80-year-old male diagnosed with double cancers of the esophagus and oropharynx underwent definitive CRT and achieved a complete response. Six years later, he became anemic, and bone marrow examination showed 3.4% blast cells with fine chromatin structures and basophilic cytoplasm. Cytogenetic analysis indicated a complex karyotype that included chromosome 5 and 7 abnormalities. These findings were consistent with t-MDS. Subsequently, he developed acute myeloid leukemia and died 8 months later. This case indicates that long-term surveillance is needed to closely monitor the risk of t-MDS in patients treated with CRT.

DOI PubMed

Successful hematopoietic cell transplantation following azacitidine treatment in an acute myeloid leukemia patient with t (3;3) (q21;q26.2) translocation and marked thrombocythemia

Masahiro Yoshida, Hiroyuki Kuroda, Saori Shimoyama, Makoto Usami, Michiko Yamada, Shigeyuki Fujii, Masahiro Maeda, Miri Fujita, Yusuke Kanari, Masanori Sato, Wataru Jornen, Satoshi Iyama, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. )  42 ( 8 ) 1013 - 1017  2015年08月  [査読有り]

　概要を見る

A 39-year-old man visited our department complaining of general malaise and appetite loss. He presented with anemia and marked thrombocythemia his plasma transforming growth factor (TGF)-β concentration was markedly increased and his thrombopoietin (TPO) concentration was decreased. Since the patient's disease had progressed to acute myeloid leukemia (AML) with an increase in the peripheral blast count, he was diagnosed with AML along with t (3 3) (q21 q26.2) through a bone marrow aspiration sample. Remission induction therapy was performed using idarubicin/cytarabine. The patient achieved complete remission. His platelet count returned to the normal range, plasma TGF-β concentration decreased, and serum TPO concentration increased. The patient was treated with azacitidine as post-remission therapy for bone marrow transplantation, following which he underwent allogeneic hematopoietic cell transplantation.

PubMed

A dose-escalation study of oxaliplatin/capecitabine/irinotecan (XELOXIRI) and bevacizumab as a first-line therapy for patients with metastatic colorectal cancer

Yasushi Sato, Hiroyuki Ohnuma, Masahiro Hirakawa, Minoru Takahashi, Takahiro Osuga, Yutaka Okagawa, Kazuyuki Murase, Kohichi Takada, Yutaka Kawano, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Kenji Okita, Toru Mizuguchi, Tomohisa Furuhata, Koichi Hirata, Junji Kato

CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER )  75 ( 3 ) 587 - 594  2015年03月  [査読有り]

　概要を見る

The aim of this study was to determine the recommended dose (RD) of a triweekly capecitabine, oxaliplatin, irinotecan, and bevacizumab (XELOXIRI/bevacizumab) regimen that was easier to administer than FOLFOXIRI/bevacizumab, using capecitabine instead of 5-fuorouracil (5-FU), in patients with metastatic colorectal cancer (mCRC). Patients received oxaliplatin (100 mg/m(2), day 1), capecitabine (1,700 mg/m(2) per day from day 2 to 15), irinotecan (100, 120, 150 mg/m(2) for dose levels 1, 2, 3, day 1), and bevacizumab (7.5 mg/kg, day 1), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first two cycles to determine the maximum tolerated dose (MTD). Twelve patients received a median of 6.5 cycles of therapy (range 2-12). The DLT was grade 4 neutropenia, observed in one of six patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m(2). The most common grade a parts per thousand yen3 toxicities were neutropenia (41 %), anemia (17 %), diarrhea (8 %), and febrile neutropenia (8 %). The response rate and median progression-free survival were 83 % and 15 months, respectively. XELOXIRI/bevacizumab is a feasible regimen for patients with mCRC, neutropenia was the DLT, and the RD of irinotecan is 150 mg/m(2). The response rate observed is very promising and warrants further investigation.

DOI PubMed

A role for peripherally inserted central venous catheters in the prevention of catheter-related blood stream infections in patients with hematological malignancies

Toshiro Sakai, Kyuhei Kohda, Yuichi Konuma, Yasuko Hiraoka, Yukari Ichikawa, Kaoru Ono, Hiroto Horiguchi, Ayumi Tatekoshi, Kouichi Takada, Satoshi Iyama, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER JAPAN KK )  100 ( 6 ) 592 - 598  2014年12月  [査読有り]

　概要を見る

Central venous catheter-related blood stream infections (CR-BSIs) are a serious complication in patients with hematological malignancies. However, it remains unclear whether there is a difference in the rate of CR-BSI associated with the conventional type of central venous catheters (cCVCs) and peripherally inserted CVCs (PICCs) in such patients. To address this question, we retrospectively investigated the incidence of CR-BSIs associated with PICCs versus cCVCs in patients with hematological malignancies. We used PICCs in all consecutive patients requiring CVC placement between February 2009 and February 2013. We compared the CR-BSI rate in patients with PICCs with that in patients with cCVCs treated between September 2006 and January 2009 (control group). Eighty-four patients received PICCs and 85 received cCVCs. The most common reason for removal due to catheter-related complications was CR-BSI. The CR-BSI rate in the PICC group was significantly lower than that in the cCVC group (PICCs: 1.23/1000 catheter days; cCVCs: 5.30/1000 catheter days; P < 0.01). Catheter-related complications other than CR-BSIs occurred at an extremely low rate in the PICC group. The median catheter-related complication-free survival duration was significantly longer in the PICC group than in the cCVC group. Our study shows that PICCs are useful in patients with hematological malignancies.

DOI PubMed

Markers of bone metabolism in multiple myeloma patients switched from zoledronic acid to denosumab.

Tatekoshi A, Sato T, Ibata S, Hashimoto A, Kamihara Y, Horiguchi H, Ono K, Takada K, Iyama S, Takimoto R, Kobune M, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 11 )  55 ( 11 ) 2271 - 2276  2014年11月  [査読有り]

　概要を見る

これまで，多発性骨髄腫における骨病変の予防や治療にはビスホスホネートであるゾレドロン酸が用いられてきた。一方，receptor activator of nuclear factor-κB ligand (RANKL)抗体であるデノスマブも使用可能となったが，両者の使い分けに関しては不明な点が多い。当科において前者から後者へ切り替えを行った多発性骨髄腫10例を後方視的に検討した。観察項目は骨吸収マーカー，骨形成マーカー，及び補正カルシウム(Ca)値やM蛋白とし，切り替え前後の値を比較した。骨吸収マーカーは切り替え後に有意な低下を認めた。一方，骨形成マーカーに上昇は認めなかった。切り替えに際し重篤な低Ca血症は出現しなかった。1例において切り替え後にM蛋白の上昇を認め，ゾレドロン酸の再開によって横ばいとなった。切り替えにより破骨細胞の更なる抑制が期待できるが，原病増悪の可能性に注意すべきと考えられた。

DOI PubMed CiNii

Anti-erythropoietin receptor antibody-associated pure red cell aplasia accompanied by Coombs-negative autoimmune hemolytic anemia in a patient with T cell/histiocyte-rich large B cell lymphoma

Akihito Fujimi, Yusuke Kamihara, Yuji Kanisawa, Akari Hashimoto, Chisa Nakajima, Naotaka Hayasaka, Naoki Uemura, Toshinori Okuda, Shinya Minami, Satoshi Iyama, Koichi Takada, Tsutomu Sato, Akinori Hara, Yasunori Iwata, Kengo Furuichi, Takashi Wada, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER JAPAN KK )  100 ( 5 ) 490 - 493  2014年11月  [査読有り]

　概要を見る

A 79-year-old female diagnosed with T cell/histiocyte-rich large B cell lymphoma in complete remission after six cycles of rituximab-combined chemotherapy developed severe anemia, reticulocytopenia, and bone marrow erythroid hypoplasia. She was diagnosed with pure red cell aplasia (PRCA) accompanied by Coombs-negative autoimmune hemolytic anemia evidenced by a lack of glycophorin-A-positive cells in the bone marrow, haptoglobin under the detection level, and a high titer of RBC-bound IgG. Anti-erythropoietin receptor (EPOR) antibody was detected in the serum, and oligoclonal alpha/beta and gamma/delta T cells were also detected in her peripheral blood by Southern blotting analysis. Parvovirus B19 DNA was not detected by PCR. Although the treatment with rituximab had limited efficacy (specifically, only for hemolysis), subsequent cyclosporine therapy led to prompt recovery of erythropoiesis with the disappearance of anti-EPOR antibody and oligoclonal T cells. This is the first case report of anti-EPOR antibody-associated PRCA in a patient with malignant lymphoma treated successfully with cyclosporine.

DOI PubMed

骨髄癌腫症を来し急激な経過を辿った悪性黒色腫の1例

澤田 匡秀, 澄川 靖之, 佐藤 さゆり, 菅 裕司, 加藤 潤史, 山下 利春, 橋本 亜香利, 井山 諭

日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 )  124 ( 10 ) 1933 - 1933  2014年09月

Effective Treatment of Metastatic Rhabdomyosarcoma with Pazopanib

Akari Hashimoto, Kohichi Takada, Rishu Takimoto, Hiroto Horiguchi, Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Kaoru Ono, Ayumi Tatekoshi, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Masayoshi Kobune, Yasuo Hirayama, Hiroshi Kitamura, Katsuya Nakanishi, Naoya Masumori, Tadashi Hasegawa, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. )  41 ( 8 ) 1041 - 1044  2014年08月  [査読有り]

　概要を見る

Pazopanib, an oral tyrosine kinase inhibitor, is the first molecular-Targeted agent approved for the treatment of advanced soft tissue sarcoma (STS). Rhabdomyosarcoma in adults is rare, accounting for less than 3% of all adult STS cases. A 57-year-old woman presented with cervical lymphadenopathy. Computed tomography revealed a heterogeneous mass in the retro-peritoneum, replacing the entire right kidney. On the basis of the above findings, the patient was diagnosed with alveolar rhabdomyosarcoma. She was first treated with 4 courses of vincristine, actinomycin D, and cyclophosphamide (VAC), which resulted in a partial response. Dose reduction and delay occurred owing to hematological toxicity and febrile neutropenia. As second-line chemotherapy, the patient was administered a single daily dose of 800 mg of pazopanib. Because of an episode of hand-foot syndrome and hepatic impairment, the 800-mg daily dose of pazopanib was reduced to a daily dose of 600 mg, which had to be further reduced to a daily dose of 400 mg owing to fatigue and anorexia. The patient maintained a partial response for a total of 4.3 months when treated with pazopanib. Therefore, this drug may be a new treatment option for patients showing metastatic STS after previous chemotherapy.

PubMed

High Level of Serum Soluble Interleukin-2 Receptor at Transplantation Predicts Poor Outcome of Allogeneic Stem Cell Transplantation for Adult T Cell Leukemia

Akio Shigematsu, Naoki Kobayashi, Hiroshi Yasui, Motohiro Shindo, Yasutaka Kakinoki, Kyuhei Koda, Satoshi Iyama, Hiroyuki Kuroda, Yutaka Tsutsumi, Masahiro Imamura, Takanori Teshima

BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION ( ELSEVIER SCIENCE INC )  20 ( 6 ) 801 - 805  2014年06月  [査読有り]

　概要を見る

The prognosis for adult T cell leukemia/lymphoma (ATL) is very poor, and only allogeneic hematopoietic stem cell transplantation (allo-SCT) has been considered to be a curative treatment for ATL. In this study, we retrospectively analyzed data for patients who had received allo-SCT for ATL in Hokkaido, the northernmost island of Japan, to determine prognostic factors. Fifty-six patients with a median age of 57 years received allo-SCT. Twenty-eight (50.0%) patients had acute type and 22 (46.4%) had lymphoma type. Twenty-three (41.1%) patients received allo-SCT in complete remission (CR), whereas the others were in non-CR. Seventeen (30.4%) patients received myeloablative conditioning and the others received reduced-intensity conditioning. With a median follow-up period of 48 months (range, 17 to 134 months), 1-year overall survival (OS) and 5-year OS rates were 55.4% and 46.1%, respectively. The survival curve reached a plateau at 22 months after stem cell transplantation (SCT). Male sex, high level of serum soluble interleukin-2 receptor (sIL-2R) at SCT, and non-CR at SCT were determined to be significant risk factors for OS. A high level of sIL-2R at SCT was a risk factor for poor OS in patients with non-CR at SCT by univariate analysis (P = .02), and it remained significant after adjustment by sex (hazard ratio, 2.73 [95% confidence interval, 1.07 to 7.90]). A high level of sIL-2R at SCT was also determined to be a risk factor for disease progression (P = .02). This region-wide study showed encouraging results for survival after allo-SCT for ATL and demonstrated for the first time that a high level of sIL-2R at SCT predicts worse SCT outcome. (C) 2014 American Society for Blood and Marrow Transplantation.

DOI PubMed

Efficacy of enteral supplementation enriched with glutamine, fiber, and oligosaccharide on mucosal injury following hematopoietic stem cell transplantation

Satoshi Iyama, Tsutomu Sato, Hiroomi Tatsumi, Akari Hashimoto, Ayumi Tatekoshi, Yusuke Kamihara, Hiroto Horiguchi, Soushi Ibata, Kaoru Ono, Kazuyuki Murase, Kohichi Takada, Yasushi Sato, Tsuyoshi Hayashi, Koji Miyanishi, Emi Akizuki, Takayuki Nobuoka, Toru Mizugichi, Rishu Takimoto, Masayoshi Kobune, Koichi Hirata, Junji Kato

Case Reports in Oncology ( S. Karger AG )  7 ( 3 ) 692 - 699  2014年04月  [査読有り]

担当区分：   筆頭著者

　概要を見る

The combination of glutamine, fiber and oligosaccharides (GFO) is thought to be beneficial for alleviating gastrointestinal mucosal damage caused by chemotherapy. A commercial enteral supplementation product (GFO) enriched with these 3 components is available in Japan. We performed a retrospective study to test whether oral GFO decreased the severity of mucosal injury following hematopoietic stem cell transplantation (HSCT). Of 44 HSCT patients, 22 received GFO and 22 did not. Severity of diarrhea/mucositis, overall survival, weight loss, febrile illness/documented infection, intravenous hyperalimentation days/hospital days, engraftment, acute and chronic GVHD, and cumulative incidence of relapse were studied. Sex, age, performance status, diagnosis, disease status, and treatment variables were similar in both groups. There were fewer days of diarrhea grade 3-4 in patients receiving GFO than in those who did not (0.86 vs. 3.27 days) the same was true for days of mucositis grade 3-4 (3.86 vs. 6.00 days). Survival at day 100 was 100% in the GFO group, but only 77.3% for the patients not receiving GFO (p = 0.0091, log-rank test). Weight loss and the number of days of intravenous hyperalimentation were better in the GFO group (p < 0.001 and p = 0.0014, respectively). Although not significant, less gut bacterial translocation with Enterococcus species developed in the GFO group (p = 0.0728) than in the non-GFO group. Other outcomes were not affected. To the best of our knowledge, this is the first comparative clinical study of GFO supplementation to alleviate mucosal injury after allo-HSCT. We conclude that glutamine, fiber and oligosaccharide supplementation is an effective supportive therapy to decrease the severity of mucosal damage in HSCT.

DOI PubMed

Narrowband ultraviolet B phototherapy ameliorates acute graft-versus-host disease by a mechanism involving in vivo expansion of CD4+CD25+Foxp3+regulatory T cells

Satoshi Iyama, Kazuyuki Murase, Tsutomu Sato, Akari Hashimoto, Ayumi Tatekoshi, Hiroto Horiguchi, Yusuke Kamihara, Kaoru Ono, Shohei Kikuchi, Kohichi Takada, Yutaka Kawano, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Satoru Mori, Junji Kato, Toshiharu Yamashita, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER JAPAN KK )  99 ( 4 ) 471 - 476  2014年04月  [査読有り]

担当区分：   筆頭著者

　概要を見る

Narrowband ultraviolet B phototherapy (NB-UVB) is a therapeutic alternative for haematopoietic stem cell transplantation-related skin graft-versus-host disease (GVHD). The beneficial effects of this intervention may be induced by direct irradiation of inflammatory cells in the skin; however, the putative involvement of indirect effects on systemic immunity has not been elucidated. To address this issue, 11 acute skin GVHD patients refractory to standard corticosteroid treatment and with no gut/liver involvement were treated with NB-UVB irradiation. The median number of treatments was 10 times, with a mean cumulative exposure of 6.36 J/cm(2). No other immunosuppressive therapy was initiated during irradiation. Eight patients achieved an objective complete response, two had a partial response, and one showed no change. None of the patients experienced progressive skin GVHD or newly diagnosed gut/liver GVHD. NB-UVB was well tolerated, with no patients discontinuing irradiation due to toxicity. We additionally demonstrated by flow cytometry that NB-UVB irradiation induces the increment of the proportion of regulatory T cell (Tregs) in patients' peripheral blood. These results suggest that NB-UVB may exert beneficial effects on steroid-refractory skin GVHD through the expansion of Tregs.

DOI PubMed

Radiation-induced leiomyosarcoma of the prostate after brachytherapy for prostatic adenocarcinoma

Hiroto Horiguchi, Kohichi Takada, Yusuke Kamihara, Soushi Ibata, Satoshi Iyama, Tsutomu Sato, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Ko Kobayashi, Yasuo Hirayama, Naoya Masumori, Tadashi Hasegawa, Junji Kato

Case Reports in Oncology ( S. Karger AG )  7 ( 2 ) 565 - 570  2014年03月  [査読有り]

　概要を見る

Radiation therapy (RTx) has been employed as a curative therapy for prostatic adenocarcinoma. RTx-induced sarcomas (RISs) are rare, late adverse events, representing less than 0.2% of all irradiated patients. RISs are more aggressive tumors than prostatic adenocarcinomas. Herein, we present a case with RTx-induced prostatic leiomyosarcoma after permanent brachytherapy for prostatic adenocarcinoma. A 69-year-old male presented with dysuria and gross hematuria. Six years previously, he had been diagnosed with localized prostate cancer and was treated by permanent brachytherapy. Urethroscopy showed stenosis by a tumor at the prostate. Transurethral prostatectomy was performed for a diagnosis. Based on pathological findings, the diagnosis was leiomyosarcoma of the prostate. He was treated with three cycles of neoadjuvant chemotherapy (CTx) that consisted of doxorubicin and ifosfamide (AI), followed by a prostatocystectomy with intrapelvic lymphadenectomy. The tumor extended from the prostate and infiltrated the bladder wall and serosa with lymphatic and venous invasion. The surgical margin was negative, and no residual prostatic adenocarcinoma was observed. The proportion of necrotic tumor cells by neoadjuvant CTx was around 50%. Subsequently, adjuvant CTx was offered, but the patient chose a follow-up without CTx. Local recurrence and lung metastasis were detected by computed tomography 3 months after the surgery. He was treated again with AI. However, CTx was not effective and he died 6 months after the operation. In conclusion, an effective treatment strategy for prostatic sarcoma should be developed in the near future, although the clinical feature of prostatic sarcoma remains unclear due to its rare incidence.

DOI PubMed

Combination chemotherapy of azacitidine and cetuximab for therapy-related acute myeloid leukemia following oxaliplatin for metastatic colorectal cancer

Akari Hashimoto, Kohichi Takada, Hiroto Horiguchi, Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Yusuke Kamihara, Kaoru Ono, Ayumi Tatekoshi, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Tomohisa Furuhata, Masayoshi Kobune, Rishu Takimoto, Koichi Hirata, Junji Kato

Case Reports in Oncology ( S. Karger AG )  7 ( 2 ) 316 - 322  2014年03月  [査読有り]

　概要を見る

Therapy-related leukemia (TRL) has been reported to occur after treatment with alkylating agents and/or topoisomerase II inhibitors. Oxaliplatin (OXP) is used as a key drug for the treatment of colorectal cancer (CRC). Cisplatin and carboplatin have been linked with TRL, but the involvement of OXP is questionable. A 74-year-old male was diagnosed with peritoneal metastasis from CRC in July 2011. The patient received nine cycles of 5-fluorouracil (5-FU), leucovorin (LV), and OXP (mFOLFOX-6 regimen) and three cycles of 5-FU and LV only, resulting in a clinical complete response. However, recurrence of CRC was detected by CT within 3 months after the last course of chemotherapy. In April 2013, laboratory tests showed pancytopenia and 15% blast cells. A bone marrow examination revealed multilineage dysplasia and 20.4% myeloblasts. Cytogenetic analysis indicated a complex karyotype that included chromosome 5 and 7 abnormalities. The patient was diagnosed with TRL and treated with a combination of azacitidine (AZA) and cetuximab (Cmab) for both cancers. AZA might be useful in TRL when a patient needs to be treated simultaneously for more than one primary cancer because of its low toxicity. Moreover, Cmab is an effective therapeutic tool in TRL patients with metastatic CRC with the wild-type K-ras gene.

DOI PubMed

A novel strategy inducing autophagic cell death in Burkitt's lymphoma cells with anti-CD19-targeted liposomal rapamycin

K. Ono, T. Sato, S. Iyama, A. Tatekoshi, A. Hashimoto, Y. Kamihara, H. Horiguchi, S. Kikuchi, Y. Kawano, K. Takada, T. Hayashi, K. Miyanishi, Y. Sato, R. Takimoto, M. Kobune, J. Kato

BLOOD CANCER JOURNAL ( NATURE PUBLISHING GROUP )  4  2014年02月  [査読有り]

　概要を見る

Relapsed or refractory Burkitt's lymphoma often has a poor prognosis in spite of intensive chemotherapy that induces apoptotic and/or necrotic death of lymphoma cells. Rapamycin (Rap) brings about autophagy, and could be another treatment. Further, anti-CD19-targeted liposomal delivery may enable Rap to kill lymphoma cells specifically. Rap was encapsulated by anionic liposome and conjugated with anti-CD19 antibody (CD19-GL-Rap) or anti-CD2 antibody (CD2-GL-Rap) as a control. A fluorescent probe Cy5.5 was also liposomized in the same way (CD19 or CD2-GL-Cy5.5) to examine the efficacy of anti-CD19-targeted liposomal delivery into CD19-positive Burkitt's lymphoma cell line, SKW6.4. CD19-GL-Cy5.5 was more effectively uptaken into SKW6.4 cells than CD2-GL-Cy5.5 in vitro. When the cells were inoculated subcutaneously into nonobese diabetic/severe combined immunodeficiency mice, intravenously administered CD19-GL-Cy5.5 made the subcutaneous tumor fluorescent, while CD2-GL-Cy5.5 did not. Further, CD19-GL-Rap had a greater cytocidal effect on not only SKW6.4 cells but also Burkitt's lymphoma cells derived from patients than CD2-GL-Rap in vitro. The specific toxicity of CD19-GL-Rap was cancelled by neutralizing anti-CD19 antibody. The survival period of mice treated with intravenous CD19-GL-Rap was significantly longer than that of mice treated with CD2-GL-Rap after intraperitoneal inoculation of SKW6.4 cells. Anti-CD19-targeted liposomal Rap could be a promising lymphoma cell-specific treatment inducing autophagic cell death.

DOI

Fucosylated TGF-beta receptors transduces a signal for epithelial-mesenchymal transition in colorectal cancer cells

M. Hirakawa, R. Takimoto, F. Tamura, M. Yoshida, M. Ono, K. Murase, Y. Sato, T. Osuga, T. Sato, S. Iyama, K. Miyanishi, K. Takada, T. Hayashi, M. Kobune, J. Kato

BRITISH JOURNAL OF CANCER ( NATURE PUBLISHING GROUP )  110 ( 1 ) 156 - 163  2014年01月  [査読有り]

　概要を見る

Background: Transforming growth factor-beta (TGF-beta) is a major inducer of epithelial-mesenchymal transition (EMT) in different cell types. TGF-beta-mediated EMT is thought to contribute to tumour cell spread and metastasis. Sialyl Lewis antigens synthesised by fucosyltransferase (FUT) 3 and FUT6 are highly expressed in patients with metastatic colorectal cancer (CRC) and are utilised as tumour markers for cancer detection and evaluation of treatment efficacy. However, the role of FUT3 and FUT6 in augmenting the malignant potential of CRC induced by TGF-beta is unclear. Methods: Colorectal cancer cell lines were transfected with siRNAs for FUT3/6 and were examined by cell proliferation, invasion and migration assays. The expression and phosphorylation status of TGF-beta downstream molecules were analysed by western blot. Fucosylation of TGF-beta receptor (T beta R) was examined by lectin blot analysis. Results: Inhibition of FUT3/6 expression by siRNAs suppressed the fucosylation of type I T beta R and phosphorylation of the downstream molecules, thereby inhibiting the invasion and migration of CRC cells by EMT. Conclusion: Fucosyltransferase 3/6 has an essential role in cancer cell adhesion to endothelial cells by upregulation of sialyl Lewis antigens and also by enhancement of cancer cell migration through TGF-beta-mediated EMT.

DOI

Successful Treatment with Entecavir for Reactivation of Hepatitis B Virus Following Systemic Chemotherapy in a Hepatitis B Surface Antigen-negative Patient with Colorectal Cancer

Yutaka Okagawa, Kohichi Takada, Hiroyuki Hisai, Yutaka Koshiba, Hironori Wada, Etsu Miyazaki, Yusuke Kanari, Yutaka Kawano, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Yasushi Sato, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Junji Kato

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  53 ( 16 ) 1759 - 1762  2014年  [査読有り]

　概要を見る

Reactivation of hepatitis B virus (HBV) has recently been reported as a fatal complication in patients undergoing cytotoxic chemotherapy. We herein describe a case of reactivation in a 76-year-old man who had undergone pelvic exenteration for colorectal cancer (CRC). He was treated with a modified FOLFOX6 chemotherapy regimen after the operation. Thirteen months later, his laboratory data showed severe liver dysfunction. His hepatitis B surface antigen (HBsAg) test was positive, and his HBV-DNA level was elevated. We diagnosed the patient with HBV reactivation as his HBsAg test was negative before starting chemotherapy. His liver dysfunction improved after administration of entecavir. This is the first report describing HBV reactivation following chemotherapy for an HBsAg-negative CRC patient.

DOI PubMed

[Hematologic improvement with deferasirox following tandem antithymocyte globulin treatment in a transfusion-dependent patient with severe aplastic anemia].

Jomen W, Kuroda H, Yamada M, Matsuno T, Sato M, Abe T, Sakurai T, Fujii S, Maeda M, Fujita M, Nagashima K, Iyama S, Miyanishi K, Kobune M, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 11 )  54 ( 11 ) 2047 - 2052  2013年11月  [査読有り]

DOI PubMed CiNii

[Successful treatment with rituximab in a patient with refractory mixed-type autoimmune hemolytic anemia].

Ono K, Sato T, Iyama S, Tatekoshi A, Hashimoto A, Kamihara Y, Horiguchi H, Kikuchi S, Takada K, Hayashi T, Miyanishi K, Sato Y, Takimoto R, Kobune M, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 11 )  54   2053 - 2055  2013年11月  [査読有り]

DOI PubMed

A case of hemosiderin deposition associated with hepatic graft-versus-host disease after peripheral blood stem cell transplantation for acute lymphocytic leukemia

Wataru Jomen, Hiroyuki Kuroda, Yohei Arihara, Michiko Yamada, Tasuku Hirako, Tomoyuki Abe, Tamaki Sakurai, Shigeyuki Fujii, Masahiro Maeda, Miri Fujita, Kazuo Nagashima, Satoshi Iyama, Koji Miyanishi, Masayoshi Kobune, Junji Kato

Acta Hepatologica Japonica   54 ( 11 ) 741 - 747  2013年  [査読有り]

　概要を見る

A 57-year-old woman was diagnosed with acute lymphocytic leukemia (ALL) in July 2009. After complete remission, she received allogenic peripheral blood stem cell transplantation (allo-PBSCT). She had had hepatic dysfunction and high serum ferritin level since February 2011. The hepatic dysfunction had continued even after administration of ursodeoxycholic acid and bezafibrate. The findings of liver biopsy suggested Graft-versus-Host Disease (GVHD) associated with hemosiderin deposition and also 8-OHdG was strongly stained on the nuclei of hepatocytes and bile duct epithelium. The hepatic dysfunction and serum ferritin level normalized after administration of cyclosporine (CsA). The second liver biopsy showed the significant improvement of the findings of GVHD and hemosiderin deposition. These findings might suggest that hemosiderin deposition was associated with hepatic GVHD. © 2013 The Japan Society of Hepatology.

DOI

Intermittent administration of recombinant human soluble thrombomodulin successfully controlled chronic disseminated intravascular coagulation in a patient with dissecting aortic aneurysm on an outpatient basis

Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, Yusuke Kamihara, Kaoru Ono, Shohei Kikuchi, Kohichi Takada, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

BLOOD COAGULATION & FIBRINOLYSIS ( LIPPINCOTT WILLIAMS & WILKINS )  23 ( 6 ) 548 - 550  2012年09月  [査読有り]

　概要を見る

Chronic disseminated intravascular coagulation (DIC) is a rare but life-threatening complication of dissecting aortic aneurysm. Although anticoagulant therapy may often proves effective for controlling DIC itself, patients would have to be hospitalized for a long period due to continuous infusion therapy. Subcutaneous injection of a highly concentrated preparation of heparin calcium may offer one alternative treatment for DIC; however, daily subcutaneous use of heparin for the treatment of DIC has impaired quality of life (QOL). The other alternative therapy is intravenous administration of recombinant human soluble thrombomodulin (rTM), which includes the active extracellular domain of thrombomodulin. Reportedly, rTM effectively resolves DIC by only 6 consecutive days of administration; however, how frequently rTM should be administered after the resolution of chronic DIC to have good control of it has been unclear. We report herein a case of chronic DIC complicated with dissecting aortic aneurysm, whose resolution of chronic DIC achieved by 6 consecutive days of rTM has been maintained by once a week administration of rTM on an outpatient basis. Blood Coagul Fibrinolysis 23:548-550 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

DOI PubMed

Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms

M. Kobune, S. Iyama, S. Kikuchi, H. Horiguchi, T. Sato, K. Murase, Y. Kawano, K. Takada, K. Ono, Y. Kamihara, T. Hayashi, K. Miyanishi, Y. Sato, R. Takimoto, J. Kato

BLOOD CANCER JOURNAL ( NATURE PUBLISHING GROUP )  2  2012年09月  [査読有り]

　概要を見る

Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34(+) cells, CD34(+) blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34(+) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO+ leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO+ leukemic cell proliferation. The demethylating agent, 5-aza-2'-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells.

DOI

Improvement of iron-mediated oxidative DNA damage in patients with transfusion-dependent myelodysplastic syndrome by treatment with deferasirox

Shohei Kikuchi, Masayoshi Kobune, Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, Yutaka Kawano, Kohichi Takada, Kaoru Ono, Yumiko Kaneko, Koji Miyanishi, Yasushi Sato, Tsuyoshi Hayashi, Rishu Takimoto, Junji Kato

FREE RADICAL BIOLOGY AND MEDICINE ( ELSEVIER SCIENCE INC )  53 ( 4 ) 643 - 648  2012年08月  [査読有り]

　概要を見る

Myelodysplastic syndrome (MDS) is characterized by dysplastic and ineffective hematopoiesis, peripheral blood cytopenias, and a risk of leukemic transformation. Most MDS patients eventually require red blood cell (RBC) transfusions for anemia and consequently develop iron overload. Excess free iron in cells catalyzes generation of reactive oxygen species that cause oxidative stress, including oxidative DNA, damage. However, it is uncertain how iron-mediated oxidative stress affects the pathophysiology of MDS. This study included MDS patients who visited our university hospital and affiliated hospitals (n=43). Among them, 13 patients received iron chelation therapy when their serum ferritin (SF) level was greater than 1000 ng/mL or they required more than 20 RBC transfusions (or 100 rnL/kg of RBC). We prospectively analyzed 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in peripheral blood mononuclear cells (PBMC) obtained from MDS patients before and after iron chelator, deferasirox, administration. We showed that the 8-OHdG levels in MDS patients were significantly higher than those in healthy volunteers and were positively correlated with SF and chromosomal abnormalities. Importantly, the 8-OHdG levels in PBMC of MDS patients significantly decreased after deferasirox administration, suggesting that iron chelation reduced oxidative DNA damage. Thus, excess iron could contribute to the pathophysiology of MDS and iron chelation therapy could improve the oxidative DNA damage in MDS patients. (C) 2012 Elsevier Inc. All rights reserved.

DOI PubMed

Targeting Anticancer Drug Delivery to Pancreatic Cancer Cells Using a Fucose-Bound Nanoparticle Approach

Makoto Yoshida, Rishu Takimoto, Kazuyuki Murase, Yasushi Sato, Masahiro Hirakawa, Fumito Tamura, Tsutomu Sato, Satoshi Iyama, Takahiro Osuga, Koji Miyanishi, Kohichi Takada, Tsuyoshi Hayashi, Masayoshi Kobune, Junji Kato

PLOS ONE ( PUBLIC LIBRARY SCIENCE )  7 ( 7 ) e39545  2012年07月  [査読有り]

　概要を見る

Owing to its aggressiveness and the lack of effective therapies, pancreatic ductal adenocarcinoma has a dismal prognosis. New strategies to improve treatment and survival are therefore urgently required. Numerous fucosylated antigens in sera serve as tumor markers for cancer detection and evaluation of treatment efficacy. Increased expression of fucosyltransferases has also been reported for pancreatic cancer. These enzymes accelerate malignant transformation through fucosylation of sialylated precursors, suggesting a crucial requirement for fucose by pancreatic cancer cells. With this in mind, we developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specifically to cancer cells. L-fucose-bound liposomes containing Cy5.5 or Cisplatin were effectively delivered into CA19-9 expressing pancreatic cancer cells. Excess L-fucose decreased the efficiency of Cy5.5 introduction by L-fucose-bound liposomes, suggesting L-fucose-receptor-mediated delivery. Intravenously injected L-fucose-bound liposomes carrying Cisplatin were successfully delivered to pancreatic cancer cells, mediating efficient tumor growth inhibition as well as prolonging survival in mouse xenograft models. This modality represents a new strategy for pancreatic cancer cell-targeting therapy.

DOI PubMed

Prognostic significance of serum ferritin level at diagnosis in myelodysplastic syndrome

Shohei Kikuchi, Masayoshi Kobune, Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, Yutaka Kawano, Kohichi Takada, Kaoru Ono, Tsuyoshi Hayashi, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER TOKYO )  95 ( 5 ) 527 - 534  2012年05月  [査読有り]

　概要を見る

Myelodysplastic syndrome (MDS) is characterized by peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Elevated serum ferritin (SF), due to ineffective erythropoiesis and increased iron absorption from the gut, is often observed in non-transfused MDS patients, suggesting involvement of iron overload in its pathogenesis. However, the prognostic value of the baseline SF is unclear. We evaluated baseline SF levels in non-transfused MDS patients. The SF level was significantly higher in the 47 MDS patients in this study than in the healthy controls ( < 0.001). The SF level of higher-risk MDS patients (int-2/high) was significantly higher than that of the lower-risk MDS patients (low/int-1) (467 +/- A 354 vs. 277 +/- A 372 ng/ml, < 0.001). The SF level in MDS patients with chromosomal abnormality was significantly higher than that in patients with normal karyotype. When patients were divided into the low SF group (< 500 ng/ml) and high SF group (a parts per thousand yen500 ng/mL), the survival time was significantly longer in the former group than the latter group (118.8 vs. 10.2 M, = 0.002). Further, leukemia-free survival (LFS) was significantly longer in the low SF group than the high SF group ( = 0.010). Baseline SF level may, therefore, be a prognostic factor for overall survival and LFS in MDS patients.

DOI PubMed

Successful Treatment by Fibrin Glue Sealant for Pneumothorax with Chronic GVHD Resistant to Autologous Blood Patch Pleurodesis

Satoshi Iyama, Tsutomu Sato, Kazuyuki Murase, Shohei Kikuchi, Yusuke Kamihara, Kaoru Ono, Kohichi Takada, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Takuro Obama, Masahiro Miyajima, Atsushi Watanabe, Tetsuya Higami, Yasuo Hirayama, Junji Kato

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  51 ( 15 ) 2011 - 2014  2012年  [査読有り]

　概要を見る

Pneumothorax associated with chronic graft-versus-host disease (cGVHD) after stem cell transplantation is a rare complication. Autologous blood has been used successfully for pleurodesis, which was less toxic than chemical agents. However, when pneumothorax is resistant to pleurodesis, no other procedure is more effective and conservative. Here, we describe a case of myelodysplastic syndromes complicated with cGVHD-related pneumothorax. His pneumothorax has been resistant to pleurodesis using autologous blood and was treated successfully with fibrin glue sealant. In our limited experience, we believe the best success could be achieved when this method is used to treat persistent pneumothorax with cGVHD.

DOI PubMed

Complete response by rituximab monotherapy in a patient with leukemic mantle cell lymphoma diagnosed by fluorescence in situ hybridization analysis

Yutaka Okagawa, Hiroyuki Kuroda, Kazuma Ishikawa, Michiko Yamada, Toshifumi Hoki, Tomoyuki Abe, Tamaki Sakurai, Shigeyuki Fujii, Masahiro Maeda, Miri Fujita, Wataru Jyomen, Satoshi Iyama, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. )  39 ( 10 ) 1547 - 1550  2012年  [査読有り]

　概要を見る

An 85-year-old male was admitted to a hospital with abdominal discomfort in October, 2010. Severe splenomegaly and mild para-aortic lymphoadenopathy were detected. In addition, an increase in atypical lymphocytes was noticed by bone marrow analyses with weak positive staining of cyclin D1. Subsequently, the fluorescence in situ hybridization (FISH) method confirmed cyclin D1 reconstruction, and the fusion signals of the BCL1 and IgH genes were detected, thus providing a definitive diagnosis of leukemic mantle cell lymphoma. After treatment with rituximab monotherapy, the Ki-67 index was stabilized to within 10%, and complete response was obtained.

PubMed

T-cell large granular lymphocyte leukemia after autologous peripheral blood stem cell transplantation for malignant lymphoma - Report of three cases and a review of the literature

Hiroyuki Kuroda, Tamaki Sakurai, Michiko Yamada, Tomoyuki Abe, Shigeyuki Fujii, Masahiro Maeda, Kyuhei Kohda, Yasuo Hirayama, Wataru Jyomen, Naoki Uemura, Michihiro Ono, Yuko Fujimi, Satoshi Iyama, Tsutomu Sato, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( 10 )  38 ( 10 ) 1727 - 1732  2011年10月  [査読有り]

　概要を見る

There have been only three reports in the literature of T-cell large granular lymphocyte (T-LGL) leukemia occurring after autologous peripheral stem cell transplantation (APBSCT). We describe 3 patients in whom a transient monoclonal T-LGL developed after APBSCT for malignant lymphoma. Case 1: A 58-year-old man with peripheral T-cell lymphoma in second complete remission (CR) who underwent APBSCT. Case 2: A 51-year-old man with follicular lymphoma in second CR who underwent APBSCT. Case 3: A 65-year-old man with diffuse large B-cell lymphoma in second CR who underwent tandem APBSCT. One month after transplant, fever followed by the proliferation of CD8+/CD57+ T-LGL in peripheral blood occurred in all three cases. Because clonal rearrangements of the T-cell receptor were detected in peripheral blood samples, T-LGL leukemia was diagnosed. The first patient had episodes of Epstein-Barr virus viremia. The other patients suffered from cytomegalovirus colitis after APBSCT. These data show that T-LGL leukemia can occur after viral infection followed by APBSCT.

PubMed

A case of ulcerative colitis accompanied with myelodysplastic syndrome successfully treated by cyclosporine

Sho Takahashi, Yasushi Sato, Tamotsu Sagawa, Shingo Tanaka, Kazuyuki Murase, Kohichi Takada, Satoshi Iyama, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Ganji Kuroiwa, Michiaki Hirayama, Tetsuro Okamoto, Junji Kato

Journal of Japanese Society of Gastroenterology ( 8 )  108 ( 8 ) 1405 - 1412  2011年08月  [査読有り]

　概要を見る

A 64-year-old man had been admitted to a previous hospital because of melena and a diagnosis of ulcerative colitis (UC, pancolitis type) had been made. He had received prednisolone and 5-ASA but steroid-induced hyperamylasemia had developed. Prednisolone had been tapered and halted, but it had resulted in UC relapse and thrombocytopenia. Then, he was referred to our hospital due to severe melena with hypovolemic shock. However, he was also positive for CMV antigen. Thus, we attempted to treat him with ganciclovir for CMV and intravenous cyclosporine (CsA) for UC. According to his clinical course, a reduction of CsA blood concentration induced leukocytopenia. Myelodysplastic syndrome (MDS, RAEB-1) was then revealed after bone marrow biopsy. A high blood CsA concentration may cause the improvement of UC and MDS conditions.

DOI PubMed

Novel missense mutation in the TMPRSS6 gene in a Japanese female with iron-refractory iron deficiency anemia

Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Yusuke Kamihara, Kaoru Ono, Shohei Kikuchi, Kohichi Takada, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER TOKYO )  94 ( 1 ) 101 - 103  2011年07月  [査読有り]

　概要を見る

Iron-refractory iron deficiency anemia (IRIDA) is a rare autosomal-recessive disorder hallmarked by hypochromic microcytic anemia, low transferrin saturation, and unresponsiveness to oral iron with partial recovery after parenteral iron administration. The disease is caused by mutations in TMPRSS6 (transmembrane protease serine 6) that prevent inactivation of membrane-bound hemojuvelin, an activator of hepcidin transcription. To date, 38 cases have been characterized and reported in European countries and the United States. In this paper, we describe the first case of a Japanese female with IRIDA, who carried a novel mutation (K253E) in the CUB (complement factor C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1) domain of the TMPRSS6 gene.

DOI PubMed

Iron chelator deferasirox rescued mice from Fas-induced fulminant hepatitis

Tsutomu Sato, Masayoshi Kobune, Kazuyuki Murase, Yukari Kado, Tetsuro Okamoto, Shingo Tanaka, Shohei Kikuchi, Hiroyuki Nagashima, Yutaka Kawano, Kohichi Takada, Satoshi Iyama, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Junji Kato

HEPATOLOGY RESEARCH ( WILEY-BLACKWELL )  41 ( 7 ) 660 - 667  2011年07月  [査読有り]

　概要を見る

Aim: Fulminant hepatitis is a disease characterized by development of hepatic failure due to severe liver cell injury. Orthotopic liver transplantation is the therapy proven to improve patient survival; however, less burdensome and safer strategies are required. In a previous study, we showed that iron was intimately involved in hepatocyte apoptosis by demonstrating that spontaneous development of fulminant hepatitis in Long-Evans cinnamon rats was prevented by feeding an iron-deficient diet. Recently, a new iron chelator, deferasirox, has become widely available for the treatment of transfusional hemosiderosis. Deferasirox demonstrated good efficacy and improved compliance due to convenient, once-daily p.o. administration. Our aim was to investigate the efficacy of deferasirox as a therapeutic drug against fulminant hepatitis. Methods: Human primary hepatocytes undergoing Fas-stimulated apoptosis were challenged with deferoxamine (DFO) in vitro. In further in vivo experiments, we tested DFO in a mice model of fulminant hepatitis induced by Fas-stimulation. Results: The apoptosis-inducing activity of anti-Fas antibody on human primary hepatocytes was inhibited by the chelation of iron with DFO. DFO suppressed the Fas-induced production of reactive oxygen species (ROS) and the activation of caspase-3, both of which were also suppressed by antioxidant, N-acetyl-L-cystein. In the in vivo experiments, deferasirox effectively reduced hepatic iron concentrations and rescued mice from Fas-induced fulminant hepatitis. Conclusion: These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase-3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.

DOI PubMed

Establishment of a simple test for iron absorption from the gastrointestinal tract

Masayoshi Kobune, Koji Miyanishi, Kohichi Takada, Yutaka Kawano, Hiroyuki Nagashima, Shohei Kikuchi, Kazuyuki Murase, Satoshi Iyama, Tsutomu Sato, Yasushi Sato, Rishu Takimoto, Junji Kato

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER TOKYO )  93 ( 6 ) 715 - 719  2011年06月  [査読有り]

　概要を見る

Recent studies on iron metabolism have begun to reveal the molecular mechanisms underlying iron absorption, which is dramatically affected in several disorders. In the clinical setting, the ability to determine the status of iron absorption would aid in the diagnosis of pathological conditions. Efforts to develop an oral iron absorption test (OIAT) date back to at least 60 years. However, previous procedures were associated with a number of problems, such as radiation exposure and low reproducibility. In an attempt to resolve these issues, we employed sodium ferrous citrate (SFC), by which the influence of various nutrients and drugs on iron absorption was markedly reduced. We found that OIAT using SFC was simple to perform in both hospitalized patients and outpatients. The increment of serum iron and % transferrin saturation at 120 min after SFC administration was useful in distinguishing iron absorption between healthy volunteers, patients with iron-deficiency anemia, and patients with anemia secondary to chronic disorders, which are respectively characterized by normal, enhanced, and reduced iron absorption. Thus, the SFC-based OIAT may represent a viable screening test for the evaluation of gastrointestinal iron absorption.

DOI PubMed

Tuberculous pleuritis with onset of refractory pleural effusion after chemoradiotherapy for esophageal cancer

Masahiro Hirakawa, Yasushi Sato, Hiroyuki Ohnuma, Tamotsu Sagawa, Hirotoshi Ishiwatari, Kazuyuki Murase, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Masayoshi Kobune, Rishu Takimoto, Junji Kato

Journal of Japanese Society of Gastroenterology ( 2 )  108 ( 2 ) 231 - 237  2011年02月  [査読有り]

　概要を見る

A 75-year-old man received chemoradiotherapy (CRT) for stage IVa esophageal cancer and complete response (CR) was obtained. However, he was referred to our department for recurrence in an area of esophagus not included in the previously irradiated field. Left pleural effusion increased after admission. Tuberculous pleuritis was eventually diagnosed by thoracoscopic pleural biopsy. It is necessary to accurately diagnose the cause of pleural effusion after CRT, because treatment strategies greatly depend on it. It is also necessary to consider the possible onset of tuberculous pleuritis, in particular, in patients with a history of tuberculosis infection.

DOI PubMed

Immune thrombocytopenia associated with de novo hepatitis B in a follicular lymphoma patient after autologous peripheral blood stem cell transplantation

Hiroyuki Kuroda, Tamaki Sakurai, Michiko Yamada, Naoki Uemura, Michihiro Ono, Tomoyuki Abe, Shigeyuki Fujii, Masahiro Maeda, Kyuhei Kohda, Yasuo Hirayama, Yuko Fujimi, Satoshi Iyama, Junji Kato

Biotherapy   25 ( 1 ) 579 - 583  2011年01月

　概要を見る

We report a patient with immune thrombocytopenic purpura (ITP) associated with de novo hepatitis B after cessation of preemptive lamivudine therapy. A 52-year-old man was diagnosed with relapse follicular lymphoma (FL) he had received five courses of rituximab plus CHOP (R-CHOP) following an autologous peripheral blood stem cell transplantation (APBSCT) in January, 2008. As he was hepatitis B virus (HBV) surface antigen-positive, lamivudine was administered simultaneously with both R-CHOP and APBSCT to prevent a HBV reactivation. He developed de novo hepatitis due to HBV reactivation 2 months after cessation of lamivudine in June, 2009. He was admitted to a hospital, complaining of purpura and oral bleeding in July, 2009. Based on his elevated level of platelet-associated IgG (PAIgG), a diagnosis of ITP was made. After intravenous immunoglobulin injections and treatment with entecavir, thrombocytopenia and viral replication were controlled. In an APBSCT recipient whose idiotypic network is still forming, there is a higher likelihood of an expression of cross-reactive auto-antibodies after HBV reactivation.

Effective treatment by both anti-androgen therapy and chemotherapy for a patient with advanced salivary duct carcinoma

Hiroyuki Kuroda, Tamaki Sakurai, Michiko Yamada, Naoki Uemura, Michihiro Ono, Tomoyuki Abe, Shigeyuki Fujii, Masahiro Maeda, Kyuhei Kohda, Masahiko Obata, Masakatsu Ando, Satoshi Iyama, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. )  38 ( 4 ) 627 - 630  2011年  [査読有り]

　概要を見る

Salivary duct carcinoma (SDC) is a high-grade malignant tumor arising predominantly in the parotid gland. Androgen receptor (AR) expression was mainly restricted to SDC in salivary cancer. We report successful treatment of a patient with advanced SDC using an endocrine chemotherapy. A 76-year-old man was hospitalized with lumbalgia and swelling of left submandibular region. Radiological examination indicated a tumor in left submandibular gland and metastatic tumors in lumbar vertebra, accompanied by swollen lymph nodes of the neck, mediastinum. Needle biopsies of both vertebral tumor and cervical lymph node revealed SDC. Positive nuclear staining was observed against AR in tumor cells of our patient by immunohistochemical analysis. He obtained a partial response after 1 course of treatment with both anti-androgen therapy and palliative chemotherapy using paclitaxel. In contrast to previous reports of poor response to chemotherapy alone and short-term survival of patients with SDC, our patient has demonstrated that chemotherapy combined with anti-androgen therapy may be an effective modality as a therapeutic regimen for SDC.

PubMed

Successful rituximab treatment of methotrexate-associated B-cell lymphoproliferative disorder arising in two patients with latency type II epstein-barr viral infection

Hiroyuki Kuroda, Tamaki Sakurai, Michiko Yamada, Naoki Uemura, Michihiro Ono, Tomoyuki Abe, Shigeyuki Fujii, Masahiro Maeda, Nanase Ishida, Kyuhei Kohda, Masahiko Obata, Masakatsu Ando, Satoshi Iyama, Junji Kato

Biotherapy   24 ( 6 ) 507 - 511  2010年11月

　概要を見る

We have encountered two patients with methotrexate (MTX)-associated B-cell lymphoproliferative disorder (B-LPD) as a complication of rheumatoid arthritis (RA). Case 1 was a 68-year-old woman. She complained of right neck swelling during low-dose MTX treatment for RA. Her neck lymph node biopsy revealed polymorphic B-LPD. Case 2 was a 67-year-old man. He has hospitalized for right neck lymph node swelling and throat pain during low-dose MTX treatment for RA. Diffuse large B cell lymphoma was diagnosed by his tonsil biopsy. The immunohistochemical analyses of B-LPD in those patients showed latency type II Epstein-Barr virus (EBV) infection. MTX withdrawal and observation for a month revealed no spontaneous regression of B-LPD in both cases. Therefore, we administered rituximab once, it had been tumor remission of B-LPD in parallel with the EBV-DNA level in peripheral blood. Thus, their arthralgia was improved, and the MMP-3 level decreased. MTX withdrawal does not necessarily lead to spontaneous remission of tumors in B-LPD patients with latency type II EBV infection. Rituximab therapy proved effective for not only MTX-associated B-LPD but also RA in our patients.

ENDOSCOPIC FINDINGS OF ENTEROPATHY-TYPE T-CELL LYMPHOMA BY DOUBLE-BALLOON ENTEROSCOPY AND CAPSULE ENDOSCOPY

Yasushi Sato, Michihiro Ono, Tamotsu Sagawa, Rishu Takimoto, Masahiro Hirakawa, Hiroyuki Ohnuma, Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Koji Miyanishi, Masayoshi Kobune, Junji Kato

DIGESTIVE ENDOSCOPY ( WILEY-BLACKWELL )  22 ( 3 ) 243 - 245  2010年07月  [査読有り]

　概要を見る

Enteropathy-type T-cell lymphoma (ETL) is a rare primary intestinal disorder, particularly in Japan, and there have been few reports on the endoscopic findings of the disease. Here we report detailed endoscopic findings of ETL based on double-balloon enteroscopy and capsule endoscopy. Double-balloon enteroscopy and capsule endoscopy may be useful tools for diagnosing and monitoring the effects of therapy in patients with ETL.

DOI PubMed

[Evaluation of the efficacy of liposomal amphotericin B].

Iyama S, Murase K, Sato T, Kikuchi S, Sato Y, Kobune M, Takimoto R, Kato J

Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases ( 2 )  84 ( 2 ) 182 - 186  2010年03月  [査読有り]

　概要を見る

2006 年12 月から2008 年4 月までの間に札幌医科大学附属病院第四内科に入院した患者の内，リポソーマルアムホテリシンB（L-AMB）が投与された患者計32 症例を対象にL-AMB の有効性と安全性を評価するために後方視的検討を行った．基礎疾患は血液疾患が87.5％と多数を占め，その内訳は急性骨髄性白血病が最も多く，全体の50％を占めており，次いで悪性リンパ腫が全体の12.5％であった．L-AMB の平均投与期間は14.2±12.9 日，累積投与量は平均1,786±2,181mg であった．予防投与の3 例を除き，何らかの真菌感染症を発症もしくは発熱性好中球減少症を発症した29 例中，21 例（72.4％）で改善効果を認めた．有害事象の重症度は，軽度9 例，中等度7 例であり，重度の副作用を認めた症例はなかった．低カリウム血症が7 例（21.9％）に，クレアチニン上昇が4 例（12.5％）に認められたがいずれも軽度であった．投与を中止した中等度副作用発生例に関しては，いずれも投与中止後に症状の正常化を確認出来た．以上のことから，これまでの海外の報告と同様に，我々の検討においてもL-AMB が高い有効性と安全性を有することが示唆された．特に確定診断がつく前の早期にL-AMB を使用開始することが良好な治療成績に結びつく可能性が考えられた．また生理食塩水の負荷など十分な補液量を行うことや，血清カリウムなどの電解質バランスを管理することでL-AMB を安全に使用できることが示唆された．従来型のアムホテリシンB では，腎毒性などの理由により使用が限られていたが，副作用が大幅に軽減されたL-AMB は真菌感染のリスクを持った血液疾患患者や既に真菌感染症を発症した血液疾患患者の治療薬として有用であると考えられた．

DOI PubMed CiNii

Pure Red Cell Aplasia Associated with Good&apos;s Syndrome Accompanied by Decreased Stem Cell Factor Production in the Bone Marrow

Kageaki Kuribayashi, Akihito Fujimi, Masayoshi Kobune, Rishu Takimoto, Shohei Kikuchi, Satoshi Iyama, Junji Kato, Yoshiro Niitsu, Naoki Watanabe

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  49 ( 5 ) 377 - 382  2010年  [査読有り]

　概要を見る

A 79-year-old Japanese woman diagnosed with pure red cell aplasia (PRCA) associated with thymoma and hypogammaglobulinemia (Good's syndrome) was successfully treated with cyclosporine-A after a thymectomy. We further studied the etiology of this case. A burst-forming unit erythroid (BFU-E) assay with SCF restored erythropoiesis in vitro. SCF production was reduced in bone marrow stromal cells; however, it was restored in vitro and in vivo after cyclosporine-A treatment.

DOI PubMed

Therapeutic results in patients with biphenotypic acute leukemia at Sapporo Medical University Hospital

Kazuyuki Murase, Satoshi Iyama, Tsutomu Sato, Rishu Takimoto, Masayoshi Kobune, Junji Kato

Japanese Journal of Cancer and Chemotherapy ( Japanese Journal of Cancer and Chemotherapy Publishers Inc. )  37 ( 10 ) 2011 - 2013  2010年  [査読有り]

　概要を見る

We reviewed the results of 6 patients with biphenotypic acute leukemia (BAL) which the diagnostic standard of the European Group for the Immunological Characterization of Leukemia (EGIL) at Sapporo Medical University Hospital between 2006 and 2008. There were 5 males and 1 females with an average age of 35 years. Among them, 4 were B lymphoid and myeloid, 2 were T lymphoid and myeloid, and one was T/B lymphoid. Two of 4 patients did not attain complete remission, and two relapsed after first treatment with acute myeloblastic leukemia (AML) protocol. On the other hand, two showed complete remission after the acute lymphoblastic leukemia (ALL) protocol. One of 4 patients survived who had been treated with hematopoietic stem cell transplantation as a post-remission therapy. The ALL protocol was good for the induction therapy. However, overall treatment-related deaths were 4 patients and considerable caution was necessary.

PubMed

ヘッジホッグ・シグナル伝達阻害剤は、CD34+白血病細胞の薬剤耐性を解除する

菊地 尚平, 小船 雅義, 村瀬 和幸, 井山 諭, 佐藤 勉, 瀧本 理修, 河野 豊, 宮西 浩嗣, 佐藤 康史, 加藤 淳二

臨床血液 ( (一社)日本血液学会-東京事務局 )  50 ( 9 ) 1113 - 1113  2009年09月  [査読有り]

[Successful induction of complete remission by gemtuzumab ozogamicin following chemotherapy in three patients with relapsed or refractory acute myeloid leukemia].

Hirayama Y, Terui T, Koike K, Neda H, Ishitani K, Kohda K, Kuroda H, Iyama S, Sato T, Kobune M, Takimoto R, Kato J

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 8 )  50 ( 8 ) 663 - 665  2009年08月  [査読有り]

DOI PubMed CiNii

シクロパミンは、CD34陽性白血病細胞の薬剤耐性を解除する(Cyclopamine dramatically restores drug resistance of CD34+ leukemic cells)

小船 雅義, 井山 諭, 佐藤 勉, 瀧本 理修, 菊地 尚平, 村瀬 和幸, 河野 豊, 宮西 浩嗣, 佐藤 康史, 加藤 淳二

日本癌学会総会記事 ( 日本癌学会 )  68回   480 - 480  2009年08月  [査読有り]

Drug resistance is dramatically restored by hedgehog inhibitors in CD34(+) leukemic cells

Masayoshi Kobune, Rishu Takimoto, Kazuyuki Murase, Satoshi Iyama, Tsutomu Sato, Shohei Kikuchi, Yutaka Kawano, Kohji Miyanishi, Yasushi Sato, Yoshiro Niitsu, Junji Kato

CANCER SCIENCE ( WILEY-BLACKWELL )  100 ( 5 ) 948 - 955  2009年05月  [査読有り]

　概要を見る

Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers and in cancer stem cells. However, the contribution of Hh signaling to leukemic cell regulation has remained unclear. In this study, we assessed the possibility that Hh pathway activation contributes to the survival and drug resistance of cluster of differentiation (CD)34(+) leukemia cells. Hh signaling in leukemic cell lines and primary leukemic cells was screened by reverse transcription - polymerase chain reaction (RT-PCR) and a Hh signaling reporter assay. We found that Hh signaling is active in several human acute myeloid leukemia (AML) cells, especially primary CD34(+) leukemic cells and cytokine-responsive CD34+ cell lines such as Kasumi-1, Kasumi-3 and TF-1. These CD34+ cells express the downstream effectors glioma-associated oncogene homolog (GLI)1 or GLI2, indicative of active Hh signaling. Moreover, inhibition of Hh signaling with the naturally derived Smoothened antagonist cyclopamine, endogenous Hh inhibitor hedgehog-interacting protein or anti-hedgehog neutralizing antibody induced apoptosis after 48 h of exposure, although these CD34(+) cell lines exhibited resistance to cytarabine (Ara-C). In contrast, cyclopamine failed to affect growth or survival in U937 and HL-60 cell lines that lack expression of Hh receptor components, confirming that the effect of Hh inhibition is specific. Furthermore, combination with 10 mu M cyclopamine significantly reduced drug resistance of CD34(+) cell lines and primary CD34(+) leukemic cells to Ara-C. These results suggest that aberrant Hh pathway activation is a feature of some CD34(+) myeloid leukemic cells and Hh inhibitors may have a therapeutic role in the treatment of AML. (Cancer Sci 2009; 100: 948-955).

DOI PubMed

Chronic idiopathic neutropenia associated with granular lymphocytic leukemia effectively treated with immunosuppressants

Yuko Fujimi, Yasuo Hirayama, Hiroyuki Kuroda, Toshiro Sakai, Yuichi Konuma, Kyuhei Kohda, Akihito Fujimi, Satoshi Iyama, Tsutomu Sato, Masayoshi Kobune, Rishu Takimoto, Junji Kato

Biotherapy   23 ( 3 ) 263 - 266  2009年05月

　概要を見る

A 64-year-old male was admitted to our hospital with diverticulitis of the large intestine, and a blood test detected neutropenia. Bone marrow aspiration found no hematological malignancy, and we considered idiopathic neutropenia. After he was injected with granulocyte colony-stimulating factor and antibiotics, abdominal pain and high fever disappeared. However, the neutropenia continued. One month after his hospitalization, we found monoclonal rearrangement of TCRβ and predominant granular lymphocyte in the peripheral blood. The diagnosis was granular lymphocytic leukemia (GLL) with neutropenia. After he was treated with immunosuppressants, the neutrophil count was normalized. We conclude that some cases of chronic idiopathic neutropenia are associated with GLL.

Treatment of hepatocellular carcinoma by AdAFPep/Rep, AdAFPep/p53, and 5-fluorouracil in mice

Tamotsu Sagawa, Yasuyuki Yamada, Minoru Takahashi, Yasushi Sato, Masayoshi Kobune, Rishu Takimoto, Junki Fukaura, Satoshi Iyama, Tsutomu Sato, Koji Miyanishi, Takuya Matsunaga, Tetsuji Takayama, Junji Kato, Katsunori Sasaki, Hirofumi Hamada, Yoshiro Niitsu

HEPATOLOGY ( JOHN WILEY & SONS INC )  48 ( 3 ) 828 - 840  2008年09月  [査読有り]

　概要を見る

Although conditionally replicable adenovirus (CRAd) has been used in the clinical treatment of hepatocellular carcinoma (HCC), it suffers from the inherent drawback of having relatively low antitumor activity. Here, we have sought to overcome this drawback. First, we combined CRAd (AdAFPep/Rep) driven by a-fetoprotein enhancer/promoter (ATPep) with a replication-incompetent adenovirus carrying a p53 transgene that is also driven by AFPep. The synergism of this combination produced a significantly improved tumoricidal effect on the human HCC cell line Hep3B, which has a relatively short doubling time in comparison with other human HCC cell lines, through the transactivation of p53 by early region 1A transcribed by AdAFPep/Rep. This synergistic interaction was augmented by the addition of a subtumoricidal dose (0.5 mu g/mL) of 5-fluorouracil (5-FU), which enhanced p53 expression and facilitated the release of virions from tumor cells. When relatively large (10-mm-diameter) Hep3B tumors grown in nude mice were injected with the two viruses in combination, they showed significantly impaired growth in comparison with those treated with each virus separately. The growth suppression effect of the virus combination was enhanced by a low dose (600 mu g) of 5-FU. Survival of the tumor-bearing mice treated with these three agents was significantly longer than that of control mice. Moreover, the tumor completely disappeared with the repeated injection of these agents. Conclusion: This combination strategy holds promise for the treatment of relatively large and rapidly growing HCCs that may be encountered clinically.

DOI PubMed

[A case of hepatosplenic gammadelta T-cell lymphoma associated hemophagocytic syndrome].

Iyama S, Matsunaga T, Sato T, Sato Y, Sagawa T, Murase K, Kida M, Kobune M, Takimoto R, Kato J, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 9 )  35   1623 - 1627  2008年09月  [査読有り]

PubMed

ヒト骨髄間質細胞は臍帯血CD34陰性細胞のCXCR4発現増強と長期造血再建能を誘導する

小船 雅義, 村瀬 和幸, 井山 諭, 佐藤 勉, 河野 豊, 瀧本 理修, 松永 卓也, 加藤 淳二

臨床血液 ( (一社)日本血液学会-東京事務局 )  49 ( 9 ) 940 - 940  2008年09月  [査読有り]

アデノウイルスベクターを用いたヘッジホッグ遺伝子の高発現は、TおよびBリンパ球の分化抑制を誘導する

加藤 淳二, 小船 雅義, 村瀬 和幸, 井山 諭, 佐藤 勉, 河野 豊, 瀧本 理修, 松永 卓也

臨床血液 ( (一社)日本血液学会-東京事務局 )  49 ( 9 ) 1085 - 1085  2008年09月  [査読有り]

Apoptosis supercedes necrosis in mitochondrial DNA-depleted Jurkat cells by cleavage of receptor-interacting protein and inhibition of lysosomal cathepsin

Tsutomu Sato, Takuro Machida, Sho Takahashi, Kazuyuki Murase, Yutaka Kawano, Tsuyoshi Hayashi, Satoshi Iyama, Kohich Takada, Kageaki Kuribayashi, Yasushi Sato, Masayoshi Kobune, Rishu Takimoto, Takuya Matsunaga, Junji Kato, Yoshiro Niitsu

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS )  181 ( 1 ) 197 - 207  2008年07月  [査読有り]

　概要を見る

In the present study, we used mitochondrial DNA-depleted Jurkat subclones (rho(0) cells) to demonstrate that Fas agonistic Ab (CH-11), at the concentrations that evoke apoptotic death of the parental Jurkat cells, induced necrosis mainly through generation of excess reactive oxygen species, lysosomal rupture, and sequential activation of cathepsins B and D, and in minor part through activation of receptor-interacting protein (RIP). In the rho(0) cells treated with CH-11, ATP supplementation converted necrosis into apoptosis by the formation of the apoptosome and subsequent activation of procaspase-3. In these ATP-supplemented rho(0) cells (ATP-rho(0)), generation of excess ROS and lysosomal rupture were still seen, yet cathepsins B and D were inactivated and RIP was degraded. The conversion of necrosis to apoptosis, RIP degradation, and cathepsin inactivation in ATP-rho(0) cells were blocked by caspase-3 inhibitors. Activities of cathepsins B and D in the lysate of necrotic rho(0) cells were inhibited by the addition of apoptotic parental Jurkat cell lysate. Thus, apoptosis may supercede necrosis.

PubMed

Ex vivo large-scale generation of human red blood cells from cord blood CD34(+) cells by co-culturing with macrophages

Akihito Fujimi, Takuya Matsunaga, Masayoshi Kobune, Yutaka Kawano, Taiko Nagaya, Ikuta Tanaka, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Tamotsu Sagawa, Yasushi Sato, Rishu Takimoto, Tetsuji Takayama, Junji Kato, Shinsei Gasa, Hiromi Sakai, Eishun Tsuchida, Kenji Ikebuchi, Hirofumi Hamada, Yoshiro Niitsu

INTERNATIONAL JOURNAL OF HEMATOLOGY ( SPRINGER TOKYO )  87 ( 4 ) 339 - 350  2008年05月  [査読有り]

　概要を見る

We generated red blood cells (RBC) from cord blood (CB) CD34(+) cells using a four-phase culture system. We first cultured CB CD34(+) cells on telomerase gene-transduced human stromal cells in serum-free medium containing stem cell factor (SCF), Flt-3/Flk-2 ligand, and thrombopoietin to expand CD34(+) cells (980-fold) and the total cells (10,400-fold) (first phase). Expanded cells from the first phase were liquid-cultured with SCF, interleukin-3 (IL-3), and erythropoietin (EPO) to expand (113-fold) and differentiate them into erythroblasts (second phase). To obtain macrophages for the next phase, we expanded CD34(+) cells from a different donor using the same co-culture system. Expanded cells from the first phase were liquid-cultured with granulocyte-macrophage colony stimulating factor, macrophage-colony stimulating factor (M-CSF), IL-3, and SCF to generate monocytes/macrophages (75-fold), which were incubated with type AB serum and M-CSF to fully differentiate them into macrophages. Erythroblasts were then co-cultured with macrophages in the presence of EPO to expand (threefold) and fully differentiate them (61% orthochromatic erythroblasts plus 39% RBC) (third phase). RBC were purified from erythroblasts and debris through a deleukocyting filter to generate 6.0 x 10(12) RBC from 1.0 unit of CB (3.0 transfusable units). Qualitatively, these RBC showed a hemoglobin content, oxygenation of hemoglobin, and in vivo clearance similar to those of adult peripheral RBC. Finally, an almost complete enucleation of orthochromatic erythroblasts (99.4%) was achieved by the cultivation method recently described by Miharada et al. in the absence of macrophages and cytokines (fourth phase). RBC were purified from remnant erythroblasts and debris by passage through a deleukocyting filter to generate 1.76 x 10(13) RBC from 1.0 unit of CB (8.8 transfusable units), the highest yield ever reported. Thus, this method may be useful for generating an alternative RBC supply for transfusions, investigating infectious agents that target erythroid cells, and as a general in vitro hematopoietic model system.

DOI PubMed

[An advanced metastatic breast cancer patient successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy].

Sato Y, Takayama T, Sagawa T, Sato T, Okamoto K, Takahashi S, Abe S, Iyama S, Murase K, Kato J, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 3 )  35   471 - 473  2008年03月  [査読有り]

PubMed

Successful treatment of chronic myeloproliferative disease-unclassifiable (CMPD-U) with no chromosomal abnormalities by imatinib mesylate

Satoshi Iyama, Takuya Matsunaga, Tsutomu Sato, Kazuyuki Murase, Naoko Araki, Rishu Takimoto, Masayoshi Kobune, Tamotsu Sagawa, Tetsuji Takayama, Yoshiro Niitsu

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  47 ( 8 ) 791 - 794  2008年  [査読有り]

　概要を見る

We report a chronic myeloproliferative disease-unclassifiable (CMPD-U) patient who achieved hematological remission following imatinib mesylate (imatinib). Chromosomal and molecular analyses demonstrated no genetic abnormalities of c-abl, bcr-abl, c-kit or platelet-derived growth factor receptor (PDGFR) genes from hematopoietic cells. Although there has been one report of CMPD-U patient with chromosomal abnormalities of the PDGFR gene having complete hematologic responses upon treatment with imatinib, there have not been similar reports of patients without chromosomal abnormalities. This is the first case report of a CMPD-U patient with no chromosomal abnormalities who completely responded to treatment with imatinib.

DOI PubMed

Successful treatment of autoimmune pancreatitis complicated with autoimmune thrombocytopenia and interstitial pneumonia by prednisolone

Kazuyuki Murase, Takuya Matsunaga, Tsuyoshi Hayashi, Hirotoshi Ishiwatari, Naoko Araki, Satoshi Iyama, Tsutomu Sato, Masayoshi Kobune, Rishu Takimoto, Koji Miyanishi, Toru Miyazaki, Hisami Ikeda, Junji Kato, Yoshiro Niitsu

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  47 ( 11 ) 1033 - 1038  2008年  [査読有り]

　概要を見る

We report the second patient diagnosed with autoimmune pancreatitis complicated with autoimmune thrombocytopenia and interstitial pneumonia. The patient was treated with prednisolone and responded favorably. We demonstrated that anti-platelet (PLT) antibody of the patient was IgG4 and that it may react with HLA, not specific antigen, on both pancreas and PLT.

DOI PubMed

[Fifth-line chemotherapy for metastatic gastric cancer--a case responding to modified FOLFOX 6].

Sagawa T, Sato Y, Takayama T, Kuroda H, Hirakawa M, Abe S, Iyama S, Sakamaki S, Kato J, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 9 )  34   1467 - 1471  2007年09月  [査読有り]

PubMed

[A case of resection of synchronous multiple liver metastases from colorectal cancer after hepatic infusion chemotherapy and systemic chemotherapy].

Tamotsu Sagawa, Yasushi Sato, Tetsuji Takayama, Masahiro Hirakawa, Seiichiro Abe, Satoshi Iyama, Koji Miyanishi, Yutaka Kawano, Kohichi Takada, Tokiko Nakamura, Junji Kato, Yoshiro Niitsu

Gan to kagaku ryoho. Cancer & chemotherapy ( 9 )  34 ( 9 ) 1481 - 4  2007年09月  [査読有り]  [国内誌]

　概要を見る

A 70-year-old man was admitted for tranverse colon cancer with multiple liver metastases. Hepatic arterial infusion chemotherapy and systemic chemotherapy (FOLFOX 4) were conducted postoperatively. Thirteen months after the first surgery, liver metastases became resectable and hepatectomy was performed. Though multiple liver metastases were unresectable at the time of the first examination, hepatectomy was possible followed by hepatic arterial infusion chemotherapy and systemic chemotherapy.

PubMed

[Reactivation of hepatitis B virus due to rituximab plus CHOP after preemptive lamivudine administration in a patient with diffuse large B-cell lymphoma].

Kaoru Ono, Satoshi Iyama, Takuya Matsunaga, Tsutomu Sato, Yasushi Sato, Toshinori Okuda, Kohichi Takada, Yutaka Kawano, Tsuyoshi Hayashi, Koji Miyanishi, Tamotsu Sagawa, Masayoshi Kobune, Rishu Takimoto, Junji Kato, Yoshiro Niitsu

Gan to kagaku ryoho. Cancer & chemotherapy ( 9 )  34 ( 9 ) 1509 - 12  2007年09月  [査読有り]  [国内誌]

　概要を見る

A 59-year-old woman received eight cycles of R-CHOP for diffuse large B-cell lymphoma from July, 2004. Pretreatment HBV serological tests were positive, however, the transaminases were within normal limits, and she remained asymptomatic. Lamivudine (LAM) was administered orally from the start of R-CHOP. HBV-DNA levels gradually decreased and were not detected until December, 2004. LAM was administered until 3 months after the end of chemotherapy, with the entire treatment lasting less than 1 year. Two months after the cessation of treatment, she was re-admitted for general malaise. A liver function test revealed severe abnormalities, and HBVDNA levels were increased. Clinically, she was experiencing acute hepatitis due to HBV reactivation. She was then treated with LAM and interferon-beta immediately. Her HBV-DNA levels soon decreased, and liver function improved.

PubMed

骨髄腫から産生されるWnt3は、RhoAシグナルを活性化し、VLA6依存性CAM-DRを惹起する

小船 雅義, 河野 豊, 村瀬 和幸, 井山 諭, 佐藤 勉, 瀧本 理修, 松永 卓也, 加藤 淳二, 新津 洋司郎

日本癌治療学会誌 ( (一社)日本癌治療学会 )  42 ( 2 ) 482 - 482  2007年09月  [査読有り]

肝動注療法および全身化学療法にて切除可能となった大腸癌肝転移の1例

佐川 保, 佐藤 康史, 高山 哲治, 平川 昌宏, 阿部 清一郎, 井山 諭, 宮西 浩嗣, 河野 豊, 高田 弘一, 中村 とき子, 加藤 淳二, 新津 洋司郎

癌と化学療法 ( (株)癌と化学療法社 )  34 ( 9 ) 1481 - 1484  2007年09月  [査読有り]

　概要を見る

症例は70歳、男性。横行結腸癌、多発性肝転移と診断した。原発巣による狭窄症状があったことより、横行結腸切除術を施行。肝転移に対しては肝動注、全身化学療法FOLFOX4を施行した。肝転移は縮小し単発となったので13ヵ月後に手術可能となり、肝切除術を施行した。肝動注、全身化学療法により切除可能となった横行結腸癌、多発性肝転移症例を経験したので報告する。(著者抄録)

Wnt3/RhoA/ROCKシグナル伝達は多発性骨髄腫の接着介在性薬物耐性へと自己分泌性に関与する(Wnt3/RhoA/ROCK signaling is involved in adhesion-mediated drug resistance of multiple myeloma in an autocline manner)

小船 雅義, 井山 諭, 佐藤 勉, 瀧本 理修, 松永 卓也, 河野 豊, 村瀬 和幸, 加藤 淳二, 新津 洋司郎

日本癌学会総会記事 ( 日本癌学会 )  66回   334 - 334  2007年08月  [査読有り]

[Superior mesenteric and portal vein thrombosis in a polycythemia vera patient with JAK2 mutation].

Naoko Araki, Rishu Takimoto, Hiroki Chiba, Hironobu Araki, Tsutomu Sato, Satoshi Iyama, Masahiro Hirakawa, Kaoru Ono, Yutaka Kawano, Koichi Takada, Koji Miyanishi, Masayoshi Kobune, Takuya Matsunaga, Junji Kato, Tokiko Nakamura, Yoshiro Niitsu

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 7 )  48 ( 7 ) 554 - 8  2007年07月  [査読有り]  [国内誌]

　概要を見る

A 47-year-old woman was admitted to our hospital in December 1994 with polycythemia. The patient's red blood cell volume was 33 ml/kg and bone marrow cytology was able to rule out other myeloproliferative diseases such as chronic myelogenous leukemia, essential thrombocytosis and myelofibrosis. The patient was diagnosed as having polycythemia vera. She had undergone only phlebotomy until 1999 when the thrombocytosis appeared, subsequent to which she was treated with oral hydroxyurea. However, in March 2006, she developed upper abdominal pain and was admitted to our hospital on March 14th, 2006. Computed tomography scan revealed thromboses in the portal and superior mesenteric veins. Anticoagulation therapy delivered intravenously via the superior mesenteric vein dramatically improved her symptoms and liver function. She is currently on anticoagulation therapy in our outpatient clinic.

DOI PubMed

[Factor XI deficiency caused by a mutation of Gly400Val].

Sato T, Iyama S, Araki N, Murase K, Sato Y, Kobune M, Takimoto R, Matsunaga T, Kato J, Kuroda H, Niitsu Y

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 2 )  48 ( 2 ) 148 - 150  2007年02月  [査読有り]

DOI PubMed CiNii

[Gastric relapse of stage I ocular adnexal mucosa-associated lymphoid tissue lymphoma].

Sato T, Takimoto R, Iyama S, Ono K, Tanaka S, Araki N, Nishiie K, Murase K, Sato Y, Kobune M, Matsunaga T, Kato J, Niitsu Y

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 1 )  48 ( 1 ) 56 - 60  2007年01月  [査読有り]

　概要を見る

症例は57歳，男性。右涙腺に原発するmucosa-associated lymphoid tissue lymphoma (MALT lymphoma)に対し，局所への放射線照射が施行された。その際の胃内視鏡検査では胃粘膜に軽度の炎症性変化が指摘され，ウレアーゼテストが陽性であったため，ピロリ菌の除菌療法が施行された。その2年後，再び胃内視鏡検査を施行したところ，MALTリンパ腫病変が検出された。涙腺病変と胃病変のIgH遺伝子をサザン法で検索したところ，全く同一の再構成パターンが得られた。このため，ピロリ菌感染による慢性炎症を母地とした異所性発癌ではなく，原発巣の胃転移と考えた。また，涙腺MALTリンパ腫のリンパ腫細胞は，リンパ球が消化管粘膜へ接着する際に必須であるintegrin α4β7を高発現していたため，この接着分子が胃転移に重要な働きをした可能性があると考えられた。

DOI PubMed CiNii

Report of an autopsy case of colon cancer with amyotrophic lateral sclerosis

Yasushi Sato, Tetsuji Takayama, Tomomi Nikaido, Yuko Wada, Tamotsu Sagawa, Seiichiro Abe, Tsutomu Sato, Satoshi Iyama, Kazuyuki Murase, Hironobu Araki, Yasuhiro Sato, Junji Kato, Yoshiro Niitsu, Hideki Chiba

Japanese Journal of Gastroenterology ( 9 )  104 ( 9 ) 1365 - 1370  2007年  [査読有り]

　概要を見る

Amyotrophic lateral sclerosis (ALS) is a degenerative disease involving both upper and lower motor neurons and the pathogenesis of this disorder is still unknown. To date, few reports have suggested that motor neuron diseases may have a paraneoplastic origin. However, it is still under discussion whether ALS occurring in cancer patients is paraneoplastic. A 60-year-old man with rectal cancer (Stage IV) having multiple lung, liver and para-aortic lymph node metastases underwent anterior resection of the rectum as palliative surgery. He was referred to our hospital for adjuvant chemotherapy. Lung and lymph node metastases decreased after 2 courses of chemotherapy using CPT-11 and 5-FU/LV but liver metastases were enlarged, following up increase in CEA. Thereafter, he suffered from muscle weakness in hands, arms, and legs and results of neurophysiologic studies were compatible with primary lateral sclerosis (ALS). For second line chemotherapy, he was treated with low-dose CDDP/5-FU over 6 courses. As a result, the size the of metastatic lesions markedly reduced and CEA was decreased to the normal level. Although significant tumor reduction was observed, his neurological symptoms rapidly progressed. He died of aspiration pneumonia 8 months after onset of the disease. Autopsy revealed that his neuropathological findings were compatible with ALS, and it was thought to be the primary cause of death in the because of absence of cancer progression. In this case the neurological syndrome was not affected by cancer therapy. Thus our case does not support the hypothesis that ALS in associated with cancer and the relationship between both disorders remains uncertain.

DOI PubMed

Ex vivo large-scale generation of human platelets from cord blood CD34(+) cells

Takuya Matsunaga, Ikuta Tanaka, Masayoshi Kobune, Yutaka Kawano, Maki Tanaka, Kageaki Kuribayashi, Satoshi Iyama, Tsutomu Sato, Yasushi Sato, Rishu Takimoto, Tetsuji Takayama, Junji Kato, Takafumi Ninomiya, Hirofumi Hamada, Yoshiro Niitsu

STEM CELLS ( ALPHAMED PRESS )  24 ( 12 ) 2877 - 2887  2006年12月  [査読有り]

　概要を見る

In the present investigation, we generated platelets (PLTs) from cord blood ( CB) CD34(+) cells using a three- phase culture system. We first cultured 500 CB CD34(+) cells on telomerase gene- transduced human stromal cells ( hTERT stroma) in serum-free medium supplemented with stem cell factor ( SCF), Flt-3/ Flk-2 ligand ( FL), and thrombopoietin ( TPO) for 14 days. We then transferred the cells to hTERT stroma and cultured for another 14 days with fresh medium containing interleukin-11 (IL- 11) in addition to the original cytokine cocktail. Subsequently, we cultured the cells in a liquid culture medium containing SCF, FL, TPO, and IL- 11 for another 5 days to recover PLT fractions from the supernatant, which were then gel- filtered to purify the PLTs. The calculated yield of PLTs from 1.0 unit of CB ( 5 x 106 CD34(+) cells) was 1.26 x 10(11) - 1.68 x 10(11) PLTs. These numbers of PLTs are equivalent to 2.5 - 3.4 units of random donorderived PLTs or 2/ 5 - 6/ 10 of single- apheresis PLTs. The CB- derived PLTs exhibited features quite similar to those from peripheral blood in morphology, as revealed by electron micrographs, and in function, as revealed by fibrinogen/ ADP aggregation, with the appearance of beta-selectin and activated glycoprotein IIb- IIIa antigens. Thus, this culture system may be applicable for large- scale generation of PLTs for future clinical use.

DOI PubMed

[Peripheral T-cell lymphoma presenting with eosinophilia due to interleukin-5 produced by lymphoma cells].

Matsunaga T, Sato T, Iyama S, Tanaka S, Murase K, Sato Y, Kobune M, Takimoto R, Kato J, Kuroda H, Niitsu Y

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 11 )  47 ( 11 ) 1457 - 1462  2006年11月  [査読有り]

　概要を見る

症例は72歳, 男性。頸部リンパ節腫脹の精査を目的に入院し, リンパ節生検の結果から, 末梢性T細胞性リンパ腫 (peripheral T cell lymphoma; PTCL) と診断した。著明な好酸球増多を認めたため, 血清Interleukin-5 (IL-5) を測定したところ高値を示した。また, 生検したリンパ節組織の免疫染色ではIL-5陽性の細胞が散見された。CHOP療法を2クール施行したところ, 腫大したリンパ節は消失し, 好酸球数は正常となった。また, これにともない血清IL-5も正常化した。PTCLでは稀に好酸球増多を合併すると報告されているが, 本症例では腫瘍細胞由来のIL-5が原因と推測された。

DOI PubMed CiNii

A phase I/II study of nedaplatin and 5-fluorouracil with concurrent radiotherapy in patients with esophageal cancer

Yasushi Sato, Tetsuji Takayama, Tamotsu Sagawa, Tetsuro Okamoto, Koji Miyanishi, Tsutomu Sato, Hironobu Araki, Satoshi Iyama, Seiichiro Abe, Kazuyuki Murase, Rishu Takimoto, Hisayasu Nagakura, Masato Hareyama, Junji Kato, Yoshiro Niitsu

CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER )  58 ( 5 ) 570 - 576  2006年11月  [査読有り]

　概要を見る

Purpose: To determine the recommended dose (RD) of cis-diammine-glycolatoplatinum (nedaplatin) when given concurrently with 5-FU and high dose radiation therapy in the treatment of esophageal cancer. The purpose of the phase II trial is to determine efficacy and further define the side effect profile. Methods: Twenty-six patients with clinical stage I to IVA squamous cell carcinoma of the esophagus were enrolled in a non-surgical treatment comprised of a fixed dose of fluorouracil (400 mg/m(2) administered as continuous intravenous infusion on days 1-5 and days 8-12) plus escalating doses of nedaplatin (40 mg/m(2) in level 1, 50 mg/m(2) in level 2, or 60 mg/m(2) in level 3 on days 1 and 8), repeated twice every 3 weeks with concurrent radiotherapy (60 Gy). Results: Between July 1998 and February 2004, a total of 26 patients entered this trial, all of whom were considered evaluable for toxicity assessment. In phase I of the study, 12 patients were treated in sequential cohorts of three to six patients per dose level. The maximum tolerated dose was reached at level 3 with two grade 4 neutropenia and one grade 4 thrombocytopenia. Thus, the recommended dosing schedule is level 2. Of the 20 patients treated at the RD level 2, including 6 patients of the RD phase I portion, 8 out of 20 patients (40%) had grade 3-4 neutropenia, 5 patients (25.0%) had grade 3-4 thrombocytopenia, 4 patients (20.0%) had grade 3 anemia and 4 patients (20.0%) had grade 3-4 esophagitis. Other toxicities were relatively mild and usually of grade 2 or less. Objective responses were noted in the 26 patients (overall response rate, 88.5%) including 11 (42.3%) complete remissions. The 1- and 3-year survival rates were 65.1 and 37.2%, respectively, with a median survival time of 21.2 months. Conclusions: The combination of nedaplatin and 5-FU with radiation is a feasible regimen that shows promising antitumor activity with an acceptable safety profile in patients with esophageal cancer.

DOI PubMed

A case of recurrent biliary cystadenocarcinoma successfully treated with 5FU/CDDP systemic chemotherapy

Satoshi Iyama, Yasuo Takahashi, Naoaki Shintani, Koshi Fujikawa, Syunichi Ohkubo, Yasushi Sato, Tsutomu Sato, Yasuhiro Sato, Keisuke Ohnuma, Yoshiro Niitsu

Japanese Journal of Gastroenterology ( 10 )  103 ( 10 ) 1163 - 1168  2006年10月  [査読有り]

　概要を見る

We report a case of biliary cystadenocarcinoma which recurred 41 months postoperatively. A 60-year-old woman was admitted for further examination of multiple metastatic tumors and a large amount of ascites. Systemic administration of 5FU and CDDP caused her CEA level to decrease gradually and abdominal computed tomography revealed considerable reduction of the metastatic tumors and ascites. Since her general condition had improved, chemotherapy was continued in the outpatient clinic.

DOI PubMed

ヒトTERT-stroma細胞を用いた末梢血CD133陽性細胞のex vivo増幅系の確立

小船 雅義, 河野 豊, 千葉 大樹, 井山 諭, 佐藤 勉, 瀧本 理修, 松永 卓也, 加藤 淳二, 濱田 洋文, 新津 洋司郎

臨床血液 ( (一社)日本血液学会-東京事務局 )  47 ( 9 ) 1151 - 1151  2006年09月  [査読有り]

[De novo CD5-positive diffuse large B-cell lymphoma associated with autoimmune hemolytic anemia presenting as erythroid hypoplasia].

Kuroda H, Matsunaga T, Iyama S, Takimoto R, Shirao S, Kida M, Watanabe H, Konuma Y, Hirayama Y, Kohda K, Niitsu Y

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 7 )  47 ( 7 ) 633 - 638  2006年07月  [査読有り]

DOI PubMed CiNii

Amelioration of murine dextran sulfate sodium-induced colitis by ex vivo extracellular superoxide dismutase gene transfer

Takatomi Oku, Satoshi Iyama, Tsutomu Sato, Yasushi Sato, Maki Tanaka, Tamotsu Sagawa, Kageaki Kuribayashi, Tetsuya Sumiyoshi, Kazuyuki Murase, Takuro Machida, Tetsuro Okamoto, Takuya Matsunaga, Tetsuji Takayama, Minoru Takahashi, Junji Kato, Hirofumi Hamada, Yoshiro Niitsu

INFLAMMATORY BOWEL DISEASES ( LIPPINCOTT WILLIAMS & WILKINS )  12 ( 7 ) 630 - 640  2006年07月  [査読有り]

　概要を見る

Background: Although the etiology of inflammatory bowel disease has not been fully clarified, reactive oxygen species is speculated to be involved. Extracellular superoxide dismutase (EC-SOD), an isozyme of SODs, is known to function mainly in body fluids. We investigated the efficacy of an ex vivo EC-SOD gene transfer into dextran sulfate sodium (DSS)-induced colitis mice. Materials and Methods: Experimental colitis was induced by providing Balb/c mice with DSS in sterile distilled water provided as desired. The syngenic fibroblasts were obtained from Balb/c mice embryos and retrovirally transduced with the hEC-SOD gene. These engineered cells were confirmed to secrete EC-SOD in culture medium by enzyme-linked immunosorbent assay and were inoculated subcutaneously in the backs of DSS-treated mice. Mucosal injury of the colon was evaluated by the disease activity index (DAI: body weight, rectal bleeding, and stool consistency), grading of histologic disease severity, and levels of cytokine (tumor necrosis factor-alpha, interieukin-1 beta) production. 8-Hydroxydeoxyguanosine (8-OHdG) levels in the mucosal tissue were assessed by immunohistochemical staining. Malondialdehyde (MDA) was measured using a colorimetric assay. Results: A significant improvement was observed in DAI score and histologic severity as well as in mucosal tissue levels of inflammatory cyrokines, 8-OHdG, and MDA of mice treated with the EC-SOD gene as compared with those without gene therapy, not only in a mild colitis model but also in a severe colitis model. Survival of treated mice in these models was significantly prolonged. Conclusions: Ex vivo transfer of the EC-SOD gene was feasible for treatment of DSS-induced colitis.

DOI PubMed

[Enteropathy-type T-cell lymphoma with CD8 and CD56 expression].

Sato T, Matsunaga T, Iyama S, Sakai T, Murase K, Sato Y, Kobune M, Takimoto R, Kato J, Niitsu Y

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 7 )  47   645 - 649  2006年07月  [査読有り]

DOI PubMed

Human herpesvirus-6 hepatitis associated with cyclosporine-A encephalitis after bone marrow transplantation for chronic myeloid leukemia

Kageaki Kuribayashi, Takuya Matsunaga, Satoshi Iyama, Koichi Takada, Tsutomu Sato, Kazuyuki Murase, Akihito Fujimi, Rishu Takimoto, Johji Kawanishi, Yoshiro Niitsu

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  45 ( 7 ) 475 - 478  2006年  [査読有り]

　概要を見る

A 31-year-old man referred to our hospital for treatment of his chronic myeloid leukemia (CML) in the first chronic phase by bone marrow transplantation. We pretreated him with cyclophosphamide and total body irradiation and bone marrow transplantation (BMT) was carried out. On day 31, the engraftment was confirmed and on day 52, acute graft versus host disease (GVHD) was observed. On day 189, he lost consciousness due to cyclosporine A-induced leukoencephalopathy and 375 mg cyclosporine A was changed to 100 mg prednisolone. On day 199, liver dysfunction (AST 410 IU/L, ALT 557 IU/L, gamma GTP 385 IU/L, ALP 363 IU/L, D-Bil 0.3 mg/dl) developed and a liver biopsy was performed. PCR analysis of DNA from the liver biopsy specimen was positive for HHV-6 and immunostaining using anti-HHV-6 and anti-HHV-6b antibodies showed positive staining in the cytosol of hepatocytes. No other viruses were found to induce hepatitis. From these results, he was diagnosed as having HHV-6 hepatitis and it was successfully treated with gancyclovir (GCV) administration.

DOI PubMed

[Two cases of primary skeletal muscle lymphoma, and a review of the literature].

Ueno A, Kuribayashi K, Iyama S, Matsunaga T, Kikuchi S, Sato T, Kobune M, Takimoto R, Kato J, Niitsu Y

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 10 )  46   1141 - 1145  2005年10月  [査読有り]

DOI PubMed

[Essential thrombocythemia associated with incomplete type intestinal Behçet disease during hydroxyurea treatment].

Kobune M, Kato J, Kuribayashi K, Iyama S, Fujimi A, Murase K, Ueno A, Kikuchi S, Satoh T, Okamoto T, Takimoto R, Matsunaga T, Niitsu Y

[Rinsho ketsueki] The Japanese journal of clinical hematology   46 ( 10 ) 1136 - 1140  2005年10月  [査読有り]

DOI PubMed

Donor cell derived acute myeloid leukemia after allogeneic cord blood transplantation in a patient with adult T-cell lymphoma

T Matsunaga, K Murase, M Yoshida, A Fujimi, S Iyama, K Kuribayashi, T Sato, K Kogawa, Y Hirayama, S Sakamaki, K Kohda, Y Niitsu

AMERICAN JOURNAL OF HEMATOLOGY ( WILEY-LISS )  79 ( 4 ) 294 - 298  2005年08月  [査読有り]

　概要を見る

We report a patient with adult T-cell lymphoma who developed acute myeloid leukemia (AML) after allogeneic cord blood transplantation (CBT). Fluorescence in situ hybridization (FISH) studies and molecular analysis using short tandem repeat (STR) sequences proved the AML to be of donor origin. Although 25 cases of donor cell leukemia (DCL) occurring after allogeneic bone marrow transplantation have previously been reported, there have been no reports of DCL after CBT. This case is the first-reported DCL patient after CBT.

DOI PubMed

Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion

Y Sato, H Araki, J Kato, K Nakamura, Y Kawano, M Kobune, T Sato, K Miyanishi, T Takayama, M Takahashi, R Takimoto, S Iyama, T Matsunaga, S Ohtani, A Matsuura, H Hamada, Y Niitsu

BLOOD ( AMER SOC HEMATOLOGY )  106 ( 2 ) 756 - 763  2005年07月  [査読有り]

　概要を見る

Hepatic transdifferentiation of bone marrow cells has been previously demonstrated by intravenous administration of donor cells, which may recirculate to the liver after undergoing proliferation and differentiation in the recipient's bone marrow. In the present study, to elucidate which cellular components of human bone marrow more potently differentiate into hepatocytes, we fractionated human bone marrow cells into mesenchymal stem cells (MSCs), CD34(+) cells, and non-MSCs/ CD34(-) cells and examined them by directly xenografting to allylalcohol (AA)- treated rat liver. Hepatocyte-like cells, as revealed by positive immunostaining for human-specific alpha-fetoprotein (AFP), albumin (Alb), cytokeratin 19 (CK19), cytokeratin 18 (CK18), and asialoglycoprotein receptor (AGPR), and by reverse transcription-polymerase chain reaction (RTPCR) for expression of AFP and Alb mRNA, were observed only in recipient livers with MSC fractions. Cell fusion was not likely involved since both human and rat chromosomes were independently identified by fluorescence in situ hybridization (FISH). The differentiation appeared to follow the process of hepatic ontogeny, reprogramming of gene expression in the genome of MSCs, as evidenced by expression of the AFP gene at an early stage and the albumin gene at a later stage. In conclusion, we have demonstrated that MSCs are the most potent component in hepatic differentiation, as revealed by directly xenografting into rat livers.

DOI PubMed

[Successful treatment with oral ribavirin of adenovirus-associated hemophagocytic syndrome in a stem cell transplantation recipient].

Iyama S, Matsunaga T, Fujimi A, Murase K, Kuribayasi K, Sato T, Hirayama Y, Sakamaki S, Kohda K, Niitsu Y

[Rinsho ketsueki] The Japanese journal of clinical hematology ( 5 )  46 ( 5 ) 363 - 367  2005年05月  [査読有り]

　概要を見る

症例は51歳，女性。重症型再生不良性貧血の診断にて，2003年1月28日にHLA一致同胞より同種末梢血幹細胞移植を施行した。Day 207にアデノウイルスによる出血性膀胱炎を発症し，adenine arabinosideの投与を開始したが改善がみられず，腎炎へと移行した。Day 228にアデノウイルス関連血球貪食症候群を併発した。経口ribavirin投与後に出血性膀胱炎，腎機能障害のみならず，血球貪食症候群による汎血球減少も改善した。これまで造血幹細胞移植後に発症するアデノウイルス感染症に対しては治療法が確立されていない。示唆に富む症例と考え報告する。

DOI PubMed CiNii

Prolonged survival of mice with multiple liver metastases of human colon cancer by intravenous administration of replicable E1B-55K-deleted adenovirus with E1A expressed by CEA promoter

T Sagawa, M Takahashi, T Sato, Y Sato, Y Lu, T Sumiyoshi, Y Yamada, S Iyama, J Fukaura, K Sasaki, H Hamada, K Miyanishi, T Takayama, J Kato, Y Niitsu

MOLECULAR THERAPY ( ACADEMIC PRESS INC ELSEVIER SCIENCE )  10 ( 6 ) 1043 - 1050  2004年12月  [査読有り]

　概要を見る

Liver is the most preferential site for metastasis of colon cancer. We, in the present study, constructed a self-replicable adenovirus in which EIIA is driven by a CEA promoter and E1B-55K is deleted from the E1B region (AdCEAp/Rep) and examined its effects on multiple metastases of a human colon cancer cell in a mouse xenograft model. We first showed effective replication of the virus in various CEA-producing human colon cancer cells (M7609, HT-29) and subsequent lysis of the infected cells in vitro. We then demonstrated that a single intratumoral injection of the virus (1 x 10(8) PFU/100 mul) induced a complete regression of subcutaneous tumors (M7609) inoculated into nude mice. Further, we demonstrated that systemic administration of the virus (1 x 10(8) PFU/100 mul) through the tail vein to nude mice, which 1 week prior had been inoculated with tumor cells (colon carcinoma cell line HT-29) via the spleen and showed apparent multiple metastases in the liver, effectively suppressed the metastasis formation. The mean survival time of the treated mice was significantly longer than that of the controls. Thus, the systemic administration of AdCEAp/Rep was considered to be effective on multiple liver metastases of CEA-positive colon cancer in a xenograft model.

DOI PubMed

Interleukin-11 as an osteoprotegerin-inducing factor in culture medium of blastic cells from a patient with acute megakaryocytic leukemia complicated with osteosclerosis

T Sato, T Matsunaga, M Kida, K Morii, T Machida, Y Kawano, K Nakamura, K Kuribayashi, K Takada, S Iyama, Y Sato, T Takayama, M Takahashi, J Kato, M Chokki, Y Niitsu

AMERICAN JOURNAL OF HEMATOLOGY ( WILEY-LISS )  77 ( 1 ) 62 - 66  2004年09月  [査読有り]

　概要を見る

We came across a rare case of acute megalkaryocytic leukemia, the clinical course of which was relatively chronic and nonaggressive. This case was complicated with generalized severe osteosclerosis (OS). The medium in which blastic cells from the patient were cultured showed a strong activity to enhance the expression of an osteosclerotic cytokine, osteoprotegerin (OPG), as revealed by real-time quantitative RT-PCR and Western blot analysis. The OPG-inducing activity of the culture medium was neutralized by the anti-interieukin-11 (IL-11) antibody. These results indicate that IL-11 produced by the blasts was a causative factor of the OS observed in this patient. (C) 2004 Wiley-Liss, Inc.

DOI PubMed

遺伝子治療 AFP産生肝癌に対する制限増殖型アデノウイルス,p53遺伝子,5-FUの3者併用は高い抗腫瘍効果を示す

山田 康之, 高橋 稔, 佐川 保, 佐藤 康史, 佐藤 勉, 深浦 純生, 井山 諭, 佐々木 勝則, 中村 公則, 濱田 洋文, 新津 洋司郎

日本癌治療学会誌 ( (一社)日本癌治療学会 )  39 ( 2 ) 397 - 397  2004年09月

Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells

T Sato, T Machida, S Takahashi, S Iyama, Y Sato, K Kuribayashi, K Takada, T Oku, Y Kawano, T Okamoto, R Takimoto, T Matsunaga, T Takayama, M Takahashi, J Kato, Y Niitsu

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS )  173 ( 1 ) 285 - 296  2004年07月  [査読有り]

　概要を見る

Generation of reactive oxygen species (ROS) and activation of caspase cascade are both indispensable in Fas-mediated apoptotic signaling. Although ROS was presumed to affect the activity of the caspase cascade on the basis of findings that antioxidants inhibited the activation of caspases and that the stimulation of ROS by itself activated caspases, the mechanism by which these cellular events are integrated in Fas signaling is presently unclear. In this study, using human T cell leukemia Jurkat cells as well as an in vitro reconstitution system, we demonstrate that ROS are required for the formation of apoptosome. We first showed that ROS derived from mitochondrial permeability transition positively regulated the apoptotic events downstream of mitochondrial permeability transition. Then, we revealed that apoptosome formation in Fas-stimulated Jurkat cells was clearly inhibited by N-acetyl-L-cysteine and manganese superoxide dismutase by using both the immunoprecipitation and size-exclusion chromatography methods. To confirm these in vivo findings, we next used an in vitro reconstitution system in which in vitro-translated apoptotic protease-activating factor 1 (Apaf-1), procaspase-9, and cytochrome c purified from human placenta were activated by dATP to form apoptosome; the formation of apoptosome was markedly inhibited by reducing reagents such as DTT or reduced glutathione (GSH), whereas hydrogen peroxide prevented this inhibition. We also found that apoptosome formation was substantially impaired by GSH-pretreated Apaf-1, but not GSH-pretreated procaspase-9 or GSH-pretreated cytochrome c. Collectively, these results suggest that ROS plays an essential role in apoptosome formation by oxidizing Apaf-1 and the subsequent activation of caspase-9 and -3.

PubMed

[A case of gastric carcinoma with multiple skin, bone, and bilateral ovary metastasis; effective treatment by chemotherapy].

Mezawa S, Homma H, Doi T, Akiyama T, Murakami K, Kogawa K, Hirata K, Kida M, Murase K, Iyama S

Gan to kagaku ryoho. Cancer & chemotherapy ( 12 )  30   1973 - 1975  2003年11月  [査読有り]

PubMed

Superselective transcatheter embolization for acute lower gastrointestinal hemorrhage after endoscopic mucosal resection: A report of 3 cases

S Mezawa, H Homma, K Murase, T Doi, S Iyama, K Takada, K Hirata, F Mezawa, Y Niitsu

HEPATO-GASTROENTEROLOGY ( H G E UPDATE MEDICAL PUBLISHING S A )  50 ( 51 ) 735 - 737  2003年05月  [査読有り]

　概要を見る

One of the most common complications related to endoscopic mucosal resection is hemorrhage; in almost every case, the bleeding is endoscopically managed, but some cases are unresponsive to the treatment. We have encountered three cases of endoscopically uncontrollable lower gastrointestinal hemorrhage after endoscopic mucosal resection in the colon which we successfully treated by urgent superselective transcatheter embolization. In our three cases, massive hemorrhage occurred immediately after endoscopic mucosal resection of a sessile polyp 25-40mm in diameter, two cases in the ascending colon and one in the rectum. Although hemoclip placement was attempted in every case, hemostasis was not achieved. Emergency angiography disclosed massive extravasation of the contrast material in the colon. Hemostasis was achieved immediately after superselective transcatheter arterial embolizations with microcoils, with no observable ischemic complications and without the need of transfusions. In conclusion, superselective transcatheter embolization with microcoils should be considered a safe and efficient treatment option for endoscopically uncontrollable lower gastrointestinal hemorrhage occurring after endoscopic mucosal resection.

PubMed

[A case responding to weekly paclitaxel (TXL) therapy as third line chemotherapy for scirrhous type gastric cancer].

Sagawa T, Tsuji Y, Takayanagi N, Hirayama Y, Sakamaki S, Chiba H, Nakajima T, Iyama S, Oku T, Sumiyoshi T, Sato Y, Takahashi M, Takayama T, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 5 )  30   707 - 710  2003年05月  [査読有り]

PubMed

[A case of irinotecan-resistant colon cancer responding to chronotherapy with oxaliplatin, 5-FU, l-LV].

Sagawa T, Tsuji Y, Takayanagi N, Hirayama Y, Sakamaki S, Chiba H, Iyama S, Oku T, Sato Y, Takahashi M, Takayama T, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 4 )  30   537 - 543  2003年04月  [査読有り]

PubMed

肝腫瘍に対する食塩水注入併用ラジオ波凝固療法による播種の危険性

太田 英敏, 新谷 直昭, 高橋 康雄, 藤川 幸司, 井山 諭, 中村 とき子

肝臓 ( 一般社団法人 日本肝臓学会 )  43 ( 12 ) 583 - 583  2002年12月

DOI CiNii

[Usefulness of CT arteriography for transcatheter peripancreatic arterial embolization to patients with advanced pancreatic cancer].

Doi T, Homma H, Mezawa S, Akiyama T, Machida T, Murakami K, Hirata K, Takanashi N, Iyama S, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 12 )  29   2298 - 2301  2002年11月  [査読有り]

PubMed

Induction of heat shock protein 47 synthesis by TGF-beta and IL-1 beta via enhancement of the heat shock element binding activity of heat shock transcription factor 1

H Sasaki, T Sato, N Yamauchi, T Okamoto, D Kobayashi, S Iyama, J Kato, T Matsunaga, R Takimoto, T Takayama, K Kogawa, N Watanabe, Y Niitsu

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS )  168 ( 10 ) 5178 - 5183  2002年05月  [査読有り]

　概要を見る

With most immunological reactions, tissue fibrosis, collagen overproduction caused by immune cytokines, is inevitably associated. Among the various immune cytokines, heat shock protein 47 (HSP47) is a procollagen-specific molecular chaperon and is essential for secretion of procollagen from cells. Induction of HSP47 by TGF-beta has been previously reported in rat skeletal myoblasts and mouse osteoblasts, but not in human diploid fibroblasts. As for IL-1beta, its effect on HSP47 has not been elucidated. In the present study, using human embryonic lung fibroblast cells, we first disclosed that both TGF-beta and IL-1beta induced HSP47 synthesis. We then revealed that the binding of the heat shock element (HSE) by heat shock transcription factor 1 (HSF1) was enhanced by both cytokines. We further demonstrated that trimer formation of HSF1, which is essential for its binding to HSE, was induced by these cytokines. The enhancement of HSP47 synthesis and their trimer formation of HSF1 were augmented by using a combination of both cytokines. Collectively, TGF-beta and IL-1beta were found to induce trimer formation of HSF1 which in turn bound to HSE of HSP47, resulting in the enhancement of HSP47 expression. Thus, HSP47 could well be a good candidate for molecular targeting in controlling tissue fibrosis, given that both principal fibrinogenetic cytokines (TGF-beta, IL-1beta) are commonly involved in its induction through HSF1 trimerization.

PubMed

E1B-55K-deleted adenovirus expressing E1A-13S by AFP-enhancer/promoter is capable of highly specific replication in AFP-producing hepatocellular carcinoma and eradication of established tumor

M Takahashi, T Sato, T Sagawa, Y Lu, Y Sato, S Iyama, Y Yamada, J Fukaura, S Takahashi, K Miyanishi, T Yamashita, K Sasaki, K Kogawa, H Hamada, J Kato, Y Niitsu

MOLECULAR THERAPY ( ACADEMIC PRESS INC ELSEVIER SCIENCE )  5 ( 5 ) 627 - 634  2002年05月  [査読有り]

　概要を見る

Here, we constructed a recombinant replication-competent adenovirus (rRCAd; AdAFPep/Rep) that expresses both E1A-13S driven by the alpha-fetoprotein (AFP) enhancer/promoter (AFPep) lacking any silencers in the 5'-flanking region of the AFP gene, and 55K-deleted E1B driven by the cytomegalovirus (CMV) promoter. We then examined the feasibility of gene therapy utilizing this virus for AFP-producing hepatocellular carcinoma (HCC). AdAFPep/Rep lysed all the AFP-producing HCC cell lines (HuH7, HepG2, PLC/PRF/5 (P5)) examined at a multiplicity of infection (MOI) as low as 0.1 and did not lyse primary human hepatocytes (Hc) at a MOI as high as 100, indicating that the rRCAd virus can lyse AFP-producing HCC cells with a higher specificity and potency than previously reported. Furthermore, this virus was capable of complete eradication of a preestablished HuH7-cell tumor by a single intratumoral injection of 10(8) plaque-forming units (pfu) of AdAFPep/Rep. Thus, AdAFPep/Rep may be applicable for clinical use.

DOI PubMed

Treatment of murine collagen-induced arthritis by ex vivo extracellular superoxide dismutase gene transfer.

Iyama S, Okamoto T, Sato T, Yamauchi N, Sato Y, Sasaki K, Takahashi M, Tanaka M, Adachi T, Kogawa K, Kato J, Sakamaki S, Niitsu Y

Arthritis and rheumatism   44 ( 9 ) 2160 - 2167  2001年09月  [査読有り]

PubMed CiNii

Hepatic and splenic arterial infusion chemotherapy after transcatheter peripancreatic arterial embolization for patients with inoperable adenocarcinoma of the pancreas

H. Homma, T. Kukitsu, S. Mezawa, T. Doi, M. Kida, K. Miyanishi, K. Takada, K. Murase, S. Iyama, Y. Niitsu

Gan to kagaku ryoho. Cancer &amp; chemotherapy   28 ( 11 ) 1558 - 1561  2001年

　概要を見る

Thirty-one patients with advanced pancreatic carcinoma and liver metastases were treated by hepatic and splenic arterial infusion chemotherapy after transcatheter peripancreatic arterial embolization. The response rate for these 31 patients was 61.3%, with a mean survival period of 17.8 +/- 3.2 months and a 50% survival period of 12 months. By site of the primary tumor, the response rate for pancreatic head and body carcinoma was 81%, with a mean survival period of 21.6 +/- 4.0 months and a 50% survival period of 17 months, whereas the response rate for pancreatic caudal carcinoma was 20%, with a mean survival period of 6.1 +/- 0.5 months and a 50% survival period of 6 months. We believe that the current chemotherapy is an effective treatment for advanced pancreatic cancer with liver metastases.

PubMed

Implantation of a dual chambers port for hepatic and splenic arterial infusion chemotherapy in advanced pancreatic carcinoma with multiple liver metastasis

T. Kukitsu, H. Homma, S. Iyama, T. Doi, M. Kida, S. Mezawa, K. Murase, K. Takada, K. Miyanishi, Y. Niitsu

Gan to kagaku ryoho. Cancer &amp; chemotherapy   28 ( 11 ) 1562 - 1564  2001年

　概要を見る

Dual chambers ports were implanted in 7 patients with advanced pancreatic carcinoma and metastatic liver tumors to connect a 3.3 Fr catheter as an indwelling catheter. In comparison with the implantation of a pair of Single chamber ports, implanting a Dual chambers port entails some technical difficulties, but has some benefits in terms of stabler placement, a smaller incision, reduction of medical fees, and improved QOL of patients.

PubMed

Synergistic suppressive effect of double transfection of tumor necrosis factor-alpha and interleukin 12 genes on tumorigenicity of Meth-A cells

H Fujiwara, N Yamauchi, Y Sato, K Sasaki, M Takahashi, T Okamoto, T Sato, S Iyama, Y Koshita, M Hirayama, H Yamagishi, Y Niitsu

JAPANESE JOURNAL OF CANCER RESEARCH ( BUSINESS CENTER ACADEMIC SOCIETIES JAPAN )  91 ( 12 ) 1296 - 1302  2000年12月  [査読有り]

　概要を見る

Tumor necrosis factor-alpha (TNF-alpha) and interleukin 12 (IL-12), both potent antitumor cytokines, are known to be involved in the host's antitumor immune surveillance in tumor bearers, via different mechanisms. The former enhances the activities of dendritic cells, natural killer/lymphocyte-activated killer (NK/LAK) and cytotoxic T lymphocyte (CTL), while the latter induces Th1-type cellular immunity and enhances the activities of natural killer T (NKT), NK/LAK and CTL. In the present study, in the expectation of synergistic actions of these cytokines in stimulating the host's immune responses, we investigated the feasibility of a cancer vaccine involving double transfection with both genes in a murine model. The expression of major histocompatibility complex (MHC) class I, class II and B7.1 on the surface of the double transfectants was enhanced as revealed by FACS analysis. A significant decrease in tumorigenicity was observed in mice inoculated with the double transfectants. Cytotoxicity assay revealed that the activities of NK/LAK and CTL from spleens of mice bearing the double transfectants were enhanced. The induction of tumor-specific immunity was confirmed by rechallenge with parental Meth-A cells in mice that had rejected the double transfectants. Thus, double transfection of TNF-alpha and IL-12 genes was considered to bring about synergistic suppressive effects on the tumorigenicity of transfectants through the activation of killer cells by produced cytokines and the enhancement of expression of MHC class I, II and B7.1 molecules.

A case of type IIa autoimmune hepatitis showing fluctuation of serum CA 19-9 level

T. Sato, J. Kato, Y. Sato, S. Iyama, K. Takada, S. Hagiwara, S. Takahashi, H. Kuroda, S. Mezawa, Y. Koshita, N. Yoshizaki, M. Takahashi, S. Sakamaki, Y. Niitsu

Acta Hepatologica Japonica ( Japan Society of Hepatology )  41 ( 9 ) 654 - 659  2000年  [査読有り]

DOI

CD4,CD8 double negative T-CLLの1例

山内 尚文, 高張 大亮, 井山 諭, 大久保 俊一, 佐々木 紀幸, 河野 豊, 佐藤 勉, 加藤 淳二, 坂牧 純夫, 新津 洋司郎

臨床血液 ( (一社)日本血液学会-東京事務局 )  40 ( 9 ) 901 - 901  1999年09月  [査読有り]

Suicide gene therapy using transferrin (Tf)-HSV-TK-gene conjugate

J. Fukaura, Y. Sato, K. Sasaki, M. Takahashi, T. Okamoto, T. Sato, S. Iyama, N. Yamauchi, Y. Niitsu

Biotherapy   13 ( 5 ) 625 - 627  1999年

　概要を見る

The transferrin receptor (Tf-R) is universally present on the surface of actively proliferating cells such as tumor cells and recycles back to the cell surface after it is bound with ligand (Tf) and is internalized. The gene conjugated with Tf therefore may be preferentially delivered to the tumor cells in vivo. In the present study, we employed a stepwise solid phase method on preparing Tf-avidin-biotin-DNA complex, using affinity chromatography, which keeps the receptor binding motif of Tf-R affinity intact. The conjugate constructed by this method was shown to provide a high transfection efficiency in vitro against tumor cells and a specific delivery of the gene to tumor tissue in vivo. Furthermore, we investigated the therapeutic effects of a suicide gene therapy of metastatic K562 cells in SCID mice using Tf-HSV-TK-gene conjugate and GCV treatment. An appreciable suppression of metastasis was observed as well as prolongation of survivals. These results indicated that the suicide gene therapy using Tf-HSV-TK-gene conjugate was shown to provide a specific delivery of the gene to tumor tissue in vivo and the potential for tumoricydal therapy.

Gene therapy for gastrointestinal cancer using adenovirus-mediated TNF receptor-p55 gene transfer followed by systemic TNF administration

M. Takahashi, N. Yamauchi, K. Sasaki, S. Iyama, Y. Yamada, T. Okamoto, Y. Sato, T. Sato, H. Sasaki, T. Hagino, Y. Niitsu

Biotherapy   12 ( 5 ) 583 - 585  1998年

　概要を見る

We have shown that local administration of TNF for advanced gastrointestinal cancers resistant to conventional treatments could induce tumor necrosis and reduce tumor markers. But no complete regression was obtained. In order to improve the therapeutic efficacy of TNF, we have investigated the augmentation of susceptibility to TNF by transduction of TNF-receptor p55 (TNFR-p55) gene, which is responsible for cytotoxicity of TNF, to pancreatic cancer cells. We previously showed that the tumor volume of TNFR-p55 gene transduced stable transformant could be reduced by systemic administration of TNF. But it is not a practical model to investigate augmentation of anti-tumor effects of TNF by transduction of TNFR-p55 gene. We applied this strategy for in vivo gene therapy for formed tumor to use replication deficient adenovirus vector expressing TNFR-p55. TNF-resistant hepatocellular carcinoma cell line (PLC/PRF/5) and colon cancer cell line (M7609) were rendered to TNF-susceptible tumor with TNF dose-dependency after AdCMV/TNFR-p55 infection in vitro. Furthermore these formed tumor were regressed by adenovirus-mediated TNFR-p55 gene transfer in vivo followed by systemic administration of TNF. Median survival was significantly prolonged with TNFR-p55 gene transfer in vivo followed by systemic administration of TNF compared with no therapy. We could also show the possibility of novel suicide-immunogenetherapy transducing TNFR-p55 gene in vivo followed by TNF administration.

Involvement of ICE-like protease and oxygen free radicals in tumor- necrosis-factor-mediated apoptosis

S. Iyama, N. Yamauchi, T. Sato, T. Okamoto, H. Sasaki, M. Takahashi, Y. Sato, T. Hagino, D. Kobayashi, N. Watanabe, Y. Niitsu

Biotherapy   12 ( 5 ) 691 - 693  1998年

　概要を見る

In the present study, we demonstrated the relationship of caspases (CPP32) and OFRs on TNF-induced apoptosis signal. The increase of OFRs production was dependent on the concentration of TNF, and TNF susceptibility was significantly correlated with the production of OFRs on human leukemic cell lines. NAC inhibited the TNF-induced OFRs production, and 100 μM of Ac- DEVD-cho, which is a specific inhibitor of CPP32, inhibited the production of OFRs completely. NAC inhibited the fragmentation of DNA induced by TNF. TNF enhanced the expression of CPP32 mRNA, and there was no effect by addition of NAC. TNF-induced CPP32 activation was suppressed by addition of Ac-DEVD-cho, but showed no significant change when treated with NAC. These results suggest that TNF can induce apoptosis by induction of enhancement of caspase, especially CPP32, and production of OFRs sequentially.