研究者詳細 - 増子　正義

論文 - 増子　正義

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Allogeneic hematopoietic stem cell transplantation using reduced intensity conditioning regimen for patients with acute myeloid leukemia not in complete remission. 国際誌

Yoshimitsu Shimomura, Tetsuhisa Kitamura, Masamitsu Yanada, Shohei Mizuno, Tadakazu Kondo, Satoshi Yoshihara, Masatsugu Tanaka, Kazuki Inai, Yuta Katayama, Makoto Onizuka, Takahiro Fukuda, Hirohisa Nakamae, Mineo Kurokawa, Shingo Yano, Miho Nara, Masayoshi Masuko, Shigesaburo Miyakoshi, Tetsuya Eto, Makoto Yoshimitsu, Fumihiko Ishimaru, Junya Kanda, Yoshiko Atsuta, Takaaki Konuma

Cytotherapy 27 ( 3 ) 316 - 323 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCI LTD

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment option for patients with refractory and relapsed acute myeloid leukemia (R/R AML) not in complete remission. Many studies investigating the prognosis of patients with R/R AML not in remission focused on patients who received myeloablative conditioning regimen (MAC). Conversely, reduced intensity conditioning regimen (RIC) could be a considerable conditioning regimen for some patients because of the high frequency of R/R AML in older patients who are not candidates for MAC. OBJECTIVE: This study aimed to evaluate the prognosis and identify factors associated with outcomes in patients with R/R AML who underwent allogeneic HSCT with RIC. STUDY DESIGN: This study included 707 adult patients with AML not in complete remission who had received RIC. The primary endpoint was progression-free survival (PFS), which was estimated using the Kaplan-Meier method. Prognostic factors were identified using a Cox proportional hazards model with multiple imputations using a chained equation approach. RESULTS: The 5-year PFS, overall survival, relapse, and nonrelapse mortality were 18.8% (95% confidence interval [CI]: 15.6-22.2), 22.0% (95% CI: 8.5-25.7), 53.6% (95% CI 49.7-57.4%) and 27.5% (95% CI: 24.0-31.2), respectively. Multivariable analysis revealed that male sex, poor performance status, karyotype risk, and blasts in the peripheral blood were significantly associated with PFS. CONCLUSIONS: This study identified prognostic factors in patients with R/R AML not in complete remission. These results can help to develop a transplant strategy for the treatment of R/R AML.

DOI： 10.1016/j.jcyt.2024.11.012

皮膚硬化型慢性GVHDに対してイブルチニブが有効であった1例

佐藤美紀, 濱菜摘, 木村春奈, 長谷川瑛人, 阿部理一郎, 諏訪部達也, 柴崎康彦, 増子正義, 阿部由紀子

日本皮膚科学会雑誌 134 ( 7 ) 1923 - 1923 2024年6月

Reduced chondroitin sulfate content prevents diabetic neuropathy through transforming growth factor-β signaling suppression. 国際誌

Hajime Ishiguro, Takashi Ushiki, Atsuko Honda, Yasuhiro Yoshimatsu, Riuko Ohashi, Shujiro Okuda, Asami Kawasaki, Kaori Cho, Suguru Tamura, Tatsuya Suwabe, Takayuki Katagiri, Yiwei Ling, Atsuhiko Iijima, Tadahisa Mikami, Hiroshi Kitagawa, Akiyoshi Uemura, Kazunori Sango, Masayoshi Masuko, Michihiro Igarashi, Hirohito Sone

iScience 27 ( 4 ) 109528 - 109528 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Diabetic neuropathy (DN) is a major complication of diabetes mellitus. Chondroitin sulfate (CS) is one of the most important extracellular matrix components and is known to interact with various diffusible factors; however, its role in DN pathology has not been examined. Therefore, we generated CSGalNAc-T1 knockout (T1KO) mice, in which CS levels were reduced. We demonstrated that diabetic T1KO mice were much more resistant to DN than diabetic wild-type (WT) mice. We also found that interactions between pericytes and vascular endothelial cells were more stable in T1KO mice. Among the RNA-seq results, we focused on the transforming growth factor β signaling pathway and found that the phosphorylation of Smad2/3 was less upregulated in T1KO mice than in WT mice under hyperglycemic conditions. Taken together, a reduction in CS level attenuates DN progression, indicating that CS is an important factor in DN pathogenesis.

DOI： 10.1016/j.isci.2024.109528

Decade-long WT1-specific CTLs induced by WT1 peptide vaccination.

Tatsuya Suwabe, Yasuhiko Shibasaki, Suguru Tamura, Takayuki Katagiri, Kyoko Fuse, Tori Ida-Kurasaki, Takashi Ushiki, Hirohito Sone, Miwako Narita, Masayoshi Masuko

International journal of hematology 119 ( 4 ) 399 - 406 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: The peptide-based cancer vaccine targeting Wilms' tumor 1 (WT1) is a promising immunotherapeutic strategy for hematological malignancies. It remains unclear how long and to what extent the WT1-specific CD8 + cytotoxic T cell (CTL) persist after WT1 peptide vaccination. METHODS: The WT1 peptide vaccine was administered with written consent to a patient with CML in the chronic phase who did not respond well to imatinib, and the patient was followed for 12 years after vaccination. Immune monitoring was performed by specific amplification of WT1-specific CTLs using a mixed lymphocyte peptide culture. T-cell receptors (TCRs) of amplified WT1-specific CTLs were analyzed using next-generation sequencing. This study was approved by the Institutional Review Board of our institution. RESULT: WT1-specific CTLs, which were initially detected during WT1 peptide vaccination, persisted at a frequency of less than 5 cells per 1,000,000 CD8 + T cells for more than 10 years. TCR repertoire analysis confirmed the diversity of WT1-specific CTLs 11 years after vaccination. CTLs exhibited WT1 peptide-specific cytotoxicity in vitro. CONCLUSION: The WT1 peptide vaccine induced an immune response that persists for more than 10 years, even after cessation of vaccination in the CML patient.

DOI： 10.1007/s12185-024-03723-1

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with BCR::ABL1 fusion. 国際誌

Shohei Mizuno, Akiyoshi Takami, Koji Kawamura, Kaito Harada, Masuko Masayoshi, Shingo Yano, Ayumu Ito, Yukiyasu Ozawa, Fumihiko Ouchi, Takashi Ashida, Yuichiro Nawa, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Atsuta, Masamitsu Yanada

EJHaem 5 ( 2 ) 369 - 378 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BCR::ABL1 fusion is found in < 1% of de novo acute myeloid leukemia (AML) cases and confers a poor prognosis. This Japanese nationwide survey analyzed patients with AML (n = 22) and mixed phenotype acute leukemia (MPAL) (n = 10) with t(9;22) or BCR::ABL1 who underwent allogeneic hematopoietic cell transplantation (allo-HCT) between 2002 and 2018. The 3-year overall survival (OS) rates were 81.3% and 56.0%, respectively (p = 0.15), and leukemia-free survival (LFS) rates were 76.2% and 42.0%, respectively (p = 0.10) in patients with AML and MPAL. The relapse rates were 9.5% and 14.0% (p = 0.93), and the non-relapse mortality (NRM) rates were 14.3% and 44.0%, respectively (p = 0.10) in patients with AML and MPAL. One in 17 patients with AML, with pre-transplant tyrosine kinase inhibitors (TKI), and three in five patients with AML, without pre-transplant TKI, did not achieve complete remission (CR) before allo-HCT (p = 0.024). Among the 20 patients with known disease status after allo-HCT, 95.0% were in hematological or molecular CR. None of the four patients who received post-transplant TKI for prophylaxis or measurable residual disease relapse experienced hematological relapse. In conclusion, our results suggest that pre-transplant TKI could improve disease status before allo-HCT. Moreover, allo-HCT resulted in high OS, high LFS, low relapse, and low NRM rates in patients with AML with BCR::ABL1.

DOI： 10.1002/jha2.877

同種移植後day30の末梢血CD8TN、CD4TEM割合は急性GVHD発症のバイオマーカーとなる

片桐隆幸, 古山悠里, 米沢穂高, 諏訪部達也, 布施香子, 柴崎康彦, 瀧澤淳, 曽根博仁, 増子正義

日本血液学会学術集会 85回 880 - 880 2023年10月

WT1ペプチドワクチン投与後10年間以上にわたり持続するWT1特異的な細胞傷害性T細胞

諏訪部達也, 柴崎康彦, 田村秀, 片桐隆幸, 井田桃里, 布施香子, 牛木隆志, 曽根博仁, 成田美和子, 増子正義

日本血液学会学術集会 85回 117 - 117 2023年10月

単一施設における節外性NK/T細胞リンパ腫、鼻腔(ENKL)における26例の後方視的解析 EBV-DNA定量の有用性

山田隆, 古山悠里, 水戸部正樹, 米沢穂高, 鈴木隆晴, 諏訪部達也, 片桐隆幸, 河本啓介, 布施香子, 柴崎康彦, 増子正義, 大島孝一, 曽根博仁, 瀧澤淳

日本血液学会学術集会 85回 294 - 294 2023年10月

BCR::ABL1融合遺伝子を有する急性骨髄性白血病に対する同種造血細胞移植成績

水野昌平, 高見昭良, 河村浩二, 原田介斗, 増子正義, 矢野真吾, 伊藤歩, 小澤幸康, 大内史彦, 芦田隆司, 名和由一郎, 一戸辰夫, 福田隆浩, 熱田由子, 柳田正光

日本血液学会学術集会 85回 31 - 31 2023年10月

Genetic manipulation resulting in decreased donor chondroitin sulfate synthesis mitigates hepatic GVHD via suppression of T cell activity. 国際誌

Suguru Tamura, Hajime Ishiguro, Tatsuya Suwabe, Takayuki Katagiri, Kaori Cho, Kyoko Fuse, Yasuhiko Shibasaki, Tadahisa Mikami, Takero Shindo, Hiroshi Kitagawa, Michihiro Igarashi, Hirohito Sone, Masayoshi Masuko, Takashi Ushiki

Scientific reports 13 ( 1 ) 13098 - 13098 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Donor T cell activation, proliferation, differentiation, and migration are the major steps involved in graft-versus-host disease (GVHD) development following bone marrow transplantation. Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and causes immune modulation by interacting with cell growth factors and inducing cell adhesion. However, its precise effects on immune function are unclear than those of other proteoglycan families. Thus, we investigated the significance of CS within donor cells in acute GVHD development utilizing CSGalNAc T1-knockout (T1KO) mice. To determine the effects of T1KO, the mice underwent allogenic bone marrow transplantation from major histocompatibility complex-mismatched donors. While transplantation resulted in hepatic GVHD with inflammatory cell infiltration of both CD4+ and CD8+ effector memory T cells, transplantation in T1KO-donors showed milder cell infiltration and improved survival with fewer splenic effector T cells. In vitro T-cell analyses showed that the ratio of effector memory T cells was significantly lower via phorbol myristate acetate/ionomycin stimulation. Moreover, quantitative PCR analyses showed significantly less production of inflammatory cytokines, such as IFN-γ and CCL-2, in splenocytes of T1KO mice. These results suggest that reduction of CS in donor blood cells may suppress the severity of acute GVHD after hematopoietic stem cell transplantation.

DOI： 10.1038/s41598-023-40367-3

皮膚硬化型慢性GVHDに対してイブルチニブが有効であった1例

佐藤美紀, 濱菜摘, 木村春奈, 長谷川瑛人, 阿部理一郎, 阿部由紀子, 諏訪部達也, 柴崎康彦, 増子正義

日本皮膚科学会雑誌 133 ( 5 ) 1420 - 1420 2023年5月

ヘパプラスチンテストを取り入れた出血原因鑑別の検査戦略後天性第V因子欠乏症における経験

松田将門, 山田隆, 古山悠里, 柴崎康彦, 関義信, 星山良樹, 寺井崇二, 瀧澤淳, 曽根博仁, 増子正義

日本血栓止血学会誌 34 ( 2 ) 262 - 262 2023年5月

Comparable survival outcomes with haploidentical stem cell transplantation and unrelated bone marrow transplantation. 国際誌

Yoshiko Atsuta, Junichi Sugita, Hirohisa Nakamae, Yumiko Maruyama, Ken Ishiyama, Souichi Shiratori, Takahiro Fukuda, Mio Kurata, Naoki Shingai, Yukiyasu Ozawa, Masayoshi Masuko, Koji Nagafuji, Satoru Takada, Shinichi Kako, Yoshinobu Kanda, Junya Kanda, Tatsuo Ichinohe, Takanori Teshima

Bone marrow transplantation 57 ( 12 ) 1781 - 1787 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

We retrospectively compared outcomes of unrelated donor bone marrow transplant (UBMT) and HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) using the Japanese registry data. Recipients of first HCT for acute leukemia and myelodysplastic syndromes between 2012 and 2015 were included. The analyzed subjects comprised UBMT recipients with 8/8 matched HLA alleles (n = 1470), 7/8 matched alleles (n = 859), 6/8 matched alleles (n = 186), and recipients of PTCy-haploPBSCT (n = 133). In multivariate analyses with 8/8 matched UBMT as the reference, PTCy-haploPBSCT showed similar overall mortality, decreased risk of non-relapse mortality (NRM), increased risk of relapse, and decreased risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD. Adjusted probabilities for 8/8 matched UBMT, PTCy-haploPBSCT, and 7/8 and 6/8 matched UBMT groups at 2 years post-transplant were 61%, 60%, 58%, and 52% for overall survival, 23%, 28%, 21%, and 19% for relapse, and 20%, 7%, 24%, and 33% for NRM. PTCy-haploPBSCT was associated with remarkably low NRM, contributing to survival outcomes that were comparable to 8/8 matched UBMT. The higher relapse rate in the PTCy-haploPBSCT group might be associated with the higher proportion of high-risk patients. PTCy-haploPBSCT may be a viable alternative when HLA-matched related donors are not available.

DOI： 10.1038/s41409-022-01822-3

Prognostic impact of complex karyotype on post-transplant outcomes of myelofibrosis. 国際誌

Yosuke Okada, Katsuto Takenaka, Makoto Murata, Yutaka Shimazu, Takayoshi Tachibana, Yukiyasu Ozawa, Naoyuki Uchida, Toshio Wakayama, Noriko Doki, Yasuhiro Sugio, Masatsugu Tanaka, Masayoshi Masuko, Hikaru Kobayashi, Kazuko Ino, Jun Ishikawa, Hirohisa Nakamae, Ken-Ichi Matsuoka, Yoshinobu Kanda, Takahiro Fukuda, Yoshiko Atsuta, Tokiko Nagamura-Inoue

Hematological oncology 40 ( 5 ) 1076 - 1085 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Chromosomal abnormalities in the role of prognostic factor for transplant patients with myelofibrosis (MF) are not fully investigated. Regarding complex karyotype (CK), we retrospectively analyzed 241 patients with primary and secondary MF who received a first allogeneic hematopoietic cell transplantation (HCT). Based on an unfavorable karyotype in the Dynamic International Prognostic Scoring System, we compared the outcomes in 3 groups: favorable karyotype, unfavorable karyotype including CK (unfavorable-CK(+)), and unfavorable karyotype not including CK (unfavorable-CK(-)). Overall survival was significantly shorter in the unfavorable-CK(+) group (hazard ratio (HR) 2.49, 95% CI: 1.46-4.24, P < 0.001), whereas there was no difference between the unfavorable-CK(-) group and the favorable group (HR 0.57, 95% CI: 0.20-1.59, P = 0.28). In addition, a significantly higher proportion of patients in the unfavorable-CK(+) group did not achieve complete remission after HCT (P = 0.007). The cumulative incidence of disease progression was significantly higher in the unfavorable-CK(+) group (HR 2.5, 95% CI 1.6-3.92, P < 0.001), whereas that in the unfavorable-CK(-) group was comparable to that in the favorable group (HR 0.49, 95% CI 0.12-1.94, P = 0.31). Further investigations will be needed to clarify the impact of CK on transplant outcomes in MF.

DOI： 10.1002/hon.3058

Comparable survival outcomes with haploidentical stem cell transplantation and cord blood transplantation. 国際誌

Junichi Sugita, Yoshiko Atsuta, Hirohisa Nakamae, Yumiko Maruyama, Ken Ishiyama, Souichi Shiratori, Takahiro Fukuda, Mio Kurata, Naoki Shingai, Yukiyasu Ozawa, Masayoshi Masuko, Koji Nagafuji, Naoyuki Uchida, Masatsugu Tanaka, Makoto Onizuka, Junya Kanda, Takafumi Kimura, Tatsuo Ichinohe, Takanori Teshima

Bone marrow transplantation 57 ( 11 ) 1681 - 1688 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCBT) are alternative to HLA-matched stem cell transplantation. We conducted a matched-pair analysis of PTCy-haplo and UCBT using the Japanese registry data. We identified 136 patients aged between 16 and 69 years who received PTCy-haplo as their first transplantation for acute leukemia or myelodysplastic syndromes. Control group included 408 UCBT recipients selected to match the PTCy-haplo group. Overall and relapse-free survival probabilities at 2 years were comparable between the PTCy-haplo and UCBT groups: 55% vs. 53% for overall survival (p = 0.46), and 47% vs. 48% for relapse-free survival (p = 0.79), respectively. The cumulative incidence of relapse was significantly higher (43% vs. 29%, respectively, p = 0.006), while the cumulative incidence of non-relapse mortality (NRM) was significantly lower (9% vs. 23%, respectively, p < 0.001) in the PTCy-haplo group. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was lower in the PTCy-haplo group compared to the UCBT group (29% vs. 41%, respectively, p = 0.016), while those of grade III-IV acute GVHD and chronic GVHD were not statistically different between the two groups. Our results suggest that both PTCy-haplo and UCBT are viable alternatives to HLA-matched stem cell transplantation.

DOI： 10.1038/s41409-022-01770-y

Comparison of transplant outcomes between haploidentical transplantation and single cord blood transplantation in non‐remission acute myeloid leukaemia: A nationwide retrospective study

Kensuke Matsuda, Takaaki Konuma, Kyoko Fuse, Masayoshi Masuko, Koji Kawamura, Masahiro Hirayama, Naoyuki Uchida, Kazuhiro Ikegame, Atsushi Wake, Tetsuya Eto, Noriko Doki, Shigesaburo Miyakoshi, Masatsugu Tanaka, Satoshi Takahashi, Makoto Onizuka, Koji Kato, Takafumi Kimura, Tatsuo Ichinohe, Nobuyuki Takayama, Hikaru Kobayashi, Hirohisa Nakamae, Yoshiko Atsuta, Junya Kanda, Masamitsu Yanada

British Journal of Haematology 2022年10月

Salvage single-unit unrelated cord blood transplantation for graft failure following initial allogeneic transplantation in adult acute myeloid leukemia: trends in outcomes over the past 20 years. 国際誌

Takaaki Konuma, Kaito Harada, Tadakazu Kondo, Masayoshi Masuko, Naoyuki Uchida, Shingo Yano, Toshiro Kawakita, Makoto Onizuka, Shuichi Ota, Emiko Sakaida, Shigesaburo Miyakoshi, Yukiyasu Ozawa, Yutaka Imamura, Takafumi Kimura, Yoshinobu Kanda, Takahiro Fukuda, Yoshiko Atsuta, Masamitsu Yanada

Bone marrow transplantation 57 ( 12 ) 1848 - 1850 2022年10月

WT1ペプチドワクチン投与後10年間以上にわたり持続するWT1特異的な細胞傷害性T細胞

諏訪部達也, 柴崎康彦, 田村秀, 片桐隆幸, 井田桃里, 布施香子, 牛木隆志, 曽根博仁, 成田美和子, 増子正義

日本血液学会学術集会 84回 117 - 117 2022年10月

単一施設における節外性NK/T細胞リンパ腫、鼻腔(ENKL)における26例の後方視的解析 EBV-DNA定量の有用性

山田隆, 古山悠里, 水戸部正樹, 米沢穂高, 鈴木隆晴, 諏訪部達也, 片桐隆幸, 河本啓介, 布施香子, 柴崎康彦, 増子正義, 大島孝一, 曽根博仁, 瀧澤淳

日本血液学会学術集会 84回 294 - 294 2022年10月

同種移植後day30の末梢血CD8TN、CD4TEM割合は急性GVHD発症のバイオマーカーとなる

片桐隆幸, 古山悠里, 米沢穂高, 諏訪部達也, 布施香子, 柴崎康彦, 瀧澤淳, 曽根博仁, 増子正義

日本血液学会学術集会 84回 880 - 880 2022年10月

Registry data analysis of hematopoietic stem cell transplantation on systemic chronic active Epstein–Barr virus infection patients in Japan

Masahide Yamamoto, Maho Sato, Yasushi Onishi, Yoji Sasahara, Hideki Sano, Masayoshi Masuko, Hirohisa Nakamae, Ken‐ichi Matsuoka, Takahide Ara, Kana Washio, Makoto Onizuka, Kenichiro Watanabe, Yoshiyuki Takahashi, Tsuneaki Hirakawa, Miwako Nishio, Chizuko Sakashita, Tohru Kobayashi, Akihisa Sawada, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Hashii, Yoshiko Atsuta, Ayako Arai

American Journal of Hematology 2022年3月

Altered microbiota by a high-fat diet accelerates lethal myeloid hematopoiesis associated with systemic SOCS3 deficiency. 査読国際誌

Kaori Cho, Takashi Ushiki, Hajime Ishiguro, Suguru Tamura, Masaya Araki, Tatsuya Suwabe, Takayuki Katagiri, Mari Watanabe, Yoko Fujimoto, Riuko Ohashi, Yoichi Ajioka, Ippei Shimizu, Shujiro Okuda, Masayoshi Masuko, Yoshimi Nakagawa, Hideyo Hirai, Warren S Alexander, Hitoshi Shimano, Hirohito Sone

iScience 24 ( 10 ) 103117 - 103117 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling required to prevent excessive cellular responses. In particular, SOCS3 is involved in the regulation of metabolic syndromes, such as obesity and diabetes, by suppressing leptin and insulin signals. SOCS3 also suppresses the inflammatory response associated with metabolic stress, but this specific role remains undefined. Wild-type mice on a high-fat diet (HFD) exhibited only fatty liver, whereas systemic deletion of SOCS3 resulted in excessive myeloid hematopoiesis and hepatic inflammation. In addition, depletion of the gut microbiota resulted in considerable improvement in excess granulopoiesis and splenomegaly, halting the progression of systemic inflammation in SOCS3KO mice on the HFD. This result suggests that intestinal dysbiosis is involved in inflammation associated with SOCS3KO. Although contributing to diet-induced obesity and fatty liver, SOCS3 is nevertheless critical to suppress excess myeloid hematopoiesis and severe systemic inflammation associated with intestinal dysbiosis on HFD.

DOI： 10.1016/j.isci.2021.103117

イノツズマブによる再寛解導入に引き続いてブリナツモマブを投与し再移植できたB-ALLの1例

米澤穂高, 布施香子, 水戸部正樹, 武田るい, 諏訪部達也, 片桐隆幸, 柴崎康彦, 瀧澤淳, 成田美和子, 曽根博仁, 増子正義

臨床血液 62 ( 10 ) 1526 - 1526 2021年10月

イノツズマブによる再寛解導入に引き続いてブリナツモマブを投与し再移植できたB-ALLの1例

米澤穂高, 布施香子, 水戸部正樹, 武田るい, 諏訪部達也, 片桐隆幸, 柴崎康彦, 瀧澤淳, 成田美和子, 曽根博仁, 増子正義

臨床血液 62 ( 10 ) 1526 - 1526 2021年10月

Syngeneic hematopoietic stem cell transplantation for acute myeloid leukemia: a propensity score-matched analysis. 査読国際誌

Shuhei Kurosawa, Shohei Mizuno, Yasuyuki Arai, Masayoshi Masuko, Junya Kanda, Kentaro Kohno, Daishi Onai, Takahiro Fukuda, Yukiyasu Ozawa, Yuta Katayama, Masatsugu Tanaka, Kazuhiro Ikegame, Naoyuki Uchida, Tetsuya Eto, Shuichi Ota, Junji Tanaka, Tatsuo Ichinohe, Yoshiko Atsuta, Masamitsu Yanada

Blood cancer journal 11 ( 9 ) 159 - 159 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

The present study evaluated outcomes and prognostic factors in adult patients with acute myeloid leukemia (AML) after syngeneic hematopoietic stem cell transplantation (HSCT). Among patients in first complete remission (CR1), outcomes of syngeneic HSCT (Syn) were compared with those of autologous HSCT (Auto), allogeneic HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), or allogeneic HSCT from HLA-matched unrelated donor (MUD). Among 11,866 patients receiving first HSCT, 26 in the Syn group were analyzed. The 5-year overall survival (OS) rate, the cumulative incidence of relapse, and the cumulative incidence of non-relapse mortality (NRM) were 47.8%, 59.6%, and 4.6%, respectively. The OS was significantly better in patients in CR1 (n = 13) than in patients in non-CR1 (P = 0.012). Furthermore, 39 patients in CR1 each were assigned to the Auto, MSD, and MUD groups using propensity score matching. The 5-year OS in the Syn (68.4%) was not significantly different from those in the Auto (55.9%, P = 0.265), MSD (62.4%, P = 0.419), or MUD (63.7%, P = 0.409) groups. A higher relapse in the Syn than in the MSD and MUD groups was offset by lower NRM. In summary, syngeneic HSCT might be an alternative option for AML patients in CR1.

DOI： 10.1038/s41408-021-00553-w

AMLにおける造血幹細胞移植後1年未満の再発は高い死亡率と相関する(Post-transplant relapse of AML within one year is associated with a high mortality rate)

片桐隆幸, 本宮奈津子, 武田ルイ, 水戸部正樹, 米沢穂高, 諏訪部達也, 布施香子, 柴崎康彦, 瀧澤淳, 曽根博仁, 増子正義

日本血液学会学術集会 83回 PS - 10 2021年9月

WT1ペプチドワクチン投与後のCML患者におけるWT1特異的CTLの持続性と多様性(Persistence and diversity of WT1-specific CTLs in a CML patient vaccinated WT1 peptide)

諏訪部達也, 柴崎康彦, 田村秀, 片桐隆幸, 布施香子, 牛木隆志, 曽根博仁, 成田美和子, 増子正義

日本血液学会学術集会 83回 PS - 1 2021年9月

ドナーリンパ球のコンドロイチン硫酸合成低下はGVHDを軽減する(Genetic manipulation resulting in decreased donor chondroitin sulfate mitigates GVHD in mice)

田村秀, 牛木隆志, 諏訪部達也, 片桐隆幸, 石黒創, 布施香子, 柴崎康彦, 進藤岳郎, 五十嵐道弘, 曽根博仁, 増子正義

日本血液学会学術集会 83回 OS3 - 1 2021年9月

Intensive oral care can reduce bloodstream infection with coagulase-negative staphylococci after neutrophil engraftment in allogeneic hematopoietic stem-cell transplantation. 査読国際誌

Tatsuya Suwabe, Kyoko Fuse, Kouji Katsura, Marie Soga, Takayuki Katagiri, Yasuhiko Shibasaki, Miwako Narita, Hirohito Sone, Masayoshi Masuko

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 30 ( 1 ) 475 - 485 2021年7月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Bloodstream infection (BSI) is a major complication of allogeneic hematopoietic stem-cell transplantation (allo-SCT). There are several causes of BSI; in particular, severe oral mucositis (OM) can induce BSI due to coagulase-negative staphylococci (CoNS). The OM severity may be reduced with intensive oral care. Thus, we evaluated whether the type of oral care affects the BSI incidence eventually. METHOD: We performed retrospective analysis on 206 recipients who underwent allo-SCT from 2006 to 2017 at our institute. Intensive oral care by a dental specialist was performed for 111 recipients (intensive-care group) and self-oral care was performed by 95 recipients (self-care group). Incidence of BSI was assessed by type of the oral care, before neutrophil engraftment (pre-E-BSI) and after neutrophil engraftment (post-E-BSI) period until 180 days after allo-SCT. RESULT: A total of 112 BSI occurred in 90 of the 206 recipients and 120 bacteria were identified, with CoNS being the most prevalent. There was no significant difference in the incidence of pre-E-BSI between the self-care and intensive-care groups (30.8% and 30.6%, respectively; P = 0.508). Meanwhile, the incidence of post-E-BSI was significantly lower in the intensive-care group than in the self-care group (14.3% and 28.6%; P = 0.008). In addition, the intensive-care group had significantly lower incidence of post-E-BSI with CoNS than the self-care group (8.5% and 21.5%, respectively; P = 0.009). CONCLUSION: Intensive oral care through the period of allo-HCT can significantly reduce the post-E-BSI occurrence, especially due to CoNS.

DOI： 10.1007/s00520-021-06447-8

Prognostic value of measurable residual disease at allogeneic transplantation for adults with core binding factor acute myeloid leukemia in complete remission. 査読国際誌

Takaaki Konuma, Tadakazu Kondo, Masayoshi Masuko, Hiroaki Shimizu, Souichi Shiratori, Takahiro Fukuda, Jun Kato, Masashi Sawa, Yukiyasu Ozawa, Shuichi Ota, Naoyuki Uchida, Yoshinobu Kanda, Shinichi Kako, Shin Fujisawa, Kentaro Fukushima, Tatsuo Ichinohe, Yoshiko Atsuta, Masamitsu Yanada

Bone marrow transplantation 56 ( 11 ) 2779 - 2787 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pretransplant measurable residual disease (MRD) has been shown to be associated with relapse incidence following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). However, it remains less clear whether pretransplant MRD status affects transplant outcomes in core binding factor AML (CBF-AML). We retrospectively evaluated the effect of pretransplant MRD, which was measured by a polymerase chain reaction of RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcripts, on transplant outcomes for a cohort of 959 adult patients with t(8;21) or inv(16) AML treated by allogeneic HCT during complete remission (CR), between 2000 and 2018. Multivariate analysis showed the absence of pretransplant MRD was significantly associated with lower relapse (hazard ratio [HR], 0.46; P < 0.001), treatment failure (HR, 0.66; P = 0.004), and overall mortality (HR, 0.72; P = 0.037) among patients with t(8;21). However, pretransplant MRD negativity was not associated with relapse (HR, 0.73; P = 0.420), treatment failure (HR, 0.64; P = 0.063), or overall mortality (HR, 0.69; P = 0.149) among patients with inv(16). In subgroup analysis, pretransplant MRD status significantly affected relapse and LFS only in patients with t(8;21) undergoing allogeneic HCT during CR2. In conclusion, our data demonstrate the different prognostic values of pretransplant MRD for CBF-AML, highlighting the need to develop effective therapeutic strategies for such MRD-positive patients.

DOI： 10.1038/s41409-021-01409-4

Single cord blood transplantation for acute myeloid leukemia patients aged 60 years or older: a retrospective study in Japan. 査読国際誌

Masamichi Isobe, Takaaki Konuma, Masayoshi Masuko, Naoyuki Uchida, Shigesaburo Miyakoshi, Yasuhiro Sugio, Shuro Yoshida, Masatsugu Tanaka, Yoshiko Matsuhashi, Norimichi Hattori, Makoto Onizuka, Nobuyuki Aotsuka, Yasushi Kouzai, Atsushi Wake, Takafumi Kimura, Tatsuo Ichinohe, Yoshiko Atsuta, Masamitsu Yanada

Annals of hematology 100 ( 7 ) 1849 - 1861 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The availability of alternative donor sources could allow elderly patients to receive allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated the outcomes of single-unit cord blood transplantation (CBT) in 1577 patients aged ≥60 years with acute myeloid leukemia (AML) in Japan between 2002 and 2017. In total, 990 (63%) patients were not in complete remission (CR) at the time of CBT. A myeloablative conditioning regimen (52%) and calcineurin inhibitor (CI) + mycophenolate mofetil (MMF)-based graft-versus-host disease (GVHD) prophylaxis (45%) were more commonly used. With a median follow-up for survivors of 31 months, the probability of overall survival and the cumulative incidence of leukemia-related mortality at 3 years was 31% and 29%, respectively. The cumulative incidence of non-relapse mortality (NRM) at 100 days and 3 years were 24% and 41%, respectively. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 100 days and extensive chronic GVHD at 2 years were 44%, 16%, and 14%, respectively. The cumulative incidence of neutrophil engraftment was 80% at 42 days. Results of multivariate analysis indicated that the following factors were significantly associated with higher overall mortality: performance status ≥1, hematopoietic cell transplantation-specific comorbidity index ≥3, adverse cytogenetics, extramedullary disease at diagnosis, and non-CR status at CBT. By contrast, female sex, HLA disparities ≥2, mycophenolate mofetil-based GVHD prophylaxis, and recent CBT were significantly associated with lower overall mortality. In conclusion, single CBT offers a curative option for AML patients aged ≥60 years with careful patient selection.

DOI： 10.1007/s00277-021-04464-5

陰茎・陰嚢病変を合併した精巣原発DLBCL

水戸部正樹, 武田ルイ, 米沢穂高, 田村秀, 諏訪部達也, 片桐隆幸, 河本啓介, 布施香子, 柴崎康彦, 増子正義, 井上佳菜子, 三好寛明, 大島孝一, 曽根博仁, 瀧澤淳

臨床血液 62 ( 6 ) 668 - 668 2021年6月

同種造血幹細胞移植後の慢性GVHDとしての類上皮肉芽腫および多発筋炎

諏訪部達也, 布施香子, 水戸部正樹, 武田ルイ, 米沢穂高, 片桐隆幸, 河本啓介, 牛木隆志, 柴崎康彦, 瀧澤淳, 成田美和子, 曽根博仁, 大島孝一, 増子正義

臨床血液 62 ( 6 ) 675 - 675 2021年6月

WT1-specific CD8 + cytotoxic T cells with the capacity for antigen-specific expansion accumulate in the bone marrow in MDS. 査読

Tatsuya Suwabe, Yasuhiko Shibasaki, Hiroyuki Sato, Suguru Tamura, Takayuki Katagiri, Hiroki Nemoto, Takuya Kasami, Takashi Kozakai, Ayako Nanba, Toshiki Kitajima, Kyoko Fuse, Takashi Ushiki, Hirohito Sone, Miwako Narita, Masayoshi Masuko

International journal of hematology 113 ( 5 ) 723 - 734 2021年5月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Wilms' tumor 1 (WT1) is a tumor-associated antigen and immunotherapy target in myelodysplastic syndrome (MDS). Further information is needed on the characteristics of WT1-specific CD8 + T cells to develop immunotherapeutic strategies for MDS. To clarify the frequency, distribution, and phenotype of WT1-specific CD8 + T cells, which occur innately in MDS patients, we analyzed paired peripheral blood (PB) and bone marrow (BM) samples from 39 patients with MDS or acute myeloid leukemia with myelodysplasia-related changes. The median frequency of WT1 tetramer-binding CD8 + T cells in the CD8 + T cell population was 0.11% in PB and 0.18% in BM. A further tetramer assay combined with mixed lymphocyte peptide culture (MLPC assay) was used to detect functional WT1-specific CD8 + T cells that could respond to the WT1 peptide. Functional WT1-specific CD8 + T cells were detected in BM in 61% of patients, which was significantly higher than in PB (23%, p = 0.001). The frequency of these cells estimated by the MLPC assay was tenfold higher in BM than in PB. The majority of WT1 tetramer-binding CD8 + T cells in BM had a unique phenotype with co-expression of CD39 and CXCR4. These findings will facilitate the development of novel immunotherapeutic strategies for MDS.

DOI： 10.1007/s12185-021-03083-0

乾燥人フィブリノゲン製剤の継続輸注で着床・妊娠継続・出産をし得た先天性低フィブリノゲン血症

関義信, 牛木隆志, 増子正義, 瀧澤淳, 曽根博仁, 奥村伸生

日本血栓止血学会誌 32 ( 2 ) 214 - 214 2021年5月

GB療法施行中にHigh-grade B-cell lymphoma with MYC and BCL2 rearrangementsで再燃したFollicular lymphoma(Grade 3A)の2症例

水戸部正樹, 本宮奈津子, 武田ルイ, 米沢穂高, 鈴木隆晴, 諏訪部達也, 片桐隆幸, 河本啓介, 布施香子, 柴崎康彦, 増子正義, 井上佳菜子, 三好寛明, 大島孝一, 曽根博仁, 瀧澤淳

日本リンパ網内系学会会誌 61 114 - 114 2021年5月

腎障害を有する高悪性度B細胞リンパ腫症例にDA-EPOCH-Rを施行した1例

水戸部正樹, 河本啓介, 鈴木隆晴, 米沢穂高, 田村秀, 諏訪部達也, 根本洋樹, 布施香子, 柴崎康彦, 増子正義, 三好寛明, 大島孝一, 曽根博仁, 瀧澤淳

臨床血液 62 ( 5 ) 532 - 532 2021年5月

ルキソルチニブ・ヒドロキシウレア併用療法が奏効した慢性好中球性白血病(CNL)の1例

武田ルイ, 布施香子, 片桐隆幸, 河本啓介, 柴崎康彦, 瀧澤淳, 成田美和子, 野本信彦, 曽根博仁, 増子正義

臨床血液 62 ( 5 ) 529 - 530 2021年5月

Distinct effects of chondroitin sulfate on hematopoietic cells and the stromal microenvironment in bone marrow hematopoiesis. 査読国際誌

Takayuki Katagiri, Shun Uemura, Takashi Ushiki, Yaeko Nakajima-Takagi, Motohiko Oshima, Tadahisa Mikami, Asami Kawasaki, Hajime Ishiguro, Tomoyuki Tanaka, Hirohito Sone, Hiroshi Kitagawa, Michihiro Igarashi, Atsushi Iwama, Masayoshi Masuko

Experimental hematology 96 52 - 62 2021年4月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

The bone marrow (BM) microenvironment, known as the BM niche, regulates hematopoiesis but is also affected by interactions with hematopoietic cells. Recent evidence indicates that extracellular matrix components are involved in these interactions. Chondroitin sulfate (CS), a glycosaminoglycan, is a major component of the extracellular matrix; however, it is not known whether CS has a physiological role in hematopoiesis. Here, we analyzed the functions of CS in hematopoietic and niche cells. CSGalNAcT1, which encodes CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, was highly expressed in hematopoietic stem and progenitor cells (HSPCs) and endothelial cells (ECs), but not in mesenchymal stromal cells (MSCs) in BM. In T1 knockout (T1KO) mice, a greater number of HSPCs existed compared with the wild-type (WT), but HSPCs from T1KO mice showed significantly impaired repopulation in WT recipient mice on serial transplantation. RNA sequence analysis revealed the activation of IFN-α/β signaling and endoplasmic reticulum stress in T1KO HSPCs. In contrast, the number of WT HSPCs repopulated in T1KO recipient mice was larger than that in WT recipient mice after serial transplantation, indicating that the T1KO niche supports repopulation of HSPCs better than the WT niche. There was no obvious difference in the distribution of vasculature and MSCs between WT and T1KO BM, suggesting that CS loss alters vascular niche functions without affecting its structure. Our results revealed distinct roles of CS in hematopoietic cells and BM niche, indicating that crosstalk between these components is important to maintain homeostasis in BM.

DOI： 10.1016/j.exphem.2021.02.003

DA-EPOCH-R therapy for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in a patient with renal dysfunction. 査読

Masaki Mitobe, Keisuke Kawamoto, Takaharu Suzuki, Tatsuya Suwabe, Yasuhiko Shibasaki, Masayoshi Masuko, Kanako Inoue, Hiroaki Miyoshi, Koichi Ohshima, Hirohito Sone, Jun Takizawa

Journal of clinical and experimental hematopathology : JCEH 61 ( 1 ) 42 - 47 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit lymphoma, has been reported as refractory to R-CHOP therapy and requires more intensive regimens. However, intensive and safe regimens for patients with renal dysfunction are unknown. Herein, we report the successful use of DA-EPOCH-R therapy for double-hit lymphoma in a 64-year-old man with renal dysfunction. The patient had lymphoma-induced bilateral ureteral obstruction. Although renal dysfunction remained after removing the obstruction using R-CHOP therapy, we completed six cycles of DA-EPOCH-R therapy without any major adverse events. DA-EPOCH-R therapy may be a safe regimen for renal dysfunction patients.

DOI： 10.3960/jslrt.20043

A multicenter phase II study of intrabone single-unit cord blood transplantation without antithymocyte globulin. 査読国際誌

Tetsuya Nishida, Takeshi Kobayashi, Masashi Sawa, Shinichi Masuda, Yasuhiko Shibasaki, Tatsunori Goto, Noriko Fukuhara, Nobuharu Fujii, Kazuhiro Ikegame, Junichi Sugita, Takashi Ikeda, Yachiyo Kuwatsuka, Ritsuro Suzuki, Yuho Najima, Noriko Doki, Tomonori Kato, Yuichiro Inagaki, Yoshikazu Utsu, Nobuyuki Aotsuka, Masayoshi Masuko, Seitaro Terakura, Yasushi Onishi, Yoshinobu Maeda, Masaya Okada, Takanori Teshima, Makoto Murata

Annals of hematology 100 ( 3 ) 743 - 752 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

To overcome the delayed or failed engraftment after unrelated cord blood transplantation (CBT), we conducted a multicenter phase II study of intrabone single-unit CBT without antithymocyte globulin (ATG) for adult patients with hematological malignancies (UMIN-CTR, UMIN000020997). Sixty-four patients received an intrabone injection of unwashed (n = 61) or washed (n = 3) cord blood after local anesthesia. All injection-related adverse events were mild and resolved spontaneously. Sixty-two patients were evaluable for the efficacy of intrabone CBT of serological HLA-A, -B, and -DR ≥ 4/6 matched cord blood with a median number of 2.57 × 107/kg cryopreserved total nucleated cells. The probability of survival with neutrophil engraftment on day 28 was 77.4% (95% confidence interval, 67.0-85.8%), which exceeded the threshold value. The cumulative incidences of neutrophils ≥ 0.5 × 109/L on day 60 was 80.6% (68.2-88.6%), with a median time to recovery of 21 days after transplantation. The cumulative incidences of platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L on day 100 were 75.8% (62.6-84.9%) and 72.6% (59.4-82.1%), respectively, with median time to platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L of 38 and 45 days after transplantation, respectively. The cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease were 29.0% and 6.5%, respectively. All responded to steroid therapy, and secondary treatments were not required. The present study suggests the efficacy of intrabone single-unit CBT without ATG in terms of early engraftment and controllable acute graft-versus-host disease.

DOI： 10.1007/s00277-020-04365-z

Marker chromosome is a strong poor prognosis factor after allogeneic HSCT for adverse-risk AML patients. 査読国際誌

Kyoko Fuse, Tomoyuki Tanaka, Yasuhiko Shibasaki, Tatsuo Furukawa, Miwako Narita, Hirohito Sone, Masayoshi Masuko

European journal of haematology 105 ( 5 ) 616 - 625 2020年11月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Chromosome analysis is necessary for the risk classification of acute myeloid leukemia (AML). Marker chromosome (MC) is a fragmented chromosome whose origin cannot be identified from other chromosomes and originates from marked genomic instability. Although AML with MC (MC+) has a poor prognosis even after intensive chemotherapy, its influence on the outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. OBJECTIVE AND METHODS: We retrospectively analyzed 162 AML patients after allo-HSCT. To evaluate the significance of MC, we compared it with other chromosomal abnormalities. RESULT: Marker chromosome was detected in 14 (8.6%, MC+) patients (vs MC-, n = 158). The 2-year overall survival (OS) in MC+ vs MC- was 26.8% vs 62.2% (P = .0098). The 2-year cumulative incidence of relapse (CIR) in MC+ vs MC- was 80.4% vs 35.5% (P = .0004). Among adverse-risk AML (AD-AML, n = 36), AD-AML/MC+ (n = 11) demonstrated a poorer 2-year OS (9.1%, vs AD-AML/MC- n = 25, 58.3%, P = .0031) and higher 2-year CIR (89.6%, vs AD-AML/MC- 44.7%, P = .002). In multivariate analysis, MC (HR 3.08, 95% CI; 1.02-9.29, P = .046) and HCT-CI (HR 3.23, 95% CI; 1.00-10.4, P = .049) were independent risk factors for CIR among AD-AML. CONCLUSION: Our study suggests MC as a new independent factor for chromosome risk classification to further classify AD-AML.

DOI： 10.1111/ejh.13495

Allogeneic hematopoietic cell transplantation efficacy in patients with Philadelphia chromosome-positive acute myeloid leukemia in complete remission. 査読国際誌

Shohei Mizuno, Masamitsu Yanada, Koji Kawamura, Masayoshi Masuko, Naoyuki Uchida, Yukiyasu Ozawa, Koji Iwato, Kazuteru Ohashi, Kazuhiro Ikegame, Sung-Won Kim, Masatsugu Tanaka, Tetsuya Eto, Yoshinobu Kanda, Takahiro Fukuda, Yoshiko Atsuta, Shingo Yano, Akiyoshi Takami

Bone marrow transplantation 56 ( 1 ) 232 - 242 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML) confers a dismal prognosis when treated with chemotherapy alone. Data on allogeneic hematopoietic cell transplantation (allo-HCT) outcomes are limited. We retrospectively analyzed 4649 AML patients who received allo-HCT and were in complete remission. Outcomes of Ph+ AML (n = 30), intermediate-risk, and poor-risk AML patients were compared. The 3-year overall survival after allo-HCT was similar in intermediate-risk (62.7%; 95% CI: 61.0-64.3%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.42); however, it differed significantly between the poor-risk (49.7%; 95% CI: 45.9-53.4%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.049). Disease-free survival in Ph+ AML patients was comparable to that in intermediate-risk patients but better than that in poor-risk patients. Relapse rates were significantly lower in Ph+ AML patients than in other groups. Non-relapse mortality (NRM) rates were similar among groups. Multivariate analysis showed that Ph+ AML was not a significant predictor of poor prognosis in terms of overall survival, disease-free survival, relapse, and NRM. Our data showed better post-transplant outcomes for Ph+ AML patients than for those with poor-risk AML. Hence, allo-HCT could be a feasible treatment option for Ph+ AML patients.

DOI： 10.1038/s41409-020-01011-0

Hypertrophic pachymeningitis associated with myelodysplastic syndrome

Akane Kaihatsu, Kyoko Fuse, Hirohito Sone, Masayoshi Masuko

eJHaem 1 ( 1 ) 12 - 13 2020年7月

The Glasgow prognostic score divides high-risk hematopoietic cell transplantation-specific comorbidity index patients into stratified subgroups in allogeneic hematopoietic cell transplantation. 査読国際誌

Yasuhiko Shibasaki, Tatsuya Suwabe, Takayuki Katagiri, Kyoko Fuse, Miwako Narita, Hirohito Sone, Masayoshi Masuko

Annals of hematology 99 ( 3 ) 671 - 673 2020年3月

Time-Varying Effects of Graft Type on Outcomes for Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation. 査読国際誌

Masamitsu Yanada, Takaaki Konuma, Satoshi Yamasaki, Yachiyo Kuwatsuka, Masayoshi Masuko, Masatsugu Tanaka, Yukiyasu Ozawa, Takashi Toya, Takahiro Fukuda, Shuichi Ota, Masashi Sawa, Naoyuki Uchida, Hirohisa Nakamae, Tetsuya Eto, Junya Kanda, Minoko Takanashi, Yoshinobu Kanda, Yoshiko Atsuta, Shingo Yano

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 26 ( 2 ) 307 - 315 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

This study aimed to investigate time-varying effects of graft type on outcomes for patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant. For this purpose we analyzed 3952 patients, 720 of whom underwent matched related bone marrow transplantation (BMT), 1004 matched related peripheral blood stem cell transplantation (PBSCT), 856 matched unrelated BMT, and 1372 umbilical cord blood transplantation (UCBT) during complete remission. The 4-year relapse-free survival (RFS) rates were 59.1%, 52.8%, 59.5%, and 50.6%, respectively. Compared with related BMT, related PBSCT, unrelated BMT, and UCBT were associated with higher risk of nonrelapse mortality and unrelated BMT and UCBT with lower risk of relapse. As a result, both RFS and overall survival were comparable between related BMT and unrelated BMT but were worse for related PBSCT and UCBT than for related BMT. Adverse impact of UCBT was observed only during the early phase of transplant, whereas that of related PBSCT continued even after 2 years post-transplant. Our findings raise concerns about the increased risk of late nonrelapse mortality with the use of PBSC grafts and suggest that related BMT is preferable to related PBSCT; matched unrelated BMT is the next choice in the absence of a matched related donor.

DOI： 10.1016/j.bbmt.2019.09.036

Role of RNF213 p.4810K variant in the development of intracranial arterial disease in patients treated with nilotinib. 査読国際誌

Masahiro Uemura, Masato Kanazawa, Takuma Yamagishi, Takahiro Nagai, Mami Takahashi, Shingo Koide, Masayoshi Tada, Junsuke Shimbo, Aiko Isami, Kunihiko Makino, Masayoshi Masuko, Kouji Nikkuni, Kouichirou Okamoto, Shuichi Igarashi, Kenichi Morita, Osamu Onodera

Journal of the neurological sciences 408 116577 - 116577 2020年1月

Using a machine learning algorithm to predict acute graft-versus-host disease following allogeneic transplantation. 査読国際誌

Yasuyuki Arai, Tadakazu Kondo, Kyoko Fuse, Yasuhiko Shibasaki, Masayoshi Masuko, Junichi Sugita, Takanori Teshima, Naoyuki Uchida, Takahiro Fukuda, Kazuhiko Kakihana, Yukiyasu Ozawa, Tetsuya Eto, Masatsugu Tanaka, Kazuhiro Ikegame, Takehiko Mori, Koji Iwato, Tatsuo Ichinohe, Yoshinobu Kanda, Yoshiko Atsuta

Blood advances 3 ( 22 ) 3626 - 3634 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Acute graft-versus-host disease (aGVHD) is 1 of the critical complications that often occurs following allogeneic hematopoietic stem cell transplantation (HSCT). Thus far, various types of prediction scores have been created using statistical calculations. The primary objective of this study was to establish and validate the machine learning-dependent index for predicting aGVHD. This was a retrospective cohort study that involved analyzing databases of adult HSCT patients in Japan. The alternating decision tree (ADTree) machine learning algorithm was applied to develop models using the training cohort (70%). The ADTree algorithm was confirmed using the hazard model on data from the validation cohort (30%). Data from 26 695 HSCT patients transplanted from allogeneic donors between 1992 and 2016 were included in this study. The cumulative incidence of aGVHD was 42.8%. Of >40 variables considered, 15 were adapted into a model for aGVHD prediction. The model was tested in the validation cohort, and the incidence of aGVHD was clearly stratified according to the categorized ADTree scores; the cumulative incidence of aGVHD was 29.0% for low risk and 58.7% for high risk (hazard ratio, 2.57). Predicting scores for aGVHD also demonstrated the link between the risk of development aGVHD and overall survival after HSCT. The machine learning algorithms produced clinically reasonable and robust risk stratification scores. The relatively high reproducibility and low impacts from the interactions among the variables indicate that the ADTree algorithm, along with the other data-mining approaches, may provide tools for establishing risk score.

DOI： 10.1182/bloodadvances.2019000934

Clinical practice recommendations for the diagnosis and management of human herpesvirus-6B encephalitis after allogeneic hematopoietic stem cell transplantation: the Japan Society for Hematopoietic Cell Transplantation. 査読国際誌

Masao Ogata, Naoyuki Uchida, Takahiro Fukuda, Kazuhiro Ikegame, Tomohiko Kamimura, Makoto Onizuka, Koji Kato, Hikaru Kobayashi, Yoji Sasahara, Masashi Sawa, Akihisa Sawada, Daiichiro Hasegawa, Masayoshi Masuko, Toshihiro Miyamoto, Shinichiro Okamoto

Bone marrow transplantation 55 ( 6 ) 1004 - 1013 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Reactivation of human herpesvirus (HHV)-6B is relatively common after allogeneic hematopoietic stem cell transplantation (HSCT) and HHV-6B diseases may consequently develop. Among them, HHV-6B encephalitis is a serious and often fatal complication. The aim of these clinical practice recommendations is to provide diagnostic and therapeutic guidance for HHV-6B encephalitis after allogeneic HSCT. In this evidence-based review, we critically evaluated data from the published literature. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assist in generating recommendations. We have summarized the findings that contribute to decision-making and we have provided our recommendations. In cases where rigorous clinical data are unavailable, recommendations have been developed in discussions with physicians who have relevant expertize.

DOI： 10.1038/s41409-019-0752-5

骨髄異形成症候群と低悪性度B細胞リンパ腫を合併し、多彩な合併症を呈した1例

海發茜, 小堺貴司, 田村秀, 片桐隆幸, 河本啓介, 難波亜矢子, 布施香子, 牛木隆志, 柴崎康彦, 森山雅人, 瀧澤淳, 成田美和子, 曽根博仁, 増子正義

臨床血液 60 ( 10 ) 1503 - 1503 2019年10月

Allogeneic hematopoietic cell transplantation for patients with a history of multiple relapses of acute myeloid leukemia. 査読国際誌

Yanada M, Mori J, Aoki J, Masuko M, Harada K, Uchida N, Doki N, Fukuda T, Sakura T, Kanamori H, Sawa M, Kondo T, Katayama Y, Kanda J, Ichinohe T, Atsuta Y, Yano S

Annals of hematology 98 ( 9 ) 2179 - 2186 2019年9月

Patient-based prediction algorithm of relapse after allo-HSCT for acute Leukemia and its usefulness in the decision-making process using a machine learning approach. 査読国際誌

Fuse K, Uemura S, Tamura S, Suwabe T, Katagiri T, Tanaka T, Ushiki T, Shibasaki Y, Sato N, Yano T, Kuroha T, Hashimoto S, Furukawa T, Narita M, Sone H, Masuko M

Cancer medicine 8 ( 11 ) 5058 - 5067 2019年9月

Rh<sub>null</sub> phenotype caused by a novel RHAG mutation, c.945+1G>A, in the Japanese population. 査読国際誌

Ushiki T, Tsuneyama H, Masuko M, Kozakai T, Kasami T, Tanaka T, Uchikawa M, Kitajima T, Kasai E, Komata T, Katagiri T, Kamimura M, Sato K, Fuse I, Ogasawara K, Nakata K

Transfusion 59 ( 8 ) 2519 - 2522 2019年8月

Hodgkin lymphomaとAnaplastic large cell lymphomaの鑑別が困難であった巨大縦隔腫瘤を呈した1例

河本啓介, 鈴木隆晴, 海發茜, 田村秀, 片桐隆之, 難波亜矢子, 布施香子, 柴崎康彦, 増子正義, 曽根博仁, 三好寛明, 大島孝一, 瀧澤淳

日本リンパ網内系学会会誌 59 133 - 133 2019年5月

Patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: trends in survival during the past two decades. 査読国際誌

Yanada M, Masuko M, Mori J, Aoki J, Mizuno S, Fukuda T, Kakihana K, Ozawa Y, Ota S, Kanamori H, Mori T, Nakamae H, Eto T, Shiratori S, Maeda T, Iwato K, Ichinohe T, Kanda Y, Tanaka J, Atsuta Y, Yano S

Bone marrow transplantation 54 ( 4 ) 578 - 586 2019年4月

Gemcitabine, Dexamethasone, and Cisplatin Regimen as an Effective Salvage Therapy for High-grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements. 査読

Mitobe M, Kawamoto K, Suzuki T, Kiryu M, Tamura S, Nanba A, Suwabe T, Tanaka T, Fuse K, Shibasaki Y, Masuko M, Miyoshi H, Ohshima K, Sone H, Takizawa J

Internal medicine (Tokyo, Japan) 58 ( 4 ) 575 - 580 2019年2月

Anaplastic large cell lymphoma, with 1,25(OH)<sub><sup>2</sup></sub>D<sub><sup>3</sup></sub>-mediated hypercalcemia: A case report. 査読

Mitobe M, Kawamoto K, Suzuki T, Kiryu M, Nanba A, Suwabe T, Tanaka T, Fuse K, Shibasaki Y, Masuko M, Miyoshi H, Ohshima K, Sone H, Takizawa J

Journal of clinical and experimental hematopathology : JCEH 59 ( 1 ) 22 - 28 2019年

Cladribine treatment for Erdheim-Chester disease involving the central nervous system and concomitant polycythemia vera: A case report. 査読

Tamura S, Kawamoto K, Miyoshi H, Suzuki T, Katagiri T, Kasami T, Nemoto H, Miyakoshi S, Kobayashi H, Shibasaki Y, Masuko M, Takeuchi K, Ohshima K, Sone H, Takizawa J

Journal of clinical and experimental hematopathology : JCEH 58 ( 4 ) 161 - 165 2018年12月

急性骨髄性白血病に対する同種造血幹細胞移植成績の過去20年間の変遷(Trends in survival of AML patients undergoing related and unrelated HCT during the past two decades)

柳田正光, 増子正義, 森甚一, 青木淳, 水野昌平, 福田隆浩, 垣花和彦, 小澤幸泰, 太田秀一, 金森平和, 森毅彦, 中前博久, 衛藤徹也, 白鳥聡一, 前田哲生, 岩戸康治, 一戸辰夫, 神田善伸, 田中淳司, 熱田由子, 矢野真吾

臨床血液 59 ( 9 ) 1485 - 1485 2018年9月

同種造血細胞移植における移植前リスク評価に用いられるGlasgow予後予測スコアの改良(Refinement of the Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation)

Shibasaki Yasuhiko, Suwabe Tatsuya, Katagiri Takayuki, Tanaka Tomoyuki, Ushiki Takashi, Fuse Kyoko, Sato Naoko, Yano Toshio, Kuroha Takashi, Hashimoto Shigeo, Narita Miwako, Furukawa Tatsuo, Sone Hirohito, Masuko Masayoshi

International Journal of Hematology 108 ( 3 ) 282 - 289 2018年9月

記述言語：英語出版者・発行元：(一社)日本血液学会

同種造血細胞移植(HCT)の移植前リスク評価に用いられるGlasgow予後予測スコア(GPS)に改良を加え、その有用性について検討した。同種HCTを施行された血液疾患患者205例(中央値46歳)を対象とした。HCT特異的GPS(HCT-GPS)の評価に際して、CRP上昇(1mg/dL超)、低アルブミン血症(3.5g/dL未満)の両者を満たす場合は2点、いずれかを呈する場合は1点、いずれも認めない場合は0点とし、さらに血清中フェリチン1000ng/mL超を呈する場合には+1点とした。検討の結果、移植前の血清フェリチン中央値は954ng/mL、アルブミン中央値は4.1g/dL、CRP中央値は0.14mg/dLであり、HCT-GPSスコアは0点が95例、1点が75例、2点が19例、3点が16例であった。一方、オリジナルのGPSスコアでは0点が158例、1点が28例、2点が19例であった。C統計量分析では非再燃死亡率(NRM)と全生存率(OS)はHCT-GPSスコアの方がGPSスコアより高値であったが有意差は認められなかった。一方、net reclassification indexesとintegrated discrimination improvementを用いた解析では有意差がみられた。また、多変量解析ではHCT-GPSスコアの1点増分はOSとNRMの不良を示す独立予測因子であることが示された。今回作成したHCT-GPSスコアは同種HCT後の早期合併症の予測に有用なツールに成りうると思われた。

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J04671&link_issn=&doc_id=20181129310007&doc_link_id=10.1007%2Fs12185-018-2463-x&url=https%3A%2F%2Fdoi.org%2F10.1007%2Fs12185-018-2463-x&type=Crossref&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00002_2.gif

Correction to: Effects of eculizumab treatment on quality of life in patients with paroxysmal nocturnal hemoglobinuria in Japan. 査読

Yasutaka Ueda, Naoshi Obara, Yuji Yonemura, Hideyoshi Noji, Masayoshi Masuko, Yoshinobu Seki, Katsuya Wada, Takahisa Matsuda, Hirozumi Akiyama, Takayuki Ikezoe, Shigeru Chiba, Yoshinobu Kanda, Tatsuya Kawaguchi, Tsutomu Shichishima, Hideki Nakakuma, Shinichiro Okamoto, Jun-Ichi Nishimura, Yuzuru Kanakura, Haruhiko Ninomiya

International journal of hematology 108 ( 2 ) 233 - 235 2018年8月

Heterogeneity of intrahepatic iron deposition in transfusion-dependent iron overload patients with hematological malignancies 査読

Hironori Kobayashi, Norihiko Yoshimura, Shun Uemura, Takayuki Katagiri, Tomoyuki Tanaka, Takashi Ushiki, Kyoko Fuse, Yasuhiko Shibasaki, Miwako Narita, Hirohito Sone, Masayoshi Masuko

Leukemia Research 70 41 - 44 2018年7月

Effects of eculizumab treatment on quality of life in patients with paroxysmal nocturnal hemoglobinuria in Japan. 査読

Yasutaka Ueda, Naoshi Obara, Yuji Yonemura, Hideyoshi Noji, Masayoshi Masuko, Yoshinobu Seki, Katsuya Wada, Takahisa Matsuda, Hirozumi Akiyama, Takayuki Ikezoe, Shigeru Chiba, Yoshinobu Kanda, Tatsuya Kawaguchi, Tsutomu Shichishima, Hideki Nakakuma, Shinichiro Okamoto, Jun-Ichi Nishimura, Yuzuru Kanakura, Haruhiko Ninomiya

International journal of hematology 107 ( 6 ) 656 - 665 2018年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

In paroxysmal nocturnal hemoglobinuria (PNH), various symptoms due to intravascular hemolysis exert a negative impact on patients' quality of life (QOL). To determine clinical factors related with improvements in QOL in PNH patients treated, we analyzed changes in QOL scales in PNH patients treated with eculizumab based on data collected from post-marketing surveillance in Japan. Summary statistics were obtained using figures from QOL scoring systems and laboratory values, and evaluated by t test. One-year administration of eculizumab improved the most QOL items in comparison with the baseline. In particular, significant improvement of EORTC QLQ-C30 was observed in fatigue, dyspnea, physical function, and global health status. Canonical correlation analysis revealed a high correlation between QOL and laboratory values. Changes in serum lactate dehydrogenase (LDH) and hemoglobin showed strong correlations with QOL improvement. Quality of life improvement was independent of patients' baseline characteristics of co-occurrence of bone marrow failure (BMF), or the degree of LDH. In this analysis, we found that the degree of QOL improvement was independent of the baseline LDH before eculizumab treatment and of co-occurrence of BMF. Paroxysmal nocturnal hemoglobinuria patients who have not received eculizumab treatment due to mild hemolysis may benefit from eculizumab treatment.

DOI： 10.1007/s12185-018-2409-3

Refinement of the Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation 査読

Yasuhiko Shibasaki, Tatsuya Suwabe, Takayuki Katagiri, Tomoyuki Tanaka, Takashi Ushiki, Kyoko Fuse, Naoko Sato, Toshio Yano, Takashi Kuroha, Shigeo Hashimoto, Miwako Narita, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

International Journal of Hematology 108 ( 3 ) 1 - 8 2018年5月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Tokyo

The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) is a widely used tool for pre-transplant risk assessment. Allogeneic hematopoietic cell transplantation (HCT) is performed on patients with diverse backgrounds, highlighting the need for other predictors to complement the HCT-CI and support bedside decision-making. There is a strong body of evidence supporting the use of pre-transplant serum ferritin (SF) in risk assessments of allogeneic HCT. We additionally found that the Glasgow Prognostic Score (GPS), which assesses inflammatory biomarkers and predicts survival of patients with solid organ malignancies, is a useful predictive marker for overall survival (OS) and non-relapse mortality (NRM) in allogeneic HCT, independent of HCT-CI and SF. In this study, we refined the GPS by adding pre-transplant SF to improve its prognostic ability and enable better stratification
we call this revised index the HCT-specific revised Glasgow Prognostic Score (HCT-GPS). We observed that the HCT-GPS more accurately predicted NRM and early-term OS than the GPS. Moreover, the HCT-GPS provides an independent prognostic factor adjusted for the HCT-CI and disease status, and stratifies patients into four risk groups by OS and NRM. Thus, the HCT-GPS is a useful index for predicting early-term complications after allogeneic HCT in patients with hematopoietic diseases.

DOI： 10.1007/s12185-018-2463-x

GDP療法がtriple-hit lymphomaの救援療法として有効であった1例

水戸部正樹, 河本啓介, 鈴木隆晴, 田村秀, 小堺貴司, 難波亜矢子, 諏訪部達也, 笠見卓哉, 田中智之, 布施香子, 柴崎康彦, 増子正義, 曽根博仁, 大島孝一, 瀧澤淳

臨床血液 59 ( 5 ) 620 - 621 2018年5月

MAGI-1 expression is decreased in several types of human T-cell leukemia cell lines, including adult T-cell leukemia 査読

Takashi Kozakai, Masahiko Takahashi, Masaya Higuchi, Toshifumi Hara, Kousuke Saito, Yuetsu Tanaka, Masayoshi Masuko, Jun Takizawa, Hirohito Sone, Masahiro Fujii

International Journal of Hematology 107 ( 3 ) 337 - 344 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Tokyo

Membrane-associated guanylate kinase with inverted orientation protein 1 (MAGI-1) is a cytoplasmic scaffold protein that interacts with various signaling molecules
it negatively controls the cell growth of various types of cells and positively controls cell–cell interaction. In T cells, MAGI-1 has been shown to inhibit Akt activity through its interaction with PTEN and MEK1. In this study we found that MAGI-1 expression is decreased in multiple (9 out of 15) human T-cell leukemia cell lines, including adult T-cell leukemia (ATL), T-cell acute lymphoblastic leukemia and chronic T-cell lymphocytic leukemia. The overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced cellular growth. While the overexpression of MAGI-1 protein in a MAGI-1-low ATL cell line reduced the Akt and MEK activities, the knockdown of MAGI-1 in a MAGI-1-high ATL cell line augmented the Akt and MEK activities. Collectively, the findings of the present study suggest that the decreased expression of MAGI-1 in human T cells contributes to the development of several types of T-cell leukemia, partly through the stimulation of the Akt and MEK pathways.

DOI： 10.1007/s12185-017-2359-1

Outcomes after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia harboring t(7;11)(p15;p15) 査読

Kaito Harada, Noriko Doki, Jun Aoki, Jinichi Mori, Shinichiro Machida, Masayoshi Masuko, Naoyuki Uchida, Yuho Najima, Takahiro Fukuda, Heiwa Kanamori, Hiroyasu Ogawa, Shuichi Ota, Kazuei Ogawa, Satoshi Takahashi, Masanobu Kasai, Akio Maeda, Koji Nagafuji, Toshiro Kawakita, Tatsuo Ichinohe, Yoshiko Atsuta

Haematologica 103 ( 2 ) e69 - e72 2018年1月

The Glasgow Prognostic Score as a pre-transplant risk assessment for allogeneic hematopoietic cell transplantation 査読

Yasuhiko Shibasaki, Tatsuya Suwabe, Takayuki Katagiri, Tomoyuki Tanaka, Hironori Kobayashi, Kyoko Fuse, Takashi Ushiki, Naoko Sato, Toshio Yano, Takashi Kuroha, Shigeo Hashimoto, Miwako Narita, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

CLINICAL TRANSPLANTATION 31 ( 11 ) 2017年11月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY

Evaluation methods, such as scoring systems for predicting complications in advance, are necessary for determining the adaptation of allogeneic hematopoietic cell transplantation (HCT) and selecting appropriate conditioning regimens. The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), which is based on functions of main organs, is a useful tool for pre-transplant risk assessments and has been widely applied in determining treatment strategies for patients with hematological diseases. However, as allogeneic HCT is performed on patients with diverse backgrounds, another factor, which reinforces the HCT-CI, is required to evaluate pre-transplant risk assessments. The Glasgow Prognostic Score (GPS), which assesses the combined C-reactive protein and albumin, was reported to predict survival of patients with solid-organ malignancies independently of receiving chemo/radiotherapy and stages of cancer. In this study, we applied the GPS for pre-transplant risk assessments for allogeneic HCT. The GPS successfully stratified the patients into three risk groups of overall survival (OS) and non-relapse mortality (NRM). Moreover, the GPS could predict outcomes independently of the HCT-CI for OS and NRM in multivariate analysis. The GPS is considered to be a useful tool and reinforces the HCT-CI for determining adaptation of allogeneic HCT for patients with hematopoietic neoplasms.

DOI： 10.1111/ctr.13103

Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies 査読

Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Shiro Tara, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Sha Si, Ichiro Manabe, Masashi Sanada, Manabu Nakayama, Masayoshi Masuko, Hirohito Sone, Haruhiko Koseki, Atsushi Iwama

JOURNAL OF EXPERIMENTAL MEDICINE 214 ( 10 ) 2901 - 2913 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ROCKEFELLER UNIV PRESS

Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (Bcor(Delta E4/gamma)) compromised the repopulating capacity of hematopoietic stem cells, Bcor(Delta E4/gamma) thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner. Myc, one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in Bcor(Delta E4/gamma) T-ALL cells. Chromatin immunoprecipitation/DNA sequencing analysis revealed that BCOR was recruited to the Myc promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. Bcl6-deficient thymocytes behaved in a manner similar to Bcor(Delta E4/gamma) thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.

DOI： 10.1084/jem.20170167

抗原特異的細胞傷害性T細胞(CTL)の増幅と機能の検討

小川彩空, 増子正義, 後藤若奈, 内山孝由, 橋本誠雄, 柴崎康彦, 瀧澤淳, 成田美和子

日臨技北日本支部医学検査学会抄録集 6回 128 - 128 2017年10月

Functional dissection of hematopoietic stem cell populations with a stemness-monitoring system based on NS-GFP transgene expression 査読

Mohamed A. E. Ali, Kyoko Fuse, Yuko Tadokoro, Takayuki Hoshii, Masaya Ueno, Masahiko Kobayashi, Naho Nomura, Ha Thi Vu, Hui Peng, Ahmed M. Hegazy, Masayoshi Masuko, Hirohito Sone, Fumio Arai, Atsushi Tajima, Atsushi Hirao

SCIENTIFIC REPORTS 7 ( 1 ) 11442 2017年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Hematopoietic stem cells (HSCs) in a steady state can be efficiently purified by selecting for a combination of several cell surface markers; however, such markers do not consistently reflect HSC activity. In this study, we successfully enriched HSCs with a unique stemness-monitoring system using a transgenic mouse in which green florescence protein (GFP) is driven by the promoter/enhancer region of the nucleostemin (NS) gene. We found that the phenotypically defined long-term (LT)-HSC population exhibited the highest level of NS-GFP intensity, whereas NS-GFP intensity was strongly downregulated during differentiation in vitro and in vivo. Within the LT-HSC population, NS-GFPhigh cells exhibited significantly higher repopulating capacity than NS-GFPlow cells. Gene expression analysis revealed that nine genes, including Vwf and Cdkn1c (p57), are highly expressed in NS-GFPhigh cells and may represent a signature of HSCs, i.e., a stemness signature. When LT-HSCs suffered from remarkable stress, such as transplantation or irradiation, NS-GFP intensity was downregulated. Finally, we found that high levels of NS-GFP identified HSC-like cells even among CD34(+) cells, which have been considered progenitor cells without long-term reconstitution ability. Thus, high NS-GFP expression represents stem cell characteristics in hematopoietic cells, making this system useful for identifying previously uncharacterized HSCs.

DOI： 10.1038/s41598-017-11909-3

Successful 5-azacytidine treatment of myeloid sarcoma and leukemia cutis associated with myelodysplastic syndrome A case report and literature review 査読

Takayuki Katagiri, Takashi Ushiki, Masayoshi Masuko, Tomoyuki Tanaka, Shukuko Miyakoshi, Kyoko Fuse, Yasuhiko Shibasaki, Jun Takizawa, Sadao Aoki, Hirohito Sone

MEDICINE 96 ( 36 ) e7975 2017年9月

記述言語：英語出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Rationale: Myeloid sarcoma (MS) and leukemia cutis (LC) are extramedullary tumors comprising myeloid blasts. They can occur de novo or concurrently with hematological disorders, usually acute myeloid leukemia (AML). AML chemotherapy is generally the initial therapy for MS and LC, and hematopoietic stem cell transplantation (HSCT) can be considered as additional therapy. However, treatment for older patients who are unable to continue intensive chemotherapy is not currently standardized.
Patientconcerns: A 71-year-old Japanese woman was diagnosed with multiple MSs associated with myelodysplastic syndrome (MDS), using bone marrow aspiration and lymph node biopsy.
Diagnoses: Additionally, LC was diagnosed by skin biopsy. Extramedullary MS and LC lesions were formed by massive infiltration of myeloblastic cells.
Interventions: Twenty courses of 5-azacytidine (5-Aza) were administrated as maintenance therapy after induction therapy with daunorubicin and cytarabine.
Outcomes: Myeloblasts decreased in the bone marrow and the LC disappeared after induction therapy. The MSs completely disappeared, except for the palatine tonsil lesion, after 5-Aza maintenance therapy. 5-Aza treatment provided long-term partial response for more than 21 months.
Lessons: 5-Aza was well tolerated and may be a good option for the treatment of MS and LC associated with MDS, especially in older patients who cannot receive HSCT.

DOI： 10.1097/MD.0000000000007975

移植前予後予測モデルとしての同種造血細胞移植特異的Glasgow Prognostic Score(HCT specific Glasgow Prognostic Score as a new predictive tool for pre-transplant risk assessments)

Shibasaki Yasuhiko, Suwabe Tatsuya, Katagiri Takayuki, Tanaka Tomoyuki, Kobayashi Hironori, Fuse Kyoko, Ushiki Takashi, Narita Miwako, Sone Hirohito, Masuko Masayoshi

臨床血液 58 ( 9 ) 1547 - 1547 2017年9月

Phase II study of intrabone single unit cord blood transplantation for hematological malignancies. 査読国際誌

Makoto Murata, Yoshinobu Maeda, Masayoshi Masuko, Yasushi Onishi, Tomoyuki Endo, Seitaro Terakura, Yuichi Ishikawa, Chisako Iriyama, Yoko Ushijima, Tatsunori Goto, Nobuharu Fujii, Mitsune Tanimoto, Hironori Kobayashi, Yasuhiko Shibasaki, Noriko Fukuhara, Yoshihiro Inamoto, Ritsuro Suzuki, Yoshihisa Kodera, Tadashi Matsushita, Hitoshi Kiyoi, Tomoki Naoe, Tetsuya Nishida

Cancer science 108 ( 8 ) 1634 - 1639 2017年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

The outcomes of cord blood transplantation with non-irradiated reduced-intensity conditioning for hematological malignancies need to be improved because of graft failure and delayed engraftment. Intrabone infusion of cord blood cells has the potential to resolve the problems. In this phase II study, 21 adult patients with hematological malignancy received intrabone transplantation of serological HLA-A, B, and DR ≥4/6 matched single cord blood with a median number of cryopreserved total nucleated cells of 2.7 × 107 /kg (range, 2.0-4.9 × 107 /kg) following non-irradiated fludarabine-based reduced-intensity conditioning. Short-term methotrexate and tacrolimus were given as graft-versus-host disease prophylaxis, and granulocyte colony-stimulating factor was given after transplantation. No severe adverse events related to intrabone injection were observed. The cumulative incidences of neutrophils ≥0.5 × 109 /L, reticulocytes ≥1%, and platelets ≥20 × 109 /L recoveries were 76.2%, 71.4%, and 76.2%, respectively, with median time to recoveries of 17, 28, and 32 days after transplantation, respectively. The probability of survival with neutrophil engraftment on day 60 was 71.4%, and overall survival at 1 year after transplantation was 52.4%. The incidences of grade II-IV and III-IV acute graft-versus-host disease were 44% and 19%, respectively, with no cases of chronic graft-versus-host disease. The present study showed the safety of direct intrabone infusion of cord blood. Further analysis is required to confirm the efficacy of intrabone single cord blood transplantation with non-irradiated reduced-intensity conditioning for adult patients with hematological malignancy. This study was registered with UMIN-CTR, number 000000865.

DOI： 10.1111/cas.13291

Donor Killer Immunoglobulin-Like Receptor Haplotype B/x Induces Severe Acute Graft-versus-Host Disease in the Presence of Human Leukocyte Antigen Mismatch in T Cell-Replete Hematopoietic Cell Transplantation 査読

Ryosuke Hosokai, Masayoshi Masuko, Yasuhiko Shibasaki, Akihiko Saitoh, Tatsuo Furukawa, Chihaya Imai

BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 23 ( 4 ) 606 - 611 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

Natural killer cells have been identified as a mediator of alloimmune reactions in allogeneic hematopoietic stem cell transplantation (HSCT). Killer immunoglobulin-like receptors (KIRs) are an important determinant of natural killer cell function. The relationship between KIR genotypes/haplotypes and clinical outcomes of allogeneic HSCT is complex and inconsistent among several reports. We assessed the clinical impact of KIR haplotype on T cell-replete allogeneic HSCTs performed in a single Japanese center for hematological malignancies (n = 106). A comparison of 2 groups, donor haplotypes A/A and B/x, revealed no significant differences in overall survival, relapse, and nonrelapse mortality. However, grade III to IV acute graft-versus-host disease (GVHD) occurred significantly more frequently in the KIR haplotype B/x group (A/A versus B/x: 4.9% versus 20.0%; P=.02). This was even more evident when HLA mismatch was present. The highest incidences of grade II to IV and grade III to IV acute GVHD were observed in patients who received allografts from HLAmismatched donors with KIR haplotype B/x. These data highlight the importance of KIR genotyping in donor matching, especially when HLA mismatch allogeneic grafting is planned. (C) 2017 American Society for Blood and Marrow Transplantation.

DOI： 10.1016/j.bbmt.2016.12.638

[Myelodysplastic syndrome with refractory hemorrhage due to reduced platelet aggregation activity]. 査読

Tanaka T, Kozakai T, Kitajima T, Fuse K, Kobayashi H, Ushiki T, Shibazaki Y, Moriyama M, Takizawa J, Sone H, Fuse I, Masuko M

[Rinsho ketsueki] The Japanese journal of clinical hematology 58 ( 12 ) 2402 - 2405 2017年

担当区分：最終著者記述言語：日本語出版者・発行元：一般社団法人日本血液学会

<p>症例は75歳の女性。血液検査で貧血と末梢血に芽球を認められたため，当院を紹介受診した。骨髄穿刺で骨髄異形成症候群（myelodysplastic syndrome with excess blasts 2, MDS-EB-2）と診断された。血球減少の進行や芽球の増加，および出血症状はなく経過していた。診断から10ヶ月後，左手母指球に外傷を負い，内出血が持続し，止血困難となったため緊急入院した。血小板数は正常範囲であったが，血小板機能検査でコラーゲン凝集能とアラキドン酸凝集能の低下を認められた。抗血小板薬の内服はなく，またこれまで出血傾向の既往もなかったことから，MDSによる2次性の血小板機能低下による出血と判断し，血小板輸血を行い止血した。MDSの患者では，潜在的に血小板凝集能が低下していることが多く，血小板数の割に出血傾向が強い場合には血小板凝集能を調べ，血小板輸血などの治療介入を検討する必要がある。</p>

DOI： 10.11406/rinketsu.58.2402

その他リンク： http://search.jamas.or.jp/link/ui/2018121562

Successful umbilical cord blood hematopoietic stem cell transplantation in a patient with adult T-cell leukemia/lymphoma initially achieving complete remission with anti-CC chemokine receptor 4 antibody combined chemotherapy. 査読

Suwabe T, Shibasaki Y, Kaihatsu A, Katagiri T, Miyakoshi S, Fuse K, Kobayashi H, Ushiki T, Moriyama M, Takizawa J, Narita M, Sone H, Masuko M

[Rinsho ketsueki] The Japanese journal of clinical hematology 58 ( 1 ) 32 - 36 2017年

Peripheral T-cell lymphoma, not otherwise specified: a retrospective single-center analysis. 査読

Suzuki T, Kawamoto K, Tamura S, Uemura S, Kaihatsu A, Nemoto H, Kobayashi H, Ushiki T, Fuse K, Shibazaki Y, Moriyama M, Masuko M, Narita M, Sone H, Aoki S, Nakamura N, Oshima K, Takizawa J

[Rinsho ketsueki] The Japanese journal of clinical hematology 58 ( 8 ) 905 - 911 2017年

輸血依存患者における肝臓内鉄含有量を評価するための二重エネルギーCTの重要性(Significance of dual-energy CT to evaluate liver iron content in transfusion-dependent patients)

Kobayashi Hironori, Yoshimura Norihiko, Suwabe Tatsuya, Katagiri Takayuki, Miyakoshi Shukuko, Ushiki Takashi, Fuse Kyoko, Shibasaki Yasuhiko, Moriyama Masato, Takizawa Jun, Narita Miwako, Sone Hirohito, Masuko Masayoshi

臨床血液 57 ( 9 ) 1524 - 1524 2016年9月

The Dinakara equation for adjusting DLCO for hemoglobin in the HCT-CI is superior to the Cotes equation for predicting high-risk patients in allogeneic hematopoietic stem cell transplantation. 査読国際誌

Yasuhiko Shibasaki, Takayuki Katagiri, Hironori Kobayashi, Takashi Ushiki, Miwako Narita, Hirohito Sone, Tatsuo Furukawa, Masayoshi Masuko

American journal of hematology 91 ( 5 ) E296 2016年5月

Clinical Significance of MYC, BCL2 and BCL6 Rearrangement and Protein Expression in GCB and Non-GCB Type Diffuse Large B-Cell Lymphoma 招待査読

Kawamoto Keisuke, Takizawa Jun, Miyoshi Hiroaki, Yoshida Noriaki, Shibasaki Yasuhiko, Masuko Masayoshi, Sone Hirohito, Nakamura Naoya, Ohshima Koichi

BLOOD 126 ( 23 ) 2015年12月

Fatal tracheal aspergillosis during rituximab combined chemotherapy for diffuse large B-cell lymphoma that developed after lung transplantation 査読

K. Kawamoto, Y. Shibasaki, S. Sato, H. Nemoto, J. Takizawa, M. Narita, M. Tsuchida, H. Sone, M. Masuko

Transplant Infectious Disease 17 ( 6 ) 872 - 875 2015年12月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Inc.

Invasive tracheal aspergillosis (ITA) is an infection that is unique to patients who have undergone lung transplantation (LT). Although the activity of this disease often appears on imaging, we encountered a case of ITA that became exacerbated, despite few computed tomography (CT) findings, during rituximab combined chemotherapy for diffuse large B-cell lymphoma. ITA developed during immunosuppressive therapy after LT. Because CT findings may show false-negative results, bronchoscopy is recommended for such cases.

DOI： 10.1111/tid.12458

Effect of Granulocyte Colony-Stimulating Factor-Combined Conditioning in Cord Blood Transplantation for Myelodysplastic Syndrome and Secondary Acute Myeloid Leukemia: A Retrospective Study in Japan. 査読

Konuma T, Takahashi S, Uchida N, Kuwatsuka Y, Yamasaki S, Aoki J, Onishi Y, Aotsuka N, Ohashi K, Mori T, Masuko M, Nakamae H, Miyamura K, Kato K, Atsuta Y, Kato S, Asano S, Takami A, Miyazaki Y, Adult Myelodysplastic Syndrome, Adult Acute Myeloid, Leukemia Working, Group of, the Japan, Society for, Hematopoietic Cell Transplantation

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 21 ( 9 ) 1632 - 1640 2015年9月

レシピエントに対する移植前評価としてのHCT-CI/年齢スコアの臨床的意義(The clinical relevance of HCT-CI/age score as pre-transplant assessment for recipients)

Katagiri Takayuki, Shibasaki Yasuhiko, Suwabe Tatsuya, Miyakoshi Shukuko, Fuse Kyoko, Kobayashi Hironori, Ushiki Takashi, Moriyama Masato, Takizawa Jun, Narita Miwako, Sone Hirohito, Masuko Masayoshi

臨床血液 56 ( 9 ) 1665 - 1665 2015年9月

HSCT後のγ/δT細胞低値およびTreg細胞高値はいずれも再発の独立リスク因子である(Both low γ/δ T cells and high Treg cells after HSCT is an independent risk factor for relapse)

Shibasaki Yasuhiko, Miyakoshi Syukuko, Suwabe Tatsuya, Katagiri Takayuki, Fuse Kyoko, Kobayashi Hironori, Ushiki Takashi, Moriyama Masato, Takizawa Jun, Narita Miwako, Sone Hirohito, Furukawa Tatsuo, Masuko Masayoshi

臨床血液 56 ( 9 ) 1666 - 1666 2015年9月

Possible Involvement of Lung Cells Harboring an Abnormal Karyotype in the Pathogenesis of Pulmonary Alveolar Proteinosis Associated with Myelodysplastic Syndrome. 査読

Moriyama M, Yano T, Furukawa T, Takada T, Ushiki T, Masuko M, Takizawa J, Sone H, Tazawa R, Saijo Y, Ishii H, Nakata K

Annals of the American Thoracic Society 12 ( 8 ) 1251 - 1253 2015年8月

The association of level of reduction of Wilms' tumor gene 1 mRNA transcript in bone marrow and outcome in acute myeloid leukemia patients 査読

Yasuhiko Shibasaki, Yoshinobu Seki, Tomoyuki Tanaka, Syukuko Miyakoshi, Kyoko Fuse, Takashi Kozakai, Hironori Kobayashi, Takashi Ushiki, Takashi Abe, Toshio Yano, Masato Moriyama, Takashi Kuroha, Noriatsu Isahai, Jun Takizawa, Miwako Narita, Satoru Koyama, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

LEUKEMIA RESEARCH 39 ( 6 ) 667 - 671 2015年6月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

We focused on the level of reduction of Wilms' tumor gene 1 (WT1) mRNA in bone marrow as minimal residual disease during chemotherapies in adult acute myeloid leukemia (AML) patients. Forty-eight patients were enrolled in this study. Log levels of reduction of WT1 mRNA transcript after induction therapy compared with those at diagnosis were associated with disease-free survival (DFS) (P = 0.0066) and overall survival (OS) (P = 0.0074) in patients who achieved complete remission. Also log levels of reduction of WT1 mRNA transcript after final consolidation therapy compared with those at diagnosis were associated with DFS (P = 0.015) and OS (P = 0.012). By multivariate analysis, log levels of reduction of WT1 mRNA transcript after induction therapy and after final consolidation therapy compared with those at diagnosis were extracted as risk factors for outcome. Our results suggest that early and deep reduction of tumor burden may be important for the outcome of AML patients. In addition, it may be useful for the decision to proceed with allogeneic SCT as post-remission therapy. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2015.03.021

A Safety and Efficacy Study of Medium-Dose Etoposide, Cyclophosphamide and Total Body Irradiation Conditioning Before Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia. 査読国際誌

Shigematsu A, Ozawa Y, Onizuka M, Fujisawa S, Suzuki R, Atsuta Y, Hatanaka K, Masuko M, Ito T, Kobayashi N, Kato J, Miyamura K, Fukuda T, Morishima Y, Imamura M

Transplantation direct 1 ( 2 ) e8 2015年3月

Late Onset Post-Transfusion Hepatitis E Developing during Chemotherapy for Acute Promyelocytic Leukemia 査読

Kyoko Fuse, Yuichi Matsuyama, Masato Moriyama, Shukuko Miyakoshi, Yasuhiko Shibasaki, Jun Takizawa, Tatsuo Furukawa, Ichiro Fuse, Hiro Matsumura, Shigeharu Uchida, Yoshifumi Takahashi, Kenya Kamimura, Hiroyuki Abe, Takeshi Suda, Yutaka Aoyagi, Hirohito Sone, Masayoshi Masuko

INTERNAL MEDICINE 54 ( 6 ) 657 - 661 2015年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

We herein report the case of a leukemia patient who developed hepatitis E seven months after undergoing a transfusion with contaminated blood products. The latency period in this case was significantly longer than that of typical hepatitis E. Recently, chronic infection with hepatitis E virus (HEV) genotype 3 has been reported in immunocompromised patients. There is a possibility that our patient was unable to eliminate the virus due to immunosuppression following chemotherapy and the administration of steroids. The prevalence of HEV in healthy Japanese individuals is relatively high and constitutes a critical source of infection via transfusion. Hepatitis E is an important post-transfusion infection, and immunocompromised patients may exhibit a long latency period before developing the disease.

DOI： 10.2169/internalmedicine.54.2332

Genetic Variants in C5 and Poor Response to Eculizumab 査読

Jun-ichi Nishimura, Masaki Yamamoto, Shin Hayashi, Kazuma Ohyashiki, Kiyoshi Ando, Andres L. Brodsky, Hideyoshi Noji, Kunio Kitamura, Tetsuya Eto, Toru Takahashi, Masayoshi Masuko, Takuro Matsumoto, Yuji Wano, Tsutomu Shichishima, Hirohiko Shibayama, Masakazu Hase, Lan Li, Krista Johnson, Alberto Lazarowski, Paul Tamburini, Johji Inazawa, Taroh Kinoshita, Yuzuru Kanakura

NEW ENGLAND JOURNAL OF MEDICINE 370 ( 7 ) 632 - 639 2014年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MASSACHUSETTS MEDICAL SOC

BackgroundEculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear.
MethodsWe assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients.
ResultsOf 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654GA, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653CT, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab.
ConclusionsThe functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.)

DOI： 10.1056/NEJMoa1311084

Manifestations of Fulminant CD8 T-cell Post-transplant Lymphoproliferative Disorder Following the Administration of Rituximab for Lymphadenopathy with a High Level of Epstein-Barr Virus (EBV) Replication after Allogeneic Hematopoietic Stem Cell Transplantation 査読

Tomoyuki Tanaka, Jun Takizawa, Shukuko Miyakoshi, Takashi Kozakai, Kyoko Fuse, Yasuhiko Shibasaki, Masato Moriyama, Koichi Ohshima, Ken Toba, Tatsuo Furukawa, Hirohito Sone, Masayoshi Masuko

INTERNAL MEDICINE 53 ( 18 ) 2115 - 2119 2014年

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

We herein report the case of a 22-year-old woman with severe aplastic anemia who underwent allogeneic hematopoietic stem cell transplantation (HSCT). After HSCT, the Epstein-Barr virus (EBV)-DNA load in the peripheral blood gradually increased, and the patient presented with a fever and lymphadenopathy on day 56 post-HSCT. Although we administered rituximab, her clinical condition worsened. After rituximab treatment, CD8 T-cells emerged and became dominant in the peripheral blood, some of which were positive on an EBV-specific tetramer analysis. However, an open biopsy of the lymphadenopathy lesions revealed the CD8 T-cells to be infected with EBV, exhibiting proliferation with oligoclonality. The patient ultimately died of multiple organ failure on day 99 post-HSCT.

DOI： 10.2169/internalmedicine.53.2384

Ustekinumab Improves Psoriasis without Suppressing Tumor Antigen-Specific Cytotoxic T Lymphocytes 査読

Miwako Narita, Yoshinori Nishizawa, Shunpei Iwaya, Eri Oiwa, Minami Iwabuchi, Takayoshi Uchiyama, Asako Matsuyama, Masayoshi Masuko, Masuhiro Takahashi

INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY 165 ( 1 ) 52 - 60 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：KARGER

Background: Ustekinumab is currently used for the treatment of psoriasis with remarkable efficiency. However, worries about the development of malignancies in ustekinumab- treated patients have not been completely resolved because of the major role of IL-12 and IL-23 in tumor immunity. In the present study, we tried to elucidate the effects of ustekinumab on antigen-specific tumor immunity. Methods: After approval by the institutional ethical committee, a 56-year-old male volunteer with psoriasis was administered with 20 doses of WT1 peptide. WT1-specific cytotoxic T lymphocytes (CTLs) were evaluated by WT1 tetramer assay after mixed lymphocyte peptide culture. Results: WT1 tetramer+ T cells with cytotoxic ability appeared in the blood after peptide administration and the frequency of WT1 tetramer+ T cells increased to more than 15 in 10(6) CD8+ T cells. Thirty months after stopping WT1 administration, the patient commenced treatment with ustekinumab for psoriasis at weeks 0 and 4, and every 12 weeks thereafter. Psoriasis plaques were almost cleared up and the response to ustekinumab has so far lasted for 30 months. The frequency of WT1 tetramer+ T cells has not changed since the initiation of ustekinumab treatment. The effects of ustekinumab on the antigen-presenting and CTL-inducing abilities of dendritic cells were explored in vitro, revealing limited effects on both immune functions. Conclusions: These in vivo/vitro findings imply that ustekinumab improves psoriasis without suppressing tumor antigen-specific CTLs and support the data of recent clinical trials showing no increased incidence of malignancies with ustekinumab treatment. (C) 2014 S. Karger AG, Basel

DOI： 10.1159/000366503

Successful Treatment of Severe Newly Diagnosed Immune Thrombocytopenia Involving an Alveolar Hemorrhage with Combination Therapy Consisting of Romiplostim, Rituximab and Vincristine 査読

Kiyoshi Okazuka, Masayoshi Masuko, Yuji Matsuo, Shukuko Miyakoshi, Tomoyuki Tanaka, Takashi Kozakai, Hironori Kobayashi, Kyoko Fuse, Yasuhiko Shibasaki, Masato Moriyama, Jun Takizawa, Ichiro Fuse, Ken Toba, Tatsuo Furukawa

INTERNAL MEDICINE 52 ( 11 ) 1239 - 1242 2013年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

A 51-year-old man was admitted due to a severe bleeding tendency. After he was diagnosed with immune thrombocytopenia (ITP), several therapies, including steroids, steroid pulse, vincristine and rituximab, were administered; however, the patient's bleeding symptoms were not sufficiently controllable with these treatments. Subsequently, a diffuse alveolar hemorrhage was observed. Treatment with a thrombopoietin receptor agonist, romiplostim, was initiated to prevent lethal hemorrhaging, although the efficacy of thrombopoietic receptor agonists in such emergency situations has not been elucidated. The initiation of romiplostim achieved prompt remission in platelets. This case suggests that combination therapy with romiplostim, rituximab and vincristine is effective in cases of newly diagnosed severe therapy-resistant ITP.

DOI： 10.2169/internalmedicine.52.0080

AMLにおいて地固め療法後のWT1転写産物の減少は予後と関連している(Reduction value of WT1 transcripts after consolidation therapy is associated with prognosis in AML)

Shibasaki Yasuhiko, Seki Yoshinobu, Koyama Satoru, Nikkuni Koji, Nomoto Nobuhiko, Isahai Noriatsu, Kuroha Takashi, Momoi Akihito, Yano Toshio, Ida Tori, Higashimura Masutaka, Kitajima Toshiki, Nanba Ayako, Kobayashi Hironori, Ushiki Takashi, Moriyama Masato, Okazuka Kiyoshi, Masuko Masayoshi, Toba Ken, Furukawa Tasuo

臨床血液 53 ( 9 ) 1179 - 1179 2012年9月

診療参加型臨床実習における骨髄穿刺シミュレーション実習の有用性

鈴木利哉, 増子正義, 古川達雄, 鳥羽健, 奈良信雄

日本内科学会雑誌 101 ( Suppl. ) 200 - 200 2012年2月

Hypocellularity and insufficient expression of angiogenic factors in implanted autologous bone marrow in patients with chronic critical limb ischemia 査読

Masato Oda, Ken Toba, Kiminori Kato, Takuya Ozawa, Takao Yanagawa, Noboru Ikarashi, Tsugumi Takayama, Tomoyasu Suzuki, Haruo Hanawa, Masayoshi Masuko, Hironori Kobayashi, Yoshifusa Aizawa

HEART AND VESSELS 27 ( 1 ) 38 - 45 2012年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

The aim of this study was to identify the clinical parameters of absolutely poor-prognosis patients with chronic critical limb ischemia (AP-CLI). Sixteen no-option CLI patients with arteriosclerosis obliterans: ASO (nine) and non-ASO patients (seven) treated with bone marrow-mononuclear cell implantation (BMI) were analyzed. There were three AP-CLI patients (all ASO). The mRNA expression of several angiogenic factors in the implanted cells was analyzed in comparison with normal donor bone marrow. To observe the response of bone marrow components to hypoxia, normal bone marrow cells were cultured for 24 h in 2.5% O-2, and mRNA expression of angiogenic factors were measured. AP-CLI patients exhibited extraordinary low bone marrow cellularity as well as the percentage of CD34-positive cells. Among angiogenic factors, only VEGF expression was maintained in response to HIF-1, while other factors such as HGF, Ang-1, PLGF, and SDF-1 decreased in the implanted bone marrow cells of the patients with CLI compared to normal bone marrow cells. HIF-1 and all of the five angiogenic factors increased in vitro in response to hypoxia. Thus it is highly likely that angiogenic factors except VEGF do not respond to chronic ischemia in bone marrow in vivo. An organ-protection system against tissue ischemia may be applied for acute hypoxia, but it may be insufficient for chronic ischemia.

DOI： 10.1007/s00380-011-0125-5

腎移植後IgA腎症再発に対し扁摘とステロイドパルス療法後に発症した免疫性血小板減少症(Immune thrombocytopenia)の1例

白野侑子, 星井達彦, 中川由紀, 斎藤和英, 佐藤大輔, 増子正義, 成田一衛, 高橋公太

腎移植・血管外科 23 ( 1 ) 108 - 111 2011年12月

記述言語：日本語出版者・発行元：腎移植・血管外科研究会

腎移植後免疫抑制療法下に発症した免疫性血小板減少症を経験したので報告する。症例は47歳男性、原疾患IgA腎症による慢性腎不全にて生体腎移植を施行した。腎移植2年後肺炎を契機に肉眼的血尿を認めた。翌年、IgA腎症が再発し、扁桃摘出、ステロイドパルス療法にて加療した。翌年、四肢の紫斑の出現と血小板が3000/μlに減少した。骨髄穿刺にて巨核球の増加を認め、諸検査より他の血液疾患を除外した上で免疫性血小板減少症と診断した。ステロイド療法、IVIG、ピロリ菌の除菌療法を施行し、免疫抑制薬は、シクロスポリン(CYA)、ミコフェノール酸モフェチル(MMF)を継続した。入院から13週間後、血小板は増加し7×10^4/μl前後となりその後も再発無く、寛解を維持している。(著者抄録)

Kinetics of pDCs, mDCs, γδT cells and regulatory T cells in association with graft versus host disease after hematopoietic stem cell transplantation. 査読

Watanabe N, Narita M, Furukawa T, Nakamura T, Yamahira A, Masuko M, Toba K, Fuse I, Aizawa Y, Takahashi M

Int J Lab Hematol. 33 ( 4 ) 378 - 390 2011年8月

WT1 peptide vaccination in a CML patient: induction of effective cytotoxic T lymphocytes and significance of peptide administration interval 査読

Anri Saitoh, Miwako Narita, Norihiro Watanabe, Nozomi Tochiki, Akie Yamahira, Takeshi Nakamura, Masami Kaji, Masayoshi Masuko, Tatsuo Furukawa, Ken Toba, Ichiro Fuse, Yoshifusa Aizawa, Masuhiro Takahashi

MEDICAL ONCOLOGY 28 ( 1 ) 219 - 230 2011年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：HUMANA PRESS INC

Although antigen-specific immune responses including cytotoxic T cells (CTLs) against antigen peptide could be enhanced after tumor antigen peptide vaccinations, the immune responses do not necessarily result in a decrease or eradication of tumor cells in the vaccination trials. We focused on whether antigen-specific CTLs could be damaged by the repeated stimulation of antigenic peptide and whether regulatory T (Treg) cells would be increased by the administration of WT1 peptide. We administered WT1 peptide 22 times over 18 months in a CML patient who was being treated with imatinib. Although WT1 peptide administration every 2 weeks did not show any beneficial effects on the minimal residual disease (copies of bcr-abl transcripts), the transcripts remarkably decreased to the level of major molecular response after changing the administration interval of WT1 peptide from 2 to 4 weeks. An ex vivo study demonstrated that re-stimulation with WT1 peptide made WT1-specific T cells less reactive to WT1 tetramers and the impaired reactivity of CTLs lasted at least for 1 week. In addition, the cytotoxicity of the T cells was hampered by re-stimulation. Treg cells increased up to more than fivefold at the end of the WT1 administration period. The present findings suggested that the administration of the peptide every 4 weeks is superior to every 2 weeks. In addition, the findings that Treg cells increased gradually in accordance with the duration of WT1 peptide administration revealed the significance of manipulating Treg cells for establishing an efficient tumor antigen peptide vaccination.

DOI： 10.1007/s12032-010-9425-3

Clinical value of assessing the response to imatinib monitored by interphase FISH and RQ-PCR for BCR-ABL in peripheral blood for long-term survival of chronic phase CML patients: results of the Niigata CML-multi-institutional co-operative clinical study 査読

Tatsuo Furukawa, Miwako Narita, Tadashi Koike, Kazue Takai, Koichi Nagai, Masashi Kobayashi, Satoru Koyama, Yoshinobu Seki, Hoyu Takahashi, Masahiro Fujiwara, Kenji Kishi, Koji Nikkuni, Noriatsu Isahai, Wataru Higuchi, Nobuhiko Nomoto, Souichi Maruyama, Masayoshi Masuko, Takashi Kuroha, Takashi Abe, Ken Toba, Masuhiro Takahashi, Yoshifusa Aizawa, Akira Shibata

INTERNATIONAL JOURNAL OF HEMATOLOGY 93 ( 3 ) 336 - 343 2011年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

This retrospective analysis investigated the prognostic value of monitoring the response to imatinib using peripheral blood (PB) samples and the impact of the response on outcome in 133 patients with chronic myeloid leukemia (CML). We divided the response into 3 categories according to the results of neutrophil (N)-FISH and BCR-ABL transcript levels in PB; more than a 3-log reduction [major molecular response (MMR)], between a 2-log and 3-log reduction or negative with N-FISH [complete cytogenetic response equivalent (CCyRe)], N-FISH positive or less than a 2-log reduction (non-CCyRe). The median follow-up was 5.46 years. At 5 years, the overall survival (OS) rate and progression-free survival (PFS) rate were 94.4 and 92.0%, respectively. The estimated rate of the CCyRe and MMR were 81.7 and 67.1%, respectively. 106 patients achieving the CCyRe had significantly better OS and PFS than 27 patients without achieving the CCyRe. Patients with MMR had significantly better survival free from death, progression, imatinib withdrawal and a loss of the CCyRe, than patients whose response level remained in the CCyRe without achieving MMR until 18 months. Our observation suggests that the response level of the CCyRe on PB serve as a prognostic indicator, and achieving MMR provides stable long-term survival.

DOI： 10.1007/s12185-011-0774-2

Successful Remission of Evans Syndrome Associated with Graves' Disease by Using Propylthiouracil Monotherapy 査読

Takashi Ushiki, Masayoshi Masuko, Koji Nikkuni, Jun Terukina-Yoshida, Ayako Momotsu-Nanba, Hiroshi Morikawa, Akio Usami, Ichiro Fuse, Ken Toba, Kazue Takai, Yoshifusa Aizawa

INTERNAL MEDICINE 50 ( 6 ) 621 - 625 2011年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

A 46-year-old woman with Graves' disease was admitted for anemia and thrombocytopenia. She had previously been treated with methimazole but she self-discontinued the treatment 6 months prior to admission. She was diagnosed with Evans syndrome associated with Graves' disease and treated with propylthiouracil without corticosteroids, which normalized her thyroglobulin level. Surprisingly, while Evans syndrome is characterized by frequent relapses, this patient has been in remission of Evans syndrome for approximately 4 years. The remission of Evans syndrome associated with Graves' disease in the absence of immunosuppressive therapy suggests that these 2 diseases have a common pathogenetic mechanism.

DOI： 10.2169/internalmedicine.50.4319

Myelodysplastic Syndrome with Ph Negative Monosomy 7 Chromosome following Transient Bone Marrow Dysplasia during Imatinib Treatment for Chronic Myeloid Leukemia 査読

Kaori Karimata, Masayoshi Masuko, Takashi Ushiki, Takashi Kozakai, Yasuhiko Shibasaki, Toshio Yano, Takashi Abe, Masato Moriyama, Ken Toba, Tatsuo Furukawa, Yoshifusa Aizawa

INTERNAL MEDICINE 50 ( 5 ) 481 - 485 2011年

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

We describe a 60-year-old Japanese patient with chronic myeloid leukemia (CML) who developed myelodysplastic syndrome (MDS) with Ph negative monosomy 7 chromosome following transient bone marrow dysplasia during imatinib treatment. Most cases that developed chromosomal abnormality in Ph negative cells during imatinib therapy were reported to have less clinical implications, while rare cases developed MDS/AML. The present case suggested that metaphase karyotype analysis and bone marrow examination should be performed for the long term follow-up under imatinib treatment in cases showing cytopenia. The results also suggested that monosomy 7 in Ph negative cells may be an indicator of a poor prognosis.

DOI： 10.2169/internalmedicine.50.4481

Correlation Between Imatinib Pharmacokinetics and Clinical Response in Japanese Patients With Chronic-Phase Chronic Myeloid Leukemia 査読

N. Takahashi, H. Wakita, M. Miura, S. A. Scott, K. Nishii, M. Masuko, M. Sakai, Y. Maeda, K. Ishige, M. Kashimura, K. Fujikawa, M. Fukazawa, T. Katayama, F. Monma, M. Narita, F. Urase, T. Furukawa, Y. Miyazaki, N. Katayama, K. Sawada

CLINICAL PHARMACOLOGY & THERAPEUTICS 88 ( 6 ) 809 - 813 2010年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Despite the outstanding results generally obtained with imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), some patients show a poor molecular response. To evaluate the relationship between steady-state trough plasma IM concentration (IM-C(min)) and clinical response in CML patients, we integrated data from six independent Japanese studies. Among 254 CML patients, the mean IM-C(min) was 1,010.5 ng/ml. Importantly, IM-C(min) was significantly higher in patients who achieved a major molecular response (MMR) than in those who did not (P=0.002). Multivariate analysis showed that an MMR was associated with both age (odds ratio (OR) = 0.97 (0.958-0.995); P = 0.0153) and with IM-C(min) (OR = 1.0008(1.0003-1.0015); P=0.0044). Given that patients with IM-C(min) values >1,002 ng/ml had a higher probability of achieving an MMR in our large cohort (P=0.0120), the data suggest that monitoring of IM levels in plasma may improve the efficacy of IM therapy for CML patients.

DOI： 10.1038/clpt.2010.186

成熟顆粒球の殆どが病的芽球から分化したt(8;21)を伴うAML(AML with t(8:21) which most of mature granulocytes differentiated from pathological blast)

Kozakai Takashi, Kobayashi Hironori, Ushiki Takashi, Kitajima Toshiki, Higashimura Masutaka, Yano Toshio, Abe Takashi, Masuko Masayoshi, Furukawa Tatsuo, Toba Ken, Aizawa Yoshifusa

臨床血液 51 ( 9 ) 1228 - 1228 2010年9月

Pharmacokinetic and pharmacodynamic analysis of cyclosporine A (CsA) to find the best single time point for the monitoring and adjusting of CsA dose using twice-daily 3-h intravenous infusions in allogeneic hematopoietic stem cell transplantation 査読

Tatsuo Furukawa, Tori Kurasaki-Ida, Masayoshi Masuko, Nobuhiro Tsukada, Kiyoshi Okazuka, Naoko Sato, Toshio Yano, Takashi Abe, Akihito Momoi, Yasuhiko Shibasaki, Masutaka Higashimura, Kaori Karimata, Masato Moriyama, Takashi Kuroha, Jun Takizawa, Ken Toba, Miwako Narita, Ichiro Fuse, Masuhiro Takahashi, Yoshifusa Aizawa

INTERNATIONAL JOURNAL OF HEMATOLOGY 92 ( 1 ) 144 - 151 2010年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

Pharmacological study is predictably effective in establishing an optimal monitoring strategy for the usage of cyclosporine A (CsA) to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation recipients. Pharmacokinetic profiling of 33 recipients administered CsA twice daily by 3-h intravenous infusion revealed that levels peaked 2-3 h after the start of infusion, and an exponential decline of CsA concentrations after the termination of infusion was observed. The correlation between the area under the curve (AUC(0-12)) and CsA concentration at various time points after infusion revealed that C (2) and C (3) correlated best with AUC(0-12) (r (2) = 0.725), while the trough concentration correlated poorly. Ex vivo T cell stimulation followed by intracellular cytokine detection with flow cytometry revealed that the capacity of T cells to produce cytokines upon stimulation was inversely proportional to the CsA concentration, and reached a minimum at about 700 ng/mL with a marginal decrease above this concentration. Extrapolation using the regression equations of this study and the data from our retrospective study leads to the assumption that the dose adjustment of CsA based on maintaining the C (3) concentration above 800 ng/mL may effectively prevent acute GVHD. To confirm this assumption, a prospective clinical study is required.

DOI： 10.1007/s12185-010-0610-0

Noninvasive Tracking of Donor Cell Homing by Near-Infrared Fluorescence Imaging Shortly after Bone Marrow Transplantation 査読

Takashi Ushiki, Shinae Kizaka-Kondoh, Eishi Ashihara, Shotaro Tanaka, Masayoshi Masuko, Hideyo Hirai, Shinya Kimura, Yoshifusa Aizawa, Taira Maekawa, Masahiro Hiraoka

PLOS ONE 5 ( 6 ) 2010年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Background: Many diseases associated with bone marrow transplantation (BMT) are caused by transplanted hematopoietic cells, and the onset of these diseases occurs after homing of donor cells in the initial phase after BMT. Noninvasive observation of donor cell homing shortly after transplantation is potentially valuable for improving therapeutic outcomes of BMT by diagnosing the early stages of these diseases.
Methodology/Principal Findings: Freshly harvested near-infrared fluorescence-labeled cells were noninvasively observed for 24 h after BMT using a photon counting device to track their homing process. In a congenic BMT model, the homing of Alexa Fluor 750-labeled donor cells in the tibia was detected less than 1 h after BMT. In addition, subsequent cell distribution in an intraBM BMT model was successfully monitored for the first time using this method. In the allogeneic BMT model, T-cell depletion decreased the near-infrared fluorescence (NIRF) signals of the reticuloendothelial system.
Conclusions/Significance: This approach in several murine BMT models revealed that the transplanted cells homed within 24 h after transplantation. NIRF labeling is useful for tracking transplanted cells in the initial phase after BMT, and this approach can contribute to in vivo studies aimed at improving the therapeutic outcomes of BMT.

DOI： 10.1371/journal.pone.0011114

WT1 PEPTIDE VACCINATION IN COMBINATION WITH IMATINIB THERAPY FOR A PATIENT WITH CML IN THE CHRONIC PHASE 査読

Miwako Narita, Masayoshi Masuko, Tohri Kurasaki, Toshiki Kitajima, Shoko Takenouchi, Anri Saitoh, Norihiro Watanabe, Tatsuo Furukawa, Ken Toba, Ichiro Fuse, Yoshifusa Aizawa, Manabu Kawakami, Yoshihiro Oka, Haruo Sugiyama, Masuhiro Takahashi

INTERNATIONAL JOURNAL OF MEDICAL SCIENCES 7 ( 2 ) 72 - 81 2010年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：IVYSPRING INT PUBL

Although tyrosine kinase inhibitors is effective for dramatically reducing CML cells, it might be difficult to eradicate completely the CML stem cells. We aimed to clarify the safety and effects of WT1 peptide vaccination in combination with imatinib therapy for a CML patient. A 51 year-old male with CML in CP, who showed a resistance against imatinib therapy for 2.5 years, began to be treated with 9mer modified-type WT1 peptides in combination with standard dose of imatinib. Although every 2-week-administration of WT1 peptides for 22 weeks did not show definite effects on the quantification of bcr-abl transcripts, by changing the administration from every 2 weeks to 4 weeks bcr-abl transcripts decreased remarkably. After 11 months of every 4-week-administration of the peptides and 12 months post cessation of the peptides bcr-abl transcripts achieved to the level below detection by RQ/RT-PCR (complete molecular response). WT1/MHC tetramer(+)CD8(+) CTLs, which appeared after the second administration of WT1 peptides and remained more than 15 in number among 10(6) CD8(+) T cells throughout the administration of WT1 peptides, are still present in the blood on 14th month post cessation of the peptides. An in vitro study as to the cytotoxicity of lymphocytes induced by mixed lymphocyte peptide culture demonstrated that cultured lymphocytes possessed cytotoxicity against WT1 expressing leukemia cells and the cytotoxicity was WT1-specific and MHC class I restricted. The present study showed that WT1 peptide vaccination in combination with TKI is feasible and effective in the therapy for imatinib-resistant CML.

Induction of antigen-specific cytotoxic T lymphocytes by using monocyte-derived DCs transfected with in vitro-transcribed WT1 or SART1 mRNA 査読

Miwako Narita, Nozomi Tochiki, Anri Saitoh, Norihiro Watanabe, Masami Kaji, Noriyuki Satoh, Akie Yamahira, Takeshi Nakamura, Masayoshi Masuko, Tatsuo Furukawa, Ken Toba, Ichiro Fuse, Yoshifusa Aizawa, Masuhiro Takahashi

MEDICAL ONCOLOGY 26 ( 4 ) 429 - 436 2009年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：HUMANA PRESS INC

To evaluate the usefulness of monocyte-derived dendritic cells transfected with tumor antigen mRNA for dendritic cell-based antitumor immunotherapy, we attempted to generate antigen-specific cytotoxic T cells by priming lymphocytes with monocyte-derived dendritic cells transfected with in vitro-transcribed tumor antigen mRNA. Mature monocyte-derived dendritic cells were generated from microbeads-separated CD14(+) cells by culturing with GM-CSF/IL-4 for 7 days and with TNF-alpha, IL-1 alpha, IL-6, and PGE(2) for the last one day. Monocyte-derived dendritic cells, lymphocytes, and target cells, which were positive for HLA-A24, were used in the present study. Although lymphocytes prestimulated with untransfected monocyte-derived dendritic cells did not possess the cytotoxic ability against the target cells in a (51)Cr-release cytotoxicity assay, lymphocytes primed with tumor antigen RNA-transfected monocyte-derived dendritic cells were cytotoxic against the tumor antigen-expressing cells but not against the target cells without the expression of the antigen. The cytotoxic ability of the lymphocytes was blocked by the addition of antibodies against MHC class I but not by antibodies against MHC class II. These findings revealed that monocyte-derived dendritic cells transfected with WT1 or SART1 mRNA are able to induce tumor antigen-specific cytotoxic T cells and applicable for antitumor dendritic cell-based cellular immunotherapy.

DOI： 10.1007/s12032-008-9142-3

Sequential adenovirus infection of type 14 hemorrhagic cystitis and type 35 generalized infection after cord blood transplantation 査読

Takashi Abe, Tatsuo Furukawa, Masayoshi Masuko, Atsunori Sugimoto, Kiyoshi Okazuka, Keiichiro Honma, Takeo Fujimura, Seitaro Iguchi, Shinichi Nishi, Mitsuhiro Ueno, Masayuki Nagahashi, Gen Watanabe, Yoichi Ajioka, Noriatsu Isahai, Koichi Nagai, Yukumasa Kazuyama, Yosifusa Aizawa

INTERNATIONAL JOURNAL OF HEMATOLOGY 90 ( 3 ) 421 - 425 2009年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

We report a case of a 29-year-old male patient with a generalized adenovirus (AdV) infection after cord blood transplantation (CBT) for acute myelocytic leukemia with maturation at 2nd complete remission. Before engraftment, hemorrhagic cystitis was caused by AdV, which resulted in hydronephrosis, renal failure, and adenoviremia on day 34. Forced diuresis, hemodialysis, withdrawal of cyclosporin A, and administration of gamma-globulin or vidarabine were not effective and the patient died of pulmonary alveolar hemorrhage on day 67. At autopsy, old inflammatory change only was observed in the bladder section. In the lungs and kidneys, granular deposits in the nucleus and a high copy number of AdV-DNA were observed. Molecular diagnosis using PCR-restriction fragment length polymorphism analysis demonstrated that AdV with the serotype 14 caused the cystitis. However, retrospective genome typing using PCR sequencing revealed the infection of AdV serotype 35 in the kidneys, lungs, and serum. The present case suggested that Adv infection could not be always caused by a single AdV serotype, and suggested that multiple serotype infection was very difficult to treat. It is desired that a consensus regarding the treatment of AdV infections is established.

DOI： 10.1007/s12185-009-0416-0

A chronic myeloid leukemia patient with atypical karyotype and BCR-ABL e13a3 transcript caused by complex chromosome rearrangement 査読

Masayoshi Masuko, Tatsuo Furukawa, Takashi Abe, Reiko Wada, Soichi Maruyama, Toshiki Kitajima, Yasuhiko Shibasaki, Ken Toba, Masahiko Okada, Yoshifusa Aizawa

INTERNATIONAL JOURNAL OF HEMATOLOGY 90 ( 2 ) 230 - 234 2009年9月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER TOKYO

Philadelphia (Ph) chromosome as a result of t (9; 22) (q34; q11) is observed in more than 90% of chromic myeloid leukemia (CML) patients. Cases in which the typical Ph chromosome is not visible at the karyotype level comprise 5-10% of CML patients. CML cases with fusion transcripts such as e13a3 in which ABL exon 3 rather than exon 2 has fused to BCR are very rare. Such reported cases with the e13a3 transcript show the Ph chromosome on karyotype analysis. We reported an atypical karyotype CML patient with the e13a3 BCR-ABL transcript caused by complex translocation. Fluorescence in situ hybridization (FISH) analysis of the metaphase led to a precise cytogenetical characterization. The patient showed favorable response to imatinib, and achieved major molecular responses.

DOI： 10.1007/s12185-009-0368-4

Risk factors for acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: retrospective analysis of 73 patients who received cyclosporin A 査読

N. Izumi, T. Furukawa, N. Sato, K. Okazuka, N. Tsukada, T. Abe, T. Yano, T. Kurasaki, M. Masuko, K. Toba, M. Takahashi, Y. Aizawa

BONE MARROW TRANSPLANTATION 40 ( 9 ) 875 - 880 2007年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Cyclosporin A (CsA) has been used most widely as an immunosuppressive agent for preventing graft-versus-host disease (GVHD). To explore the risk factors including CsA blood levels for grades II-IV acute GVHD, we retrospectively analyzed the data of patients who underwent allogeneic hematopoietic stem cell transplantation in our hospital between March 1989 and July 2001. Seventy-three patients ( 47 males and 26 females) received CsA and short-term methotrexate for GVHD prophylaxis. CsA 1.5 mg/kg was administered as a 3-h infusion twice daily from day -1 until the patient recovered from the toxic gastrointestinal complication. Methotrexate was given at a dose of 15 mg/m(2) on day 1 and 10 mg/m2 on days 3, 6 and 11. Grades II-IV acute GVHD occurred in 18 patients ( 24.7%). Multivariate Cox regression analysis revealed that higher C-5 ( the whole-blood CsA concentration at 5 h after the start of infusion) before the onset of acute GVHD reduced the onset of grades II-IV acute GVHD with a hazard ratio of 0.994 (95% confidence interval 0.989-0.999) for every increase of 1 ng/ml. Our data indicate that inadequate exposures of CsA can be a vital risk for developing acute GVHD. From our results, we consider that precise monitoring of CsA concentrations and adjustment of CsA dose using the concentration may be effective to prevent the onset of severe acute GVHD. To confirm this finding, further prospective study will be needed.

DOI： 10.1038/sj.bmt.1705834

Successful all-trans retinoic acid treatment of acute promyelocytic leukemia in a patient with NPM/RAR fusion 査読

Kiyoshi Okazuka, Masayoshi Masuko, Yoshinobu Seki, Hitomi Hama, Noriyuki Honma, Tatsuo Furukawa, Ken Toba, Kenji Kishi, Yoshifusa Aizawa

INTERNATIONAL JOURNAL OF HEMATOLOGY 86 ( 3 ) 246 - 249 2007年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：CARDEN JENNINGS PUBL CO LTD

Acute promyelocytic leukemia (APL) is characterized by a reciprocal chromosomal translocation involving the gene for retinoic acid receptor alpha (RAR). Most APL patients have a t(15;17) translocation that generates the PML-RAR fusion gene, and such patients respond well to treatment with all-trans retinoic acid (ATRA). Some APL cases also involve rearrangements that fuse RAR to partner genes other than PML, including nucleophosmin (NPM), promyelocytic leukemia zinc finger (PLZF), nuclear mitotic apparatus (NUMA), and Stat5b, but the clinical characteristics of APL without PML-RAR have not been fully clarified. We describe a 64-year-old man with NPM-RAR-positive APL who was receiving hemodialysis therapy for chronic uremia. Complete remission was achieved with ATRA monotherapy and was maintained for 18 months with consolidation chemotherapy. These findings suggest that ATRA can be used to treat APL patients with NPM/RAR as well as APL with PML/RAR.

DOI： 10.1532/IJH97.07036

臍帯血移植(CBT)後の免疫抑制療法の至適化に向けた移植後リンパ球の免疫動態の解析

塚田信弘, 石毛真行, 小沼貴晶, 友成章, 大井淳, 高橋聡, 渡辺信和, 中内啓光, 増子正義, 古川達雄, 相澤義房, 東條有伸

臨床血液 48 ( 9 ) 890 - 890 2007年9月

Identification of an overexpressed gene, HSPA4L, the product of which can provoke prevalent humoral immune responses in leukemia patients 査読

Hidenobu Takahashi, Tatsuo Furukawa, Toshio Yano, Naoko Sato, Jun Takizawa, Tori Kurasaki, Takashi Abe, Miwako Narita, Masayoshi Masuko, Satoru Koyama, Ken Toba, Masuhiro Takahashi, Yoshifusa Aizawa

EXPERIMENTAL HEMATOLOGY 35 ( 7 ) 1091 - 1099 2007年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

Objective. To identify leukemia-associated antigens, we applied the serological identification of antigens by the recombinant expression cloning (SEREX) method to a chronic myelogenous leukemia (CML) patient who achieved a cytogenetic response to interferon-alpha.
Materials and Methods. Immunoscreening of the cDNA library was performed with sera from a CML patient. Two isolated antigens were used to evaluate the expression pattern using Northern blot analysis and quantitative reverse transcriptase polymerase chain reaction. Western blotting and enzyme-linked immunosorbent assay were also performed for serological analysis.
Results. We identified 14 positive clones, representing five different antigens. Of these, two genes were further validated. One (clone 70) was the human polyribonucleotide nucleotidyltransferase 1 (PNPT1), which is the type I interferon (alpha/beta-responsive gene). The mRNA of clone 70 was ubiquitously expressed in normal human tissues. The other gene (clone 57) was the heat shock 70-kDa protein 4-like (HSPA4L), which is a member of the heat shock protein 110 family, whose mRNA is strongly expressed in normal human testis and overexpressed in leukemia cells. Seroactivity against HSPA4L was detected in 6 of 9 acute myeloid leukemia patients, 4 of 10 acute lymphoblastic leukemia patients, 9 of 11 CML patients, and none of 10 healthy volunteers. Leukemia patients had higher titer of the antibodies against the protein than healthy volunteers.
Conclusions. These results suggest that HSPA4L, a member of heat shock protein, is highly expressed by leukemia cells, and elicit humoral immune responses in leukemia patients, and it might be a potential target for antileukemia therapy and an antigen-specific immunotherapy for leukemia.

DOI： 10.1016/j.exphem.2007.03.015

Plasma brain natriuretic peptide during myeloablative stem cell transplantation. 査読

Masuko M, Ito M, Kurasaki T, Yano T, Takizawa J, Toba K, Aoki S, Fuse I, Kodama M, Furukawa T, Aizawa Y

Internal medicine (Tokyo, Japan) 46 ( 9 ) 551 - 555 2007年

担当区分：筆頭著者,　責任著者記述言語：英語出版者・発行元：The Japanese Society of Internal Medicine

<b>Objective:</b> Cardiovascular complication is one of the serious complications in stem cell transplantation (SCT). We measured plasma brain natriuretic peptide (BNP) concentrations in patients who received SCT to evaluate possible cardiac toxicity of the regimens employed in SCT.<br> <b>Patients:</b> Ten patients with allogeneic SCT and 5 patients with autologous SCT using myeloablative conditioning regimens were enrolled. The preparative chemotherapy for 8 patients with allogeneic SCT included cyclophosphamide (60 mg/kg i.v. for 2 days) and other drugs and that for autologous SCT included cyclophosphamide (50 mg/kg for 2 days) and other drugs. Total body irradiation (TBI) was employed only in the patients who received allogeneic SCT.<br> <b>Method:</b> Plasma BNP was measured using a radioimmunoassay for human BNP before and after SCT.<br> <b>Results:</b> In 13 of 15 patients, BNP levels were elevated after SCT. In patients who received a total body irradiation (TBI) of 13.2 Gy, BNP levels were higher than those without irradiation (p=0.01). The BNP level reached a peak within 6 months after SCT in most patients and fell thereafter. But 7 of the 15 patients (46.7%) had an abnormally high level of plasma BNP even after 6 months of SCT which suggests subclinical myocardial damage.<br> <b>Conclusion:</b> A rise in plasma BNP was frequently observed after SCT, and may be considered to represent cardiac damage caused by the preparative chemotherapy and/or total body irradiation. Since a rise was noted 6 months after SCT, long-term evaluation of cardiac function is important.<br>

DOI： 10.2169/internalmedicine.46.6188

その他リンク： http://search.jamas.or.jp/link/ui/2007315596

Persistence of various chromosomal aberrations in recipient cells during complete remission after bone marrow transplantation followed by graft rejection 査読

M Masuko, T Furukawa, O Yersser, M Narita, K Toba, T Koike, Y Aizawa

LEUKEMIA RESEARCH 29 ( 9 ) 1083 - 1087 2005年9月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

A 16-year-old boy in a second remission of acute lymphoblastic leukemia (ALL) had undergone transplantation of bone marrow from an unrelated donor. The conditioning regimen consisted of high-dose cytarabine, etoposide and 12 Gy of total-body irradiation. Although the donor marrow was rejected, hematopoiesis by the recipient himself recovered and he has remained in complete remission for more than 8 years after stem tell transplantation (SCT). Bone marrow karyotype analysis I month after SCT showed random chromosomal aberrations. Although complete remission was maintained, various chromosomal aberrations were detected in marrow cells, and in peripheral blood cells under phytohemagglutinin stimulation over 8 years. Moreover, a clone including del(20)(q11) appeared in marrow cells 7 months after SCT and thereafter was also detected 5 years later in the peripheral blood. This persistence of various chromosomal aberrations and a stable clone without evolution to myelodysplastic syndrome or leukemia support the multi step theory of leukemogenesis. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.leukres.2005.01.018

High-dose cytosine arabinoside and etoposide with total body irradiation as a preparatory regimen for allogeneic hematopoietic stem-cell transplantation in patients with acute lymphoblastic leukemia 査読

N. Sato, Tatsouf Furukawa, T. Kuroha, S. Hashimoto, M. Masuko, H. Takahashi, T. Yano, T. Abe, I. Fuse, T. Koike, K. Kishi, Y. Aizawa

Bone Marrow Transplantation 34 ( 4 ) 299 - 303 2004年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

One approach to improving the outcome of allogeneic hematopoietic stem-cell transplantation for acute lymphoblastic leukemia (ALL) is to intensify the pretransplant conditioning regimen without increasing toxicity. We used an intensified conditioning regimen consisting of high-dose cytosine arabinoside (3 g/m2 twice daily i.v. for 3 consecutive days, total six doses), high-dose etoposide (1 g/m2 once daily i.v. during the first 2 days) and total body irradiation (TBI) (HDACE-TBI) in ALL patients. We retrospectively analyzed 21 patients treated with HDACE-TBI, of whom 18 were in complete remission (CR) and three were in non-CR at transplantation. Although gastrointestinal toxicities were common, critical regimen-related toxicities were not seen in any patients. One patient demonstrated veno-occlusive disease, which could be controlled conservatively. The disease-free survival rate of 18 patients in CR at transplantation was 61%. These results demonstrate that the HDACE-TBI combination regimen is a feasible alternative to other preparatory regimens and does not increase the regimen-related toxicity. © 2004 Nature Publishing Group All rights reserved.

DOI： 10.1038/sj.bmt.1704575

Acute promyelocytic leukemia developing in untreated essential thrombocythemia 査読

Naoaki Sato, Tatsuo Furukawa, Masayoshi Masuko, Shigeo Hashimoto, Hidenobu Takahashi, Miyako Baba, Koichi Inano, Noriatsu Suzuki, Ken Toba, Ichiro Fuse, Yoshifusa Aizawa

American Journal of Hematology 71 ( 2 ) 114 - 116 2002年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

We describe a patient with untreated essential thrombocythemia (ET) who developed microgranular variant of acute promyelocytic leukemia, 9 years after the initial diagnosis of ET. He achieved complete remission (CR) but relapsed 11 months later. After achieving the second CR, he received peripheral stem cell transplantation from his HLA complete-matched sibling. Five months after the transplantation, he relapsed again with meningeal infiltration of leukemic cells. In this paper, we review cases of promyelocytic transformation of myeloproliferative diseases (MPD) other than chronic myeloid leukemia (CML). To our knowledge, this is the first case of promyelocytic transformation of Philadelphia chromosome negative untreated ET, in whom both t(15
17) and PML-RARα fusion were proven. © 2002 Wiley-Liss, Inc.

DOI： 10.1002/ajh.10195

JAK2, complemented by a second signal from c-kit or flt-3, triggers extensive self-renewal of primary multipotential hemopoietic cells 査読

SM Zhao, K Zoller, M Masuko, P Rojnuckarin, XXO Yang, E Parganas, K Kaushansky, JN Ihle, T Papayannopoulou, DM Willerford, T Clackson, CA Blau

EMBO JOURNAL 21 ( 9 ) 2159 - 2167 2002年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Defining signals that can support the self-renewal of multipotential hemopoietic progenitor cells (MHPCs) is pertinent to understanding leukemogenesis and may be relevant to developing stem cell-based therapies. Here we define a set of signals, JAK2 plus either c-kit or flt-3, which together can support extensive MHPC self-renewal. Phenotypically and functionally distinct populations of MHPCs were obtained, depending on which receptor tyrosine kinase, c-kit or flt-3, was activated. Self-renewal was abrogated in the absence of STAT5a/b, and in the presence of inhibitors targeting either the mitogen-activated protein kinase or phosphatidylinositol 3' kinase pathways. These findings suggest that a simple two-component signal can drive MHPC self-renewal.

DOI： 10.1093/emboj/21.9.2159

Receptor specificity in the self-renewal and differentiation of primary multipotential hemopoietic cells 査読

H Zeng, M Masuko, LQ Jin, T Neff, KG Otto, CA Blau

BLOOD 98 ( 2 ) 328 - 334 2001年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC HEMATOLOGY

To determine whether cytokine-induced signals generate unique responses in multipotential hemopoietic progenitor cells, the signaling domains of 3 different growth factor receptors (MpI, granulocyte-colony-stimulating factor [G-CSF] receptor, and Flt-3) were inserted into mouse primary bone marrow cells. To circumvent the activation of endogenous receptors, each signaling domain was incorporated into an FK506 binding protein (FKBP) fusion to allow for its specific activation using synthetic FKBP ligands, Each signaling domain supported the growth of Ba/F3 cells; however, only MpI supported the sustained growth of transduced marrow cells, with a dramatic expansion of multipotential progenitors and megakaryocytes. These findings demonstrate that the self-renewal and differentiation of multipotential progenitor cells can be influenced through distinct, receptor-initiated signaling pathways. (C) 2001 by The American Society of Hematology.

DOI： 10.1182/blood.V98.2.328

The coxsackievirus-adenovirus receptor protein as a cell adhesion molecule in the developing mouse brain 査読

T Honda, H Saitoh, M Masuko, T Katagiri-Abe, K Tominaga, Kozakai, I, K Kobayashi, T Kumanishi, YG Watanabe, S Odani, R Kuwano

MOLECULAR BRAIN RESEARCH 77 ( 1 ) 19 - 28 2000年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

In an attempt to elucidate the molecular mechanisms underlying neuro-network formation in the developing brain, we analyzed 130 proteolytic cleavage peptides of membrane proteins purified from newborn mouse brains. We describe here the characterization of a membrane protein with an apparent molecular mass of 46 kDa, a member of the immunoglobulin superfamily of which the cDNA sequence was recently reported, encoding the mouse homologue of the human coxsackievirus and adenovirus receptor (mCAR). Western and Northern blot analyses demonstrated the abundant expression of mCAR in the mouse brain, the highest level being observed in the newborn mouse brain, and its expression was detected in embryos as early as at 10.5 days post-coitus (dpc), but decreased rapidly after birth. On in situ hybridization, mCAR mRNA expression was observed throughout the newborn mouse brain. In primary neurons from the hippocampi of mouse embryos the expression of mCAR was observed throughout the cells including those in growth cones on immunohistochemistry. In order to determine whether or not mCAR is involved in cell adhesion, aggregation assays were carried out. C6 cells transfected with mCAR cDNA aggregated homophilically, which was inhibited by specific antibodies against the extracellular domain of mCAR. In addition to its action as a virus receptor, mCAR may function naturally as an adhesion molecule involved in neuro-network formation in the developing nervous system. (C) 2000 Elsevier Science BN. All rights reserved.

DOI： 10.1016/S0169-328X(00)00036-X

Expression of coxsackievirus and adenovirus receptor in hearts of rats with experimental autoimmune myocarditis 査読

M Ito, M Kodama, M Masuko, M Yamaura, K Fuse, Y Uesugi, S Hirono, Y Okura, K Kato, Y Hotta, T Honda, R Kuwano, Y Aizawa

CIRCULATION RESEARCH 86 ( 3 ) 275 - 280 2000年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

The expression of coxsackievirus and adenovirus receptor (CAR) was dominant in the brains and hearts of mice until the newborn phase. There is no detailed information concerning the relation between the expression of CAR and development of hearts. It is also uncertain whether CAR is able to be induced in adult hearts after cardiac injury. We demonstrated that CAR was abundant in the hearts of newborn rats but was barely detectable in the hearts of adult rats. The expression of CAR in rat hearts with experimental autoimmune myocarditis, which was induced by immunization of purified cardiac myosin, was serially investigated. Active myocarditis was observed from day 15 after immunization. By immunohistochemistry, cardiomyocytes were strongly stained for CAR antibody from days 24 to 42. CAR mRNA was also detected from days LX to 30 by using reverse transcription-polymerase chain reaction. In the next experiment, the induction of CAR on isolated cardiomyocytes was investigated. CAR was barely detectable in cultured cardiomyocytes by Western blot analysis after isolation. This molecule gradually appeared along with the creation of clusters and beating of cardiomyocytes. Furthermore, the induction of CAR in cultured cardiomyocytes increased after supplement with conditioned medium of rat splenocytes activated by concanavalin A. In conclusion, rat CAR is expressed strongly in the hearts of newborn rats and is suppressed in those of adult rats. The expression of CAR is enhanced during the active phase of experimental autoimmune myocarditis and is induced by inflammatory mediators, CAR may play a role in cell-to-cell contact and adhesion of cardiomyocytes.

Cyclosporine A-associated fatal central nervous system angiopathy in a bone marrow transplant recipient: An autopsy case 査読

T. Koide, M. Yamada, T. Takahashi, S. Igarashi, M. Masuko, T. Furukawa, T. Kuroha, T. Koike, M. Sato, R. Tanaka, S. Tsuji, H. Takahashi

Acta Neuropathologica 99 ( 6 ) 680 - 684 2000年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Verlag

We report here the case of a 32-year-old woman who suffered from a unique angiopathy in the central nervous system (CNS). She died of multiple infarcts in the brain stem and cerebellum during treatment with cyclosporine A after bone marrow transplantation for refractory anemia with excess of blasts. The autopsy findings showed segmental narrowing of the basilar artery, in which circumferential dissection of the internal elastic lamina had occurred. The distal portion of the basilar artery was obstructed by upward dislocation of the dissected intima. Similar angiopathy was also observed at multiple sites along the basilar artery branches. These findings suggest endothelial damage, including vasoconstriction and dissection of the CNS arteries.

DOI： 10.1007/s004010051179

Novel technique for the direct flow cytofluorometric analysis of human basophils in unseparated blood and bone marrow, and the characterization of phenotype and peroxidase of human basophils 査読

Ken Toba, Tadashi Koike, Akira Shibata, Shigeo Hashimoto, Masuhiro Takahashi, Masayoshi Masuko, Takaaki Azegami, Hidenobu Takahashi, Yoshifusa Aizawa

Cytometry 35 ( 3 ) 249 - 259 1999年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley-Liss Inc.

Background: No technique has been reported to analyze directly the antigen expression on basophil leukocytes when using a flow cytometer
therefore, the exact phenotype of human basophils and the character of the peroxidase in basophils are not well understood. Methods: Human blood basophils were purified by using an antibody against high-affinity Fc epsilon receptor (hFcεR) and a MACS(TM) magnetic cell sorting system and then cytochemically stained. The phenotype and peroxidase of the human basophils were flow cytofluorometrically analyzed directly in unseparated blood and bone marrow samples as hFcεR+/MBP+ (major basic protein)/Hist+ (histamine) light-density cells distributed in the high sidescatter area of lymphocytes on light scattergrams. Results: The peroxidase granules of human basophils were stained by an anti-eosinophil peroxidase (EPO) antobody. The human blood basophils had common granulocyte markers plus CD25, i.e., they were CD11a/CD1lb/CD11c/CD25/CD38/CD13/CD33/hFcεR/MBP/Hist/EPO positive, CD71 dim positive, CD14/CD15 partially positive, and CD2/CD3/CD7/CD122/CD16/CD56/CD57/CD10/CD19/CD20/CD22/HLA-DR/MPO (myeloperoxidase)/CD23 negative. Further examination was done to analyze the expression of colony-stimulating factor receptors on three lineages of granulocytes, i.e., basophils, eosinophils, and neutrophils. The neutrophils were CD114 (G-CSFR)/CD116 (GM-CSFR)/CD124 [interleukin (IL)-4R]/CD126 (IL- 6R) positive and CD123 (IL-3R)/CD125 (IL-5R) negative. In contrast, the eosinophils and basophils were CD116/CD123/CD125/CD126 positive and CD114/CD124 negative. Conclusions: This novel technique for directly characterizing human basophil leukocytes with flow cytometry may be a convenient way to screen the expression of surface antigens and the cytoplasmic expression of CD antigens and other proteins in human blood basophils and to analyze alterations of the character of basophils by cytokines and other biological substances in vivo and in vitro.

DOI： 10.1002/(SICI)1097-0320(19990301)35:3<249::AID-CYTO8>3.0.CO;2-O

Expression of eosinophil peroxidase in the immature basophil cell line KU812-F 査読

M Masuko, T Koike, K Toba, K Kishi, T Kuroha, T Furukawa, Fuse, I, M Takahashi, R Kuwano, A Shibata, Y Aizawa

LEUKEMIA RESEARCH 23 ( 2 ) 99 - 104 1999年2月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Although peroxidase activity in basophils can be detected by optical and ultrastructural cytochemistry, its characteristics remain to be determined. We have demonstrated the characteristics of peroxidase activity induced in the immature basophil cell line, KU812-F. Ultrastructurally, peroxidase activity was detected in granules as well as in the perinuclear space and endoplasmic reticulum. Immunocytochemistry revealed that KU812-F cells were stained by anti-eosinophil peroxidase antibodies, and eosinophil peroxidase mRNA, not myeloperoxidase, was detected in the cells using Northern hybridization and reverse transcription-polymerase chain reaction. Eosinophil peroxidase can be one of the molecules shared with eosinophils and basophils. The biological function of eosinophil peroxidase detected in basophils remains uncertain. (C) 1999 Elsevier Science Ltd. All rights reserved.

Hematopoietic cytokine-dependent differentiation to eosinophils and neutrophils in a newly established acute promyelocytic leukemia cell line with t(15;17) 査読

K. Kishi, K. Toba, T. A. Azegami, N. Tsukada, Y. Uesugi, M. Masuko, H. Niwano, S. Hashimoto, M. Sakaue, T. Furukawa, T. Koike, H. Takahashi, T. Maekawa, T. Abe, Y. Aizawa

Experimental Hematology 26 ( 2 ) 135 - 142 1998年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier Inc.

We recently established an acute promyelocytic leukemia (APL) cell line (HT93) that has the capacity to differentiate into neutrophils and eosinophils in response to all-trans retinoic acid (ATRA) and human hematopoietic cytokines. The cells had a myeloblastic morphology, were positive for surface CD33, CD34, and CD56, and showed the following karyotypes: 46, XY, t(1
12)(q25
p13), 2q+, t(4
6)(q12
q13), and t(15
17)(q22
q11). When the cells were cultured with ATRA, they showed nuclear segmentation and developed secondary granules consisting in part of neutrophils and eosinophils. In the presence of ATRA and granulocyte colony- stimulating factor (G-CSF), the cells showed polymorphonuclear neutrophil differentiation accompanied by expression of surface CD11b, CD15, CD10, positive activity for neutrophil alkaline phosphatase (NAP), anti NAP mRNA expression. In cultures with ATRA and granulocyte-macrophage colony- stimulating factor (GM-CSF), IL (interleukin)-3, or IL-5, HT93 showed remarkable eosinophil maturation at day 8 as determined by luxol fast blue staining, in addition to expression of eosinophil peroxidase and major basic protein. These results indicate that HT93 is an APL cell line with the ability to differentiate into neutrophils anti eosinophils, and that these lineages are dependent on the CSF added. HT 93 should prove to be a useful model in analyzing the effects of hematopoietic cytokines on proliferation, differentiation, and maturation of hematopoietic progenitors.

Confiscation of autonomous proliferation from p2l0bcr-abl transfected cells by re-transfection with DNA for homologous recombination

M. Takahashi, N. Shigeno, N. Suzuki, H. Takahashi, K. Nikkuni, M. Masuko, M. Sakaue, T. Furukawa, K. Kishi, T. Koike, Y. Aizawa

Transgenics 2 ( 3 ) 241 - 247 1998年

記述言語：英語掲載種別：研究論文（学術雑誌）

Ideally, somatic gene therapy for genetic diseases is designed to replace an abnormal gene with a normal gene and to normalize the characteristics of abnormal cells. Up to now, repair of an abnormal gene can be accomplished only by homologous recombination between that abnormal gene and the gene for correction. Our study was designed to discover whether or not homologous recombination occurs in hematopoietic cells and whether it is possible to establish gene therapy using homologous recombination. A murine hematopoietic cell line, FDC-P2, which was factor-dependent but became factor-independent by being transfected with p210bcr-abl was used for the target cell for homologous recombination. The plasmid for homologous recombination was made by inserting the neo-gene in the region of bcr-abl, thymidine kinase-gene in the region outside of bcr-abl, and placing the bcr-abl region reversely for defining the homologous recombination region to bcr-abl. Transfection was done by electroporation and selection was performed by adding G418 and gancyclovir. One clone was established and confirmed to be replaced by the plasmid made for homologous recombination by RT-PCR findings of thymidine kinase (-), neo (+), bcr-abl (-) and a reasonable change of the band by Southern blot analysis. The clone became factor-independent. These findings suggest the possibility of homologous recombination-associated gene replacement therapy for hematological diseases including leukemia.

Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor 査読

Tatsuo Furukawa, Miwako Narita, Minori Sakaue, Tomio Otsuka, Takashi Kuroha, Masayoshi Masuko, Takuaki Azegami, Kenji Kishi, Masuhiro Takahashi, Jirou Utsumi, Tadashi Koike, Yoshifusa Aizawa

British Journal of Haematology 99 ( 1 ) 222 - 227 1997年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Ltd

Primary familial and congenital polycythaemia (PFCP) is a rare disease characterized by congenital erythrocytosis inherited in an autosomal dominant fashion. Recently, mutations in the erythropoietin receptor (EpoR) have been identified in PFCP families. We describe a Japanese family with an autosomal dominant inheritance of PFCP. An in vitro colony assay demonstrated hypersensitivity of erythroid progenitors to erythropoietin (Epo) in affected family members. Sequence analysis of RT-PCR products amplified from the C- terminal region of EpoR transcripts in affected family members revealed that they were all heterozygous for C and T bases at position 5986, which suggested a genetic mutation (C to T) on one allele of EpoR. This mutation gave rise to a translation termination codon TAG at amino acid 435. Thus, the resulting EpoR is a truncated protein product lacking all 74 amino acids downstream of the mutation. To date, all genetic mutations affecting a family with PFCP, including this one, have been located in the cytoplasmic negative regulatory region of the EpoR. All mutations gave rise to truncated Epo receptors between Tyrosine 427 and Tyrosine 455. The phosphotyrosines in this region of EpoR have been demonstrated to be binding sites for SHP-1 phosphatase. Therefore PFCP is presumably brought about as a result of genetic mutations which cause the loss of the SFIP-1 binding site in the cytoplasmic region of EpoR.

DOI： 10.1046/j.1365-2141.1997.3583172.x

Profile of cell cycle in hematopoietic malignancy by DNA/RNA quantitation using 7AAD/PY 査読

K. Toba, K. Kishi, T. Koike, E. F. Winton, H. Takahashi, K. Nagai, S. Maruyama, T. Furukawa, S. Hashimoto, M. Masuko, Y. Uesugi, T. Kuroha, N. Tsukada, A. Shibata

Experimental Hematology 24 ( 8 ) 894 - 901 1996年

記述言語：英語掲載種別：研究論文（学術雑誌）

Using 7-amino-actinomycin-D/pyronin Y (7AAD/PY), we analyzed the surface phenotypes and cell cycle of 22 hematopoietic cell lines based on their cellular DNA/RNA content. Populations of G(1a), G(1b), S, and G2M, the DNA index (DI), and the RNA index of S phase (SRI) were calculated by means of DNA/RNA dot plots. Two new parameters were extracted from the cell-cycle profiles: the nucleic acid index of S phase (NI) and the coefficient of variations in the RNA at S phase (SCV). DNA/RNA dot plots of cell lines revealed four characteristic profiles of the cell cycle, defined with the calculated NI and SCV. These were type 0 (small NI, large SCV), type I(small NI, small SCV), type II (large NI, small SCV), and type III (large NI, large SCV). Type 0 included four stem cell lines: one t(1
19) leukemia, two Ph1+ acute lymphocytic leukemia (ALL), and one biphenotypic crisis of chronic granulocytic leukemia (CGL). Type I included five ALL cell lines: three T-ALL and two common B-ALL. Type II contained 10 myeloid cell lines: five AML and five myeloid crisis of CGL. Type III contained three relatively immature lymphoma cell lines: two Burkitt's lymphoma and one follicular center lymphoma. Calculated NI/SCV (%) were as follows: type 0, 2.27 ± 0.19/16.7 ± 3.7
type I, 2.20 ± 0.30/11.1 ± 0.7
type II, 3.64 ± 0.52/11.8 ± 1.0
and type III, 3.60 ± 0.53/17.5 ± 1.9. Cell-cycle analysis of blasts using 7AAD/PY combined with surface phenotyping may yield important information for classifying hematopoietic malignancy within 2 hours of patient admission.

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