Faculty Profiles - FUJII Nobuharu

Papers - FUJII Nobuharu

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藤井敬子, 清家圭介, 三道康永, 中村真, 高木尚江, 閘結稀, 池田亮, 浅野尚美, 小郷博昭, 藤井伸治, 大塚文男

日本輸血細胞治療学会誌 63 ( 6 ) 823 - 823 2017.12

A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study) Reviewed

Kobayashi T, Nannya Y, Ichikawa M, Oritani K, Kanakura Y, Tomita A, Kiyoi H, Kobune M, Kato J, Kawabata H, Shindo M, Torimoto Y, Yonemura Y, Hanaoka N, Nakakuma H, Hasegawa D, Manabe A, Fujishima N, Fujii N, Tanimoto M, Morita Y, Matsuda A, Fujieda A, Katayama N, Ohashi H, Nagai H, Terada Y, Hino M, Sato K, Obara N, Chiba S, Usuki K, Ohta M, Imataki O, Uemura M, Takaku T, Komatsu N, Kitanaka A, Shimoda K, Watanabe K, Tohyama K, Takaori-Kondo A, Harigae H, Arai S, Miyazaki Y, Ozawa K, Kurokawa M

Am J Hematol. 2017.9

Successful use of etoposide for pyoderma gangrenosum associated with myelodysplastic syndrome and trisomy 8: cytokine profiles during treatment Reviewed

Dan Fujiwara, Toshihisa Hamada, Osamu Yamasaki, Yasuhisa Sando, Kyosuke Saeki, Nobuharu Fujii, Yoshio Kawakami, Keiji Iwatsuki

EUROPEAN JOURNAL OF DERMATOLOGY 27 ( 5 ) 525 - 527 2017.9

Predictors of vasovagal reactions during preoperative autologous blood donation: a single-institution analysis. Reviewed

Hisakazu Nishimori, Nobuharu Fujii, Keiko Fujii, Tohru Ikeda, Naomi Asano, Hiroaki Ogo, Miwa Yamakawa, Naoe Takagi, Fumio Otsuka, Kazuma Ikeda

International journal of hematology 105 ( 6 ) 812 - 818 2017.6

Language：English Publishing type：Research paper (scientific journal)

Studies examining risk factors associated with vasovagal reactions (VVRs) during autologous blood donations, especially in younger subjects, have been limited. The aim of the present study was to define risk factors for VVRs during preoperative autologous blood donation in patients, including those younger than 18 years old. We retrospectively analyzed 4192 autologous, preoperative blood donations between 2007 and 2015 at Okayama University Hospital. Eighty-seven (2.08%) of the patients experienced VVRs. VVRs occurred approximately three times as often in patients 0-17 years old (16/320, 5.0%) than in patients 18 years and older (71/3872, 1.8%). In particular, VVRs occurred more frequently in those 10-13 years old, and decreased with older age (P = 0.006). In a univariate analysis, younger age, lower body mass index, lower systolic blood pressure, lower body weight, lower total blood volume, female gender, first-time collection, and higher heart rate were associated with a higher incidence of VVRs. In a multivariate analysis, lower systolic blood pressure (P < 0.001), higher heart rate (P = 0.007), and first-time collection (P = 0.015), remained independent predictors of VVRs. These results emphasize the need for careful attention during blood collection.

DOI： 10.1007/s12185-017-2204-6

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Graft-versus-leukemia effect with a WT1-specific T-cell response induced by azacitidine and donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation. Reviewed International journal

Tatsunori Ishikawa, Nobuharu Fujii, Masahide Imada, Michinori Aoe, Yusuke Meguri, Tomoko Inomata, Hiromi Nakashima, Keiko Fujii, Shohei Yoshida, Hisakazu Nishimori, Ken-Ichi Matsuoka, Eisei Kondo, Yoshinobu Maeda, Mitsune Tanimoto

Cytotherapy 19 ( 4 ) 514 - 520 2017.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown. CASE REPORT: Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft-versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect. DISCUSSION: A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation. CONCLUSION: Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.

DOI： 10.1016/j.jcyt.2016.12.007

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Phase II study of intrabone single unit cord blood transplantation for hematological malignancies Reviewed

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, Japanese Journal of Cancer Research, Gann, The Japanese Journal of Cancer Research 202 - 16 2017.1

Ruxolitinib treatment for GvHD in patients with myelofibrosis Reviewed

Y. Mori ,K. Ikeda,T. Inomata ,G. Yoshimoto,N. Fujii*,H. Ago,T. Teshima

Bone Marrow Transplantation 51 ( 12 ) 1584 - 1587 2016.12

Treatment of thrombotic microangiopathy after hematopoietic stem cell transplantation with recombinant human soluble thrombomodulin. Reviewed International journal

Hideaki Fujiwara, Yoshinobu Maeda, Yasuhisa Sando, Makoto Nakamura, Katsuma Tani, Tatsunori Ishikawa, Hisakazu Nishimori, Ken-Ichi Matsuoka, Nobuharu Fujii, Eisei Kondo, Mitsune Tanimoto

Transfusion 56 ( 4 ) 886 - 92 2016.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic stem cell transplantation (HSCT) remains a severe complication associated with underlying endothelial damage. TMA has a high mortality rate with no definite treatments and effective treatments are needed. STUDY DESIGN AND METHODS: The study objective was to retrospectively analyze the outcome of patients receiving recombinant human soluble thrombomodulin (rTM), which has cytoprotective effects against calcineurin inhibitor-induced endothelial cell damage, or other therapeutics for TA-TMA from 254 consecutive HSCT recipients between 2009 to 2014 at a single institution. We hypothesized that patients receiving rTM as a first-line treatment would receive a benefit. RESULTS: Sixteen patients were diagnosed as TA-TMA. Of these 16 patients, nine were treated with rTM (rTM group), and seven received treatment other than rTM (control group) as a first-line therapy. Seven of the nine patients in the rTM group recovered from TA-TMA without complications, but none in the control group recovered. The rTM group showed a significantly better overall survival after TA-TMA onset than did the control group (median, 123.0 days vs. 45.5 days, respectively; p = 0.045). The cumulative incidence of acute graft-versus-host disease was the same in both groups (56% vs. 57%, respectively; p = 0.52) on Day 100 after TA-TMA onset. CONCLUSION: This is the first report evaluating rTM administration for TA-TMA compared with previous treatments. Our data suggests that rTM might offer a better clinical outcome in patients with TA-TMA.

DOI： 10.1111/trf.13437

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Vigorous inflammatory responses in noninfectious pulmonary complication induced by donor lymphocyte infusion. Reviewed International journal

Miyuki Nishie, Nobuharu Fujii, Yusuke Mimura, Takeru Asano, Yuka Mimura-Kimura, Keisuke Aoe, Michinori Aoe, Hiromi Nakashima, Hideaki Fujiwara, Hisakazu Nishimori, Ken-Ichi Matsuoka, Eisei Kondo, Yoshinobu Maeda, Mitsune Tanimoto

Transfusion 56 ( 1 ) 231 - 236 2016.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Donor lymphocyte infusion (DLI) is used for treatment of hematologic malignancy relapse or mixed chimerism after allogeneic hematopoietic stem cell transplantation. Although graft-versus-host disease is well recognized as one of the adverse effects of DLI, there are limited reports on noninfectious pulmonary complications (NIPCs) after DLI. CASE REPORT: A 55-year-old woman with acute myeloid leukemia received DLI for conversion from recipient predominant to complete donor chimerism on Day +193 after allogeneic HSCT. Eight weeks later, she complained of dyspnea with fever; chest computed tomography revealed diffuse, bilateral, ground glass opacity and reticular appearance. She was diagnosed as having NIPC based on serum and bronchoalveolar lavage fluid (BALF) findings. She was successfully treated with prednisolone (PSL) and completely recovered. DISCUSSION: We analyzed the cell profile from the BALF and 27 cytokines and chemokines in the serum using the Bio-Plex platform. The cells consisted of recipient predominant macrophages and T cells. The serum cytokine and chemokine profile showed significant elevation of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, macrophage inflammatory protein (MIP)-1α, and MIP-1β, which declined with the improvement of symptoms after initiation of PSL treatment. CONCLUSION: Inflammatory effectors by recipient cells, rather than allogeneic responses by donor cells, played an important role in the pathogenesis of NIPCs after DLI in the present case.

DOI： 10.1111/trf.13283

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Magnifying Endoscopic Observation of Duodenal Involvement of Follicular Lymphoma before and after Chemotherapy Reviewed

Iwamuro Masaya, Okada Hiroyuki, Takata Katsuyoshi, Fujii Nobuharu, Kawano Seiji, Kawahara Yoshiro, Yoshino Tadashi, Yamamoto Kazuhide

Japanese Journal of Medicine 54 ( 14 ) 1741 - 1745 2015.7

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Internal Medicine

A 60-year-old Japanese man was diagnosed with systemic follicular lymphoma with duodenal, jejunal, and ileal involvement. The duodenal lesion showed typical endoscopic features with multiple whitish granules. Chemotherapy with bendamustine and rituximab was administered, and complete remission was confirmed by CT scanning and positron emission tomography scanning. Although the duodenal granular lesions did not completely disappear, magnifying observation for the remaining lesions showed no evidence of residual lymphoma. Complete remission was pathologically confirmed by biopsy examinations. This case suggests the usefulness of magnifying observation in evaluating the effects of treatment for duodenal follicular lymphoma lesions.<br>

DOI： 10.2169/internalmedicine.54.4390

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Other Link： http://search.jamas.or.jp/link/ui/2016310064

Anti-IL-12/23 p40 antibody attenuates experimental chronic graft-versus-host disease via suppression of IFN-γ/IL-17-producing cells. Reviewed International journal

Sachiyo Okamoto, Hideaki Fujiwara, Hisakazu Nishimori, Ken-ichi Matsuoka, Nobuharu Fujii, Eisei Kondo, Takehiro Tanaka, Akihiko Yoshimura, Mitsune Tanimoto, Yoshinobu Maeda

Journal of immunology (Baltimore, Md. : 1950) 194 ( 3 ) 1357 - 1363 2015.2

Language：English Publishing type：Research paper (scientific journal)

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17(-)) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17(+) CD4(+) T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.

DOI： 10.4049/jimmunol.1400973

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多発転移に伴い血小板減少を合併した頭部血管肉腫の1例 Reviewed

(瀧口徹也, 山崎修, 牧野麻貴,) 佐伯恭昌, 藤井伸治, (濱田和俊, 岩月啓氏)

Skin Cancer 29 ( 3 ) 323 - 327 2015.2

Language：English Publishing type：Research paper (scientific journal) Publisher：(一社)日本皮膚悪性腫瘍学会

35歳、男性。2012年3月より前頭部に紅斑が出現し、その後結節病変が徐々に隆起し周囲に紫斑が拡大した。近医での生検にて血管肉腫と診断され、5月に当院紹介受診。前頭部に暗紫色の嚢腫状結節を認め、周囲に出血斑を伴っていた。6月より電子線照射とweeklyパクリタキセル療法4コース、monthlyパクリタキセル療法3コース施行。2013年1月に血小板14000/μLと急激な減少のため、入院した。抗血小板抗体陰性、PA-IgG陽性、ヘリコバクター・ピロリIgG陽性。DICの所見は認めなかった。骨髄生検では巨核球十分、腫瘍の浸潤も認めなかった。ITPが疑われ、血小板輸血を施行し、免疫グロブリン大量療法とプレドニゾロン(PSL)を開始した。入院後のCT、MRIで両側耳下腺、胸椎、右寛骨、肺転移を認め、緩和目的に骨転移に対してX線治療した。その後、血小板は上昇したためPSLを漸減し、3月よりweeklyドセタキセル療法を開始した。しかし転移は徐々に進行し、血小板は再度減少した。10月肺転移による呼吸不全のため永眠された。臨床経過からは血小板減少は転移の進行による腫瘍内での血小板消費と考えた。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J02197&link_issn=&doc_id=20150316140017&doc_link_id=10.5227%2Fskincancer.29.323&url=https%3A%2F%2Fdoi.org%2F10.5227%2Fskincancer.29.323&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Primary Duodenal Follicular Lymphoma Treated With Rituximab Monotherapy and Followed-up for 15 Years Reviewed

Seki A, Iwamuro M, Yoshioka M, Fujii N, Okada H, Nose S, Takata K, Yoshino T, Yamamoto K

Acta Med Okayama 69 ( 5 ) 2015.1

With regard to our manuscripts on the commercial saliva substitute, Oralbalance®--its formula has been changed. Reviewed International journal

Yuko Sugiura, Yoshihiko Soga, Ichiro Tanimoto, Susumu Kokeguchi, Sachiko Morishige-Nishide, Kotoe Itami-Kono, Kanayo Takahashi, Nobuharu Fujii, Fumihiko Ishimaru, Mitsune Tanimoto, Kokoro Yamabe, Soichiro Tsutani, Fusanori Nishimura, Shogo Takashiba

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 22 ( 12 ) 3121 - 3122 2014.12

PD-1 pathway in host tissues ameliorates Th17/Th1 mediated experimental chronic graft-versus-host disease Reviewed

Fujiwara H, Maeda Y, Kobayashi K, Nishimori H, Matsuoka K, Fujii N, Kondo E, (Tanaka T, Chen L, Azuma M, Yagita H), Tanimoto M.

J Immunol 193 ( 5 ) 2565 - 2573 2014.9

Programmed death-1 pathway in host tissues ameliorates Th17/Th1-mediated experimental chronic graft-versus-host disease Reviewed

Hideaki Fujiwara, Yoshinobu Maeda, Koichiro Kobayashi, Hisakazu Nishimori, Ken-Ichi Matsuoka, Nobuharu Fujii, Eisei Kondo, Takehiro Tanaka, Lieping Chen, Miyuki Azuma, Hideo Yagita, Mitsune Tanimoto

Journal of Immunology 193 ( 5 ) 2565 - 2573 2014.9

Language：English Publishing type：Research paper (scientific journal) Publisher：American Association of Immunologists

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the role of the programmed death-1 (PD-1) pathway in chronic GVHD using a well-defined mouse model of B10.D2 (H-2d) donor to BALB/c (H-2d) recipients. PD-1 expression on allogeneic donor T cells was upregulated continuously in chronic GVHD development, whereas PD-L1 expression in host tissues was transiently upregulated and declined to basal levels in the late posttransplant period. Blockade of the PD-1 pathway by anti-PD-1, anti-PDL1, or anti-PD-L2 mAbs exacerbated clinical and pathologic chronic GVHD. Chimeric mice revealed that PD-L1 expression in host tissues suppressed expansion of IL-17+IFN-γ+T cells, and that PD-L1 expression on hematopoietic cells plays a role in the development of regulatory T cells only during the early transplantation period but does not affect the severity of chronic GVHD. Administration of the synthetic retinoid Am80 overcame the IL-17+IFN-γ+T cell expansion caused by PD-L1 deficiency, resulting in reduced chronic GVHD damage in PD-L1-/-recipients. Stimulation of the PD-1 pathway also alleviated chronic GVHD. These results suggest that the PD-1 pathway contributes to the suppression of Th17/Th1-mediated chronic GVHD and may represent a new target for the prevention or treatment of chronic GVHD.Copyright

DOI： 10.4049/jimmunol.1400954

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非血縁者間同種骨髄移植後にドナー由来の抗Jraが検出された慢性骨髄性白血病の1例 Reviewed

池田亮、小郷博昭、浅野尚美、浅田騰、藤井敬子、藤井伸治

Japanese Journal of Transfusion and Cell Therapy 60 ( 3 ) 483 - 487 2014.7

Low-grade B-cell lymphoma presenting primarily in the bone marrow Reviewed

Iwatani Kayoko, Takata Katsuyoshi, Sato Yasuharu, Miyata-Takata Tomoko, Iwaki Noriko, Cui Wei, Sawada-Kitamura Seiko, Sonobe Hiroshi, Tamura Maiko, Saito Katsuhiko, Miyatani Katsuya, Yamasaki Rie, Yamadori Ichiro, Fujii Nobuharu, Terasaki Yasushi, Maeda Yoshinobu, Tanimoto Mitsune, Nakamura Naoya, Yoshino Tadashi

Human Pathology 45 ( 7 ) 1379 - 1387 2014.7

Primary cutaneous γδT-cell lymphomaに対し、臍帯血移植を施行した1例 Reviewed

佐伯恭昌, 石川立則, 谷勝真, 山本宜和, 塩手康弘, 松岡賢市, 藤井伸治, 近藤英生, 前田嘉信, 品川克至, 谷本光音

臨床血液 55 ( 5 ) 587 - 587 2014.5

慢性C型肝炎ウイルス感染症の血清AFP値を除鉄療法は改善する Reviewed

(木村文昭, 三島康男, 重戸伸幸, 福田智子, 山原茂裕, 佐原亜衣, 松村正,) 藤井伸治, 谷本光音

日本老年医学会雑誌 51 ( 3 ) 293 - 293 2014.5

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Papers - FUJII Nobuharu