2023年07月, 国立研究開発法人科学技術振興機構, 第48回（令和5年度）井上春成賞　　　　　　　　　　　　　　　
新型コロナウイルス抗原定量試薬による唾液検査の開発と空港検疫への応用

2023年02月, 北海道総合政策部次世代社会戦略局科学技術振興課, 令和4年度北海道科学技術賞　　　　　　　　　　　　　　　
新型コロナウイルス感染症の唾液診断法の開発

2022年12月, 第一生命保険株式会社, 第74回 保健文化賞　　　　　　　　　　　　　　　

2022年10月, 一般社団法人 日本血液学会, 第11回 日本血液学会学会賞　　　　　　　　　　　　　　　

2021年10月, 北海道新聞社, 北海道新聞文化賞（学術部門）　　　　　　　　　　　　　　　

2021年06月, 一般社団法人 減災サステナブル技術協会, 防災・減災×サステナブル大賞 サステナブル部門 グローバル賞　　　　　　　　　　　　　　　
唾液採取による新型コロナＰＣＲ検査

2021年02月, 国立大学法人北海道大学, 令和２年度北海道大学教育研究総長表彰　　　　　　　　　　　　　　　

2020年10月, 公益財団法人伊藤医薬学術交流財団, 令和2年度 伊藤太郎特別賞　　　　　　　　　　　　　　　

2019年03月, 一般社団法人日本造血細胞移植学会, 第1回日本造血細胞移植学会学会賞　　　　　　　　　　　　　　　
豊嶋 崇徳

2016年, 北海道大学大学院医学研究科・医学部医学科, 平成27年度北海道大学大学院医学研究科・医学部医学科 優秀研究賞　　　　　　　　　　　　　　　
豊嶋 崇徳

2012年10月, International Journal of Hematology 編集長賞　　　　　　　　　　　　　　　
豊嶋 崇徳

2005年, 武田科学振興財団, 一般研究奨励賞　　　　　　　　　　　　　　　
豊嶋 崇徳

1999年, Travel Award, 1999 Annual Meeting of American Society of Hematology　　　　　　　　　　　　　　　
豊嶋 崇徳

1999年, Best Abstract Award, 1999 American Society of Blood and Marrow Transplantation　　　　　　　　　　　　　　　

Ruxolitinib for steroid-refractory chronic graft-versus-host disease: Japanese subgroup analysis of REACH3 study.
Souichi Shiratori, Kentaro Fukushima, Yasushi Onishi, Noriko Doki, Tatsunori Goto, Masaya Okada, Hirohisa Nakamae, Yoshinobu Maeda, Koji Kato, Takayuki Ishikawa, Tadakazu Kondo, Masako Toyosaki, Takashi Ikeda, Naoyuki Uchida, Akio Maki, Fumika Shimada, Takeshi Tajima, Tommaso Stefanelli, Takanori Teshima
International journal of hematology, 120, 6, 705, 716, 2024年12月, ［国内誌］
英語, 研究論文（学術雑誌）, Ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, has demonstrated safety and efficacy in patients with graft-versus-host disease (GvHD). This phase 3 randomized trial (REACH3) evaluated the efficacy and the safety of ruxolitinib 10 mg twice daily compared with investigator-selected best available therapy (BAT) in a subgroup of Japanese patients (n = 37) with steroid-refractory or dependent (SR/D) chronic GvHD. At data cut-off, treatment was ongoing in 17 patients and discontinued in 20. The overall response rate (complete or partial) at week 24 was greater with ruxolitinib than BAT (50% vs. 20%; odds ratio, 4.13 [95% CI, 0.90-18.9]). The best overall response rate (complete or partial response at any time point up to week 24) was higher with ruxolitinib than BAT (68.2% vs. 46.7%; odds ratio, 2.69 [95% CI, 0.66-10.9]). Ruxolitinib led to longer median failure-free survival than BAT (18.6 months vs. 3.7 months; hazard ratio, 0.34; [95% CI, 0.14-0.85]). The most common grade ≥ 3 adverse events up to week 24 were anemia (ruxolitinib: 22.7%; BAT: 6.7%) and pneumonia (22.7% and 20.0%, respectively). Ruxolitinib showed a higher response rate and improvement in failure-free survival in Japanese patients with SR/D chronic GvHD, with a safety profile consistent with the overall study population.

Genome-wide CRISPR screen identifies MAD2L1BP and ANAPC15 as targets for brentuximab vedotin sensitivity in CD30+ peripheral T-cell lymphoma.
Keito Suto, Norio Takei, Keito Yokoyama, Masahiro Chiba, Takashi Ishio, Michiyuki Maeda, Hideki Goto, Tomoyuki Endo, Takanori Teshima, Yibin Yang, Masao Nakagawa
Leukemia, 2024年10月21日, ［国際誌］
英語, 研究論文（学術雑誌）

Ruxolitinib in steroid-refractory acute graft-vs-host disease: Japanese subgroup analysis of the randomized REACH2 trial.
Takanori Teshima, Yasushi Onishi, Koji Kato, Shuichi Taniguchi, Koichi Miyamura, Kentaro Fukushima, Jun Kato, Takayuki Ishikawa, Noriko Doki, Hirohisa Nakamae, Yoshinobu Maeda, Yoshihiro Inamoto, Masaya Okada, Akio Maki, Fumika Shimada, Takeshi Tajima, Monika Wroclawska, Robert Zeiser, Makoto Onizuka
International journal of hematology, 120, 1, 106, 116, 2024年07月, ［国内誌］
英語, 研究論文（学術雑誌）, Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6 months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25 months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results.

GVHD targets organoid-forming bile duct stem cells via a TGF-β-dependent manner.
Yuta Hasegawa, Daigo Hashimoto, Zixuan Zhang, Toru Miyajima, Yumika Saito, Wenyu Li, Ryo Kikuchi, Hajime Senjo, Tomoko Sekiguchi, Takahiro Tateno, Xuanzhong Chen, Emi Yokoyama, Shuichiro Takahashi, Hiroyuki Ohigashi, Takahide Ara, Eiko Hayase, Isao Yokota, Takanori Teshima
Blood, 2024年06月21日, ［国際誌］
英語, 研究論文（学術雑誌）, Graft-versus-host disease (GVHD) is a major life-threatening complication that occurs after allogeneic hematopoietic cell transplantation (HCT). While adult tissue stem cells have been identified as targets of GVHD in the skin and gut, their role in hepatic GVHD is yet to be clarified. In the current study, we explored the fate of bile duct stem cells (BDSCs), capable of generating liver organoids in vitro, during hepatic GVHD after allogeneic HCT. We observed a significant expansion of biliary epithelial cells (BECs) upon injury early after allogeneic HCT. Organoid-forming efficiency from the bile duct was also significantly increased early after allogeneic HCT. Subsequently, the organoid-forming efficiency from bile ducts was markedly decreased in association with the reduction of BECs and the elevation of plasma concentrations of bilirubin, suggesting that GVHD targets BDSCs and impairs the resilience of BECs. The growth of liver organoids in the presence of liver-infiltrating mononuclear cells from allogeneic recipients, but not from syngeneic recipients, significantly reduced in a TGF--dependent manner. Administration of SB-431542, an inhibitor of TGF-β signaling, from day 14 to day 28 protected organoid-forming BDSCs against GVHD and mitigated biliary dysfunction after allogeneic HCT, suggesting that BDSCs are a promising therapeutic target for hepatic GVHD.

Event-free survival at 36 months is a suitable endpoint for diffuse large B-cell lymphoma patients treated with immunochemotherapy: real-world evidence from the North Japan Hematology Study Group.
Koh Izumiyama, Tasuku Inao, Hideki Goto, Shinpei Harada, Hajime Senjo, Keito Suto, Junichi Hashiguchi, Reiki Ogasawara, Tomoyuki Saga, Tetsuyuki Igarashi, Kentaro Wakasa, Ikumi Kasahara, Yukari Takeda, Keisuke Yamaguchi, Akio Shigematsu, Mutsumi Takahata, Katsuya Fujimoto, Yoshihito Haseyama, Takahiro Nagashima, Hajime Sakai, Yasutaka Kakinoki, Mitsutoshi Kurosawa, Isao Yokota, Takanori Teshima
Haematologica, 2024年06月13日, ［国際誌］
英語, 研究論文（学術雑誌）, Information regarding follow-up duration after treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL) is important. However, a clear endpoint has yet to be established. We totally enrolled 2182 patients newly diagnosed with DLBCL between 2008 and 2018. The median age of the patients was 71 years. All patients were treated with rituximab- and anthracycline-based chemotherapies. Each overall survival (OS) was compared with the age- and sex-matched Japanese general population (GP) data. At a median follow-up of 3.4 years, 985 patients experienced an event and 657 patients died. Patients who achieved an event-free survival (EFS) at 36 months (EFS36) had an OS equivalent to that of the matched GP (standard mortality ratio [SMR], 1.17; P=0.1324), whereas those who achieved an EFS24 did not have an OS comparable to that of the matched GP (SMR, 1.26; P=0.0095). Subgroup analysis revealed that relatively old patients (>60 years), male patients, those with limited-stage disease, those with a good performance status, and those with low levels of soluble interleukin 2 receptor already had a comparable life expectancy to the matched GP at an EFS24. In contrast, relatively young patients had a shorter life expectancy than matched GP, even with an EFS36. In conclusion, an EFS36 was shown to be a more suitable endpoint for newly diagnosed DLBCL patients than an EFS24. Of note, younger patients require a longer EFS period than older patients in order to obtain an equivalent life expectancy to the matched GP.

Novel CAR T cell therapies for patients with large B cell lymphoma.
Hideki Goto, Masahiro Onozawa, Takanori Teshima
International journal of hematology, 2024年05月25日, ［国内誌］
英語, 研究論文（学術雑誌）, Approximately 60-70% of patients with large B cell lymphoma (LBCL) achieve long-term remission or a cure after initial treatment. However, patients who relapse or are refractory to initial treatment have a poor prognosis. Chimeric antigen receptor (CAR) T cell therapy has recently attracted attention for its potential to provide a cure or long-term remission even for LBCL that has relapsed or is refractory to conventional chemotherapy. Currently, three CAR T cell products are clinically available for LBCL: tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel). These CAR T cell products were initially approved as third- or later-line therapies worldwide. Recently, axi-cel and liso-cel have become feasible as second-line therapies for patients with early relapsed or refractory disease after first-line chemotherapy. Although a large body of data on CAR T cell therapy has been accumulated, the clinical question of how to choose between these three available CAR T cell products has yet to be resolved. The appropriate approach to treatment selection for patients who relapse after CAR T cell therapy also remains unclear. This review discusses treatment strategies to maximize the benefits of CAR T cell therapy.

Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update.
Martin Dreyling, Nathan Hale Fowler, Michael Dickinson, Joaquin Martinez-Lopez, Arne Kolstad, Jason Butler, Monalisa Ghosh, Leslie Popplewell, Julio C Chavez, Emmanuel Bachy, Koji Kato, Hideo Harigae, Marie José Kersten, Charalambos Andreadis, Peter A Riedell, P Joy Ho, José Antonio Pérez-Simón, Andy I Chen, Loretta J Nastoupil, Bastian von Tresckow, Andrés José María Ferreri, Takanori Teshima, Piers E M Patten, Joseph P McGuirk, Andreas L Petzer, Fritz Offner, Andreas Viardot, Pier Luigi Zinzani, Ram Malladi, Ines Paule, Aiesha Zia, Rakesh Awasthi, Xia Han, Davide Germano, Darragh O'Donovan, Roberto Ramos, Harald J Maier, Aisha Masood, Catherine Thieblemont, Stephen J Schuster
Blood, 143, 17, 1713, 1725, 2024年04月25日, ［国際誌］
英語, 研究論文（学術雑誌）, Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.

Acute onset of constrictive pericarditis due to acute myelomonocytic leukemia: A case and literature review.
Naoki Kosaka, Takanori Uchiyama, Masahiro Onozawa, Jun Nagai, Jiro Koya, Suguru Ishizaka, Toshiyuki Nagai, Yohei Ikebe, Kenjiro Kato, Zen-Ichi Tanei, Jun Sakakibara-Konishi, Yuta Hasegawa, Hiroyuki Ohigashi, Hideki Goto, Daigo Hashimoto, Hideki Ujiie, Satoshi Hirano, Satoshi Konno, Toshihisa Anzai, Koji Taniguchi, Shinya Tanaka, Takanori Teshima
Internal medicine (Tokyo, Japan), 2024年04月16日, ［国内誌］
英語, 研究論文（学術雑誌）, We herein present a fatal case of constrictive pericarditis (CP) due to acute myelomonocytic leukemia (AMML) in a patient who initially complained of an acute onset of chest pain two days after COVID-19 vaccination. An autopsy revealed pericardial infiltration of leukemic cells. CP is rarely associated with leukemia and only 14 cases have been reported in the literature. The etiology of CP in previous reports included leukemic infiltration, graft-versus-host disease, drug-induced, post-radiation, autoimmune, and otherwise unidentified. This case indicates that leukemic infiltration can cause CP and that clinicians should include leukemia in the differential diagnosis of CP.

Patent blue interferes with the measurement of lipemia index in a patient with sentinel lymph node.
Keiichi Nakano, Masanori Seimiya, Kojiro Yamazaki, Keiko Yasuda, Naoki Yamashita, Hideki Goto, Takanori Teshima
Laboratory medicine, 2024年04月15日, ［国際誌］
英語, 研究論文（学術雑誌）, Lipids interfere with absorbance measurements conducted using colorimetric methods. To monitor lipemia, some systems measure absorbance using an analyzer. This report describes a novel case of interference with the lipemia index without lipemia. A 64-year-old woman with giant basal cell carcinoma underwent resection and sentinel lymph node biopsy. The patient had been subcutaneously injected with patent blue during sentinel lymph node resection. After surgery, her serum and urine were yellow-green, and the lipemia index, calculated by measuring absorbance at 658 nm (main wavelength) and 694 nm (secondary wavelength) using a JCA-BM8040 chemistry analyzer, was high. The absorbance spectrum of the patient's serum and patent blue solution were compared to determine the cause of the high lipemia index. The patient's serum and the patent blue solution showed absorption at wavelengths between 540 and 698 nm. Moreover, the absorbance was concentration-dependent for patent blue. These results thus indicated that the patient's serum contained patent blue. Here, we report a case wherein patent blue affected the lipemia index. Thus, it must be noted that patent blue injection may yield inaccurate results when evaluating lipemia index.

Relative impact of THPO mutation causing hereditary thrombocythemia.
Hiroyuki Kimura, Masahiro Onozawa, Toshihiro Matsukawa, Hideki Goto, Takeshi Kondo, Takanori Teshima
Experimental hematology, 104208, 104208, 2024年03月26日, ［国際誌］
英語, 研究論文（学術雑誌）, Germline mutations of THPO were reported as causes of hereditary thrombocythemia. Six previously reported distinct sites of the mutation were clustered at the 5'-untranslated region or the exon 3 splicing donor site of the THPO gene. Each mutation was identified in an independent pedigree and the difference in the mutations were not compared. We cloned 6 distinct THPO mutations (THPO c.-47delG, THPO c.-31G>T, THPO c.13G>A, THPO c.13+1G>A, THPO c.13+2T>C, and THPO c.13+5G>A) and compared the molecular mechanisms that underlie the increased production of THPO protein. At the transcript level, all of the mutations except THPO c.-47delG showed an exon 3 skipping transcript including 2 mutations (THPO c.-31G>T and THPO c.13+5G>A) that were distant from the splicing donor site. THPO c.-47delG showed the same full-length transcript as that of the wild-type transcript. At the protein level, all mutations resulted in a higher level of production of THPO protein compared to wild-type THPO. There are only two distinct patterns of mechanisms for increased production of THPO: 1) exon 3 skipping that deleted upstream suppressive open reading frame (ORF) 7 and 2) one base deletion that shifted ORF7 to connect to the initial codon of THPO in-frame. The common mechanisms of hereditary thrombocytosis due to THPO mutation are unleashed THPO translation that is usually suppressed by upstream out-of-frame ORF7.

R-Spondin1 protects gastric stem cells and mitigates gastric GVHD in allogeneic hematopoietic stem cell transplantation.
Eiko Hayase, Takahide Ara, Yumika Saito, Shuichiro Takahashi, Kosuke Yoshioka, Hiroyuki Ohigashi, Reiki Ogasawara, Emi Yokoyama, Tomohiro Yamakawa, Ko Ebata, Yuta Hasegawa, Kazuma Tomizuka, Takanori Teshima
Blood advances, 8, 3, 725, 731, 2024年02月13日, ［国際誌］
英語, 研究論文（学術雑誌）, Graft-versus-host disease (GVHD) is the major obstacle to performing allogeneic hematopoietic cell transplantation (allo-HCT). We and others have shown that intestinal stem cells are targeted in lower gastrointestinal GVHD. A leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)-expressing gastric stem cells (GSCs) reside at the base of the gastric glands in mice. After experimental allo-HCT, Lgr5+ GSCs significantly decreased. Parietal cells, which underwent continuous renewal by GSCs, were injured in gastric GVHD, leading to failure of gastric acidification and aerobic bacterial overgrowth in the duodenum. Fate-mapping analysis demonstrated that administration of R-Spondin1 (R-Spo1) that binds to Lgr5 for 6 days in naïve mice significantly increased proliferating epithelial cells derived from Lgr5+ GSCs. R-Spo1 administered on days -3 to -1 and from days +1 to +3 of allo-HCT protected GSCs, leading to amelioration of gastric GVHD and restoration of gastric acidification, and suppression of aerobic bacterial overgrowth in the duodenum. In conclusion, Lgr5+ GSCs were targeted by gastric GVHD, resulting in disruption of the gastric homeostasis, whereas R-Spo1 protected Lgr5+ GSCs from GVHD and maintained homeostasis in the stomach.

肺小細胞癌の治療中に白血球増多と線維素性心外膜炎を認めた一例　　　　　　　　　　　　　　　
山内 智仁, 種井 善一, 長井 淳, 小田 義崇, 菊池 遼, 小野澤 真弘, 津田 真寿美, 田中 敏, 豊島 崇徳, 田中 伸哉
日本病理学会会誌, 113, 1, 463, 463, (一社)日本病理学会, 2024年02月
日本語

ハイブリッド視察によるI&A受審を経験して
伊藤 誠, 増田 裕弥, 南 昭子, 佐々木 麻記, 山下 直樹, 渡邊 千秋, 後藤 秀樹, 豊嶋 崇徳
日本輸血細胞治療学会誌, 70, 1, 51, 51, (一社)日本輸血・細胞治療学会, 2024年02月
日本語

Novel stratification for newly diagnosed acute myeloid leukaemia treated with venetoclax-based therapy in the real world: Hokkaido Leukemia Net Study.
Naoki Miyashita, Masahiro Onozawa, Toshihiro Matsukawa, Akio Mori, Daisuke Hidaka, Koichiro Minauchi, Akio Shigematsu, Junichi Hashiguchi, Tetsuyuki Igarashi, Yasutaka Kakinoki, Yutaka Tsutsumi, Makoto Ibata, Kentaro Wakasa, Katsuya Fujimoto, Toshimichi Ishihara, Hajime Sakai, Satoshi Iyama, Tatsuo Oyake, Takeshi Kondo, Takanori Teshima
British journal of haematology, 2024年01月18日, ［国際誌］
英語, 研究論文（学術雑誌）

Hereditary thrombocythemia due to splicing donor site mutation of THPO in a Japanese family.
Hiroyuki Kimura, Masahiro Onozawa, Junichi Hashiguchi, Daisuke Hidaka, Minoru Kanaya, Toshihiro Matsukawa, Hiromi Okada, Takeshi Kondo, Yoshihiro Matsuno, Takanori Teshima
Annals of hematology, 103, 1, 89, 96, 2024年01月, ［国際誌］
英語, 研究論文（学術雑誌）, Thrombopoietin (THPO) is an essential factor for platelet production. Hereditary thrombocythemia (HT) is caused by a germline mutation of THPO, MPL, or JAK2 and is inherited in an autosomal-dominant manner. We identified a Japanese family with HT due to a point mutation of the splicing donor site of the THPO gene (THPO c.13 + 1G > A). Bone marrow biopsy showed increased megakaryocytes mimicking essential thrombocythemia. One affected family member developed chronic myeloid leukemia. We cloned the mutation and developed mutated and wild type THPO expression vectors. Molecular analysis showed that the mutation causes an exon 3 skipping transcript of THPO that abrogates a suppressive untranslated upstream open reading frame. Although the transcript levels of THPO mRNA were comparable, mutated transcripts were more efficiently translated and THPO protein expression was significantly higher than that of the wild type.

Whole genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in Adult T-cell leukemia/lymphoma.
Masahiro Chiba, Joji Shimono, Keito Suto, Takashi Ishio, Tomoyuki Endo, Hideki Goto, Hiroo Hasegawa, Michiyuki Maeda, Takanori Teshima, Yibin Yang, Masao Nakagawa
Blood, 2023年12月24日, ［国際誌］
英語, 研究論文（学術雑誌）, Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis and limited treatment options. Programmed cell death ligand 1(PD-L1) is recognized to be involved in the pathobiology of ATLL. However, what molecules control PD-L1 expression and whether genetic or pharmacological intervention might modify PD-L1 expression in ATLL cells is still unknown. In order to comprehend the regulatory mechanisms of PD-L1 expression in ATLL cells, we performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening in this work. In ATLL cells, we discovered that the neddylation-associated genes NEDD8, NAE1, UBA3, and CUL3 negatively regulated PD-L1 expression while STAT3 positively did so in ATLL cells. We verified, in line with the genetic results, that treatment with the JAK1/2 inhibitor ruxolitinib or the neddylation pathway inhibitor pevonedistat resulted in a decrease in PD-L1 expression in ATLL cells or an increase in it. It is significant that these results held true regardless of whether ATLL cells had the PD-L1 3' structural variant, a known genetic anomaly that promotes PD-L1 overexpression in certain primary ATLL patients. Pevonedistat alone showed cytotoxicity for ATLL cells, but compared to each single modality, pevonedistat improved the cytotoxic effects of the anti-PD-L1 monoclonal antibody Avelumab and chimeric antigen receptor T-cells targeting PD-L1 in vitro. As a result, our work provided insight into a portion of the complex regulatory mechanisms governing PD-L1 expression in ATLL cells and demonstrated the in vitro preliminary preclinical efficacy of PD-L1-directed immunotherapies by using pevonedistat to upregulate PD-L1 in ATLL cells.

Posttransplant cyclophosphamide in unrelated and related peripheral blood stem cell transplantation from HLA-matched and 1 allele mismatched donor.
Junichi Sugita, Takashi Kuroha, Jun Ishikawa, Tetsuya Eto, Kentaro Fukushima, Isao Yokota, Koichi Akashi, Shuichi Taniguchi, Mine Harada, Takanori Teshima
Bone marrow transplantation, 2023年12月19日, ［国際誌］
英語, 研究論文（学術雑誌）, Posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been increasingly used in HLA-haploidentical transplantation and recent studies also demonstrated the efficacy of PTCy in HLA-matched transplantation. We conducted a prospective multicenter phase II study to evaluate the safety and efficacy of PTCy with tacrolimus and mycophenolate mofetil in 43 patients who underwent HLA-matched (n = 21), 1 allele mismatched (n = 20), or 2 allele mismatched (n = 2) peripheral blood stem cell transplantation (PBSCT) following myeloablative (n = 28) or reduced-intensity (n = 15) conditioning. The incidence of grade III-IV acute GVHD at 100 days was 2.3%. The incidences of grades II-IV acute GVHD, all grade chronic GVHD, and moderate to severe chronic GVHD at 2 years were 16.3%, 14.0%, and 4.7%, respectively. Overall survival, disease-free survival, and non-relapse mortality at 2 years were 75.3%, 74.0%, and 7.0%, respectively. GVHD-free, relapse-free survival at 2 years was 67.0%. The rate of off-immunosuppressants in patients who survived without relapse at 2 years was 85.4%. These results indicate that PTCy is a valid option for GVHD prophylaxis in both HLA-matched and HLA 1-2 allele mismatched PBSCT.

再発難治性びまん性大細胞型B細胞リンパ腫に対するCAR-T細胞療法後にpseudo-progressionを認めた1例　　　　　　　　　　　　　　　
藤井 文彰, 千葉 雅尋, 橋田 里妙, 長谷川 祐太, 大東 寛幸, 安本 篤史, 後藤 秀樹, 山口 圭介, 小野澤 真弘, 橋本 大吾, 豊嶋 崇徳
臨床血液, 64, 12, 1523, 1524, (一社)日本血液学会-東京事務局, 2023年12月
日本語

Efficacy and Safety of Single-dose Pegfilgrastim for CD34+ Cell Mobilization in Healthy Volunteers: A Phase 2 Study.
Hideki Goto, Junichi Sugita, Yuta Hasegawa, Koji Hayasaka, Kana Sunagoya, Rie Hatase, Mutsumi Nishida, Yuki Ichihashi, Mitsuhiko Odera, Hajime Senjo, Shota Yokoyama, Takahide Ara, Souichi Shiratori, Tomoyuki Endo, Masayuki Hino, Yoshinobu Maeda, Masashi Sawa, Norihiro Sato, Takanori Teshima
Transplantation, 2023年11月28日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Pegfilgrastim, a long-acting form of granulocyte-colony stimulating factor, with a convenient single-injection dosage, is being investigated for peripheral blood stem cell (PBSC) mobilization in healthy volunteers. However, data on the adequate dose of pegfilgrastim for PBSC mobilization are limited. This phase 2, single-arm study evaluated the efficacy and safety of pegfilgrastim for PBSC mobilization in healthy volunteers. METHODS: The study comprised 2 phases: pilot (steps 1-3, dose escalation, a single subcutaneous dose of 3.6, 7.2, and 10.8 mg pegfilgrastim, respectively) and evaluation (step 4, efficacy and safety assessments). The primary endpoint was the proportion of subjects who achieved mobilization of ≥20 × 106/L cluster of differentiation 34 positive (CD34+) cells. RESULTS: Thirty-five subjects (6 each in steps 1 and 2 and 23 in step 4) were included. In the pilot phase, step 3 with a 10.8 mg dose was not conducted due to favorable outcomes in step 2 (desired CD34+ cell count), at 7.2 mg pegfilgrastim, which was identified as the optimal dose for the evaluation phase. In the evaluation phase, successful CD34+ mobilization was achieved in all 23 subjects. The mean peripheral blood CD34+ cells count peaked on day 5. Back pain, thrombocytopenia, transient elevations of alkaline phosphatase, and lactate dehydrogenase were the most common adverse events. All adverse events were mild, and none led to study discontinuation. CONCLUSIONS: A single-dose pegfilgrastim successfully mobilized an optimal number of CD34+ cells and was well tolerated. Pegfilgrastim could be an alternative option for PBSC mobilization in healthy volunteers. The trial was registered at www.clinicaltrials.gov (NCT03993639).

High-precision rapid testing of omicron SARS-CoV-2 variants in clinical samples using AI-nanopore.
Kaoru Murakami, Shimpei I Kubota, Kumiko Tanaka, Hiroki Tanaka, Keiichiroh Akabane, Rigel Suzuki, Yuta Shinohara, Hiroyasu Takei, Shigeru Hashimoto, Yuki Tanaka, Shintaro Hojyo, Osamu Sakamoto, Norihiko Naono, Takayui Takaai, Kazuki Sato, Yuichi Kojima, Toshiyuki Harada, Takeshi Hattori, Satoshi Fuke, Isao Yokota, Satoshi Konno, Takashi Washio, Takasuke Fukuhara, Takanori Teshima, Masateru Taniguchi, Masaaki Murakami
Lab on a chip, 23, 22, 4909, 4918, 2023年11月07日, ［国際誌］
英語, 研究論文（学術雑誌）, A digital platform that can rapidly and accurately diagnose pathogenic viral variants, including SARS-CoV-2, will minimize pandemics, public anxiety, and economic losses. We recently reported an artificial intelligence (AI)-nanopore platform that enables testing for Wuhan SARS-CoV-2 with high sensitivity and specificity within five minutes. However, which parts of the virus are recognized by the platform are unknown. Similarly, whether the platform can detect SARS-CoV-2 variants or the presence of the virus in clinical samples needs further study. Here, we demonstrated the platform can distinguish SARS-CoV-2 variants. Further, it identified mutated Wuhan SARS-CoV-2 expressing spike proteins of the delta and omicron variants, indicating it discriminates spike proteins. Finally, we used the platform to identify omicron variants with a sensitivity and specificity of 100% and 94%, respectively, in saliva specimens from COVID-19 patients. Thus, our results demonstrate the AI-nanopore platform is an effective diagnostic tool for SARS-CoV-2 variants.

2022年度HIV-1薬剤耐性検査外部精度評価の報告　　　　　　　　　　　　　　　
吉田 繁, 松田 昌和, 今橋 真弓, 岡田 清美, 齊藤 浩一, 林田 庸総, 佐藤 かおり, 藤澤 真一, 遠藤 知之, 西澤 雅子, 椎野 禎一郎, 潟永 博之, 豊嶋 崇徳, 杉浦 亙, 吉村 和久, 菊地 正
日本エイズ学会誌, 25, 4, 443, 443, (一社)日本エイズ学会, 2023年11月
日本語

2022年度HIV-1薬剤耐性検査外部精度評価の報告　　　　　　　　　　　　　　　
吉田 繁, 松田 昌和, 今橋 真弓, 岡田 清美, 齊藤 浩一, 林田 庸総, 佐藤 かおり, 藤澤 真一, 遠藤 知之, 西澤 雅子, 椎野 禎一郎, 潟永 博之, 豊嶋 崇徳, 杉浦 亙, 吉村 和久, 菊地 正
日本エイズ学会誌, 25, 4, 443, 443, (一社)日本エイズ学会, 2023年11月
日本語

2022年の国内新規診断未治療HIV感染者・AIDS患者における薬剤耐性HIV1の動向　　　　　　　　　　　　　　　
菊地 正, 西澤 雅子, 小島 潮子, 大谷 眞智子, Runtwene Lucky, 椎野 禎一郎, 豊嶋 崇徳, 伊藤 俊広, 林田 庸総, 潟永 博之, 岡 慎一, 古賀 道子, 長島 真美, 貞升 健志, 佐野 貴子, 近藤 真規子, 宇野 俊介, 谷口 俊文, 猪狩 英俊, 寒川 整, 中島 秀明
日本エイズ学会誌, 25, 4, 444, 444, (一社)日本エイズ学会, 2023年11月
日本語

Virological outcomes of various first-line ART regimens in patients harbouring HIV-1 E157Q integrase polymorphism: a multicentre retrospective study
Shunsuke Uno, Hiroyuki Gatanaga, Tsunefusa Hayashida, Mayumi Imahashi, Rumi Minami, Michiko Koga, Sei Samukawa, Dai Watanabe, Teruhisa Fujii, Masao Tateyama, Hideta Nakamura, Shuzo Matsushita, Yusuke Yoshino, Tomoyuki Endo, Masahide Horiba, Toshibumi Taniguchi, Hiroshi Moro, Hidetoshi Igari, Shigeru Yoshida, Takanori Teshima, Hideaki Nakajima, Masako Nishizawa, Yoshiyuki Yokomaku, Yasumasa Iwatani, Atsuko Hachiya, Shingo Kato, Naoki Hasegawa, Kazuhisa Yoshimura, Wataru Sugiura, Tadashi Kikuchi
Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), 2023年10月19日, ［査読有り］
研究論文（学術雑誌）, Abstract

Background

Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated mutation E157Q, a highly prevalent (2%–5%) polymorphism of the HIV-1 (human immunodeficiency virus type 1) integrase gene, has limited data on optimal first-line ART regimens. We assessed the virological outcomes of various first-line ART regimens in PLWH with E157Q in real-world settings.

Methods

A multicentre retrospective observational study was conducted on PLWH who underwent integrase genotypic drug-resistance testing before ART initiation between 2008 and 2019 and were found to have E157Q. Viral suppression (<50 copies/mL) rate at 24 and 48 weeks, time to viral suppression and time to viral rebound (≥100 copies/mL) were compared among the first-line ART regimens.

Results

E157Q was detected in 167 (4.1%) of 4043 ART-naïve PLWH. Among them, 144 had available clinical data after ART initiation with a median follow-up of 1888 days. Forty-five started protease inhibitors + 2 NRTIs (PI group), 33 started first-generation INSTI (raltegravir or elvitegravir/cobicistat) + 2 NRTIs (INSTI-1 group), 58 started once-daily second-generation INSTI (dolutegravir or bictegravir) + 2 NRTIs (INSTI-2 group) and eight started other regimens. In the multivariate analysis, the INSTI-2 group showed similar or favourable outcomes compared with the PI group for viral suppression rates, time to viral suppression and time to viral rebound. Two cases in the INSTI-1 group experienced virological failure.

Conclusions

The general guideline recommendation of second-generation INSTI-based first-line ART for most PLWH is also applicable to PLWH harbouring E157Q.

Prolonged shedding of viable SARS‐CoV‐2 in immunocompromised patients with haematological malignancies: A prospective study
Takaya Ichikawa, Tomokazu Tamura, Mutsumi Takahata, Takashi Ishio, Makoto Ibata, Ikumi Kasahara, Koichiro Minauchi, Satoshi Yamamoto, Takanori Teshima, Takasuke Fukuhara
British Journal of Haematology, 204, 3, 815, 820, Wiley, 2023年10月05日
研究論文（学術雑誌）, Summary

Prolonged SARS‐CoV‐2 infection in immunocompromised individuals has been scattered, but the details remain unclear. We conducted a prospective study with 26 COVID‐19 patients with haematological malignancies to determine viral shedding kinetics and characteristics. We obtained nasopharyngeal swabs from the patients 21–28 days post‐onset for a PCR test and performed virus isolation from the PCR‐positive samples. A viable virus was detected in five patients (19.2%), all of whom had malignant lymphoma. Those patients had significantly lower CD4⁺ T‐cell counts than the PCR‐negative patients. A comparison of previous chemotherapy showed that anti‐CD20 antibodies and bendamustine may be risk factors for prolonged viral shedding.

悪性リンパ腫へのtisagenlecleucelの治療効果に関するPET/CTで評価されたMTHとDmaxのインパクト　　　　　　　　　　　　　　　
後藤 秀樹, 北脇 年雄, 加藤 光次, 藤井 伸治, 大西 康, 福原 規子, 山内 拓司, 虎谷 和則, 下茂 雅俊, 小林 宏紀, 小野寺 晃一, 吉田 匠汰, 千丈 創, 小野澤 真弘, 平田 健司, 横田 勲, 豊嶋 崇徳
日本血液学会学術集会, 85回, 1193, 1193, (一社)日本血液学会, 2023年10月
英語

臨床症状および抗核抗体パターンと矛盾した各種自己抗体陽性を認めた1症例
菊地 菜海, 山下 直樹, 安田 慶子, 後藤 秀樹, 豊嶋 崇徳
北臨技会誌, 21, 2, 71, 76, (一社)北海道臨床衛生検査技師会, 2023年10月
日本語, 抗核抗体検査は主に自己免疫疾患が疑われる場合にスクリーニング検査として実施され,そのパターンから出現する疾患特異抗体がある程度推測可能である.一方,疾患特異抗体の検査は自己免疫疾患の診断や分類基準に用いられる.本症例は,抗核抗体が320倍・均質型であったのに対し,抗Sm抗体,抗CENP-B抗体,抗Jo-1抗体など7種類の疾患特異抗体が陽性となった.臨床症状等はなく非特異反応が疑われたため精査したところ,DID法・抗原添加試験の結果から検体中に疾患特異抗体は存在せず,第2試薬(R2)成分との反応性確認試験および抗体クラス別の反応性確認試験の結果から,検体中のIgM抗体により非特異反応が生じた可能性が高いと考えられた.抗核抗体パターンと矛盾した自己抗体陽性を認めた場合,他の検査や所見等も確認し,非特異反応も念頭に置いて結果を判断する必要がある.(著者抄録)

Prognostic Value of Hematogones in Patients With Hematopoietic Disorders After Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.
Hirotaka Mori, Daisuke Koyama, Yuki Sato, Yuki Kataoka, Shunsuke Taito, Takashi Ishio, Takanori Teshima, Isao Yokota
Cureus, 15, 10, e47184, 2023年10月, ［国際誌］
英語, 研究論文（学術雑誌）, This systematic review and meta-analysis aimed to determine whether hematogones in patients with hematopoietic disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are associated with clinical outcomes. We searched the MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform databases from their inception to March 2023. The primary outcome in the summary of findings was three-year relapse-free survival (RFS), and secondary outcomes in the summary of findings included three-year relapse, non-relapse mortality (NRM), overall survival (OS), acute and chronic graft-versus-host disease (GVHD), and infection. The certainty of evidence was determined using the grading of recommendation assessment, development, and evaluation approaches. A systematic review and meta-analysis of outcome measures were conducted using a random-effects model. This study protocol was registered in the Open Science Framework. A total of six studies (including 888 patients) were included in the meta-analysis. Hematogones were related to favorable three-year RFS (risk ratio (RR) = 1.84; 95% confidence interval (CI) = 1.01 to 3.34) and favorable NRM (RR = 0.14; 95% CI = 0.04 to 0.51), OS (RR = 1.51; 95% CI = 1.13 to 2.02), and acute GVHD (RR = 0.44; 95% CI = 0.33 to 0.59). The certainty of the evidence was low for RFS, NRM, OS, and acute GVHD. Evidence regarding the association between hematogones, relapse, and infections is uncertain. Hematogones may be a prognostic factor for long-term prognosis and acute adverse events in patients with hematopoietic disorders after allo-HSCT. Further studies are required to address the long-term life-threatening events.

Incidence and course of Epstein-Barr virus viremia after allogeneic hematopoietic stem cell transplant for adult-onset systemic chronic active Epstein-Barr virus disease.
Preeti Prerna M Vaswani, Masahiro Onozawa, Yuta Hasegawa, Hiroyuki Ohigashi, Takahide Ara, Toshihiro Matsukawa, Atsushi Yasumoto, Souichi Shiratori, Hideki Goto, Masao Nakagawa, Kaoru Kahata, Tomoyuki Endo, Daigo Hashimoto, Takanori Teshima
Bone marrow transplantation, 2023年09月05日, ［国際誌］
英語

Factors associated with household transmission of SARS-CoV-2 omicron variant to health care workers: A retrospective cohort study.
Keisuke Kagami, Reiko Oyamada, Tsubasa Watanabe, Sho Nakakubo, Takahiro Hayashi, Sumio Iwasaki, Tatsuya Fukumoto, Takayuki Usami, Kasumi Hayasaka, Shinichi Fujisawa, Chiaki Watanabe, Mutsumi Nishida, Takanori Teshima, Yusuke Niinuma, Isao Yokota, Yoh Takekuma, Mitsuru Sugawara, Nobuhisa Ishiguro
International journal of nursing practice, 29, 5, e13195, 2023年08月24日, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: The aim of this study was to determine the risk factors for household transmission of the omicron variant of SARS-CoV-2. BACKGROUND: The household infection rate has been reported to be higher for the omicron variant than for non-omicron variants of SARS-CoV-2. Determination of the risk factors for household transmission of the omicron variant is therefore important. DESIGN: A Retrospective Cohort Study was conducted. METHODS: When family members of health care workers (HCWs) were found to be infected with SARS-CoV-2, the HCWs had to receive two nucleic acid amplification tests for SARS-CoV-2: immediately after and 5 to 10 days after the onset of COVID-19 in the family members. Risk factors of household transmission were analysed by comparing cases (HCWs infected with SARS-CoV-2) and controls (HCWs not infected with SARS-CoV-2) using multivariable analysis. RESULTS: Unvaccinated status (OR: 3.97), age of index cases (≤6 years) (OR: 1.94) and staying at home with index cases (OR: 10.18) were risk factors for household transmission. CONCLUSION: If there is a strong desire to avoid household infection, family members infected with SARS-CoV-2 should live separately during the period of viral shedding.

Dominant-negative type of IKZF1 deletion showed a favorable prognosis in adult B-cell acute lymphoblastic leukemia.
Hiroyuki Kimura, Masahiro Onozawa, Shota Yoshida, Naoki Miyashita, Shota Yokoyama, Toshihiro Matsukawa, Shinsuke Hirabayashi, Hideki Goto, Tomoyuki Endo, Satoshi Oguri, Shinichi Fujisawa, Akio Mori, Takeshi Kondo, Daisuke Hidaka, Kohei Okada, Shuichi Ota, Yasutaka Kakinoki, Yutaka Tsutsumi, Satoshi Yamamoto, Takuto Miyagishima, Junichi Hashiguchi, Takahiro Nagashima, Makoto Ibata, Kentaro Wakasa, Yoshihito Haseyama, Katsuya Fujimoto, Toshimichi Ishihara, Hajime Sakai, Takanori Teshima
Annals of hematology, 2023年08月19日, ［国際誌］
英語, 研究論文（学術雑誌）, IKZF1 deletion is a recurrent genomic alteration in B-cell acute lymphoblastic leukemia (B-ALL) and is divided into dominant-negative (DN) and loss of function (LOF) deletions. The prognostic impact of each deletion has not been fully elucidated. We retrospectively analyzed 117 patients with adult B-ALL including 60 patients with BCR::ABL1-positive B-ALL and 57 patients with BCR::ABL1-negative B-ALL by the fluorescence in situ hybridization (FISH) method for IKZF1 deletion and multiplex PCR for the 4 most common IKZF1 deletions (∆4-7, ∆2-7, ∆2-8, and ∆4-8). Samples, in which IKZF1 deletion was detected by FISH but a specific type of deletion was not identified by the PCR, were categorized as "other." Patients were classified into a DN group that had at least 1 allele of ∆4-7 (n = 23), LOF and other group (n = 40), and wildtype group (n = 54). DN type IKZF1 deletions were found in 33.3% of BCR::ABL1-positive cases and 5.2% of BCR::ABL1-negative cases. LOF and other type IKZF1 deletions were found in 43.4% of BCR::ABL1-positive cases and 24.6% of BCR::ABL1-negative cases. Patients with the DN group showed significantly higher overall survival (OS) than that of the LOF and other and WT groups (P = 0.011). Multivariate analysis including age, WBC counts, complex karyotype, and DN type IKZF1 deletion showed that the DN type of IKZF1 deletion (HR = 0.22, P = 0.013) had a positive impact and age ≥ 65 (HR = 1.92, P = 0.029) had a negative impact on OS. The prognostic impact of IKZF1 deletion depends on the type of deletion and DN type of IKZF1 deletion showed better prognosis in adult B-ALL patients.Clinical trial registration This study was part of a prospective observational study (Hokkaido Leukemia Net, UMIN000048611). It was conducted in compliance with ethical principles based on the Helsinki Declaration and was approved by the institutional review board of Hokkaido University Hospital (#015-0344).

抗トロポニンI抗体vs.抗トロポニンT抗体の存在様式と出現頻度　　　　　　　　　　　　　　　
中野 恵一, 村上 聡, 清宮 正徳, 安田 慶子, 山下 直樹, 後藤 秀樹, 豊嶋 崇徳
医療検査と自動化, 48, 4, 386, 386, (一社)日本医療検査科学会, 2023年08月
日本語

Clinical implications of NUP98::NSD1 fusion at diagnosis in adult FLT3-ITD positive AML.
Toru Miyajima, Masahiro Onozawa, Shota Yoshida, Naoki Miyashita, Hiroyuki Kimura, Shogo Takahashi, Shota Yokoyama, Toshihiro Matsukawa, Hideki Goto, Junichi Sugita, Shinichi Fujisawa, Daisuke Hidaka, Reiki Ogasawara, Akio Mori, Satomi Matsuoka, Akio Shigematsu, Kentaro Wakasa, Ikumi Kasahara, Tomoyuki Saga, Junichi Hashiguchi, Yukari Takeda, Makoto Ibata, Tsutsumi Yutaka, Katsuya Fujimoto, Takeshi Kondo, Takanori Teshima
European journal of haematology, 2023年07月19日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: The cryptic fusion oncogene NUP98::NSD1 is known to be associated with FLT3-ITD mutation in acute myeloid leukemia (AML), and an independent poor prognostic factor in pediatric AML. However, there are little data regarding the clinical significance of NUP98::NSD1 in adult cohort. METHODS: We conducted a multicenter retrospective study to investigate the prevalence, clinical characteristics, and prognostic impact of NUP98::NSD1 in adult FLT3-ITD-positive AML patients. RESULTS: In a total of 97 FLT3-ITD-positive AML patients, six cases (6.2%) were found to harbor the NUP98::NSD1 fusion transcript. NUP98::NSD1 positive cases had significantly higher platelet counts and a higher frequency of FAB-M4 morphology than NUP98::NSD1 negative cases. NUP98::NSD1 was found to be mutually exclusive with NPM1 mutation, and was accompanied by the WT1 mutation in three of the six cases. The presence of NUP98::NSD1 fusion at the time of diagnosis predicted poor response to cytarabine-anthracycline-based intensive induction chemotherapy (induction failure rate: 83% vs. 36%, p = .038). Five of the six cases with NUP98::NSD1 underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two of the five cases have successfully maintained remission, with one of them being rescued through a second HSCT. CONCLUSIONS: Detecting NUP98::NSD1 in adult FLT3-ITD-positive AML is crucial to recognizing chemotherapy-resistant group.

Assessment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome using different scanning approaches for the ultrasonographic evaluation of portal vein blood flow and hepatic artery resistive index in hematopoietic stem cell transplant recipients.
Momoka Kikuchi, Takahito Iwai, Mutsumi Nishida, Yusuke Kudo, Satomi Omotehara, Megumi Sato, Junichi Sugita, Hideki Goto, Isao Yokota, Takanori Teshima
Journal of medical ultrasonics (2001), 2023年07月04日, ［国内誌］
英語, 研究論文（学術雑誌）, PURPOSE: Sinusoidal obstruction syndrome (SOS) is a fatal complication of hematopoietic stem cell transplantation (HSCT). Previously, we established a scoring system (Hokkaido ultrasound-based scoring system-10; HokUS-10) comprising 10 ultrasound parameters for SOS diagnosis. In HokUS-10, the portal vein time-averaged flow velocity (PV TAV) and hepatic artery resistive index (HA RI) are measured using subcostal scanning. However, measurement errors and delineation difficulties occur. Therefore, we aimed to prospectively evaluate PV TAV and HA RI measurements obtained via intercostal scanning as an alternative method to subcostal scanning and determine their cutoff values. METHODS: HokUS-10 was administered before and after HSCT. PV TAV and HA RI were measured on subcostal and right intercostal scans. RESULTS: We performed 366 scans on 74 patients. The median value (range) of PV TAV in the main and right portal veins was 15.0 cm/s (2.2-49.6 cm/s) and 10.5 cm/s (1.6-22.0 cm/s), respectively. A low correlation was observed between the two values (r = 0.39, p < 0.01). The highest diagnostic value of the right portal vein was less than 8.0 cm/s. The median value (range) of HA RI in the proper and right hepatic arteries was 0.72 (0.52-1.00) and 0.70 (0.51-1.00), respectively. A strong correlation was observed between the two values (r = 0.65, p < 0.01). The highest diagnostic value of the right HA RI was 0.72 or higher. CONCLUSION: Quantitative measurement of PV TAV and HA RI using intercostal scanning can be appropriately performed as an alternative method to using subcostal scanning.

Corrigendum to "IgG4-IgE complex in patients with IgG4-related disease" [Clin. Chim. Acta 531 (2022) 261-264].
Keiichi Nakano, Junichi Sugita, Masanori Seimiya, Keiko Yasuda, Chiaki Watanabe, Takanori Teshima
Clinica chimica acta; international journal of clinical chemistry, 547, 117454, 117454, 2023年07月01日, ［国際誌］
英語

Type 1 Cryoglobulinemic Vasculitis Due to Monoclonal Gammopathy of Undetermined Significance Successfully Treated by Bortezomib Plus Dexamethasone.
Ryo Kikuchi, Masahiro Onozawa, Jun Nagai, Satomi Okada, Yuta Hasegawa, Hiroyuki Ohigashi, Shintaro Mitamura, Taku Maeda, Emi Takakuwa, Yuichiro Fujieda, Hideki Goto, Daigo Hashimoto, Yoshihiro Matsuno, Takanori Teshima
Internal medicine (Tokyo, Japan), 2023年06月14日, ［国内誌］
英語, 研究論文（学術雑誌）, Cryoglobulins are immunoglobulins that precipitate in cold conditions. Type I cryoglobulinemic vasculitis is associated with hematological malignancies. We herein report a case of steroid-resistant type 1 cryoglobulinemic vasculitis associated with monoclonal gammopathy of undetermined significance (MGUS) in a 47-year-old woman. By immunofixation of cryoglobulin, we found that the main component of cryoglobulin was the M protein due to MGUS, so treatment of MGUS was needed. Bortezomib+dexamethasone therapy resulted in a rapid decrease in cryoglobulin and improvement in the symptoms of cryoglobulinemic vasculitis. In refractory type I cryoglobulinemic vasculitis, treatment of the underlying gammaglobulinopathy should be considered.

Association of demographics, HCV co‐infection, HIV‐1 subtypes and genetic clustering with late HIV diagnosis: a retrospective analysis from the Japanese Drug Resistance HIV‐1 Surveillance Network
Machiko Otani, Teiichiro Shiino, Atsuko Hachiya, Hiroyuki Gatanaga, Dai Watanabe, Rumi Minami, Masako Nishizawa, Takanori Teshima, Shigeru Yoshida, Toshihiro Ito, Tsunefusa Hayashida, Michiko Koga, Mami Nagashima, Kenji Sadamasu, Makiko Kondo, Shingo Kato, Shunsuke Uno, Toshibumi Taniguchi, Hidetoshi Igari, Sei Samukawa, Hideaki Nakajima, Yusuke Yoshino, Masahide Horiba, Hiroshi Moro, Tamayo Watanabe, Mayumi Imahashi, Yoshiyuki Yokomaku, Haruyo Mori, Teruhisa Fujii, Kiyonori Takada, Asako Nakamura, Hideta Nakamura, Masao Tateyama, Shuzo Matsushita, Kazuhisa Yoshimura, Wataru Sugiura, Tetsuro Matano, Tadashi Kikuchi
Journal of the International AIDS Society, 26, 5, Wiley, 2023年05月23日, ［査読有り］
研究論文（学術雑誌）

Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT
Hajime Senjo, Shinpei Harada, Shimpei I Kubota, Yuki Tanaka, Takahiro Tateno, Zixuan Zhang, Satomi Okada, Xuanzhong Chen, Ryo Kikuchi, Naoki Miyashita, Masahiro Onozawa, Hideki Goto, Tomoyuki Endo, Yuta Hasegawa, Hiroyuki Ohigashi, Takahide Ara, Yoshinori Hasegawa, Masaaki Murakami, Takanori Teshima, Daigo Hashimoto
Blood Journal, American Society of Hematology, 2023年05月22日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis is standard in allogeneic hematopoietic stem cell transplantation (HCT) but fails to induce long-term tolerance without chronic GVHD in a considerable number of patients. In this study, we addressed this long-standing question in mouse models of HCT. After HCT, alloreactive donor T cells rapidly differentiated into PD-1+ TIGIT+ terminally exhausted T cells (terminal-Tex). GVHD prophylaxis with cyclosporine (CSP) suppressed donor T-cell expression of TOX, a master regulator to promote differentiation of transitory exhausted T cells (transitory-Tex), expressing both inhibitory receptors and effector molecules, into terminal-Tex, and inhibited tolerance induction. Adoptive transfer of transitory-Tex, but not terminal-Tex, into secondary recipients developed chronic GVHD. Transitory-Tex maintained alloreactivity and thus PD-1 blockade restored graft-versus-leukemia (GVL) activity of transitory-Tex, not terminal-Tex. In conclusion, CSP inhibits tolerance induction by suppressing the terminal exhaustion of donor T cells, while maintaining GVL effects to suppress leukemia relapse.

Hepatitis C Virus (HCV)-Ribonucleic Acid (RNA) As a Biomarker for Lymphoid Malignancy with HCV Infection
Yutaka Tsutsumi, Shinichi Ito, Souichi Shiratori, Takanori Teshima
Cancers, 15, 10, 2852, 2852, MDPI AG, 2023年05月21日, ［査読有り］, ［最終著者］
研究論文（学術雑誌）, The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy. There are also cases in which the disappearance of lymphoid malignancy has been observed by treating HCV and suppressing HCV-Ribonucleic acid (RNA), as well as cases of recurrence with an increase in HCV-RNA. While HCV-associated lymphoma has a poor prognosis, improving the prognosis with Direct Acting Antivirals (DAA) has recently been reported. The reduction and eradication of HCV-RNA by means of DAA is thus important for the treatment of lymphoid malignancy associated with HCV infection, and HCV-RNA can presumably play a role as a biomarker. This review provides an overview of what is currently known about HCV-associated lymphoma, its epidemiology, the mechanisms underlying the progression to lymphoma, its treatment, the potential and limits of HCV-RNA as a therapeutic biomarker, and biomarkers that are expected now that DAA therapy has been developed.

Pseudotumor of the skin due to Mycobacterium genavense.
Suguru Kurosawa, Keisuke Imafuku, Sho Nakakubo, Sumio Iwasaki, Takanori Teshima, Hideki Goto, Hideyuki Ujiie
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2023年05月15日, ［国際誌］
英語, Mycobacterium genavense is a rare type of non-tuberculous mycobacterium (NTM) that has been reported to cause disseminated infections in immunocompromised patients. Because M. genavense is slow-growing and poorly able to form colonies on Ogawa's medium, genetic and molecular analyses are necessary to identify this pathogen. NTM infections present with various cutaneous manifestations. Of these, rare cases have been reported to present with mycobacterial pseudotumors. However, there are no reports of M. genavense with cutaneous pseudotumors. In this paper, we report a case of a pseudotumor due to M. genavense infection that was observed only in a cutaneous lesion. The patient was taking 5 mg of prednisolone and was aware of a tumor on the right lower leg. Biopsy samples showed diffuse spindle-shaped histiocytes and various other inflammatory cell infiltrates, and Ziehl-Neelsen staining detected mycobacterium. Since no colonies formed on Ogawa medium, genetic testing was performed, and M. genavense was identified by DNA sequence analysis. There were no other disseminated lesions beyond the skin, including in the lungs and liver. Since the patient was immunosuppressed, in accordance with previous literature, a combination therapy of clarithromycin, ethambutol, and rifampicin for 4 months was recommended. When no growth is observed on Ogawa's medium in cases of infection, it is essential to identify the infectious pathogen by genetic analysis.

Mycobacterium genavenseによる限局性の皮膚感染症を呈した1例　　　　　　　　　　　　　　　
黒澤 卓, 今福 恵輔, 宮澤 元, 中久保 祥, 岩崎 澄央, 後藤 秀樹, 豊嶋 崇徳, 氏家 英之
日本臨床皮膚科医会雑誌, 40, 3, 470, 470, 日本臨床皮膚科医会, 2023年05月
日本語

Defibrotide plus best standard of care compared with best standard of care alone for the prevention of sinusoidal obstruction syndrome (HARMONY): a randomised, multicentre, phase 3 trial
Stephan A Grupp, Selim Corbacioglu, Hyoung Jin Kang, Takanori Teshima, Seong Lin Khaw, Franco Locatelli, Johan Maertens, Matthias Stelljes, Polina Stepensky, Paty Lopez, Vian Amber, Antonio Pagliuca, Paul G Richardson, Mohamad Mohty
The Lancet Haematology, 10, 5, e333, e345, Elsevier BV, 2023年05月, ［査読有り］
研究論文（学術雑誌）

Safety and efficacy of tisagenlecleucel in patients with relapsed or refractory B-cell lymphoma: the first real-world evidence in Japan
Hideki Goto, Toshio Kitawaki, Nobuharu Fujii, Koji Kato, Yasushi Onishi, Noriko Fukuhara, Takuji Yamauchi, Kazunori Toratani, Hiroki Kobayashi, Shota Yoshida, Masatoshi Shimo, Koichi Onodera, Hajime Senjo, Masahiro Onozawa, Kenji Hirata, Isao Yokota, Takanori Teshima
International Journal of Clinical Oncology, 28, 6, 816, 826, Springer Science and Business Media LLC, 2023年04月18日, ［査読有り］, ［最終著者］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Tisagenlecleucel, an autologous CD19-directed T-cell immunotherapy, can induce a durable response in adult patients with relapsed/refractory (r/r) B-cell lymphoma. METHODS: To elucidate the outcome of chimeric antigen receptor (CAR) T-cell therapy in Japanese, we retrospectively analyzed the outcomes of 89 patients who received tisagenlecleucel for r/r diffuse large B-cell lymphoma (n = 71) or transformed follicular lymphoma (n = 18). RESULTS: With a median follow-up of 6.6-months, 65 (73.0%) patients achieved a clinical response. The overall survival (OS) and event-free survival (EFS) rates at 12 months were 67.0% and 46.3%, respectively. Overall, 80 patients (89.9%) had cytokine release syndrome (CRS), and 6 patients (6.7%) had a grade ≥ 3 event. ICANS occurred in 5 patients (5.6%); only 1 patient had grade 4 ICANS. Representative infectious events of any grade were cytomegalovirus viremia, bacteremia and sepsis. The most common other adverse events were ALT elevation, AST elevation, diarrhea, edema, and creatinine elevation. No treatment-related mortality was observed. A Sub-analysis showed that a high metabolic tumor volume (MTV; ≥ 80 ml) and stable disease /progressive disease before tisagenlecleucel infusion were both significantly associated with a poor EFS and OS in a multivariate analysis (P < 0.05). Notably, the combination of these 2 factors efficiently stratified the prognosis of these patients (HR 6.87 [95% CI 2.4-19.65; P < 0.05] into a high-risk group). CONCLUSION: We report the first real-world data on tisagenlecleucel for r/r B-cell lymphoma in Japan. Tisagenlecleucel is feasible and effective, even in late line treatment. In addition, our results support a new algorithm for predicting the outcomes of tisagenlecleucel.

Subclinical minute FLT3-ITD clone can be detected in clinically FLT3-ITD-negative acute myeloid leukaemia at diagnosis
Shota Yokoyama, Masahiro Onozawa, Shota Yoshida, Naoki Miyashita, Hiroyuki Kimura, Shogo Takahashi, Toshihiro Matsukawa, Hideki Goto, Shinichi Fujisawa, Kosuke Miki, Daisuke Hidaka, Junichi Hashiguchi, Kentaro Wakasa, Makoto Ibata, Yukari Takeda, Akio Shigematsu, Katsuya Fujimoto, Yutaka Tsutsumi, Akio Mori, Toshimichi Ishihara, Yasutaka Kakinoki, Takeshi Kondo, Daigo Hashimoto, Takanori Teshima
British Journal of Haematology, 201, 6, 1144, 1152, Wiley, 2023年04月17日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Recent advances in next-generation sequencing (NGS) have enabled the detection of subclinical minute FLT3-ITD. We selected 74 newly diagnosed, cytogenetically normal acute myeloid leukaemia (AML) samples in which FLT3-ITD was not detected by gel electrophoresis. We sequenced them using NGS and found minute FLT3-ITDs in 19 cases. We compared cases with clinically relevant FLT3-ITD (n = 37), cases with minute FLT3-ITD (n = 19) and cases without detectable FLT3-ITD (n = 55). Molecular characteristics (location and length) of minute FLT3-ITD were similar to those of clinically relevant FLT3-ITD. Survival of cases with minute FLT3-ITD was similar to that of cases without detectable FLT3-ITD, whereas the relapse rate within 1 year after onset was significantly higher in cases with minute FLT3-ITD. We followed 18 relapsed samples of cases with clinically FLT3-ITD-negative at diagnosis. Two of 3 cases with minute FLT3-ITD relapsed with progression to clinically relevant FLT3-ITD. Two of 15 cases in which FLT3-ITD was not detected by NGS relapsed with the emergence of minute FLT3-ITD, and one of them showed progression to clinically relevant FLT3-ITD at the second relapse. We revealed the clonal dynamics of subclinical minute FLT3-ITD in clinically FLT3-ITD-negative AML. Minute FLT3-ITD at the initial AML can expand to become a dominant clone at relapse.

Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study
David Bernard Miklos, Mohammad Abu Zaid, Julian P. Cooney, Jörn C. Albring, Mary Flowers, Alan P. Skarbnik, Ibrahim Yakoub-Agha, Bor-Sheng Ko, Benedetto Bruno, Edmund K. Waller, Jean Yared, Sang Kyun Sohn, Claude-Eric Bulabois, Takanori Teshima, David Jacobsohn, Hildegard Greinix, Ahmad Mokatrin, Yihua Lee, Justin T. Wahlstrom, Lori Styles, Gerard Socie
Journal of Clinical Oncology, 41, 10, 1876, 1887, American Society of Clinical Oncology (ASCO), 2023年04月01日, ［査読有り］
研究論文（学術雑誌）, PURPOSE

To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD).

METHODS

Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety.

RESULTS

Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients.

CONCLUSION

There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.

Subcutaneous Panniculitis-like T-cell Lymphoma Lacking Subcutaneous Tumor Mimicking Adult-onset Still's Disease.
Maria Tada, Shion Kachi, Masahiro Onozawa, Yuichiro Fujieda, Shota Yoshida, Yotaro Oki, Kazuro Kamada, Jun Nagai, Satomi Okada, Ryo Kikuchi, Ryo Hisada, Yuta Hasegawa, Hiroyuki Ohigashi, Hideki Goto, Daigo Hashimoto, Shinichi Nakazato, Yoshihiro Matsuno, Takanori Teshima, Tatsuya Atsumi
Internal medicine (Tokyo, Japan), 2023年03月15日, ［国内誌］
英語, 研究論文（学術雑誌）, We herein report a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) resembling adult-onset Still's disease (AOSD). A 40-year-old woman presented with a fever, erythema, and painful subcutaneous nodules on the trunk. Laboratory data and a bone marrow analysis showed hemophagocytic syndrome. Although AOSD was suspected, based on a histopathological evaluation of the erythema, she was diagnosed with SPTCL. She was refractory to combination chemotherapy but achieved durable remission with cyclosporine monotherapy. Genetic testing revealed a homozygous HAVCR2 c.245A>G variant (rs184868814) that had caused NLRP3 inflammasome activation. SPTCL and AOSD share a pathogenesis in terms of NLRP3 inflammasome activation, so the clinical phenotype of SPTCL reasonably mimics AOSD.

Decreased Paneth cell α-defensins promote fibrosis in a choline-deficient L-amino acid-defined high-fat diet-induced mouse model of nonalcoholic steatohepatitis via disrupting intestinal microbiota
Shunta Nakamura, Kiminori Nakamura, Yuki Yokoi, Yu Shimizu, Shuya Ohira, Mizu Hagiwara, Zihao Song, Li Gan, Tomoyasu Aizawa, Daigo Hashimoto, Takanori Teshima, Andre J. Ouellette, Tokiyoshi Ayabe
Scientific Reports, 13, 1, Springer Science and Business Media LLC, 2023年03月09日, ［査読有り］
研究論文（学術雑誌）, Abstract

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fibrosis that develops from fatty liver. Disruption of intestinal microbiota homeostasis, dysbiosis, is associated with fibrosis development in NASH. An antimicrobial peptide α-defensin secreted by Paneth cells in the small intestine is known to regulate composition of the intestinal microbiota. However, involvement of α-defensin in NASH remains unknown. Here, we show that in diet-induced NASH model mice, decrease of fecal α-defensin along with dysbiosis occurs before NASH onset. When α-defensin levels in the intestinal lumen are restored by intravenous administration of R-Spondin1 to induce Paneth cell regeneration or by oral administration of α-defensins, liver fibrosis is ameliorated with dissolving dysbiosis. Furthermore, R-Spondin1 and α-defensin improved liver pathologies together with different features in the intestinal microbiota. These results indicate that decreased α-defensin secretion induces liver fibrosis through dysbiosis, further suggesting Paneth cell α-defensin as a potential therapeutic target for NASH.

Humoral response to mRNA-based COVID-19 vaccine and booster effect of a third dose in patients with mature T cell and NK-cell neoplasms
Mirei Kobayashi, Akio Mori, Masahiro Onozawa, Shihori Tsukamoto, Hajime Senjo, Takashi Ishio, Emi Yokoyama, Minoru Kanaya, Koh Izumiyama, Makoto Saito, Haruna Muraki, Masanobu Morioka, Takanori Teshima, Takeshi Kondo
Annals of Hematology, 102, 4, 819, 827, Springer Science and Business Media LLC, 2023年03月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Abstract

Patients with lymphoid malignancies have impaired humoral immunity caused by the disease itself and its treatment, placing them at risk for severe coronavirus disease-19 (COVID-19) and reduced response to vaccination. However, data for COVID-19 vaccine responses in patients with mature T cell and NK-cell neoplasms are very limited. In this study of 19 patients with mature T/NK-cell neoplasms, anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike antibodies were measured at 3 months, 6 months, and 9 months after the second mRNA-based vaccination. At the time of the second and third vaccinations, 31.6% and 15.4% of the patients were receiving active treatment. All patients received the primary vaccine dose and the third vaccination rate was 68.4%. In patients with mature T/NK-cell neoplasms, both seroconversion rate (p < 0.01) and antibody titers (p < 0.01) after the second vaccination were significantly lower than those in healthy controls (HC). In individuals who received the booster dose, patients had significantly lower antibody titers than those in HC (p < 0.01); however, the seroconversion rate in patients was 100%, which was the same as that in HC. The booster vaccine resulted in a significant increase of antibodies in elderly patients who had shown a response that was inferior to that in younger patients after two doses of vaccination. Since higher antibody titers and higher seroconversion rate reduced the incidence of infection and mortality, vaccination more than three times may have the advantage for patients with mature T/NK-cell neoplasms, especially in elderly patients. Clinical trial registration number: UMIN 000,045,267 (August 26th, 2021), 000,048,764 (August 26th, 2022).

Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study
Naoki Miyashita, Masahiro Onozawa, Shota Yoshida, Hiroyuki Kimura, Shogo Takahashi, Shota Yokoyama, Toshihiro Matsukawa, Shinsuke Hirabayashi, Shinichi Fujisawa, Akio Mori, Shuichi Ota, Yasutaka Kakinoki, Yutaka Tsutsumi, Satoshi Yamamoto, Takuto Miyagishima, Takahiro Nagashima, Makoto Ibata, Kentaro Wakasa, Yoshihito Haseyama, Katsuya Fujimoto, Toshimichi Ishihara, Hajime Sakai, Takeshi Kondo, Takanori Teshima
International Journal of Hematology, 118, 1, 36, 46, Springer Science and Business Media LLC, 2023年02月28日, ［査読有り］, ［最終著者］, ［国内誌］
英語, 研究論文（学術雑誌）, Mutation status of FLT3, NPM1, and CEBPA is used to classify the prognosis of acute myeloid leukemia, but its significance in patients with cytogenetically normal (CN) AML is unclear. We prospectively analyzed these genes in 295 patients with CN-AML and identified 76 (25.8%) FLT3-ITD, 113 (38.3%) NPM1 mutations, and 30 (10.2%) CEBPA biallelic mutations. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. The results suggest that analyzing these gene mutations at diagnosis can inform selection of the optimal intensity of therapy for patients with CN-AML.

IgG4-IgE複合体の保有頻度とIgE、IgG4濃度の比較に関する研究
中野 恵一, 安田 慶子, 清宮 正徳, 渡邊 千秋, 後藤 秀樹, 豊嶋 崇徳
生物試料分析, 46, 1, 51, 51, (NPO)生物試料分析科学会, 2023年02月
日本語

IgG4-IgE complex interferes with measurement of IgE concentration
Keiichi Nakano, Junichi Sugita, Masanori Seimiya, Keiko Yasuda, Chiaki Watanabe, Hideki Goto, Takanori Teshima
Clinical Biochemistry, 112, 11, 16, Elsevier BV, 2023年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND AIMS: Patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) have elevated immunoglobulin E (IgE) concentration compared to that in healthy individuals, which suggests the occurrence of IgE-mediated allergic reactions. We have previously shown that IgG4 and IgE form a complex in some patients with IgG4-RD. However, it is currently unknown whether and how the presence of the IgG4-IgE complex affects IgE concentration measurements by different assays. MATERIALS AND METHODS: Twenty patients with confirmed presence or absence of IgG4-IgE complex were evaluated. We compared IgE concentrations measured by ST AIA-PACK IgE II (AIA-PACK), Elecsys IgE II Immunoassay (Elecsys), and Iatroace IgE (Iatroace) and evaluated to what extent the IgG4-IgE complex interfered with these measurements. RESULTS: In patients with the IgG4-IgE complex, IgE concentrations measured using Iatroace were significantly lower than those measured using Elecsys and tended to be lower than those measured using AIA-PACK. IgE concentrations determined by Iatroace were significantly different in patients with and without the IgG4-IgE complex, whereas no significant differences between these groups were detected when IgE concentrations were measured by AIA-PACK or Elecsys. CONCLUSION: The formation of the IgG4-IgE complex underestimates measured IgE concentrations depending on the method used. Therefore, caution should be exercised when selecting a specific IgE assay for patients with IgG4-RD.

Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation.
Roni Shouval, Nicholas R Waters, Antonio L C Gomes, Corrado Zuanelli Brambilla, Teng Fei, Sean M Devlin, Chi L Nguyen, Kate A Markey, Anqi Dai, John B Slingerland, Annelie G Clurman, Emily Fontana, Luigi A Amoretti, Roberta J Wright, Tobias M Hohl, Ying Taur, Anthony D Sung, Daniela Weber, Daigo Hashimoto, Takanori Teshima, Nelson J Chao, Ernst Holler, Michael Scordo, Sergio A Giralt, Miguel-Angel Perales, Jonathan U Peled, Marcel R M van den Brink
Clinical cancer research : an official journal of the American Association for Cancer Research, 29, 1, 165, 173, 2023年01月04日, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. EXPERIMENTAL DESIGN: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. RESULTS: We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)-thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine-cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. CONCLUSIONS: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.

Breaking away from an endemic state of multidrug-resistant Pseudomonas aeruginosa by daily sink disinfection.
Sumio Iwasaki, Rikako Sato, Keisuke Kagami, Kouji Akizawa, Kasumi Hayasaka, Tatsuya Fukumoto, Keisuke Taki, Yusuke Niinuma, Takehiro Yamada, Reiko Oyamada, Tsubasa Watanabe, Sho Nakakubo, Chiaki Watanabe, Takanori Teshima, Nobuhisa Ishiguro
Antimicrobial stewardship & healthcare epidemiology : ASHE, 3, 1, e209, 2023年, ［国際誌］
英語, 研究論文（学術雑誌）, The detection rate of multidrug-resistant Pseudomonas aeruginosa in patients admitted to 2 wards and the intensive care unit decreased from 20.3% (129 of 636 isolates) to 4.2% (37 of 889 isolates) after the start of disinfection of hand washing sinks using alkyl diaminoethylglycine hydrochloride.

Clinical features of complex karyotype in newly diagnosed acute myeloid leukemia
Shota Yoshida, Masahiro Onozawa, Naoki Miyashita, Hiroyuki Kimura, Shogo Takahashi, Shota Yokoyama, Toshihiro Matsukawa, Shinsuke Hirabayashi, Akio Mori, Daisuke Hidaka, Koichiro Minauchi, Akio Shigematsu, Junichi Hashiguchi, Tetsuyuki Igarashi, Yasutaka Kakinoki, Yutaka Tsutsumi, Makoto Ibata, Hajime Kobayashi, Yoshihito Haseyama, Katsuya Fujimoto, Toshimichi Ishihara, Hajime Sakai, Shuichi Ota, Takeshi Kondo, Takanori Teshima
International Journal of Hematology, 117, 4, 544, 552, Springer Science and Business Media LLC, 2022年12月26日, ［査読有り］, ［最終著者］, ［国内誌］
英語, 研究論文（学術雑誌）, Complex karyotype acute myeloid leukemia (CK-AML) has been classified as an adverse-risk subtype. Although a few reports have further classified CK-AML as typical (including monosomy of chromosomes 5, 7 and 17 or deletion of 5q, 7q and/or 17p) or atypical, the clinical features of these subtypes in Japanese patients remain unclear. We retrospectively analyzed a total of 115 patients with CK-AML, including 77 with typical CK-AML and 38 with atypical CK-AML. Median overall survival (OS) was significantly shorter in patients with typical CK-AML than atypical CK-AML (143 days vs. 369 days, P = 0.009). Among patients with typical CK-AML, those with monosomy 17 or deletion of 17p had significantly shorter OS than patients without such abnormalities (105 days vs. 165 days, P = 0.033). TP53 mutations were more predominant in patients with typical CK-AML than in patients with atypical CK-AML (69.7% vs. 32.4%, P < 0.001). Patients with typical CK-AML had a poor prognosis regardless of TP53 mutation status. Among patients with atypical CK-AML, however, prognosis was worse for those with the TP53 mutation than those without the mutation. In conclusion, prognosis is extremely poor for both typical CK-AML and atypical CK-AML with TP53 mutation.

Effect of the COVID-19 pandemic on allogeneic stem cell transplantation in Japan
Yoshimitsu Shimomura, Tetsuhisa Kitamura, Masashi Nishikubo, Tomotaka Sobue, Naoyuki Uchida, Noriko Doki, Masatsugu Tanaka, Ayumu Ito, Jun Ishikawa, Takahide Ara, Shuichi Ota, Makoto Onizuka, Masashi Sawa, Yukiyasu Ozawa, Yumiko Maruyama, Kazuhiro Ikegame, Yoshinobu Kanda, Tatsuo Ichinohe, Takahiro Fukuda, Shinichiro Okamoto, Takanori Teshima, Yoshiko Atsuta
International Journal of Hematology, 117, 4, 590, 597, Springer Science and Business Media LLC, 2022年12月14日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The coronavirus disease 2019 (COVID-19) pandemic affected healthcare quality and access worldwide and may also have negatively affected the frequency and outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the effect of the pandemic on allogeneic HSCT in Japan. Our subjects were patients who received allogeneic HSCT during January 2018-December 2020 in Japan. We assessed differences in yearly number of allogeneic HSCTs and 1-year outcomes in 2020 versus both 2019 and 2018. The total number of patients who received allogeneic HSCT increased from 3621 patients in 2018 and 3708 patients in 2019 to 3865 patients in 2020. Some following changes in allogeneic HSCT methods were observed: patients were older, fewer patients received bone marrow transplantation, fewer patients received transplants from unrelated donors, fewer patients received transplants from matched donors, more patients received reduced-intensity conditioning, and fewer patients received anti-thymocyte globulin in 2020 compared with previous years. HSCT outcomes were not affected, as 1-year overall survival was not significantly different (65.8% in 2020, vs. 66.5% in 2019 and 66.4% in 2018). Our results suggest that we can maintain transplant care during the pandemic by controlling the spread of COVID-19 and modifying HSCT methods.

Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees
Takeshi Inoue, Ryo Shinnakasu, Chie Kawai, Hiromi Yamamoto, Shuhei Sakakibara, Chikako Ono, Yumi Itoh, Tommy Terooatea, Kazuo Yamashita, Toru Okamoto, Noritaka Hashii, Akiko Ishii-Watabe, Noah S. Butler, Yoshiharu Matsuura, Hisatake Matsumoto, Shinya Otsuka, Kei Hiraoka, Takanori Teshima, Masaaki Murakami, Tomohiro Kurosaki
Journal of Experimental Medicine, 220, 2, Rockefeller University Press, 2022年12月13日, ［査読有り］
研究論文（学術雑誌）, In contrast to a second dose of the SARS-CoV-2 mRNA vaccine, a third dose elicits potent neutralizing activity against the Omicron variant. To address the underlying mechanism for this differential antibody response, we examined spike receptor-binding domain (RBD)–specific memory B cells in vaccinated individuals. Frequency of Omicron-reactive memory B cells increased ∼9 mo after the second vaccine dose. These memory B cells show an altered distribution of epitopes from pre-second memory B cells, presumably due to an antibody feedback mechanism. This hypothesis was tested using mouse models, showing that an addition or a depletion of RBD-induced serum antibodies results in a concomitant increase or decrease, respectively, of Omicron-reactive germinal center (GC) and memory B cells. Our data suggest that pre-generated antibodies modulate the selection of GC and subsequent memory B cells after the second vaccine dose, accumulating more Omicron-reactive memory B cells over time, which contributes to the generation of Omicron-neutralizing antibodies elicited by the third vaccine dose.

Ultrasonographic monitoring of sinusoidal obstruction syndrome in patients treated with inotuzumab ozogamicin.
Takahito Iwai, Mutsumi Nishida, Junichi Sugita, Atsushi Yasumoto, Yuta Hasegawa, Tomoko Morimoto, Daishi Nakayama, Kohei Okada, Akio Mori, Takanori Teshima
International journal of hematology, 116, 6, 973, 975, 2022年12月, ［国内誌］
英語

Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia
Sandra Dupouy, Ibtissam Marchiq, Thibaud Derippe, Maria Almena-Carrasco, Agnieszka Jozwik, Sylvain Fouliard, Yasmina Adimy, Julia Geronimi, Charlotte Graham, Nitin Jain, Marcela V. Maus, Mohamad Mohty, Nicolas Boissel, Takanori Teshima, Koji Kato, Reuben Benjamin, Svetlana Balandraud
Cancer Research Communications, 2, 11, 1520, 1531, American Association for Cancer Research (AACR), 2022年11月30日, ［査読有り］
研究論文（学術雑誌）, Background:

UCART191 is an “off-the-shelf” genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells.

Methods:

UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities, and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology.

Results:

Responder patients (12/25) had higher UCART19 expansion (Cmax) and exposure (AUCTlast) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR+ T cells did not exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC0-28.

Conclusions:

UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection.

Significance:

First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population.

Reactive granulopoiesis depends on T-cell production of IL-17A and neutropenia-associated alteration of gut microbiota.
Xuanzhong Chen, Daigo Hashimoto, Ko Ebata, Shuichiro Takahashi, Yu Shimizu, Ryuga Shinozaki, Yuta Hasegawa, Ryo Kikuchi, Hajime Senjo, Kazuki Yoneda, Zixuan Zhang, Shinpei Harada, Eiko Hayase, Takahide Ara, Hiroyuki Ohigashi, Yoichiro Iwakura, Kiminori Nakamura, Tokiyoshi Ayabe, Takanori Teshima
Proceedings of the National Academy of Sciences of the United States of America, 119, 48, e2211230119, 2022年11月29日, ［国際誌］
英語, 研究論文（学術雑誌）, Granulopoiesis in the bone marrow adjusts cellular output as demand for neutrophils changes. Reactive granulopoiesis is induced by profound neutropenia, but its mechanism remains to be clarified. We herein explored its mechanisms using mouse models of syngeneic hematopoietic stem cell transplantation (SCT) and 5-fluorouracil-induced neutropenia. After SCT, T cell production of IL-17A was up-regulated. Neutrophil recovery was significantly delayed in IL-17A-deficient or T cell-deficient RAG1-/- mice, and adoptive transfer of wild-type (WT) T cells facilitated neutrophil engraftment. Gut decontamination with oral antibiotics suppressed T cell production of IL-17A and impaired neutrophil recovery. Transplantation of fecal microbiota collected from neutropenic, not naive, mice promoted neutrophil recovery in these mice, suggesting that neutropenia-associated microbiota had a potential to stimulate reactive granulopoiesis. Our study uncovered a cross talk between gut microbiota and neutropenia after SCT and chemotherapy.

Humoral response to mRNA-based COVID-19 vaccine in patients with immune thrombocytopenia
Akio Mori, Masahiro Onozawa, Mirei Kobayashi, Shihori Tsukamoto, Hajime Senjo, Takashi Ishio, Emi Yokoyama, Koh Izumiyama, Makoto Saito, Haruna Muraki, Masanobu Morioka, Takanori Teshima, Takeshi Kondo
British Journal of Haematology, 200, 6, 717, 721, Wiley, 2022年11月28日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Data for COVID-19 vaccine response in patients with immune thrombocytopenia (ITP) are very limited. In a study of 28 patients with ITP, anti-severe acute respiratory syndrome coronavirus 2 spike antibody titres were measured after vaccination. The seroconversion rate for ITP patients was 91.3%, comparable to that in healthy controls (HCs). However, the antibody titre in ITP patients was significantly lower than that in HCs and declined with ageing. Furthermore, the antibody titre in ITP patients who received a minimum prednisolone dose of at least 5 mg/day at any time-point at or after initial vaccination was lower than that in other patients.

Efficacy and safety of tisagenlecleucel in adult Japanese patients with relapsed or refractory follicular lymphoma: results from the phase 2 ELARA trial.
Noriko Fukuhara, Koji Kato, Hideki Goto, Tajima Takeshi, Mayu Kawaguchi, Kota Tokushige, Koichi Akashi, Takanori Teshima, Hideo Harigae, Stephen J Schuster, Catherine Thieblemont, Martin Dreyling, Nathan Fowler
International journal of hematology, 117, 2, 251, 259, 2022年11月21日, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Tisagenlecleucel yielded a high durable response rate in patients with relapsed/refractory (r/r) follicular lymphoma (FL) in the global phase 2 ELARA trial. Here, we report the efficacy, safety, and cellular kinetics of tisagenlecleucel in a subgroup of Japanese patients with r/r FL from ELARA. METHODS: ELARA (NCT03568461) is a global single-arm trial of tisagenlecleucel in patients with r/r FL who received ≥ 2 prior lines of therapy. The primary endpoint was the complete response rate (CRR), and the secondary endpoints were the overall response rate, duration of response, progression-free survival, overall survival, safety, and cellular kinetics. RESULTS: As of March 29, 2021, nine Japanese patients were enrolled and received tisagenlecleucel with a median follow-up of 13.6 months (range, 10.5‒19.3). Per independent review committee, CRR was 100% (95% CI 63.1‒100). Within 8 weeks of infusion, cytokine release syndrome (CRS) of any grade was reported in 6 patients (66.7%); however, no grade ≥ 3 CRS or any grade serious neurological events or treatment-related deaths were observed. CONCLUSION: Tisagenlecleucel showed high efficacy and manageable safety in adult Japanese patients with r/r FL. Moreover, the clinical outcomes were similar to the global population, which supports the potential of tisagenlecleucel in Japanese patients with r/r FL.

A phase 2 study of axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma in Japan: 1-year follow-up and biomarker analysis.
Koji Kato, Nobuharu Fujii, Shinichi Makita, Hideki Goto, Junya Kanda, Kazuyuki Shimada, Koichi Akashi, Koji Izutsu, Takanori Teshima, Natsuko Fukuda, Tokuhito Sumitani, Shota Nakamura, Hiroyuki Sumi, Shinji Shimizu, Yasuyuki Kakurai, Kenji Yoshikawa, Kensei Tobinai, Noriko Usui, Kiyohiko Hatake
International journal of hematology, 2022年11月18日, ［国内誌］
英語, 研究論文（学術雑誌）, Axicabtagene ciloleucel (axi-cel) is an autologous, CD19-targeting chimeric antigen receptor T‑cell therapy. We recently reported the 3-month follow-up results of a phase 2, multicenter, open‑label, single-arm study of axi-cel in Japanese patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (JapicCTI-183914). Here, we present 1-year efficacy and safety data and biomarker analysis data regarding mechanisms of resistance to axi-cel. Primary and secondary endpoints included investigator-assessed objective response rate (ORR), serious adverse events, and treatment-emergent adverse events. Axi-cel pharmacokinetics were also examined. Biomarker analysis was performed by cytokine measurement, immunohistochemistry, RNA sequencing, and whole-exome sequencing. At a median follow-up of 13.4 months, ORR was 86.7% (13/15 patients), and the complete response (CR) rate improved to 53.3% (8/15 patients) due to response conversion. Seven patients experienced disease progression, and one achieved CR after re-treatment with axi-cel. No new safety concerns were detected. Plausible resistance mechanisms to axi-cel varied among patients but included CD19 downregulation, programmed death-ligand 1 upregulation, and increased macrophage and angiogenesis signatures. The 1-year efficacy and safety of axi-cel were confirmed in Japanese patients with R/R LBCL. Resistance to treatment may involve multiple factors, including target antigen loss and an unfavorable tumor environment.Clinical trial registration: Japan Clinical Trials Information; JapicCTI-183914.

Frequencies of Anti-Troponin I vs Anti-Troponin T Autoantibodies and Degrees of Interference on Troponin Assays.
Keiichi Nakano, Satoshi Sugawa, Masanori Seimiya, Satoshi Murakami, Keiko Yasuda, Chiaki Watanabe, Hideki Goto, Takanori Teshima
Laboratory medicine, 2022年11月02日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Presence of autoantibodies against troponin I (cTnI) or T (cTnT) has been reported to interfere with troponin assays. However, the extent of the interference with the measurement has not been explored sufficiently. The aims of this study were to examine the frequencies of autoantibodies against troponin I and troponin T and how much these antibodies would affect the measurement. METHODS: The study comprised 52 subjects who visited Hokkaido University Hospital with suspected ischemic heart diseases. To evaluate the presence of autoantibodies, we calculated the recoveries of cTnI or cTnT after immunoglobulin G depletion, and the distributions of peaks reactive with cTnI or cTnT by high-performance liquid chromatography were examined. RESULTS: Autoantibodies against cTnI and cTnT were identified in 8 subjects (15.4%) and 1 subject (1.9%), respectively. Although the greatest difference between cTnI and cTnT was 32-fold, the distributions of cTnI-to-cTnT ratios in groups with and without anti-cTnI were not statistically different. CONCLUSION: Autoantibodies against cTnI were more frequent by several fold than those against cTnT. Their presence did not significantly expand the discrepancy between cTnI and cTnT assays.

2021年度HIV-1薬剤耐性検査外部精度評価の報告　　　　　　　　　　　　　　　
吉田 繁, 松田 昌和, 今橋 真弓, 岡田 清美, 齊藤 浩一, 林田 庸総, 佐藤 かおり, 藤澤 真一, 遠藤 知之, 西澤 雅子, 椎野 禎一郎, 潟永 博之, 豊嶋 崇徳, 杉浦 亙, 吉村 和久, 菊地 正
日本エイズ学会誌, 24, 4, 401, 401, (一社)日本エイズ学会, 2022年11月
日本語

国内HIV-1CRF07_BCの流行動向に関する研究　　　　　　　　　　　　　　　
大谷 眞智子, 椎野 禎一郎, 西澤 雅子, 林田 庸総, 潟永 博之, 豊嶋 崇徳, 渡邊 大, 今橋 真弓, 俣野 哲朗, 菊地 正
日本エイズ学会誌, 24, 4, 438, 438, (一社)日本エイズ学会, 2022年11月
日本語

2021年の国内新規診断未治療HIV感染者・AIDS患者における薬剤耐性HIV-1の動向　　　　　　　　　　　　　　　
菊地 正, 西澤 雅子, 小島 潮子, 大谷 眞智子, 椎野 禎一郎, 俣野 哲朗, 佐藤 かおり, 豊嶋 崇徳, 伊藤 俊広, 林田 庸総, 潟永 博之, 岡 慎一, 古賀 道子, 長島 真美, 貞升 健志, 近藤 真規子, 宇野 俊介, 谷口 俊文, 猪狩 英俊, 寒川 整, 中島 秀明, 吉野 友祐, 堀場 昌英, 茂呂 寛, 渡邉 珠代, 蜂谷 敦子, 今橋 真弓, 松田 昌和, 重見 麗, 岡崎 玲子, 岩谷 靖雅, 横幕 能行, 渡邊 大, 阪野 文哉, 森 治代, 藤井 輝久, 高田 清式, 中村 麻子, 南 留美, 山本 政弘, 松下 修三, 饒平名 聖, 仲村 秀太, 健山 正男, 藤田 次郎, 吉村 和久, 杉浦 亙
日本エイズ学会誌, 24, 4, 401, 401, (一社)日本エイズ学会, 2022年11月
日本語

大腿骨人工骨頭インプラント周囲に発症したALK陰性未分化大細胞型リンパ腫の1例　　　　　　　　　　　　　　　
森 祐斗, 荒 隆英, 中川 雅夫, 吉田 匠汰, 斎藤 祐美花, 横山 翔大, 松川 敏大, 白鳥 聡一, 遠藤 知之, 豊嶋 崇徳
臨床血液, 63, 11, 1592, 1593, (一社)日本血液学会-東京事務局, 2022年11月
日本語

SARS-CoV-2 Omicron detection by antigen tests using saliva.
Kaoru Murakami, Sumio Iwasaki, Satoshi Oguri, Kumiko Tanaka, Rigel Suzuki, Kasumi Hayasaka, Shinichi Fujisawa, Chiaki Watanabe, Satoshi Konno, Isao Yokota, Takasuke Fukuhara, Masaaki Murakami, Takanori Teshima
Journal of clinical virology plus, 2, 4, 100109, 100109, 2022年11月, ［国際誌］
英語, 研究論文（学術雑誌）, The Omicron emerged in November 2021 and became the predominant SARS-CoV-2 variant globally. It spreads more rapidly than ancestral lineages and its rapid detection is critical for the prevention of disease outbreaks. Antigen tests such as immunochromatographic assay (ICA) and chemiluminescent enzyme immunoassay (CLEIA) yield results more quickly than standard polymerase chain reaction (PCR). However, their utility for the detection of the Omicron variant remains unclear. We herein evaluated the performance of ICA and CLEIA in saliva from 51 patients with Omicron and 60 PCR negative individuals. The sensitivity and specificity of CLEIA were 98.0% (95%CI: 89.6-100.0%) and 100.0% (95%CI: 94.0-100.0%), respectively, with fine correlation with cycle threshold (Ct) values. The sensitivity and specificity of ICA were 58.8% (95%CI: 44.2-72.4%) and 100.0% (95%CI: 94.0-100.0%), respectively. The sensitivity of ICA was 100.0% (95%CI: 80.5-100.0%) when PCR Ct was less than 25. The Omicron can be efficiently detected in saliva by CLEIA. ICA also detects high viral load Omicron using saliva.

The preceding hyponatremia is a useful hallmark for the diagnosis of HHV-6 encephalitis after allogeneic hematopoietic stem cell transplantation.
Shota Yoshida, Takahide Ara, Kohei Okada, Yuto Mori, Shihori Tsukamoto, Naoki Miyashita, Kohei Kasahara, Ko Ebata, Junko Iwasaki, Shojiro Takahashi, Akio Shigematsu, Koichiro Minauchi, Naoki Kobayashi, Masahiro Ogasawara, Masahiro Imamura, Takanori Teshima, Shuichi Ota
Bone marrow transplantation, 58, 1, 97, 99, 2022年10月15日, ［国際誌］
英語

UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial.
Reuben Benjamin, Nitin Jain, Marcela V Maus, Nicolas Boissel, Charlotte Graham, Agnieszka Jozwik, Deborah Yallop, Marina Konopleva, Matthew J Frigault, Takanori Teshima, Koji Kato, Floriane Boucaud, Svetlana Balandraud, Athos Gianella-Borradori, Florence Binlich, Ibtissam Marchiq, Sandra Dupouy, Maria Almena-Carrasco, Matthieu Pannaux, Sylvain Fouliard, Eolia Brissot, Mohamad Mohty
The Lancet. Haematology, 2022年10月10日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. METHODS: This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan. Adult patients aged 16-70 years with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10-3 and had exhausted standard treatment options were enrolled in the study, which comprised a dose-escalation phase of up to three UCART19 doses followed by a safety expansion phase. Patients underwent lymphodepletion with fludarabine (30 mg/m2 per day intravenously for 3 days) and cyclophosphamide (500 mg/m2 per day intravenously for 3 days) with or without alemtuzumab (1 mg/kg or 40 mg or 60 mg over 5 days) and received UCART19 doses of 6 × 106, 6-8 × 107, or 1·8-2·4 × 108 total CAR T cells intravenously, followed by safety evaluation and disease response assessments. The primary endpoint was incidence and severity of adverse events. Secondary endpoints were the overall response rate, duration of response, relapse-free survival, progression-free survival, and overall survival. This trial is registered with ClinicalTrials.gov (NCT02746952) and is complete. FINDINGS: Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8-24·8). Median age was 37 years (IQR 28-45). 14 (56%) patients were male and 11 (44%) female. 17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient. Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months (IQR 2·8-24·8), overall response rate was 48% (95% CI 28-69; 12 of 25 patients), duration of response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable), progression-free survival was 2·1 months (95% CI 1·2-2·8), and overall survival was 13·4 months (95% CI 4·8-23·0). INTERPRETATION: UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia. FUNDING: Servier.

Neurolymphomatosis in Intravascular Large B-cell Lymphoma.
Toru Miyajima, Hiroyuki Ohigashi, Hiroaki Yaguchi, Takanori Teshima
Internal medicine (Tokyo, Japan), 2022年10月05日, ［国内誌］
英語, 研究論文（学術雑誌）

DLBCLにおける適切なエンドポイントはEFS36である　　　　　　　　　　　　　　　
泉山 康, 稲尾 翼, 後藤 秀樹, 原田 晋平, 千丈 創, 須藤 啓斗, 橋口 淳一, 小笠原 励起, 佐賀 智之, 五十嵐 哲祥, 若狭 健太郎, 笠原 郁美, 武田 紫, 山口 圭介, 重松 明男, 高畑 むつみ, 藤本 勝也, 長谷山 美仁, 永嶋 貴博, 酒井 基, 柿木 康孝, 黒澤 光俊, 横田 勲, 豊嶋 崇徳
日本血液学会学術集会, 84回, 916, 916, (一社)日本血液学会, 2022年10月
英語

Characteristics of Graft-Versus-Host Disease (GvHD) After Post-Transplantation Cyclophosphamide Versus Conventional GvHD Prophylaxis.
Rima M Saliba, Amin M Alousi, Joseph Pidala, Mukta Arora, Stephen R Spellman, Michael T Hemmer, Tao Wang, Camille Abboud, Sairah Ahmed, Joseph H Antin, Amer Beitinjaneh, David Buchbinder, Michael Byrne, Jean-Yves Cahn, Hannah Choe, Rabi Hanna, Peiman Hematti, Rammurti T Kamble, Carrie L Kitko, Mary Laughlin, Lazaros Lekakis, Margaret L MacMillan, Rodrigo Martino, Parinda A Mehta, Taiga Nishihori, Sagar S Patel, Miguel-Angel Perales, Hemalatha G Rangarajan, Olov Ringdén, Joseph Rosenthal, Bipin N Savani, Kirk R Schultz, Sachiko Seo, Takanori Teshima, Marjolein van der Poel, Leo F Verdonck, Daniel Weisdorf, Baldeep Wirk, Jean A Yared, Jeffrey Schriber, Richard E Champlin, Stefan O Ciurea
Transplantation and cellular therapy, 28, 10, 681, 693, 2022年10月, ［国際誌］
英語, 研究論文（学術雑誌）, Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin (ATG), grade 3-4 aGvHD (28% versus 39%, P = .001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% versus 21%, P = .01), and chronic GI GvHD (21% versus 31%, P = .006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGvHD rate after Haplo/PTCY was also lower (hazard ratio [HR] = .4, P < .001) in comparison with MUD/conventional transplantation without ATG in the nonmyeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR = .6, P = .01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rates (HR = .6, P = .04). Mortality rate was higher (HR = 1.6, P = .03) during, but not after (HR = .9, P = .6) the first 6 months after cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate.

Antiretroviral therapy achieved metabolic complete remission of hepatic AIDS related Epstein-Barr virus-associated smooth muscle tumor.
Takahide Ara, Tomoyuki Endo, Hideki Goto, Kohei Kasahara, Yuta Hasegawa, Shota Yokoyama, Souichi Shiratori, Masao Nakagawa, Ken Kuwahara, Emi Takakuwa, Satoshi Hashino, Takanori Teshima
Antiviral therapy, 27, 5, 13596535221126828, 13596535221126828, 2022年10月, ［国際誌］
英語, 研究論文（学術雑誌）, Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a rare mesenchymal tumor which occurs in immunocompromised patients. The immune status is an important factor in the treatment of EBV-SMTs, but the efficacy of antiretroviral therapy (ART) is not elucidated in acquired immune deficiency syndrome (AIDS) related EBV-SMTs. Here, we report the first successful case of a 29-year-old man with hepatic AIDS related EBV-SMT treated with ART solely. Positron emission tomography scan was useful for the evaluation of disease status. Recent advances in ART that enables to restore patient's immune status rapidly may change the treatment strategy in AIDS related EBV-SMT.

Zandelisib (ME-401) in Japanese patients with relapsed or refractory indolent non-Hodgkin's lymphoma: an open-label, multicenter, dose-escalation phase 1 study.
Hideki Goto, Koji Izutsu, Daisuke Ennishi, Yuko Mishima, Shinichi Makita, Koji Kato, Miyoko Hanaya, Satoshi Hirano, Kazuya Narushima, Takanori Teshima, Hirokazu Nagai, Kenichi Ishizawa
International journal of hematology, 116, 6, 911, 921, 2022年09月15日, ［国内誌］
英語, 研究論文（学術雑誌）, The selective phosphatidylinositol 3-kinase δ inhibitor zandelisib demonstrated favorable safety and efficacy [objective response rate (ORR) 79%] in patients with B-cell malignancies in a phase 1b study in the US and Switzerland. In this phase 1 dose-escalation study (NCT03985189), 9 Japanese patients with relapsed/refractory indolent non-Hodgkin's lymphoma (R/R iNHL) received zandelisib on a continuous daily schedule (45 or 60 mg) until progressive disease/unacceptable toxicity. No dose-limiting toxicities were observed. The maximum tolerated dose was not reached. At a median follow-up of 17.5 months, Grade ≥ 3 treatment-emergent adverse events that occurred in 2 or more patients were neutrophil count decreased (55.6%; 5/9) and diarrhea (33.3%; 3/9). Immune-related toxicities, including hepatobiliary disorder, aspartate/alanine aminotransferase increased, diarrhea/colitis, organizing pneumonia, stomatitis, and rash, led to zandelisib discontinuation in 4 patients. The investigator-assessed ORR, based on modified Lugano criteria, was 100%, including 2 complete responses (22.2%; in follicular lymphoma patients receiving 60 mg/day). Median duration of response, progression-free survival, and time to response were 7.9, 11.1, and 1.9 months, respectively. Zandelisib demonstrated a manageable safety profile at 60 mg, the recommended phase 2 dose (RP2D) in Japanese patients. The RP2D resulted in favorable pharmacokinetics and anti-tumor efficacy in Japanese patients with R/R iNHL.Trial registration. NCT03985189 (ClinicalTrials.gov).

Humoral response to mRNA-based COVID-19 vaccine in patients with de novo and pre-existing immune thrombocytopenia with exacerbation of thrombocytopenia after vaccination.
Akio Mori, Masahiro Onozawa, Mirei Kobayashi, Shihori Tsukamoto, Takashi Ishio, Emi Yokoyama, Koh Izumiyama, Makoto Saito, Haruna Muraki, Masanobu Morioka, Takanori Teshima, Takeshi Kondo
British journal of haematology, 2022年09月12日, ［国際誌］
英語

Comparable survival outcomes with haploidentical stem cell transplantation and unrelated bone marrow transplantation.
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09月12日, ［国際誌］
英語, 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.

Ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma: CARTITUDE-1 (phase 2) Japanese cohort.
Masaki Ri, Kenshi Suzuki, Tadao Ishida, Junya Kuroda, Taku Tsukamoto, Takanori Teshima, Hideki Goto, Carolyn C Jackson, Huabin Sun, Lida Pacaud, Ei Fujikawa, Tzu-Min Yeh, Tomoyoshi Hatayama, Kensuke Aida, Yoshihiro Sunagawa, Shinsuke Iida
Cancer science, 2022年09月02日, ［国際誌］
英語, 研究論文（学術雑誌）, Chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen have shown positive responses in patients with multiple myeloma (MM). The phase 2 portion of the CARTITUDE-1 study of ciltacabtagene autoleucel (cilta-cel) included a cohort of Japanese patients with relapsed/refractory MM. Following a conditioning regimen of cyclophosphamide (300 mg/m2 ) and fludarabine (30 mg/m2 ), patients received a single cilta-cel infusion at a target dose of 0.75 × 106 (range, 0.5-1.0 × 106 ) CAR-positive viable T cells/kg. The primary endpoint was overall response rate (ORR; defined as partial response or better) by International Myeloma Working Group criteria. A key secondary endpoint was the rate of very good partial response (VGPR) or better (defined as VGPR, complete response, stringent complete response). This first analysis was performed at 6 months after the last patient received cilta-cel. Thirteen patients underwent apheresis, nine of whom received cilta-cel infusion. Eight patients who received cilta-cel at the target dose responded, yielding an ORR of 100%. Seven of eight (87.5%) patients achieved a VGPR or better. One additional patient who received a below-target dose of cilta-cel also achieved a best response of VGPR. MRD negativity (10-5 threshold) was achieved in all six evaluable patients. Eight of nine (88.9%) patients who received cilta-cel infusion experienced a grade 3 or 4 adverse event, and eight (88.9%) patients experienced cytokine release syndrome (all grade 1 or 2). No CAR-T cell neurotoxicity was reported. A positive benefit/risk profile for cilta-cel was established for heavily pretreated Japanese patients with relapsed or refractory MM.

Serum levels of albumin and creatinine predict the outcome of sinusoidal obstruction syndrome after allogeneic HSCT.
Souichi Shiratori, Kohei Okada, Satomi Matsuoka, Shinichi Ito, Junichi Sugita, Takanori Teshima
Annals of hematology, 101, 9, 2117, 2118, 2022年09月, ［国際誌］
英語

Creation of Philadelphia chromosome by CRISPR/Cas9-mediated double cleavages on BCR and ABL1 genes as a model for initial event in leukemogenesis.
Minori Tamai, Shinichi Fujisawa, Thao T T Nguyen, Chiaki Komatsu, Keiko Kagami, Kenji Kamimoto, Kohei Omachi, Shin Kasai, Daisuke Harama, Atsushi Watanabe, Koshi Akahane, Kumiko Goi, Kazuhito Naka, Tadashi Kaname, Takanori Teshima, Takeshi Inukai
Cancer gene therapy, 2022年08月23日, ［国際誌］
英語, 研究論文（学術雑誌）, The Philadelphia (Ph) chromosome was the first translocation identified in leukemia. It is supposed to be generated by aberrant ligation between two DNA double-strand breaks (DSBs) at the BCR gene located on chromosome 9q34 and the ABL1 gene located on chromosome 22q11. Thus, mimicking the initiation process of translocation, we induced CRISPR/Cas9-mediated DSBs simultaneously at the breakpoints of the BCR and ABL1 genes in a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent human leukemia cell line. After transfection of two single guide RNAs (sgRNAs) targeting intron 13 of the BCR gene and intron 1 of the ABL1 gene, a factor-independent subline was obtained. In the subline, p210 BCR::ABL1 and its reciprocal ABL1::BCR fusions were generated as a result of balanced translocation corresponding to the Ph chromosome. Another set of sgRNAs targeting intron 1 of the BCR gene and intron 1 of the ABL1 gene induced a factor-independent subline expressing p190 BCR::ABL1. Both p210 and p190 BCR::ABL1 induced factor-independent growth by constitutively activating intracellular signaling pathways for transcriptional regulation of cell cycle progression and cell survival that are usually regulated by GM-CSF. These observations suggested that simultaneous DSBs at the BCR and ABL1 gene breakpoints are initiation events for oncogenesis in Ph+ leukemia. (200/200 words).

Comparable survival outcomes with haploidentical stem cell transplantation and cord blood transplantation.
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08月20日, ［国際誌］
英語, 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.

Genome-wide CRISPR screens identify CD48 defining susceptibility to NK cytotoxicity in peripheral T-cell lymphomas.
Masahiro Chiba, Joji Shimono, Takashi Ishio, Norio Takei, Kohei Kasahara, Reiki Ogasawara, Takahide Ara, Hideki Goto, Koh Izumiyama, Satoko Otsuguro, Liyanage P Perera, Hiroo Hasegawa, Michiyuki Maeda, Satoshi Hashino, Katsumi Maenaka, Takanori Teshima, Thomas A Waldmann, Yibin Yang, Masao Nakagawa
Blood, 140, 18, 1951, 1963, 2022年08月03日, ［国際誌］
英語, 研究論文（学術雑誌）, Adult T-cell leukemia/lymphoma (ATLL) is one of the aggressive peripheral T-cell neoplasms with a poor prognosis. Accumulating evidence demonstrates that escape from adaptive immunity is a hallmark for ATLL pathogenesis. However, the mechanisms by which ATLL cells evade NK-cell-mediated immunity have been poorly understood. Here we show that CD48 expression in ATLL cells determines the sensitivity for NK-cell-mediated cytotoxicity against ATLL cells. We performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening using two ATLL derived cell lines and discovered CD48 as one of the best enriched genes whose knockout conferred resistance to YT-1 NK cell line mediated cytotoxicity. The ability of CD48-knockout ATLL cells to evade NK cell effector function was confirmed using human primary NK cells with reduced IFNg induction and degranulation. We found that primary ATLL cells had reduced CD48 expression along with disease progression. Furthermore, other subgroups among aggressive peripheral T-cell lymphomas (PTCL) also expressed lower levels of CD48 than normal T-cells, suggesting that CD48 is a key molecule in malignant T-cell evasion of NK cell surveillance. Thus, this study demonstrates that CD48 expression is likely critical for malignant T-cell lymphoma cell regulation of NK cell mediated immunity and provides a rationale for future evaluation of CD48 as a molecular biomarker in NK cell-associated immunotherapies.

Ultrasonographic scoring system of late-onset sinusoidal obstruction syndrome/veno-occlusive disease after hematopoietic stem cell transplantation.
Mutsumi Nishida, Junichi Sugita, Takahito Iwai, Megumi Sato, Yusuke Kudo, Satomi Omotehara, Tatsunori Horie, Ryosuke Sakano, Yuta Hasegawa, Atsushi Yasumoto, Yuko Cho, Takanori Teshima
Bone marrow transplantation, 57, 8, 1338, 1340, 2022年08月, ［国際誌］
英語

Unilateral recurrent laryngeal nerve palsy detected by PET/CT in a patient with mediastinal T-cell lymphoblastic lymphoma.
Toru Miyajima, Yuta Hasegawa, Daigo Hashimoto, Takanori Teshima
International journal of hematology, 116, 1, 3, 4, 2022年07月, ［国内誌］
英語

Long-term safety for patients with tisagenlecleucel-treated relapsed/refractory diffuse large B-cell lymphoma.
Ulrich Jaeger, Constantine S Tam, Peter Borchmann, Joseph P McGuirk, Marianne Johansen, Edmund K Waller, Samantha M Jaglowski, Charalambos Andreadis, Ronan Ronan Foley, Jason R Westin, Isabelle Fleury, P Joy Ho, Stephan Mielke, Takanori Teshima, Gilles Andre Salles, Stephen J Schuster, Fiona C He, Richard T Maziarz, Sebastian A Mayer, Shinichi Makita, Marie José Kersten, Monalisa Ghosh, Nina D Wagner-Johnston, Koji Kato, Paolo Corradini, Hideki Goto, Silvia Colicino, Abhijit Agarwal, Chiari Lobetti Lobetti-Bodoni, Michael R Bishop
Blood advances, 6, 16, 4816, 4820, 2022年06月10日, ［国際誌］
英語, 研究論文（学術雑誌）

IgG4-IgE complex in patients with IgG4-related disease.
Keiichi Nakano, Junichi Sugita, Masanori Seimiya, Keiko Yasuda, Chiaki Watanabe, Takanori Teshima
Clinica chimica acta; international journal of clinical chemistry, 531, 261, 264, 2022年06月01日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease characterized by high IgE levels; however, the physiological significance of elevated IgE levels in patients with IgG4-RD is unclear. Previously, we reported the formation of IgG4-IgE complex in IgG4-RD patients with elevated IgE levels. In this study, we examined the frequency of this complex formation and its relationship with the clinical features in IgG4-RD patients. METHODS: The IgG4-IgE complex was evaluated in 33 and 17 patients with and without IgG4-RD, respectively. The IgG4-IgE complex was evaluated by performing the immunoadsorption of IgG4 using anti-IgG4 antibody-conjugated matrices. RESULTS: The frequency of IgG4-IgE complex formation in patients with IgG4-RD was significantly higher than that in those without IgG4-RD (21.2% vs. 0%). No significant differences were observed between the groups in terms of clinical characteristics and laboratory data. However, the IgG4-IgE complex-positive group had a significantly higher frequency of pancreatic lesions (85.7% vs. 42.3%) and a significantly lower rate of retroperitoneal fiber/periarterial lesions (0% vs. 38.5%) than the IgG4-IgE complex-negative group. CONCLUSION: The IgG4-IgE complex was found only in patients with IgG4-RD which may provide some clues to the pathogenesis and etiology of IgG4-RD.

Humoral response to mRNA-based COVID-19 vaccine in patients with myeloid malignancies.
Akio Mori, Masahiro Onozawa, Shihori Tsukamoto, Takashi Ishio, Emi Yokoyama, Koh Izumiyama, Makoto Saito, Haruna Muraki, Masanobu Morioka, Takanori Teshima, Takeshi Kondo
British journal of haematology, 197, 6, 691, 696, 2022年06月, ［国際誌］
英語, 研究論文（学術雑誌）, Data on the response to the COVID-19 vaccine in patients with myeloid malignancy, who are at severe risk in case of infection, have not emerged. In a study of 69 patients with myeloid malignancies, including 46 patients with acute myeloid leukaemia (AML) and 23 patients with myelodysplastic syndrome (MDS), anti-spike SARS-CoV-2 antibody titres were measured 3 months after the second mRNA-based vaccination. Seroconversion rates for AML and MDS were 94.7% and 100% respectively, with no significant difference from healthy controls (HCs). Patients with MDS showed a significantly lower antibody titre than that in HCs or AML patients. In AML patients, the antibody titres were comparable to those in HCs when treatment was completed, but lower in patients under maintenance therapy. The response to COVID-19 vaccine appears to be related to disease and treatment status. Patients with myeloid malignancies may be more responsive to vaccines than patients with lymphoid malignancies.

Dynamic change in peripheral blood WT1 mRNA levels within three cycles of azacitidine predict treatment response in patients with high-risk myelodysplastic syndromes.
Shinpei Harada, Masahiro Onozawa, Daisuke Hidaka, Shota Yokoyama, Hajime Senjo, Shogo Takahashi, Reiki Ogasawara, Minoru Kanaya, Akio Mori, Shuichi Ota, Takeshi Kondo, Takanori Teshima
Annals of hematology, 101, 6, 1239, 1250, 2022年06月, ［国際誌］
英語, 研究論文（学術雑誌）, Azacitidine (AZA) improves overall survival (OS) in patients with high-risk myelodysplastic syndromes (MDS). However, predictive factors for response to AZA remain largely unknown. To elucidate whether dynamic change in peripheral blood (PB) Wilms' Tumor 1 (WT1) mRNA levels could predict response to AZA, we retrospectively identified 75 treatment-naïve patients with high-risk MDS who received at least 3 cycles of AZA. We classified patients into 4 groups, low-increase (LI), low-stable (LS), high-decrease (HD), and high-stable (HS) based on the dynamic change in PB WT1 mRNA levels within 3 cycles of AZA. Cumulative incidence of overall response after 10 cycles of AZA was significantly higher in LS/HD than in HS/LI (75.5% vs 4.5%, P < 0.001). The median OS for LS/HD was 18.2 months (95% CI, 12.8-28.1 months), whereas it was 11.6 months for HS/LI (95% CI, 6.6-14.1 months; P < 0.001). Multivariate analysis demonstrated that poor-/very poor-IPSS-R cytogenetic risk and HS/LI were independently associated with poor OS (poor-/very poor-IPSS-R cytogenetic risk: HR, 2.26; 95% CI, 1.10-4.68, P = 0.03, HS/LI: HR, 2.32; 95% CI, 1.21-4.46, P = 0.01). Patients with HS/LI did not show any further response to continuous AZA, and they should be considered for alternative therapy from earlier cycles.

High CRP-albumin ratio predicts poor prognosis in transplant ineligible elderly patients with newly diagnosed acute myeloid leukemia.
Hajime Senjo, Masahiro Onozawa, Daisuke Hidaka, Shota Yokoyama, Satoshi Yamamoto, Yutaka Tsutsumi, Yoshihito Haseyama, Takahiro Nagashima, Akio Mori, Shuichi Ota, Hajime Sakai, Toshimichi Ishihara, Takuto Miyagishima, Yasutaka Kakinoki, Mitsutoshi Kurosawa, Hajime Kobayashi, Hiroshi Iwasaki, Daigo Hashimoto, Takeshi Kondo, Takanori Teshima
Scientific reports, 12, 1, 8885, 8885, 2022年05月25日, ［国際誌］
英語, 研究論文（学術雑誌）, Acute myeloid leukemia (AML) patients older than 65 years have a poor prognosis. Recently, CAR (C-reactive-protein/albumin ratio) has been actively reported as a prognostic index reflecting the nutritional and inflammatory status of elderly patients with solid tumors, but the usefulness of this index as a prognostic indicator in transplant-ineligible elderly AML patients has not been investigated. We studied genetic alterations and CARs in 188 newly diagnosed AML patients aged 65 years or older who were treated in a multicenter setting and had treated without HSCT. Both NCCN 2017 risk group, reflecting the genetic component of the tumor, and CAR, reflecting the inflammatory and nutritional status of the patient, successfully stratified the overall survival (OS) of the patients (2-year OS; CAR low vs high, 42.3% vs 17.8%, P < 0.001). Furthermore, in multivariate analysis, NCCN 2017 poor group and high CAR were extracted as independent poor prognostic factors predicting 2-year OS in the current study. We found, for the first time, that CAR at diagnosis predicted the prognosis of elderly patients with newly diagnosed AML treated without HSCT.

MEdical Database AnaLysIS of Japanese multiple myeloma patienTs with apheresis #2 (MEDALIST-2): the impact of plerixafor use on costs and healthcare resources during mobilization and stem cell transplantation.
Shinsuke Iida, Tadao Ishida, Toshihiro Miyamoto, Satoshi Teramukai, Heigoroh Shirai, Rie Kanamori, Yuki Tajima, Bruce Crawford, Jingbo Yi, Takanori Teshima
International journal of hematology, 116, 3, 411, 422, 2022年05月13日, ［国内誌］
英語, 研究論文（学術雑誌）, Treatment for multiple myeloma (MM) can involve apheresis to mobilize hematopoietic stem cells for later autologous stem cell transplantation (ASCT), which can become costly over time. This retrospective claims database study examined healthcare resource use and medical costs associated with plerixafor, a selective CXCR4 inhibitor that mobilizes hematopoietic stem cells and minimizes apheresis times. Medical data were sampled from Japanese MM patients between April 2017 and September 2019, after the Japanese launch of plerixafor. The study population (190 plerixafor users and 180 non-users) was identified from the Medical Data Vision database, and further stratified into those using granulocyte-colony stimulating factor in monotherapy or in combination with cyclophosphamide to trigger apheresis. A descriptive comparison of patient characteristics, healthcare resource use, and medical costs across the mobilization and ASCT phases indicated plerixafor is associated with higher average total medical costs. However, plerixafor-treated patients received fewer concomitant medications and spent less time in apheresis than non-users. A comparison of non-users with a similar analysis conducted pre-plerixafor launch (2013-2017) showed general improvements to treatment independent of plerixafor. The results of this research can inform guidelines for the role of plerixafor in balancing cost-effectiveness and drug efficacy in MM treatment.

Gilteritinib enhances graft-versus-leukemia effects against FLT3-ITD mutant leukemia after allogeneic hematopoietic stem cell transplantation.
Zixuan Zhang, Yuta Hasegawa, Daigo Hashimoto, Hajime Senjo, Ryo Kikuchi, Xuanzhong Chen, Kazuki Yoneda, Tomoko Sekiguchi, Tatsuya Kawase, Hirofumi Tsuzuki, Takashi Ishio, Takahide Ara, Hiroyuki Ohigashi, Masao Nakagawa, Takanori Teshima
Bone marrow transplantation, 57, 5, 775, 780, 2022年05月, ［国際誌］
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative therapy for FLT3 internal tandem duplication mutant (FLT3-ITD+) acute myeloid leukemia, but relapse rate is high. A recent study showed that sorafenib, a first generation FLT3 and multikinase inhibitor, enhanced graft-versus-leukemia (GVL) effects against FLT3-ITD+ leukemia via interleukin-15 (IL-15) production. However, it remains to be clarified whether this effect could be mediated by selective FLT3 inhibition. We investigated whether gilteritinib, a selective FLT3 inhibitor, could enhance GVL effects against FLT3-ITD transfected Ba/F3 leukemia (Ba/F3-FLT3-ITD) in mice. Oral administration of gilteritinib from day +5 to +14 after allo-SCT reduced expression of the co-inhibitory receptors PD-1 and TIGIT on donor CD8+ T cells and enhanced IL-15 expression in Ba/F3-FLT3-ITD. Bioluminescent imaging using luciferase-transfected Ba/F3-FLT3-ITD demonstrated that gilteritinib significantly suppressed leukemia expansion after allo-SCT, whereas it did not impact the morbidity or mortality of graft-versus-host disease (GVHD), resulting in significant improvement of overall survival. In conclusion, short-term administration of gilteritinib after allo-SCT enhanced GVL effects against FLT3-ITD+ leukemia without exacerbating GVHD.

IgG4-IgE complex in a patient with IgG4-related disease.
Keiichi Nakano, Junichi Sugita, Naoki Mafune, Masanori Seimiya, Keiko Yasuda, Chiaki Watanabe, Takanori Teshima
Clinica chimica acta; international journal of clinical chemistry, 528, 52, 55, 2022年03月01日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: IgE concentrations are occasionally elevated in patients with IgG4-related disease (IgG4-RD). In this report, we describe a novel case of IgG4-RD in which IgE concentrations were discordant between measuring reagents. CASE: An 81-year-old man was diagnosed with IgG4-RD and histological autoimmune pancreatitis, which ensued without treatment. The IgE concentrations measured using Elecsys IgE II Immunoassay and Iatroace IgE were 1287.0 IU/mL and 60.9 IU/mL, respectively. IgG4 concentration was 675 mg/dL. METHODS: To identify IgG and IgG4 directly bound to IgE, purification using protein G and anti-IgG4 antibody-conjugated matrixes and size-exclusion high-performance liquid chromatography (HPLC) were performed. RESULTS: In purification analysis, the IgE concentration of the flow-through and bound fractions were 6.8 IU/mL (10.8%) and 56.2 IU/mL (89.2%) for IgG purification and 6.8 IU/mL (12.2%) and 49.0 IU/mL (87.8%) for IgG4 purification. IgE was eluted as a single peak (640 kDa) using size-exclusion HPLC. In the elution pattern of IgG4, a minor peak (640 kDa) and a major peak (170 kDa) were observed. These results indicate that IgG4 binds to IgE and forms a complex, resulting in a discrepancy between reagents. CONCLUSIONS: In this report, we present an IgG4-IgE complex in a patient with IgG4-RD, which affected the discrepancy in IgE concentrations between IgE reagents. This report points to the significance of increased IgE production in IgG4-RD.

Antithymocyte Globulin Potentially Could Overcome an Adverse Effect of Acute Graft-versus-Host Disease in Matched-Related Peripheral Blood Stem Cell Transplantation.
Kotaro Miyao, Yachiyo Kuwatsuka, Makoto Murata, Koji Nagafuji, Takanori Teshima, Yuki Takeuchi, Souichi Shiratori, Yuho Najima, Naoyuki Uchida, Masatsugu Tanaka, Masashi Sawa, Shuichi Ota, Takahiro Fukuda, Yukiyasu Ozawa, Shinichi Kako, Toshiro Kawakita, Takahide Ara, Junji Tanaka, Yoshinobu Kanda, Yoshiko Atsuta, Junya Kanda, Seitaro Terakura
Transplantation and cellular therapy, 28, 3, 153.e1-153.e11, 2022年03月, ［国際誌］
英語, 研究論文（学術雑誌）, Previous Japanese studies have shown that bone marrow transplantation (BMT) is associated with better survival compared with peripheral blood stem cell transplantation (PBSCT) from a matched related donor (MRD). PBSCT recipients have shown higher incidences of severe graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) compared with BMT recipients. In recent years, the efficacy and safety of antithymocyte globulin (ATG) for PBSCT recipients has been evaluated worldwide. In the present study, we aimed to compare BMT and PBSCT recipients to identify current improvements and unmet needs among MRD PBSCT recipients. In addition, we evaluated the impact of ATG administration on the outcomes of PBSCT recipients. We retrospectively analyzed patients age ≥16 years with acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia who underwent their first BMT or PBSCT from an MRD between 2009 and 2018 in Japan. A total of 3599 transplantations were performed (BMT, n = 1218; PBSCT without ATG [PBSCT-ATG(-)], n = 2288; PBSCT with ATG [PBSCT-ATG(+)], n = 93). The PBSCT-ATG(-) group had a higher NRM (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.08 to 1.57; P = .005) and lower overall survival (OS) (HR, 1.16; 95% CI, 1.04 to 1.30; P = .011) compared with the BMT group. Furthermore, the PBSCT-ATG(-) group had higher incidences of grade III-IV, stage 2-4 gut, high-risk, and steroid-refractory acute GVHD compared with the BMT group. Acute GVHD had a negative impact on NRM and OS. The PBSCT-ATG(-) group also was associated with an elevated risk of chronic GVHD (HR, 1.89; 95% CI, 1.24 to 2.57; P < .001) and extensive chronic GVHD (HR, 1.44; 95% CI, 1.23 to 1.68; P < .001). The incidences of acute GVHD, chronic GVHD, and NRM and chronic GVHD-free relapse-free survival rates were comparable between the PBSCT-ATG(+) and BMT groups. The OS of patients with acute GVHD was similar in the 3 donor groups. Patients treated with reduced-intensity conditioning in the PBSCT-ATG(+) group had a higher relapse rate and lower OS rate compared with those in the BMT group. In this Japanese cohort, standard calcineurin inhibitor-based GVHD prophylaxis was not sufficient for recipients of MRD PBSCT because of the high incidence of severe acute GVHD. Prophylactic ATG was found to be a promising strategy against GVHD.

HIV関連悪性リンパ腫の臨床的特徴
遠藤 知之, 後藤 秀樹, 荒 隆英, 長谷川 祐太, 横山 翔大, 高橋 承吾, 米田 和樹, 橋本 大吾, 橋野 聡, 豊嶋 崇徳
日本エイズ学会誌, 24, 1, 13, 20, (一社)日本エイズ学会, 2022年02月
日本語, 背景:HIV関連悪性リンパ腫は、死亡率の高い予後不良な合併症である。HIV感染者では、背景に免疫不全が存在するため、その臨床的特徴はHIV非感染者に発生する悪性リンパ腫とは異なっていることが指摘されており、至適治療法に関しても定まったものがない。方法:2006年4月から2020年3月までに当院において悪性リンパ腫の診断・治療を行ったHIV感染症患者を対象とし、患者基本情報、悪性リンパ腫の診断・臨床経過等を診療録から収集し後方視的に解析した。また、同時期に当院で初発時治療を行ったHIV非感染悪性リンパ腫359例と比較した。結果:対象症例は12例で全例男性であった。リンパ腫発症時の年齢中央値は47.5歳(33～64歳)、末梢血CD4陽性リンパ球数の中央値は54/μL(3～267/μL)であった。組織型はdiffuse large B-cell lymphoma 8例、Burkitt lymphoma 2例、Hodgkin lymphoma 1例、T-cell lymphoma 1例であった。また、HIV非感染者と比較してEBER陽性例が有意に多く、Ki-67高値例も多い傾向があった。さらに、治療時の血球減少が高度で、全例でgrade 4の好中球減少があり、治療中の感染症も有意に多く認められた。5年全生存率は83.3%であり、HIV非感染悪性リンパ腫症例の5年全生存率84.0%と同等であった。考察:HIV関連悪性リンパ腫は、病理組織のみでは診断が困難なことがあるため、表面形質や遺伝子検査などの情報も含めて総合的に判断する必要がある。HIV感染者ではHIV非感染者と比べて治療時の血球減少が高度であったが、治療を完遂できればHIV非感染者と同等の生命予後が得られる可能性があるため、治療開始早期の感染症対策が重要と考えられた。(著者抄録)

Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial.
Nathan Hale Fowler, Michael Dickinson, Martin Dreyling, Joaquin Martinez-Lopez, Arne Kolstad, Jason Butler, Monalisa Ghosh, Leslie Popplewell, Julio C Chavez, Emmanuel Bachy, Koji Kato, Hideo Harigae, Marie José Kersten, Charalambos Andreadis, Peter A Riedell, P Joy Ho, José Antonio Pérez-Simón, Andy I Chen, Loretta J Nastoupil, Bastian von Tresckow, Andrés José María Ferreri, Takanori Teshima, Piers E M Patten, Joseph P McGuirk, Andreas L Petzer, Fritz Offner, Andreas Viardot, Pier Luigi Zinzani, Ram Malladi, Aiesha Zia, Rakesh Awasthi, Aisha Masood, Oezlem Anak, Stephen J Schuster, Catherine Thieblemont
Nature medicine, 28, 2, 325, 332, 2022年02月, ［国際誌］
英語, 研究論文（学術雑誌）, Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8-20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8-78.3) and ORR 86.2% (95% confidence interval, 77.5-92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.

Non-age-related neoplastic loss of sex chromosome correlated with prolonged survival in real-world CBF-AML patients.
Akio Mori, Masahiro Onozawa, Daisuke Hidaka, Shota Yokoyama, Toru Miyajima, Emi Yokoyama, Reiki Ogasawara, Koh Izumiyama, Makoto Saito, Shinichi Fujisawa, Shuichi Ota, Yasutaka Kakinoki, Yutaka Tsutsumi, Satoshi Yamamoto, Takuto Miyagishima, Takahiro Nagashima, Hiroshi Iwasaki, Hajime Kobayashi, Yoshihito Haseyama, Mitsutoshi Kurosawa, Masanobu Morioka, Takanori Teshima, Takeshi Kondo
International journal of hematology, 115, 2, 188, 197, 2022年02月, ［国内誌］
英語, 研究論文（学術雑誌）, In this real-world clinical study, in which we determined eligibility for allogenic hematopoietic stem cell transplantation by prognostic factors and minimal residual disease status, we retrospectively evaluated cytogenetic, genetic, and clinical features in 96 patients with core-binding factor acute myeloid leukemia (CBF-AML) including 62 patients with RUNX1/RUNX1T1 and 34 patients with CBFβ/MYH11. Multivariate analyses for 5-year overall survival (OS) in CBF-AML patients revealed that age of 50 years or older (HR: 3.46, 95% CI 1.47-8.11, P = 0.004) and receiving 2 or more induction cycles (HR: 3.55, 95% CI 1.57-8.05, P = 0.002) were independently associated with worse OS and that loss of sex chromosome (LOS) was independently associated with better OS (HR: 0.09, 95% CI 0.01-0.71, P = 0.022). At the time of complete remission, all 21 karyotyped patients with LOS had a normal karyotype. Furthermore, in all 9 patients with LOS who had a mosaic of metaphase cells with and without t(8;21) or inv(16), the metaphase cells without t(8;21)/inv(16) showed a normal karyotype. These results proved that LOS was not age-related and physiological, but rather a neoplastic chromosomal abnormality.

[Bing-Neel syndrome successfully treated with tirabrutinib].
Keito Yokoyama, Hiroyuki Ohigashi, Toru Miyajima, Naoki Miyashita, Satomi Okada, Yuta Hasegawa, Junichi Sugita, Masahiro Onozawa, Daigo Hashimoto, Takanori Teshima
[Rinsho ketsueki] The Japanese journal of clinical hematology, 63, 8, 870, 875, 2022年, ［国内誌］
日本語, 研究論文（学術雑誌）, Bing-Neel syndrome (BNS) is a rare disease manifestation of Waldenström's macroglobulinemia characterized by abnormal lymphoplasmacytoid cells infiltration of the central nervous system. In September 2019, a 46-year-old man presented to a previous hospital with hand tremors, nausea, and dysuria. Demyelination of cerebral white matter and the spinal cord was discovered using MRI. Steroid pulse therapy was used to treat inflammatory demyelinating disease, and it provided temporary relief, but the symptoms returned when the steroids were stopped. He was referred to our hospital in June 2020, for further evaluation with the possibility of hematological malignancy. BNS was diagnosed based on the presence of abnormal lymphoplasmacytoid cells in the bone marrow and cerebrospinal fluid (CSF), as well as the presence of the MYD88L265P mutation in the CSF specimen. In July 2020, BR (bendamustine, rituximab) therapy was administered, but it was ineffective. Oral administration of tirabrutinib, which was recently approved for WM, began in August 2020. He has achieved long-term remission and steroid withdrawal, with no notable side effects. This is the second report of successful treatment of BNS with tirabrutinib. More research is needed to confirm tirabrutinib's efficacy in the treatment of BNS.

A Rare Case of BCL2-Positive Multiple Myeloma Complicated with Follicular Lymphoma.
Yutaka Tsutsumi, Shinich Ito, Mirei Kobayashi, Takanori Teshima
Case reports in hematology, 2022, 3076968, 3076968, 2022年, ［国際誌］
英語, A 68-year-old woman presented with follicular lymphoma complicated by IgG kappa-positive multiple myeloma. In this case, both follicular lymphoma and plasma cells were positive for BCL2 by immunostaining. T-cell association in the FL and MM was also analyzed in this case. Some CD3-positive T-cells were found around the plasma cells. These cells were mainly CD8-positive T-cells and not CD4-positive T-cells. These results suggest that CD4-positive T-cells were not associated with the proliferation of the plasma cells in this case. Although the FL that developed was initially positive for BCL2 protein, this does not indicate that plasma cells were derived from FL cells because of the eventual complication that occurred in this case. Furthermore, in this case, rituximab and bendamustine were effective for FL. They were not effective for MM, however, demonstrating that additional treatment options are necessary for the simultaneous treatment of BCL2-positive MM with FL.

Aleukemic Extramedullary Blast Crisis as an initial presentation of Chronic Myeloid Leukemia with E1A3 BCR-ABL1 Fusion Transcript
Naoki Miyashita, Masahiro Onozawa, Keito Suto, Shinichi Fujisawa, Nanase Okazaki, Daisuke Hidaka, Hiroyuki Ohigashi, Atsushi Yasumoto, Junichi Sugita, Daigo Hashimoto, Yoshihiro Matsuno, Takanori Teshima
Internal Medicine, Japanese Society of Internal Medicine, 2022年, ［査読有り］
研究論文（学術雑誌）

今月の特集 移植医療と臨床検査 造血幹細胞移植と臨床検査
安本 篤史, 加畑 馨, 豊嶋 崇徳
臨床検査, 65, 12, 1310, 1316, 株式会社医学書院, 2021年12月15日

【移植医療と臨床検査】造血幹細胞移植と臨床検査
安本 篤史, 加畑 馨, 豊嶋 崇徳
臨床検査, 65, 12, 1310, 1316, (株)医学書院, 2021年12月
日本語, ＜文献概要＞POINT ●ヒト白血球型抗原(HLA)タイピングはドナーとレシピエントの組織適合性を判断するうえで最も重要な検査である.次世代シーケンシングによる超高解像度HLA遺伝子検査が可能となった.●HLA不適合移植では抗HLA抗体の検出が重要である.ルミネックス(Luminex )法による抗HLA抗体の検出だけでなく,免疫複合体キャプチャー(ICFA)法によるHLA交差適合検査も併せて評価する.●CD34陽性細胞測定法はシングルプラットフォーム法が標準である.●サイトメガロウイルス(CMV)感染症の診断は国際的に定量PCR法が標準である.わが国でもようやく認可された.

Myelomonocytic differentiation of leukemic blasts accompanied by differentiation syndrome in a case of FLT3-ITD-positive AML treated with gilteritinib.
Takeshi Kondo, Masahiro Onozawa, Shinichi Fujisawa, Shinpei Harada, Reiki Ogasawara, Koh Izumiyama, Makoto Saito, Masanobu Morioka, Akio Mori, Takanori Teshima
Hematology (Amsterdam, Netherlands), 26, 1, 256, 260, 2021年12月, ［国際誌］
英語, 研究論文（学術雑誌）, Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myelogenous leukemia (AML) and the mutation is associated with poor prognosis of patients. Two distinct types of activating mutations have been identified in AML samples. One is internal tandem duplications in the juxtamembrane domain (FLT3-ITD) and the other is point mutations in the tyrosine kinase domain (FLT3-TKD). Gilteritinib is a FLT3 inhibitor that inhibits both FLT3-ITD and FLT3-TKD. It was reported that differentiation of leukemic blasts accompanied by differentiation syndrome occurs in some patients treated with gilteritinib. However, information about the precise clinical course is limited, and appropriate management of differentiation syndrome has not been established. We report a case of relapsed AML with FLT3-ITD that was treated with gilteritinib. Analysis of the FLT3-ITD variant allele frequency (VAF) revealed that FLT3-ITD VAF was not decreased despite achievement of complete remission with incomplete hematologic recovery. Remarkable increases of monocytes and granulocytes accompanied by differentiation syndrome were observed at 6 months after the initiation of gilteritinib treatment. Intermittent chemotherapy with low-dose cytarabine and mitoxantrone was effective for reducing myelomonocytosis and resolving differentiation syndrome.

Equivalent SARS-CoV-2 viral loads by PCR between nasopharyngeal swab and saliva in symptomatic patients
Isao Yokota, Takeshi Hattori, Peter Y. Shane, Satoshi Konno, Atsushi Nagasaka, Kimihiro Takeyabu, Shinichi Fujisawa, Mutsumi Nishida, Takanori Teshima
Scientific Reports, 11, 1, 4500, 4500, Springer Science and Business Media LLC, 2021年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Emerging evidences have shown the utility of saliva for the detection of SARS-CoV-2 by PCR as alternative to nasopharyngeal swab (NPS). However, conflicting results have been reported regarding viral loads between NPS and saliva. We conducted a study to compare the viral loads between NPS and saliva in 42 COVID-19 patients. Viral loads were estimated by the cycle threshold (Ct) values. SARS-CoV-2 was detected in 34 (81%) using NPS with median Ct value of 27.4, and 38 (90%) using saliva with median Ct value of 28.9 (P = 0.79). Kendall’s W was 0.82, showing a high degree of agreement, indicating equivalent viral loads in NPS and saliva. After symptom onset, the Ct values of both NPS and saliva continued to increase over time, with no substantial difference. Self-collected saliva has a detection sensitivity comparable to that of NPS and is a useful diagnostic tool with mitigating uncomfortable process and the risk of aerosol transmission to healthcare workers.

Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in Adult T-cell leukemia/lymphoma.
Takashi Ishio, Sarvesh Kumar, Joji Shimono, Anusara Daenthanasanmak, Sigrid Dubois, Yuquan Lin, Bonita R Bryant, Michael N Petrus, Emmanuel Bachy, Da Wei Huang, Yandan Yang, Patrick L Green, Hiroo Hasegawa, Michiyuki Maeda, Hideki Goto, Tomoyuki Endo, Takashi Yokota, Kanako C Hatanaka, Yutaka Hatanaka, Shinya Tanaka, Yoshihiro Matsuno, Yibin Yang, Satoshi Hashino, Takanori Teshima, Thomas A Waldmann, Louis M Staudt, Masao Nakagawa
Blood, 139, 10, 1541, 1556, 2021年11月24日, ［国際誌］
英語, 研究論文（学術雑誌）, Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.

Multiple introductions of SARS-CoV-2 B.1.1.214 lineages from mainland Japan preceded the third wave of the COVID-19 epidemic in Hokkaido.
Takako Shimura, Kodai Abe, Toshiki Takenouchi, Mamiko Yamada, Hisato Suzuki, Makoto Suematsu, Sho Nakakubo, Keisuke Kamada, Satoshi Konno, Takanori Teshima, Kenjiro Kosaki
Travel medicine and infectious disease, 44, 102210, 102210, 2021年11月22日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The third wave of the COVID-19 epidemic in the island of Hokkaido, the second largest island in Japan, began abruptly in October 2020. METHODS: We conducted a phylodynamic analysis of the SARS-CoV-2 genome sequences obtained from tertiary medical centers in the Greater Tokyo Area and Sapporo, the largest city in the island of Hokkaido, and genome sequences published by GISAID, an international SARS-CoV-2 genome database. We also analyzed the statistics on the person-nights of travelers in the island of Hokkaido from the Greater Tokyo Area in 2019 versus 2020. RESULTS: At least eight sub-lineages belonging to the B.1.1.214 lineage were introduced to the island of Hokkaido from the island of Honshu, the mainland of Japan from late July to November 2020, during the governmental travel promotion program. Five of the eight sub-lineages originated from the Greater Tokyo Area. Comparison of the monthly ratios of the person-nights of travelers in the island of Hokkaido from the Greater Tokyo Area in 2019 and 2020 revealed that the highest value occurred in October 2020. CONCLUSION: We contend that the Japanese governmental travel promotion program contributed to the introduction of the B.1.1.214 sub-lineages from the main island of Honshu to the island of Hokkaido, and drove the third wave in Hokkaido, even if we are unable to establish the causality.

E157Q変異を有する未治療HIV-1感染者におけるインテグラーゼ阻害薬をキードラッグとした抗HIV薬開始後の臨床経過　　　　　　　　　　　　　　　
宇野 俊介, 菊地 正, 林田 庸総, 今橋 真弓, 南 留美, 古賀 道子, 寒川 整, 渡邊 大, 藤井 輝久, 健山 正男, 松下 修三, 吉野 友祐, 遠藤 知之, 堀場 昌英, 谷口 俊文, 猪狩 英俊, 吉田 繁, 豊嶋 崇徳, 中島 秀明, 横幕 能行, 岩谷 靖雅, 蜂谷 敦子, 潟永 博之, 吉村 和久, 杉浦 亙
日本エイズ学会誌, 23, 4, 423, 423, (一社)日本エイズ学会, 2021年11月
日本語

Ruxolitinib for Chronic Graft-versus-Host Disease. Reply.
Robert Zeiser, Takanori Teshima, Franco Locatelli
The New England journal of medicine, 385, 17, 1631, 1632, 2021年10月21日, ［国際誌］
英語

Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study
Stephen J Schuster, Constantine S Tam, Peter Borchmann, Nina Worel, Joseph P McGuirk, Harald Holte, Edmund K Waller, Samantha Jaglowski, Michael R Bishop, Lloyd E Damon, Stephen Ronan Foley, Jason R Westin, Isabelle Fleury, P Joy Ho, Stephan Mielke, Takanori Teshima, Murali Janakiram, Jing-Mei Hsu, Koji Izutsu, Marie José Kersten, Monalisa Ghosh, Nina Wagner-Johnston, Koji Kato, Paolo Corradini, Marcela Martinez-Prieto, Xia Han, Ranjan Tiwari, Gilles Salles, Richard T Maziarz
The Lancet Oncology, 22, 10, 1403, 1415, Elsevier BV, 2021年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. METHODS: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing. FINDINGS: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. INTERPRETATION: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). FUNDING: Novartis Pharmaceuticals.

Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma
Koji Kato, Shinichi Makita, Hideki Goto, Junya Kanda, Nobuharu Fujii, Kazuyuki Shimada, Koichi Akashi, Koji Izutsu, Takanori Teshima, Natsuko Fukuda, Tokuhito Sumitani, Hiroyuki Sumi, Shinji Shimizu, Yasuyuki Kakurai, Kenji Yoshikawa, Kensei Tobinai, Noriko Usui, Kiyohiko Hatake
International Journal of Clinical Oncology, 27, 1, 213, 223, Springer Science and Business Media LLC, 2021年10月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）,

Axicabtagene ciloleucel (axi-cel) is an autologous chimeric antigen receptor T-cell based anti-CD19 therapy. The ZUMA-1 study, multicenter, single-arm, registrational Phase 1/2 study of axi-cel demonstrated high objective response rate in patients with relapsed/refractory large B-cell lymphoma. Here, we present the results of the bridging study to evaluate the efficacy and safety of axi-cel in Japanese patients (JapicCTI-183914).




This study was the phase 2, multicenter, open-label, single-arm trial. Following leukapheresis, axi-cel manufacturing and lymphodepleting chemotherapy, patients received a single infusion of axi-cel (2.0 × 10⁶ cells/kg). Bridging therapy between leukapheresis and conditioning chemotherapy was not allowed. The primary endpoint was objective response rate.




Among 17 enrolled patients, 16 received axi-cel infusion. In the 15 efficacy evaluable patients, objective response rate was 86.7% (95% confidence interval: 59.5–98.3%); complete response/partial response were observed in 4 (26.7%)/9 (60.0%) patients, respectively. No dose-limiting toxicities were observed. Grade ≥ 3 treatment-emergent adverse events occurred in 16 (100%) patients—most commonly neutropenia (81.3%), lymphopenia (81.3%) and thrombocytopenia (62.5%). Cytokine release syndrome occurred in 13 (81.3%) patients (12 cases of grade 1 or 2 and 1 case of grade 4). No neurologic events occurred. Two patients died due to disease progression, but no treatment-related death was observed by the data-cutoff date (October 23, 2019).




The efficacy and safety of axi-cel was confirmed in Japanese patients with relapsed/refractory large B-cell lymphoma who have otherwise limited treatment options.




JapicCTI-183914.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report
Daniel Wolff, Vedran Radojcic, Robert Lafyatis, Resat Cinar, Rachel K. Rosenstein, Edward W. Cowen, Guang-Shing Cheng, Ajay Sheshadri, Anne Bergeron, Kirsten M. Williams, Jamie L. Todd, Takanori Teshima, Geoffrey D.E. Cuvelier, Ernst Holler, Shannon R. McCurdy, Robert R. Jenq, Alan M. Hanash, David Jacobsohn, Bianca D. Santomasso, Sandeep Jain, Yoko Ogawa, Philipp Steven, Zhonghui Katie Luo, Tina Dietrich-Ntoukas, Daniel Saban, Ervina Bilic, Olaf Penack, Linda M. Griffith, Meredith Cowden, Paul J. Martin, Hildegard T. Greinix, Stefanie Sarantopoulos, Gerard Socie, Bruce R. Blazar, Joseph Pidala, Carrie L. Kitko, Daniel R. Couriel, Corey Cutler, Kirk R. Schultz, Steven Z. Pavletic, Stephanie J. Lee, Sophie Paczesny
Transplantation and Cellular Therapy, 27, 10, 817, 835, Elsevier BV, 2021年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.

Off-the-shelf bone marrow-derived mesenchymal stem cell treatment for acute graft-versus-host disease: real-world evidence
Makoto Murata, Seitaro Terakura, Atsushi Wake, Kotaro Miyao, Kazuhiro Ikegame, Naoyuki Uchida, Keisuke Kataoka, Toshihiro Miyamoto, Makoto Onizuka, Tetsuya Eto, Noriko Doki, Shuichi Ota, Maho Sato, Yoshiko Hashii, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Atsuta, Shinichiro Okamoto, Takanori Teshima
Bone Marrow Transplantation, 56, 10, 2355, 2366, Springer Science and Business Media LLC, 2021年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Temcell is a cryopreserved, human bone marrow-derived mesenchymal stem cell (MSC) product approved for the treatment of patients of all ages with acute graft-versus-host disease (GVHD). Initial experience with Temcell in a real-world setting from a cellular therapy registry in Japan is presented. A total of 381 consecutive patients were enrolled since its approval in 2016. The median cell number infused was 2.00 × 106/kg. The most common number of infusions was 8 in 100 patients. Of the 306 evaluable patients, the overall response rate (ORR) on day 28 after the start of MSC therapy was 56%. Of the 151 evaluable patients who received it as second-line therapy following first-line steroid therapy for classic acute GVHD, the ORR was 61%. Liver involvement of GVHD and ≥14 days from first-line steroid therapy to second-line MSC therapy was associated with a lower ORR. Day 28 ORR, patient age, GVHD grade, GVHD organ involvement, and a number of GVHD therapies before MSC therapy were associated with nonrelapse mortality. Overall survival at 6 months in 381 patients was 40%. This study suggests that Temcell is one of the treatment options for steroid-refractory acute GVHD until a new treatment with survival benefit is developed.

Application of the proximal isovelocity surface area method for estimation of the effective orifice area in aortic stenosis
Masahiro Nakabachi, Hiroyuki Iwano, Michito Murayama, Hisao Nishino, Shinobu Yokoyama, Shingo Tsujinaga, Yasuyuki Chiba, Suguru Ishizaka, Ko Motoi, Kazunori Okada, Sanae Kaga, Mutsumi Nishida, Takanori Teshima, Toshihisa Anzai
Heart and Vessels, 37, 4, 638, 646, Springer Science and Business Media LLC, 2021年09月25日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Although the echocardiographic effective orifice area (EOA) calculated using the continuity equation is widely used for the assessment of severity in aortic stenosis (AS), the existence of high flow velocity at the left ventricular outflow tract (LVOT) potentially causes its overestimation. The proximal isovelocity surface area (PISA) method could be an alternative tool for the estimation of EOA that limits the influence of upstream flow velocity. EOA was calculated using the continuity equation (EOACont) and PISA method (EOAPISA), respectively, in 114 patients with at least moderate AS. The geometric orifice area (GOA) was also measured using the planimetry method in 51 patients who also underwent three-dimensional transesophageal echocardiography. Patients were divided into two groups according to the median LVOT flow velocity. EOAPISA could be obtained in 108 of the 114 patients (95%). Although there was a strong correlation between EOACont and EOAPISA (r = 0.78, P < 0.001), EOACont was statistically significantly larger than EOAPISA (0.86 ± 0.33 vs 0.75 ± 0.29 cm2, P < 0.001). Both EOACont and EOAPISA similarly correlated with GOA (r = 0.70, P < 0.001 and r = 0.77, P < 0.001, respectively). However, a fixed bias, which is hydrodynamically supposed to exist between EOA and GOA, was not observed between EOACont and GOA. In contrast, there was a negative fixed bias between EOAPISA and GOA with smaller EOAPISA than GOA. The difference between EOACont and GOA was significantly greater with a larger EOACont relative to GOA in patients with high LVOT flow velocity than in those without (0.16 ± 0.25 vs - 0.07 ± 0.10 cm2, P < 0.001). In contrast, the difference between EOAPISA and GOA was consistent regardless of the LVOT flow velocity (- 0.07 ± 0.12 vs - 0.07 ± 0.15 cm2, P = 0.936). The PISA method was applied to estimate EOA in patients with AS. EOAPISA could be an alternative parameter for AS severity grading in patients with high LVOT flow velocity in whom EOACont would potentially overestimate the orifice area.

Non-classical manifestations of acute GVHD
Robert Zeiser, Takanori Teshima
Blood, 138, 22, 2165, 2172, American Society of Hematology, 2021年09月05日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Acute graft-versus-host disease (GVHD) is a major life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). The classical target organs of acute GVHD include the intestines, liver, and skin. The damage of these organs is relatively easy to detect for the clinician as diarrhea, increased bilirubin, and rash. However, there is increasing evidence that also other organs, where the acute damage is less apparent or more difficult to distinguish from drug toxicity, such as the central nervous system, the lungs, the ovaries and testis, the thymus, the bone marrow and the kidney, can be target organs of acute GVHD. Here, we review current evidence for non-classical manifestations of acute GVHD in rodent models and in patients and discuss them in the context of novel emerging therapies for GVHD. A better understanding of the involvement of the non-classical GVHD target organs may help to improve patient outcomes after allo-HCT.

Graft-Versus-Host Disease Prophylaxis Using Low-Dose Antithymocyte Globulin in Peripheral Blood Stem Cell Transplantation—A Matched-Pair Analysis
Souichi Shiratori, Mio Kurata, Junichi Sugita, Shuichi Ota, Senji Kasahara, Jun Ishikawa, Kazunori Imada, Yasushi Onishi, Ken Ishiyama, Takashi Ashida, Yoshinobu Kanda, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Atsuta, Takanori Teshima
Transplantation and Cellular Therapy, 27, 12, 995.e1-995.e6, Elsevier BV, 2021年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Antithymocyte globulin (ATG) decreases chronic graft-versus-host disease (cGVHD) in peripheral blood stem cell transplantation (PBSCT); however, the optimal ATG dose has not been elucidated. We conducted a matched-pair analysis to evaluate whether low-dose ATG could inhibit cGVHD in HLA-matched PBSCT after myeloablative conditioning. A total of 70 patients who were enrolled in the JSCT-ATG15 study, a multicenter phase II clinical trial of 2 mg/kg of ATG (thymoglobulin) given on days -2 and -1, were compared with 210 patients not receiving ATG, who were matched for age, sex, disease, and calcineurin inhibitor selected from the database in Japan. The primary endpoint, cumulative incidence of extensive cGVHD at 2 years was significantly less in the ATG group than that in the non-ATG group (8.7% [95% CI, 3.5%-16.8%] versus 26.2% [95% CI, 20.3%-32.5%], P = .002). ATG significantly reduced the incidence of overall cGVHD and inhibited multiple organ involvement. The ATG group had favorable outcome compared to the non-ATG group in GVHD-free, and relapse-free survival at 2 years. In conclusion, low-dose ATG effectively inhibits chronic GVHD in PBSCT.

Phase II study of tazemetostat for relapsed or refractory B‐cell non‐Hodgkin lymphoma with EZH2 mutation in Japan
Koji Izutsu, Kiyoshi Ando, Momoko Nishikori, Hirohiko Shibayama, Takanori Teshima, Junya Kuroda, Koji Kato, Yoshitaka Imaizumi, Kisato Nosaka, Rika Sakai, Seiichiro Hojo, Tadashi Nakanishi, Shinya Rai
Cancer Science, 112, 9, 3627, 3635, Wiley, 2021年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Tazemetostat is a selective, reversible, small-molecule inhibitor of the histone methyltransferase enzyme, enhancer of zest homolog 2 (EZH2). In this multicenter, open-label, phase II study, we assessed the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma harboring the EZH2 mutation. Tazemetostat (800 mg twice daily) was given orally (28-day cycle) until disease progression or unacceptable toxicity. Among the 20 eligible patients, 17 were enrolled in cohort 1 (follicular lymphoma [FL]), and three were enrolled in cohort 2 (diffuse large B-cell lymphoma). At data cut-off, the objective response rate in cohort 1 was 76.5%, including six patients (35.3%) with complete response and seven patients (41.2%) with partial response (PR). All three patients in cohort 2 achieved PR. In cohort 1, median progression-free survival (PFS) was not reached at the median follow-up of 12.9 months. The estimated PFS rate at 12 and 15 months was 94.1% and 73.2%, respectively. The most common grade 3 treatment-emergent adverse event (TEAE) was lymphopenia (n = 2). Grade 4 TEAEs included hypertriglyceridemia and pneumonia aspiration (n = 1 each), which were not related to tazemetostat. Treatment-emergent adverse events leading to study drug discontinuation were reported in four of the 20 patients, indicating that the safety profile of tazemetostat was acceptable and manageable. Tazemetostat 800 mg twice daily showed encouraging efficacy in patients with R/R EZH2 mutation-positive FL with a manageable safety profile in the overall population. Thus, tazemetostat could be a potential treatment for R/R EZH2 mutation-positive FL.

Low-dose antithymocyte globulin inhibits chronic graft-versus-host disease in peripheral blood stem cell transplantation from unrelated donors
Souichi Shiratori, Junichi Sugita, Shigeo Fuji, Jun Aoki, Masashi Sawa, Yukiyasu Ozawa, Daigo Hashimoto, Ken-ichi Matsuoka, Kazunori Imada, Noriko Doki, Takashi Ashida, Yasunori Ueda, Masatsugu Tanaka, Yasushi Sawayama, Tatsuo Ichinohe, Seitaro Terakura, Satoko Morishima, Yoshiko Atsuta, Takahiro Fukuda, Takanori Teshima
Bone Marrow Transplantation, 56, 9, 2231, 2240, Springer Science and Business Media LLC, 2021年09月, ［査読有り］
研究論文（学術雑誌）

Logistic advantage of two-step screening strategy for SARS-CoV-2 at airport quarantine
Isao Yokota, Peter Y. Shane, Takanori Teshima
Travel Medicine and Infectious Disease, 43, 102127, 102127, Elsevier BV, 2021年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Airport quarantine is required to reduce the risk of entry of travelers infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, it is challenging for both high accuracy and rapid turn-around time to coexist in testing; polymerase chain reaction (PCR) is time-consuming with high accuracy, while antigen testing is rapid with less accuracy. However, there are few data on the concordance between PCR and antigen testing. METHODS: Arrivals at three international airports in Japan between July 29 and September 30, 2020 were tested for SARS-CoV-2 using self-collected saliva by a screening strategy with initial chemiluminescent enzyme immunoassay (CLEIA) followed by confirmatory nucleic acid amplification tests (NAAT) only for intermediate range antigen concentrations. RESULTS: Among the 95,457 persons entering Japan during the period, 88,924 (93.2%) were tested by CLEIA, and 0.29% (254/88,924) were found to be SARS-CoV-2 antigen positive (≥4.0 pg/mL). NAAT was required for confirmatory testing in 0.58% (513/88,924) with intermediate antigen concentrations (0.67-4.0 pg/mL) whereby the virus was detected in 6.6% (34/513). This two-step strategy reduced the utilization of NAAT to one out of every 173 test subjects. The estimated performance of this strategy did not show significant increase in false negatives as compared to performing NAAT in all subjects. CONCLUSIONS: Point of care testing by quantitative CLEIA using self-collected saliva is less labor-intensive and yields results rapidly, thus suitable as an initial screening test. Reserving NAAT for CLEIA indeterminate cases may prevent compromising accuracy while significantly improving the logistics of administering mass-screening at large venues.

Relevance of early-diastolic mitral regurgitation in dilated heart
Asuka Tanemura, Michito Murayama, Hiroyuki Iwano, Yasuyuki Chiba, Mutsumi Nishida, Takanori Teshima, Toshihisa Anzai
Journal of Echocardiography, 21, 1, 50, 52, Springer Science and Business Media LLC, 2021年08月30日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Performance of Qualitative and Quantitative Antigen Tests for SARS-CoV-2 Using Saliva
Isao Yokota, Takayo Sakurazawa, Junichi Sugita, Sumio Iwasaki, Keiko Yasuda, Naoki Yamashita, Shinichi Fujisawa, Mutsumi Nishida, Satoshi Konno, Takanori Teshima
Infectious Disease Reports, 13, 3, 742, 747, MDPI AG, 2021年08月24日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The rapid detection of SARS-CoV-2 is critical for the prevention of disease outbreaks. Antigen tests such as immunochromatographic assay (ICA) and chemiluminescent enzyme immunoassay (CLEIA) can yield results more quickly than PCR. We evaluated the performance of ICA and CLEIA using 34 frozen PCR-positive (17 saliva samples and 17 nasopharyngeal swabs [NPS]) and 309 PCR-negative samples. ICA detected SARS-CoV-2 in only 14 (41%) samples, with positivity rates of 24% in saliva and 59% in NPS. Notably, ICA detected SARS-CoV-2 in 5 of 6 samples collected within 4 days after symptom onset. CLEIA detected SARS-CoV-2 in 31 (91%) samples, with a positivity of 82% in saliva and 100% in NPS. These results suggest that the use of ICA should be limited to an earlier time after symptom onset and CLEIA is more sensitive and can be used in situations where quick results are required.

The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models
Takanori Teshima, Geoffrey R. Hill
Frontiers in Immunology, 12, 715424, 715424, Frontiers Media SA, 2021年08月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for hematologic malignancies, bone marrow failure syndromes, and inherited immunodeficiencies and metabolic diseases. Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic HCT. New insights into the pathophysiology of GVHD garnered from our understanding of the immunological pathways within animal models have been pivotal in driving new therapeutic paradigms in the clinic. Successful clinical translations include histocompatibility matching, GVHD prophylaxis using cyclosporine and methotrexate, posttransplant cyclophosphamide, and the use of broad kinase inhibitors that inhibit cytokine signaling (e.g. ruxolitinib). New approaches focus on naïve T cell depletion, targeted cytokine modulation and the inhibition of co-stimulation. This review highlights the use of animal transplantation models to guide new therapeutic principles.

Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease Using Commercial Mesenchymal Stem Cell Products
Makoto Murata, Takanori Teshima
Frontiers in Immunology, 12, 724380, 724380, Frontiers Media SA, 2021年08月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Acute graft-versus-host disease (GVHD) is a life-threatening complication that can develop after allogeneic hematopoietic stem cell transplantation. In particular, the prognosis of patients with steroid-refractory acute GVHD is extremely poor. Ryoncil™ (remestemcel-L), a human bone marrow-derived mesenchymal stem cell (MSC) product, failed to show superiority over placebo in patients with steroid-refractory acute GVHD, but it was approved for use in pediatric patients in Canada and New Zealand based on the results of a subgroup analysis. Temcell^®, an equivalent manufactured MSC product to remestemcel-L, was approved in Japan based on small single-arm studies by using a regulation for regenerative medicine in 2016. The efficacy of Temcell was evaluated in 381 consecutive patients treated with Temcell during the initial 3 years after its approval. Interestingly, its real-world efficacy was found to be equivalent to that observed in a prospective study of remestemcel-L with strict eligibility criteria. In this article, the potential of MSC therapy in the treatment of acute GVHD is discussed. A meticulous comparison of studies of remestemcel-L and Temcell, remestemcel-L/Temcell and ruxolitinib, and remestemcel-L/Temcell and thymoglobulin showed that the precise position of remestemcel-L/Temcell therapy in the treatment of acute GVHD remains to be determined.

Graft-versus-host disease: a disorder of tissue regeneration and repair
Ronjon Chakraverty, Takanori Teshima
Blood, 138, 18, 1657, 1665, American Society of Hematology, 2021年08月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Regenerative failure at barrier surfaces and maladaptive repair leading to fibrosis are hallmarks of graft-versus-host disease (GVHD). Although immunosuppressive treatment can control inflammation, impaired tissue homeostasis leads to prolonged organ damage and impaired quality of life. In this Spotlight article, we review recent research that addresses the critical failures in tissue regeneration and repair that underpin treatment-resistant GVHD. We highlight current interventions designed to overcome these defects and provide our assessment of the future therapeutic landscape.

Patients with marginal zone dural lymphoma successfully treated with rituximab and bendamustine: A report of two cases
Yutaka Tsutsumi, Shinichi Ito, Jun Nagai, Takahiro Tateno, Takanori Teshima
Molecular and Clinical Oncology, 15, 4, 208, 208, Spandidos Publications, 2021年08月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Primary dural low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a rare disease whose main treatment has been local surgery or radiotherapy. Until now, there have been no cases of dural MALT lymphoma treatment of a patient with several relapses or systemic disease. The present study included two patients with dural MALT lymphoma who had several relapses or systemic disease. Since local therapy was not enough to control the disease for these patients, they were treated with systemic chemotherapy. The patients were administered rituximab (375 mg/m2) and two days of bendamustine (90 mg/m2). Both patients recovered from their clinical symptoms immediately, and their tumors were reduced. During and after rituximab and bendamustine therapy, no central nervous system (CNS) metastasis or cerebrospinal fluid invasion of MALT were observed. The current approach using rituximab and bendamustine treatment was effective against dural MALT lymphoma and may prevent its invasion of the CNS.

Mass Screening of Asymptomatic Persons for Severe Acute Respiratory Syndrome Coronavirus 2 Using Saliva
Isao Yokota, Peter Y Shane, Kazufumi Okada, Yoko Unoki, Yichi Yang, Tasuku Inao, Kentaro Sakamaki, Sumio Iwasaki, Kasumi Hayasaka, Junichi Sugita, Mutsumi Nishida, Shinichi Fujisawa, Takanori Teshima
Clinical Infectious Diseases, 73, 3, e559, e565, Oxford University Press (OUP), 2021年08月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）,


Coronavirus disease 2019 (COVID-19) has rapidly evolved to become a global pandemic, largely owing to the transmission of its causative virus through asymptomatic carriers. Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in asymptomatic people is an urgent priority for the prevention and containment of disease outbreaks in communities. However, few data are available in asymptomatic persons regarding the accuracy of polymerase chain reaction testing. In addition, although self-collected saliva samples have significant logistical advantages in mass screening, their utility as an alternative specimen in asymptomatic persons is yet to be determined.





We conducted a mass screening study to compare the utility of nucleic acid amplification, such as reverse-transcription polymerase chain reaction testing, using nasopharyngeal swab (NPS) and saliva samples from each individual in 2 cohorts of asymptomatic persons: the contact-tracing cohort and the airport quarantine cohort.





In this mass screening study including 1924 individuals, the sensitivities of nucleic acid amplification testing with NPS and saliva specimens were 86% (90% credible interval, 77%–93%) and 92% (83%–97%), respectively, with specificities &gt;99.9%. The true concordance probability between the NPS and saliva tests was estimated at 0.998 (90% credible interval, .996–.999) given the recent airport prevalence of 0.3%. In individuals testing positive, viral load was highly correlated between NPS and saliva specimens.





Both NPS and saliva specimens had high sensitivity and specificity. Self-collected saliva specimens are valuable for detecting SARS-CoV-2 in mass screening of asymptomatic persons.

Clinical outcomes of intervention for carbapenems and anti-methicillin-resistant Staphylococcus aureus antibiotics by an antimicrobial stewardship team
Keisuke Kagami, Nobuhisa Ishiguro, Takehiro Yamada, Yusuke Niinuma, Sumio Iwasaki, Keisuke Taki, Tatsuya Fukumoto, Kasumi Hayasaka, Mutsumi Nishida, Junichi Sugita, Takanori Teshima, Mitsuru Sugawara, Yoh Takekuma
American Journal of Infection Control, 49, 12, 1493, 1498, Elsevier BV, 2021年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: There are no reports on the effects of interventions, such as discontinuation and change and/or de-escalation of carbapenems and anti-methicillin-resistant Staphylococcus aureus (MRSA) antibiotics by an antimicrobial stewardship team focusing on detailed patient outcomes. This study aimed to evaluate these effects. METHODS: This retrospective cohort study was conducted at a tertiary care hospital from December 2018 to November 2019. RESULTS: Favorable clinical responses were obtained in 165 of 184 cases (89.7%) in the intervention-accepted group, higher than those in the not accepted group (14/19 cases, 73.7%; P = .056). All-cause 30 day mortality was lower in the accepted group than in the not accepted group (1.1% and 10.5%, respectively; P = .045). The microbiological outcomes were similar between the two groups. Duration of carbapenem and anti-MRSA antibiotic use in the accepted group was significantly lower than that in the not accepted group (median [interquartile range]: 8 days [5-13] versus 14 days [8-15], respectively, P = .026 for carbapenem; 10 days [5.3-15] vs 15.5 days [13.8-45.3], respectively, P = .014 for anti-MRSA antibiotic). CONCLUSIONS: This is the first study to investigate the effects of interventions such as discontinuation and change and/ or de-escalation of antibiotics on detailed outcomes. Our intervention could reduce the duration of carbapenem and anti-MRSA antibiotic use without worsening clinical and microbiological outcomes.

A novel strategy for SARS-CoV-2 mass screening with quantitative antigen testing of saliva: a diagnostic accuracy study
Isao Yokota, Peter Y Shane, Kazufumi Okada, Yoko Unoki, Yichi Yang, Sumio Iwasaki, Shinichi Fujisawa, Mutsumi Nishida, Takanori Teshima
The Lancet Microbe, 2, 8, e397, e404, Elsevier BV, 2021年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Quantitative RT-PCR (RT-qPCR) of nasopharyngeal swab (NPS) samples for SARS-CoV-2 detection requires medical personnel and is time consuming, and thus is poorly suited to mass screening. In June, 2020, a chemiluminescent enzyme immunoassay (CLEIA; Lumipulse G SARS-CoV-2 Ag kit, Fujirebio, Tokyo, Japan) was developed that can detect SARS-CoV-2 nucleoproteins in NPS or saliva samples within 35 min. In this study, we assessed the utility of CLEIA in mass SARS-CoV-2 screening. Methods: We did a diagnostic accuracy study to develop a mass-screening strategy for salivary detection of SARS-CoV-2 by CLEIA, enrolling hospitalised patients with clinically confirmed COVID-19, close contacts identified at community health centres, and asymptomatic international arrivals at two airports, all based in Japan. All test participants were enrolled consecutively. We assessed the diagnostic accuracy of CLEIA compared with RT-qPCR, estimated according to concordance (Kendall's coefficient of concordance, W), and sensitivity (probability of CLEIA positivity given RT-qPCR positivity) and specificity (probability of CLEIA negativity given RT-qPCR negativity) for different antigen concentration cutoffs (0·19 pg/mL, 0·67 pg/mL, and 4·00 pg/mL; with samples considered positive if the antigen concentration was equal to or more than the cutoff and negative if it was less than the cutoff). We also assessed a two-step testing strategy post hoc with CLEIA as an initial test, using separate antigen cutoff values for test negativity and positivity from the predefined cutoff values. The proportion of intermediate results requiring secondary RT-qPCR was then quantified assuming prevalence values of RT-qPCR positivity in the overall tested population of 10%, 30%, and 50%. Findings: Self-collected saliva was obtained from 2056 participants between June 12 and Aug 6, 2020. Results of CLEIA and RT-qPCR were concordant in 2020 (98·2%) samples (Kendall's W=0·99). Test sensitivity was 85·4% (76 of 89 positive samples; 90% credible interval [CrI] 78·0-90·3) at the cutoff of 0·19 pg/mL; 76·4% (68 of 89; 68·2-82·8) at the cutoff of 0·67 pg/mL; and 52·8% (47 of 89; 44·1-61·3) at the cutoff of 4·0 pg/mL. Test specificity was 91·3% (1796 of 1967 negative samples; 90% CrI 90·2-92·3) at the cutoff of 0·19 pg/mL, 99·2% (1952 of 1967; 98·8-99·5) at the cutoff of 0·67 pg/mL, and 100·0% (1967 of 1967; 99·8-100·0) at the cutoff of 4·00 pg/mL. Using a two-step testing strategy with a CLEIA negativity cutoff of 0·19 pg/mL (to maximise sensitivity) and a CLEIA positivity cutoff of 4·00 pg/mL (to maximise specificity), the proportions of indeterminate results (ie, samples requiring secondary RT-qPCR) would be approximately 11% assuming a prevalence of RT-qPCR positivity of 10%, 16% assuming a prevalence of RT-qPCR positivity of 30%, and 21% assuming a prevalence of RT-qPCR positivity of 50%. Interpretation: CLEIA testing of self-collected saliva is simple and provides results quickly, and is thus suitable for mass testing. To improve accuracy, we propose a two-step screening strategy with an initial CLEIA test followed by confirmatory RT-qPCR for intermediate concentrations, varying positive and negative thresholds depending on local prevalence. Implementation of this strategy has expedited sample processing at Japanese airports since July, 2020, and might apply to other large-scale mass screening initiatives. Funding: Ministry of Health, Labour and Welfare, Japan.

Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease
Robert Zeiser, Nicola Polverelli, Ron Ram, Shahrukh K. Hashmi, Ronjon Chakraverty, Jan Moritz Middeke, Maurizio Musso, Sebastian Giebel, Ant Uzay, Peter Langmuir, Norbert Hollaender, Maanasa Gowda, Tommaso Stefanelli, Stephanie J. Lee, Takanori Teshima, Franco Locatelli
New England Journal of Medicine, 385, 3, 228, 238, Massachusetts Medical Society, 2021年07月15日, ［査読有り］
研究論文（学術雑誌）

XIAP欠損症に対して非血縁者間骨髄移植を施行して移植後赤芽球癆を認めた1例　　　　　　　　　　　　　　　
千葉 雅尋, 杉田 純一, 宮下 直樹, 須藤 啓斗, 日高 大輔, 大東 寛幸, 安本 篤史, 小野澤 真弘, 橋本 大吾, 豊嶋 崇徳
臨床血液, 62, 7, 848, 849, (一社)日本血液学会-東京事務局, 2021年07月
日本語

髄外腫瘤で発症したe1a3 BCR-ABL陽性慢性骨髄性白血病　　　　　　　　　　　　　　　
宮下 直樹, 小野澤 真弘, 須藤 啓斗, 日高 大輔, 大東 寛幸, 安本 篤史, 杉田 純一, 橋本 大吾, 豊嶋 崇徳
臨床血液, 62, 7, 849, 849, (一社)日本血液学会-東京事務局, 2021年07月
日本語

A case of immune checkpoint inhibitor-associated gastroenteritis detected by ultrasonography.
Satomi Omotehara, Mutsumi Nishida, Kana Yamanashi, Kensuke Sakurai, Takehiko Katsurada, Yoshito Komatsu, Ai Shimizu, Hitoshi Shibuya, Naofumi Shinagawa, Junichi Sugita, Takanori Teshima
Journal of clinical ultrasound : JCU, 49, 6, 605, 609, 2021年07月, ［国際誌］
英語, While immune checkpoint inhibitors (ICIs) have antitumor effects, they also have characteristic side effects, including colitis. However, gastritis has rarely been reported. We report a case of a patient with lung adenocarcinoma who presented with epigastric pain and diarrhea following pembrolizumab administration. Sonography of the abdomen demonstrated diffuse, although mild, gastric wall thickening (mainly in the submucosa), as well as a slight decrease in echogenicity throughout the gastric wall. While the mucosal surface was relatively smooth, color Doppler examination showed increased vascularity. Esophagogastroduodenoscopy and pathological examination confirmed the diagnosis of ICI-related gastroenteritis.

Effect of varying storage conditions on diagnostic test outcomes of SARS-CoV-2
Satoshi Oguri, Shinichi Fujisawa, Keisuke Kamada, Sho Nakakubo, Yu Yamashita, Junichi Nakamura, Hiroshi Horii, Kazuki Sato, Mutsumi Nishida, Takanori Teshima, Yoichi Ohiro, Ayato Takada, Satoshi Konno
Journal of Infection, 83, 1, 119, 145, Elsevier BV, 2021年07月, ［査読有り］
研究論文（学術雑誌）

Refined ultrasonographic criteria for sinusoidal obstruction syndrome after hematopoietic stem cell transplantation
Mutsumi Nishida, Junichi Sugita, Shuichiro Takahashi, Takahito Iwai, Megumi Sato, Yusuke Kudo, Satomi Omotehara, Tatsunori Horie, Ryosuke Sakano, Hitoshi Shibuya, Isao Yokota, Akihiro Iguchi, Takanori Teshima
International Journal of Hematology, 114, 1, 94, 101, Springer Science and Business Media LLC, 2021年07月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Hepatic sinusoidal obstruction syndrome (SOS)/veno-occlusive disease is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). We previously reported the efficacy of the Hokkaido Ultrasonography (US)-based scoring system (HokUS-10) for US findings. To establish easier-to-use criteria, we retrospectively evaluated US findings from 441 patients, including 30 patients with SOS using the HokUS-10 scoring system. Using logistic regression analysis, we established the novel diagnostic criteria HokUS-6. In the presence of ascites, US diagnosis was made in the presence of two of the following 6 parameters: moderate amount of ascites, the appearance of a paraumbilical vein blood flow signal, gallbladder wall thickening, portal vein dilatation, portal vein velocity decrease, and hepatic artery resistive index increase. The AUC, sensitivity, and specificity of HokUS-6 were 0.974 (95% confidence interval 0.962-0.990), 95.2%, and 96.9%, respectively. The scores were significantly higher in patients with severe SOS than in those with non-severe SOS (p = 0.013). Furthermore, the scores before HSCT were significantly higher in patients who developed SOS than in controls (p = 0.001). The HokUS-6 is an easy and useful way to diagnose and identify the risk of SOS.

Platelet decrease and efficacy of platelet‐rich plasma return following peripheral blood stem cell apheresis
Takahiro Shima, Teppei Sakoda, Tomoko Henzan, Yuya Kunisaki, Takeshi Sugio, Kenjiro Kamezaki, Hiromi Iwasaki, Takanori Teshima, Takahiro Maeda, Koichi Akashi, Toshihiro Miyamoto
Journal of Clinical Apheresis, 36, 5, 687, 696, Wiley, 2021年06月16日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Peripheral blood stem cell (PBSC) transplantation is a key treatment option for hematological diseases and is widely performed in clinical practice. Platelet loss is one of the major complications of PBSC apheresis, and platelet-rich plasma (PRP) return is considered in case of platelet decrease following apheresis; however, little is known about the frequency and severity of platelet loss and the efficacy of PRP return postapheresis. METHODS: We assessed changes in platelet counts following PBSC-related apheresis in 270 allogeneic (allo)- and 105 autologous (auto)-PBSC settings. We also evaluated the efficacy of PRP transfusion on platelet recovery postapheresis. RESULTS: In both allo- and auto-PBSC settings, the preapheresis platelet count (range, 84-385 and 33-558 × 109 /L, respectively) decreased postapheresis (range, 57-292 and 20-429 × 109 /L, respectively), whereas severe platelet decrease (<50 × 109 /L) was only observed in auto-PBSC patients (n = 9). We confirmed that platelet count before apheresis was a risk factor for severe platelet decrease (<50 × 109 /L) following auto-PBSC apheresis (odds ratio 0.749, P < .049). PRP return postapheresis facilitated platelet recovery in more than 80% of cases in both allo and auto settings. CONCLUSION: Lower platelet count preapheresis is a useful predictor of severe platelet decrease following auto-PBSC apheresis and PRP return is an effective process to facilitate platelet recovery postapheresis.

Cost Effectiveness Analysis of Tisagenlecleucel for the Treatment of Adult Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma in Japan
Shiho Wakase, Takanori Teshima, Jie Zhang, Qiufei Ma, Taizo Fujita, Hongbo Yang, Xinglei Chai, Cynthia Z. Qi, Qing Liu, Eric Q. Wu, Ataru Igarashi
Transplantation and Cellular Therapy, 27, 6, 506.e1, 506.e10, Elsevier BV, 2021年06月, ［査読有り］
英語, 研究論文（学術雑誌）, There are limited treatment options and substantial unmet needs for adult patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) in Japan. In 2019, tisagenlecleucel, a CD19-directed chimeric antigen receptor T cell therapy, was approved for r/r DLBCL in Japan. The efficacy and safety of tisagenlecleucel were demonstrated in the pivotal phase II single-arm JULIET trial. The objective of the current study was to assess the cost-effectiveness of tisagenlecleucel treatment strategy versus current standard of care (salvage chemotherapy treatment strategy) for the treatment of patients with r/r DLBCL in Japan. A three-state partitioned survival model was constructed from a Japanese public healthcare payer's perspective, with the following three health states: progression-free survival, progressive/relapsed disease, and death. Because the tisagenlecleucel arm included patients who did or did not receive the infusion, a decision-tree structure was used to partition patients based on their infusion status. Treatment efficacy and costs were based on tisagenlecleucel-infused patients for those who received the infusion; for non-infused patients, they were based on standard salvage chemotherapy. The efficacy inputs for tisagenlecleucel-infused patients and salvage chemotherapy were based on observed data in the JULIET trial and the international SCHOLAR-1 meta-analysis, respectively, before year 3. Afterward, all patients were assumed to have no further progression and to incur the mortality risk of long-term DLBCL survivors. The base case analysis explored a lifetime horizon (44 years), with costs and effectiveness discounted 2.0% annually, and it used a monthly model cycle. Direct costs were considered in the base case, composed of pretreatment costs, treatment costs, adverse events management costs, follow-up costs before progression, subsequent SCT costs, post-progression costs, and terminal care costs. Total incremental costs, life years (LYs), and quality-adjusted life years (QALYs) were compared for tisagenlecleucel versus salvage chemotherapy. The incremental cost-effectiveness ratio (ICER) was estimated as the costs per QALY gained, and a threshold of \7.5 million was used to assess whether tisagenlecleucel is cost effective. Deterministic and probabilistic sensitivity analyses were performed. The total LYs (discounted) for tisagenlecleucel and salvage chemotherapy were 7.24 and 4.35 years, respectively; the corresponding QALYs were 5.42 and 2.57 years, respectively. The discounted incremental LYs and QALYs comparing tisagenlecleucel to salvage chemotherapy were estimated as 2.89 and 2.85 years, respectively. Over a lifetime horizon, the model estimated that tisagenlecleucel had a total incremental cost of \15,590,335 (discounted) versus salvage chemotherapy. Tisagenlecleucel was associated with an ICER of \5,476,496 per QALY gained compared to salvage chemotherapy. Extensive sensitivity analyses supported the base-case findings. Tisagenlecleucel is a cost-effective treatment strategy for r/r DLBCL compared to salvage chemotherapy treatment strategy from a Japanese public healthcare payer's perspective.

High lymphocyte counts before antithymocyte globulin administration predict acute graft-versus-host disease
Souichi Shiratori, Hiroyuki Ohigashi, Takahide Ara, Atsushi Yasumoto, Hideki Goto, Masao Nakagawa, Junichi Sugita, Masahiro Onozawa, Kaoru Kahata, Tomoyuki Endo, Daigo Hashimoto, Takanori Teshima
Annals of Hematology, 100, 5, 1321, 1328, Springer Science and Business Media LLC, 2021年05月, ［査読有り］
研究論文（学術雑誌）

音響特性を考慮した乳腺病変の最適な超音波画像撮像条件の検討　　　　　　　　　　　　　　　
岩井 孝仁, 工藤 悠輔, 西田 睦, 畑瀬 理恵, 表原 里実, 大栗 拓真, 嵯峨 早友佳, 神山 直久, 杉田 純一, 豊嶋 崇徳
超音波医学, 48, Suppl., S790, S790, (公社)日本超音波医学会, 2021年04月
日本語

Extramedullary hematopoiesis of the cranial dura.
Keito Suto, Junichi Sugita, Daigo Hashimoto, Hiroyuki Kameda, Tomoko Mitsuhashi, Takanori Teshima
International journal of hematology, 113, 3, 315, 317, 2021年03月, ［国内誌］
英語

Cost-Effectiveness Analysis of Tisagenlecleucel for the Treatment of Pediatric and Young Adult Patients with Relapsed or Refractory B Cell Acute Lymphoblastic Leukemia in Japan
Shiho Wakase, Takanori Teshima, Jie Zhang, Qiufei Ma, Yoko Watanabe, Hongbo Yang, Cynthia Z. Qi, Xinglei Chai, Yanwen Xie, Eric Q. Wu, Ataru Igarashi
Transplantation and Cellular Therapy, 27, 3, 241.e1, 241.e11, Elsevier BV, 2021年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Until recently, treatment options were relatively limited for children and young adults with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL). Tisagenlecleucel is a chimeric antigen receptor T cell (CAR-T) immunotherapy with promising efficacy and manageable safety that was approved in Japan in 2019 for the treatment of CD19-positive r/r B cell ALL (B-ALL). However, there is no publication assessing the cost-effectiveness of CAR-T in Japan. The objective of this study was to assess the cost-effectiveness of a tisagenlecleucel treatment strategy compared to a blinatumomab treatment strategy and a clofarabine combination treatment strategy (i.e., clofarabine + cyclophosphamide + etoposide) in Japan for pediatric and young adult patients up to 25 years of age with r/r B-ALL. A partitioned survival model with a lifetime horizon and monthly cycle was constructed from a Japanese public healthcare payer's perspective. Patients were distributed across the following partitioned health states: event-free survival (EFS), progressive disease, and death, which were informed by the EFS and overall survival (OS) data of respective clinical trials before year 5. For the tisagenlecleucel arm, a decision-tree structure was used to partition patients based on the infusion status; those who discontinued prior to receiving infusion were assigned efficacy and cost inputs of blinatumomab and those who received infusion were assigned efficacy and costs inputs based on tisagenlecleucel-infused patients. As trial data for blinatumomab and clofarabine ended before year 5, matching-adjusted indirect comparisons were used to extrapolate OS between the end of trial observation and up to year 5. All surviving patients followed the mortality risk of long-term ALL survivors without additional risk of disease relapse after year 5, regardless of initial treatment strategies. The model accounted for pretreatment costs, treatment costs, adverse event costs, follow-up costs, subsequent allogeneic hematopoietic stem cell transplantation costs, and terminal care costs. Incremental cost-effectiveness ratios (ICERs) per life-years (LYs) gained and ICERs per quality-adjusted life-years (QALYs) gained were evaluated using a 2% discount rate, and a threshold of \7.5 million was used to assess cost-effectiveness. Deterministic and probabilistic sensitivity analyses were performed. The total LYs (discounted) for tisagenlecleucel, blinatumomab, and clofarabine combination treatment strategies were 13.3, 4.0, and 2.7 years, respectively; the corresponding QALYs were 11.6, 3.1, and 2.1 years, respectively. The ICERs per QALY gained for tisagenlecleucel were \2,035,071 versus blinatumomab and \2,644,702 versus clofarabine combination therapy. Extensive sensitivity analyses supported the findings. Tisagenlecleucel is a cost-effective treatment strategy for pediatric and young adult patients with r/r B-ALL from a Japanese public healthcare payer's perspective.

A multicenter phase II study of intrabone single-unit cord blood transplantation without antithymocyte globulin
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, Springer Science and Business Media LLC, 2021年03月, ［査読有り］, ［国際誌］
英語, 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.

Efficacy and safety of colistin for the treatment of infections caused by multidrug-resistant gram-negative bacilli
Keisuke Kagami, Nobuhisa Ishiguro, Takehiro Yamada, Yusuke Niinuma, Sumio Iwasaki, Keisuke Taki, Tatsuya Fukumoto, Kasumi Hayasaka, Reiko Oyamada, Tsubasa Watanabe, Mutsumi Nishida, Junichi Sugita, Takanori Teshima, Mitsuru Sugawara, Yoh Takekuma
Journal of Infection and Chemotherapy, 27, 3, 473, 479, Elsevier BV, 2021年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The efficacy and safety of colistin for the treatment of infections caused by multidrug-resistant gram-negative bacilli have been poorly investigated in Japanese patients. This study was performed to investigate the efficacy and safety of colistin in Japanese patients by analyzing a considerable number of cases. Furthermore, we evaluated the relationship between the plasma concentration and efficacy and safety of colistin in some cases. METHODS: A retrospective cohort study was conducted at Hokkaido University Hospital, analyzing patients treated with colistin (colistimethate sodium) during the period from January 2007 to December 2019. RESULTS: Overall, 42 cases were enrolled. Favorable clinical response was observed in 25 cases (59.5%), with an all-cause 30-day mortality of 33.3% (14/42 cases). Microbiological eradication was achieved in 18 cases (42.9%). Nephrotoxicity was observed in 20 cases (47.6%) and was mild and reversible in all cases. Plasma trough concentrations of colistin determined in nine patients correlated with changes in serum creatinine concentration (⊿) and creatinine clearance (%). The cutoff value of colistin trough concentration for nephrotoxicity was 2.02 μg/mL. CONCLUSION: Our results showed approximately 60% clinical efficacy of colistin therapy against infections caused by multidrug-resistant gram-negative bacilli in the patients. Further studies with larger populations are needed to elucidate the efficacy and safety of colistin in Japanese patients.

Reduced dose of posttransplant cyclophosphamide in HLA-haploidentical peripheral blood stem cell transplantation
Junichi Sugita, Tomohiko Kamimura, Takayuki Ishikawa, Shuichi Ota, Tetsuya Eto, Takashi Kuroha, Yasuhiko Miyazaki, Hiroaki Kumagai, Keitaro Matsuo, Koichi Akashi, Shuichi Taniguchi, Mine Harada, Takanori Teshima
Bone Marrow Transplantation, 56, 3, 596, 604, Springer Science and Business Media LLC, 2021年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Posttransplant cyclophosphamide (PTCy:100 mg/kg) has been increasingly used in allogeneic hematopoietic stem cell transplantation, however, few studies compared different doses of PTCy. We conducted two consecutive prospective multicenter phase II studies to evaluate the safety and efficacy of 80 mg/kg of PTCy in 137 patients who underwent HLA-haploidentical peripheral blood stem cell transplantation (haploPBSCT) following reduced-intensity conditioning (RIC). GVHD prophylaxis consisted of PTCy at a dose of 40 mg/kg/day on days 3 and 4, tacrolimus, and mycophenolate mofetil. Neutrophil engraftment was achieved in 97% and 96% in the first and second studies, respectively. The incidences of grades II-IV acute GVHD, III-IV acute GVHD, all grade chronic GVHD, and moderate to severe chronic GVHD at 2 years were 26%, 5%, 35%, and 18% in the first study, and 23%, 1%, 28%, and 15% in the second study, respectively. Overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) at 2 years were 51%, 42%, and 18% in the first study, and 58%, 48%, and 16% in the second study, respectively. The rates of off-immunosuppressants in patients who survived without relapse at 2 years were 83 and 76%. Our results suggest that 80 mg/kg of PTCy is a valid option in haploPBSCT following RIC.

Effect of methotrexate dose in graft-versus-host disease prophylaxis after single-unit cord blood transplantation in adult acute myeloid leukemia
Seitaro Terakura, Yachiyo Kuwatsuka, Junichi Sugita, Satoshi Takahashi, Yukiyasu Ozawa, Kazutaka Ozeki, Satoshi Yoshioka, Hirohisa Nakamae, Toshiro Kawakita, Masashi Sawa, Satoshi Morishige, Yuho Najima, Yuna Katsuoka, Emiko Sakaida, Yasuji Kouzai, Takafumi Kimura, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Atsuta, Makoto Murata, Takanori Teshima
International Journal of Hematology, 113, 6, 840, 850, Springer Science and Business Media LLC, 2021年02月21日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, To investigate the association between methotrexate (MTX) dosage and engraftment, graft-versus-host disease (GVHD) incidence, and survival in umbilical cord blood transplantation (UCBT), we compared transplant outcomes after UCBT with various GVHD prophylaxis regimens, using registry data with additional data collection. Patients transplanted for acute myeloid leukemia with a calcineurin inhibitor (CNI) and either MTX or mycophenolate mofetil (MMF) combination were selected. In total, 888 single-unit UCBTs (MTX15-10-10, 415; MTX10-7-7, 294; MTX5-5-5, 71; MMF, 108) were included. In multivariate analyses with MTX15-10-10 as the reference, the likelihood of neutrophil and platelet engraftment was significantly worse in the MTX10-7-7 group, and similarly better in MMF group compared with MTX15-10-10. All variables including CyA vs Tac and 4-group GVHD prophylaxis became significant for the risk of grade II-IV acute GVHD in the final multivariate model. We observed significant additional effects of combined MTX dose in the Tac group, which were larger with lower MTX dose and MMF. No significant difference was observed in survival risk among GVHD prophylaxis groups. Despite the potential background differences in the combined CNI and conditioning regimen, we conclude that the recommended GVHD prophylaxis is a combination of CyA plus MTX15-10-10 or Tac plus MMF.

Factors for the Variability of Three Acceptable Maximal Expiratory Flow–Volume Curves in Chronic Obstructive Pulmonary Disease
Masafumi Yamamoto, Satoshi Konno, Hironi Makita, Katsuaki Nitta, Kaoruko Shimizu, Masaru Suzuki, Mutsumi Nishida, Junichi Sugita, Takanori Teshima, Masaharu Nishimura
International Journal of Chronic Obstructive Pulmonary Disease, Volume 16, 415, 422, Informa UK Limited, 2021年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Generally, the maximal expiratory flow-volume (MEFV) curve must be measured for the diagnosis and staging of chronic obstructive pulmonary disease (COPD). As this test is effort dependent, international guidelines recommend that three acceptable trials are required for each test. However, no study has examined the magnitude and factors for the variability in parameters among three acceptable trials. Methods: We evaluated the intra-individual variations in several parameters among three acceptable MEFV curves obtained at one-time point in patients with COPD (n = 28, stage 1; n = 36, stage 2; n = 21, stages 3-4). Next, the factors for such variations were examined using forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). Results: The averages of coefficient of variation (CV) for FEV1 and FVC were 2.0% (range: 1.0-3.0%) and 1.6% (0.9-2.2%), respectively. Both parameters were significantly better than peak expiratory flow rate, forced expiratory flow at 50% of expired FVC, and forced expiratory flow at 75% of expired FVC (CVs: 5.0-6.9%). A higher spirometric stage was significantly associated with higher CVs for FVC and FEV1, and older age was significantly correlated with a higher variation in FEV1 alone. Furthermore, a significantly inverse association was observed between emphysema severity, and the CVs for FEV1, but not that for FVC, regardless of spirometric stage. Conclusion: Both FVC and FEV1 are highly reproducible; nevertheless, older age, lower FEV1 at baseline, and non-emphysema phenotype are factors for a higher variability in FEV1 in patients with COPD.

SARS-CoV-2 detection by fluorescence loop-mediated isothermal amplification with and without RNA extraction
Keisuke Taki, Isao Yokota, Tatsuya Fukumoto, Sumio Iwasaki, Shinichi Fujisawa, Masayoshi Takahashi, Saeki Negishi, Kasumi Hayasaka, Kaori Sato, Satoshi Oguri, Mutsumi Nishida, Junichi Sugita, Satoshi Konno, Tomoya Saito, Takanori Teshima
Journal of Infection and Chemotherapy, 27, 2, 410, 412, Elsevier BV, 2021年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Rapid and simple point-of-care detection of SARS-CoV-2 is an urgent need to prevent pandemic. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) can detect SARS-CoV-2 more rapidly than RT-PCR. Saliva is non-invasive specimen suitable for mass-screening, but data comparing utility of nasopharyngeal swab (NPS) and saliva in RT-LAMP test are lacking and it remains unclear whether SARS-CoV-2 could be detected by direct processing of samples without the need for prior RNA extraction saliva. In this study, we compared utility of saliva and NPS samples for the detection of SARS-CoV-2 by a novel RT-fluorescence LAMP (RT-fLAMP). The sensitivity and specificity of the RT-fLAMP with RNA extraction were 97% and 100%, respectively, with equivalent utility of NPS and saliva. However, sensitivity was decreased to 71% and 47% in NPS and saliva samples without RNA extraction, respectively, suggesting that RNA extraction process may be critical for the virus detection by RT-fLAMP.

Medical database analysis of japanese multiple myeloma patients with planned stem cell transplantation (MEDALIST) – a focus on healthcare resource utilization and cost
Shinsuke Iida, Tadao Ishida, Katsuhisa Horimoto, Hirotaka Kazama, Hyunchung Kim, Bruce Crawford, Takanori Teshima
International Journal of Hematology, 113, 2, 271, 278, Springer Science and Business Media LLC, 2021年02月, ［査読有り］
研究論文（学術雑誌）

[Emergence of mutation in the colony-stimulating factor 3 receptor gene during follow-up of unclassifiable myeloproliferative neoplasm].
Shinpei Harada, Kohei Okada, Shota Yokoyama, Daisuke Hidaka, Eiko Hayase, Masahiro Onozawa, Hideki Goto, Daigo Hashimoto, Kaoru Kahata, Tomoyuki Endo, Takanori Teshima
[Rinsho ketsueki] The Japanese journal of clinical hematology, 62, 11, 1609, 1614, 2021年, ［国内誌］
日本語, 研究論文（学術雑誌）, A 25-year-old male with a medical history of stress polycythemia was admitted to a previous hospital for leukocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed left-shifted myeloid hyperplasia without increased blasts and normal male karyotype. No mutations of JAK2, V617F, and colony-stimulating factor 3 receptor gene (CSF3R) were detected. Fluorescence in-situ hybridization for BCR-ABL1 and FIP1L1-PDGFRA were negative. Based on these findings, a diagnosis of an unclassifiable myeloproliferative neoplasm was made, and he was started on hydroxyurea treatment. He was referred to our hospital in April 2016 for transfusion dependence. Bone marrow examination performed at our hospital revealed granulocytic dysplasia and CSF3R T618I was detected. After induction therapy, CSF3R T618I became undetectable, and he went on to undergo allogeneic stem cell transplantation in October 2016. He has been in remission for >4 years posttransplantation. CSF3R T618I is one of the genes responsible for chronic neutrophilic leukemia and atypical chronic myeloid leukemia, suggesting its involvement in the pathogenesis of this case.

心内圧波形に基づく拡張早期僧帽弁逆流の発生機序に関する考察
種村 明日香, 村山 迪史, 岩野 弘幸, 西野 久雄, 横山 しのぶ, 中鉢 雅大, 本居 昂, 辻永 真吾, 岡田 一範, 加賀 早苗, 西田 睦, 豊嶋 崇徳
超音波検査技術抄録集, 46, S132, S132, 一般社団法人 日本超音波検査学会, 2021年
日本語

Two cases of chronic obstructive pulmonary disease with undetectable diffusing capacity for carbon monoxide.
Ayumi Ohara, Satoshi Konno, Kaoruko Shimizu, Masaru Suzuki, Masafumi Yamamoto, Asako Mitani, Mutsumi Nishida, Takanori Teshima, Masaharu Nishimura
Respiratory investigation, 59, 1, 145, 148, 2021年01月, ［国際誌］
英語, 研究論文（学術雑誌）, Pulmonary diffusing capacity for carbon monoxide (DLCO) is a valuable pulmonary function test to evaluate the gas exchange capacity of the lungs. Generally, DLCO values are significantly lower in patients with chronic obstructive pulmonary disease (COPD), particularly in those with a predominantly emphysema phenotype. However, it is extremely rare that DLCO values cannot be obtained for reasons other than technical errors. Herein, we report two patients with COPD in whom DLCO values were undetectable without prolonging the breath-holding time for the test. We discuss possible mechanisms for these peculiar findings.

急性前骨髄球性白血病に対する同種造血幹細胞移植27年後に発症したドナー細胞由来未分化大細胞リンパ腫の1例　　　　　　　　　　　　　　　
菊池 遼, 小野澤 真弘, 今本 鉄平, 高橋 秀一郎, 杉田 純一, 橋本 大吾, 橋野 聡, 松野 吉宏, 豊嶋 崇徳
日本内科学会雑誌, 110, 1, 92, 98, (一社)日本内科学会, 2021年01月, ［査読有り］
日本語, 54歳男性。右鼠径リンパ節腫脹を主訴とした。27歳時に急性前骨髄球性白血病に対しHLA適合の兄から骨髄移植を受けていた。53歳時に右大腿外側部にケロイド様皮疹が出現し、皮膚生検の診断はanaplastic lymphoma kinase(ALK)陰性の未分化大細胞リンパ腫(ALCL)であった。電子線治療で皮膚病変は消失したが、7ヵ月後にFDG-PETで全身のリンパ節病変(鎖骨上窩、傍大動脈、右鼠径部)を認めた。再発病変を疑い、右鼠径リンパ節を生検したところ、右大腿皮膚生検同様の組織所見を認め、ALK陰性ALCLと診断した。末梢血をドナー細胞、頬粘膜をレシピエント細胞としてキメリズム解析を行い、ドナー由来のALCLと診断した。ALCLに対しCHOP療法(cyclophosphamide、doxorubicin、vincristine、prednisolone)を行ったが、病変の増大を認め、brentuximab vedotin(BV)単剤による治療に変更した。経過は良好で、現在まで完全奏効を維持している。

The Combined Usage of the Global Leadership Initiative on Malnutrition Criteria and Controlling Nutrition Status Score in Acute Care Hospitals
Asako Mitani, Takahito Iwai, Toshiaki Shichinohe, Hiroshi Takeda, Satomi Kumagai, Mutsumi Nishida, Junichi Sugita, Takanori Teshima
Annals of Nutrition and Metabolism, 77, 3, 178, 184, S. Karger AG, 2021年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, <b><i>Introduction:</i></b> The Global Leadership Initiative on Malnutrition (GLIM) lacks reliable blood tests for evaluating the nutrition status. We retrospectively compared the GLIM criteria, Controlling Nutrition Status (CONUT) score, and Subjective Global Assessment (SGA) to establish effective malnutrition screening and provide appropriate nutritional interventions according to severity. <b><i>Methods:</i></b> We classified 177 patients into 3 malnutrition categories (normal/mild, moderate, and severe) according to the GLIM criteria, CONUT score, and SGA. We investigated the malnutrition prevalence, concordance of malnutrition severity, predictability of clinical outcome, concordance by etiology, and clinical outcome by inflammation. <b><i>Results:</i></b> The highest prevalence of malnutrition was found using the GLIM criteria (87.6%). Concordance of malnutrition severity was low between the GLIM criteria and CONUT score. Concordance by etiology was low in all groups but was the highest in the “acute disease” group. The area under the curve of clinical outcome and that of the “with inflammation group” were significantly higher when using the CONUT score versus using the other tools (0.679 and 0.683, respectively). <b><i>Conclusion:</i></b> The GLIM criteria have high sensitivity, while the CONUT score can effectively predict the clinical outcome of malnutrition. Their combined use can efficiently screen for malnutrition and patient severity in acute care hospitals.

Reliability of an ultrasonographical scoring system for diagnosis of sinusoidal obstruction syndrome/veno-occlusive disease in patients with hematopoietic stem cell transplantation
Takahito Iwai, Mutsumi Nishida, Junichi Sugita, Yusuke Kudo, Rika Takasugi, Isao Yokota, Ryo Takagi, Hitoshi Shibuya, Shuichiro Takahashi, Takanori Teshima
Journal of Medical Ultrasonics, 48, 1, 45, 52, Springer Science and Business Media LLC, 2021年01月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, PURPOSE: Sinusoidal obstruction syndrome (SOS)/hepatic veno-occlusive disease (VOD) is a fatal complication after hematopoietic stem cell transplantation. We previously reported the usefulness of an ultrasonographical (US) scoring system, the Hokkaido US-based scoring system consisting of ten parameters (HokUS-10): (1) hepatomegaly in the left lobe and (2) right lobe, (3) dilatation of the main portal vein (PV), (4) hepatofugal flow in the main PV, (5) decreased velocity of the PV, (6) dilatation of the para-umbilical vein (PUV), (7) appearance of blood flow signal in the PUV, (8) gallbladder (GB) wall thickening, (9) ascites, and (10) increased resistive index of the hepatic artery, for the diagnosis of SOS/VOD. However, the reliability of this system among operators remains elusive. Therefore, we prospectively evaluated the reliability of HokUS-10. METHODS: Twenty-four healthy volunteers and 40 patients with liver dysfunction were enrolled. Inter- and intra-operator reliabilities were analyzed using three sonographers. RESULTS: The median concordance rate of HokUS-10 among three sonographers and intra-operator in 24 volunteers was 92% (95% CI: 73-98%) and 98% (95% CI: 92-100%), respectively. In all 64 cases, in terms of the reliability between two sonographers for three representative US parameters (amount of ascites, GB wall thickening, and appearance of PUV blood flow signal), the median concordance rate was more than 98% (95% CI: 86-106%). CONCLUSION: The inter- and intra-reliabilities of HokUS-10 were excellent. Thus, US might be a reliable tool for SOS/VOD diagnosis.

Older age is associated with sustained detection of SARS-CoV-2 in nasopharyngeal swab samples
Takeshi Hattori, Masaru Amishima, Daisuke Morinaga, Keisuke Kamada, Sho Nakakubo, Yu Yamashita, Yasuo Shichinohe, Shinichi Fujisawa, Mutsumi Nishida, Yasuyuki Nasuhara, Takanori Teshima, Satoshi Konno
Journal of Infection, 82, 1, 159, 198, Elsevier BV, 2021年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation
Souichi Shiratori, Junichi Sugita, Shuichi Ota, Senji Kasahara, Jun Ishikawa, Takayoshi Tachibana, Yoshiki Hayashi, Goichi Yoshimoto, Tetsuya Eto, Hiromi Iwasaki, Mine Harada, Keitaro Matsuo, Takanori Teshima
Bone Marrow Transplantation, 56, 1, 129, 136, Springer Science and Business Media LLC, 2021年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of severe acute and chronic graft-versus-host disease (GVHD) compared to bone marrow transplantation. Anti-thymocyte globulin (ATG) can reduce severe acute and chronic GVHD in PBSCT; however, an optimal dose of ATG remains undefined. We conducted a multicenter phase II study to investigate safety and efficacy of low-dose ATG (a total of 2 mg/kg Thymoglobulin) in patients undergoing HLA-matched PBSCT after myeloablative conditioning. The primary endpoint was grades III-IV GVHD at 100 days. Seventy-seven patients were enrolled and 72 patients with a median age of 46.5 years were eligible for analysis. The primary endpoint, cumulative incidence of grades III-IV acute GVHD at 100 days was 1.4% (95% CI, 0.1-6.7%), which was greatly less than our pre-defined statistical threshold value (18.0%). The incidence of chronic GVHD at 1 year was also low (all-grade; 15.3%, moderate to severe; 5.6%). Non-relapse mortality, relapse, overall survival, disease-free survival, and GVHD-free, relapse-free survival at 1 year were 4.2%, 20.8%, 84.7%, 75.0%, and 69.4%, respectively. Low dose thymoglobulin is promising to reduce severe acute and chronic GVHD in HLA-matched PBSCT following myeloablative conditioning.

Pharmacokinetics of mycophenolic acid after haplo-hematopoietic stem cell transplantation in Japanese recipients
Kazuki Uchiyama, Yoshitaka Saito, Yoh Takekuma, Junichi Sugita, Takanori Teshima, Mitsuru Sugawara
Journal of Oncology Pharmacy Practice, 28, 1, 107815522098081, 107815522098081, SAGE Publications, 2020年12月22日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) prodrug, is used to prevent graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). Although previous studies have reported that enterohepatic circulation (EHC) of MPA, which is usually observed in MMF-treated patients, does not occur in HSCT patients, it is unclear what happens in haploidentical–HSCT (haplo-HSCT) patients, who are using post-transplant cyclophosphamide. This study was conducted to investigate MPA pharmacokinetics in haplo-HSCT patients.

Seventeen haplo-HSCT patients, who received MMF for GVHD prophylaxis, were enrolled in this study. We collected blood samples on days 14 and 28, and plasma MPA concentrations were measured by high-performance liquid chromatography; pharmacokinetic parameters such as area under the curve (AUC), mean residence time (MRT), and apparent oral clearance (CL/F) were measured with moment analysis. We also evaluated EHC as AUC_6-12h/AUC_0-12h.

There was no significant difference in MPA pharmacokinetic parameters between days 14 and 28. There was also no difference between the pharmacokinetic parameter changes and diarrhea. Additionally, varying plasma MPA concentrations suggested that MPA EHC did not occur.

In this study, we revealed the pharmacokinetics of MMF in Japanese haplo-HSCT recipients. Additionally, our study demonstrated that MPA EHC might not occur in Japanese haplo-HSCT recipients.

A novel nutritional index “simplified CONUT” and the disease risk index independently stratify prognosis of elderly patients with acute myeloid leukemia
Hajime Senjo, Masahiro Onozawa, Daisuke Hidaka, Shota Yokoyama, Satoshi Yamamoto, Yutaka Tsutsumi, Yoshihito Haseyama, Takahiro Nagashima, Akio Mori, Shuichi Ota, Hajime Sakai, Toshimichi Ishihara, Takuto Miyagishima, Yasutaka Kakinoki, Mitsutoshi Kurosawa, Hajime Kobayashi, Hiroshi Iwasaki, Daigo Hashimoto, Takeshi Kondo, Takanori Teshima
Scientific Reports, 10, 1, Springer Science and Business Media LLC, 2020年12月, ［査読有り］
研究論文（学術雑誌）,
Elderly patients aged 65 or older with acute myeloid leukemia (AML) have poor prognosis. The risk stratification based on genetic alteration has been proposed in national comprehensive cancer network (NCCN) guideline but its efficacy was not well verified especially in real world elderly patients. The nutritional status assessment using controlling nutritional status (CONUT) score is a prognostic biomarker in elderly patients with solid tumors but was not examined in elderly AML patients. We performed prospective analysis of genetic alterations of 174 patients aged 65 or older with newly diagnosed AML treated without hematopoietic stem cell transplantation (HSCT) and developed simplified CONUT (sCONUT) score by eliminating total lymphocyte count from the items to adapt AML patients. In this cohort, both the NCCN 2017 risk group and sCONUT score successfully stratified the overall survival (OS) of the elderly patients. A multivariable analysis demonstrated that adverse group in NCCN 2017 and high sCONUT score were independently associated with poor 2-year OS. Both risk stratification based on NCCN 2017 and sCONUT score predict prognosis in the elderly patients with newly diagnosed AML.

Association of Epstein–Barr virus with regression after withdrawal of immunosuppressive drugs and subsequent progression of iatrogenic immunodeficiency‐associated lymphoproliferative disorders in patients with autoimmune diseases
Katsuya Fujimoto, Kanako C. Hatanaka, Yutaka Hatanaka, Ikumi Kasahara, Satoshi Yamamoto, Takahiro Tsuji, Masanobu Nakata, Yasunari Takakuwa, Yoshihito Haseyama, Yumiko Oyamada, Masakatsu Yonezumi, Hiroaki Suzuki, Hajime Sakai, Hiroko Noguchi, Akio Mori, Hiroshi Nishihara, Takanori Teshima, Yoshihiro Matsuno
Hematological Oncology, 38, 5, 799, 807, Wiley, 2020年12月, ［査読有り］
研究論文（学術雑誌）

Validation and comparison of prognostic values of GNRI, PNI, and CONUT in newly diagnosed diffuse large B cell lymphoma
Toshihiro Matsukawa, Keito Suto, Minoru Kanaya, Koh Izumiyama, Koichiro Minauchi, Shota Yoshida, Hisashi Oda, Takuto Miyagishima, Akio Mori, Shuichi Ota, Daigo Hashimoto, Takanori Teshima
Annals of Hematology, 99, 12, 2859, 2868, Springer Science and Business Media LLC, 2020年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma. Emerging evidence indicates that poor nutritional status determined with nutritional indices such as geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status score (CONUT) was associated with poor prognosis of DLBCL. We conducted this multicenter retrospective study to validate and compare prognostic values of the three indices in 615 newly diagnosed DLBCL patients. The overall survival (OS) in patients with poor nutritional status determined with each of these nutritional indices were significantly inferior compared with that in those without nutritional risks (5-year OS in patients with GNRI < 95.7 and GNRI ≥ 95.7 were 56.4% and 83.5%, P < 0.001; PNI < 42.4 and PNI ≥ 42.4 were 56.1% and 81.0%, P < 0.001; CONUT > 4 and CONUT ≤ 4 were 53.1% and 77.1%, P < 0.001). GNRI and CONUT were independent prognostic predictors for OS (GNRI < 95.7, hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.22-2.74, P = 0.0032; CONUT > 4, HR 1.53, 95% CI 1.05-2.23, P = 0.028) after multivariate analyses. Nutritional status determined with GNRI affected OS more strongly in the patients with nongerminal center B cell-like (nonGCB) DLBCL compared with that in those with GCB-type DLBCL. In conclusion, baseline poor nutritional status determined based on GNRI or CONUT was an independent risk factor of newly diagnosed DLBCL, and GNRI was also useful as an independent prognostic factor for patients with nonGCB-type DLBCL.

SOS/VOD評価における超音波検査スコアHokUS-3の検者再現性に関する検討　　　　　　　　　　　　　　　
岩井 孝仁, 西田 睦, 工藤 悠輔, 高杉 莉佳, 横田 勲, 高木 諒, 渋谷 斉, 高橋 秀一郎, 杉田 純一, 豊嶋 崇徳
超音波医学, 47, Suppl., S344, S344, (公社)日本超音波医学会, 2020年11月
日本語

Pembrolizumab plus lenalidomide and dexamethasone in treatment-naive multiple myeloma (KEYNOTE-185): subgroup analysis in Japanese patients
Naoki Takezako, Hiroshi Kosugi, Morio Matsumoto, Shinsuke Iida, Takayuki Ishikawa, Yukio Kondo, Kiyoshi Ando, Hirokazu Miki, Itaru Matsumura, Kazutaka Sunami, Takanori Teshima, Hiromi Iwasaki, Yasushi Onishi, Masahiro Kizaki, Koji Izutsu, Dai Maruyama, Kensei Tobinai, Razi Ghori, Mohammed Farooqui, Jason Liao, Patricia Marinello, Kenji Matsuda, Yasuhiro Koh, Takashi Shimamoto, Kenshi Suzuki
International Journal of Hematology, 112, 5, 640, 649, Springer Science and Business Media LLC, 2020年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The global, randomized, open-label KEYNOTE-185 study closed early after an interim analysis showed an unfavorable benefit-risk profile with pembrolizumab plus lenalidomide and low-dose dexamethasone (Rd) versus Rd alone in treatment-naive, transplant-ineligible multiple myeloma. This subgroup analysis reported outcomes in the Japanese population. Patients were randomly assigned (1:1) to pembrolizumab plus Rd or Rd alone, stratified by age and International Staging System. The primary end point was progression-free survival (PFS). Fifty-two Japanese patients were randomly assigned to pembrolizumab plus Rd (n = 27) or Rd (n = 25). The median follow-up was 7.2 months (range, 0.4-13.8). The median PFS was not reached (NR); 6-month PFS was 91.2% versus 86.2% with pembrolizumab plus Rd versus Rd [hazard ratio (HR), 0.31; 95% CI, 0.06-1.63]. The median overall survival (OS) was NR; 6-month OS was 96.2% versus 95.7% with pembrolizumab plus Rd versus Rd (HR, 0.33; 95% CI, 0.03-3.72). With pembrolizumab plus Rd versus Rd, grade 3-5 adverse events occurred in 70.4% versus 69.6% of patients; serious adverse events occurred in 40.7% versus 52.5%. Although in the Japanese subgroup of KEYNOTE-185 adding pembrolizumab to Rd did not show an unfavorable risk-benefit, the analysis is limited by short follow-up and small sample size, affecting generalizability of the results.

Safety and efficacy of anti-programmed cell death-1 monoclonal antibodies before and after allogeneic hematopoietic cell transplantation for relapsed or refractory Hodgkin lymphoma: a multicenter retrospective study
Ayumu Ito, Sung-Won Kim, Ken-ichi Matsuoka, Toshiro Kawakita, Takashi Tanaka, Yoshihiro Inamoto, Tomomi Toubai, Shin-ichiro Fujiwara, Masafumi Fukaya, Tadakazu Kondo, Junichi Sugita, Miho Nara, Yuna Katsuoka, Yosuke Imai, Hideyuki Nakazawa, Ichiro Kawashima, Rika Sakai, Arata Ishii, Makoto Onizuka, Tomonari Takemura, Seitaro Terakura, Hiroatsu Iida, Mika Nakamae, Kohei Higuchi, Shinobu Tamura, Satoshi Yoshioka, Kazuto Togitani, Noriaki Kawano, Ritsuro Suzuki, Junji Suzumiya, Koji Izutsu, Takanori Teshima, Takahiro Fukuda
International Journal of Hematology, 112, 5, 674, 689, Springer Science and Business Media LLC, 2020年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, We conducted a multicenter study on anti-programmed cell death-1 monoclonal antibodies (anti-PD-1 mAbs) before/after allogeneic hematopoietic cell transplantation (allo-HCT) for Hodgkin lymphoma. Anti-PD-1 mAbs were administered to 25 patients before allo-HCT and to 20 after allo-HCT. In pre-allo-HCT setting, the median interval from the last administration to allo-HCT was 59 days. After allo-HCT, 12 patients developed non-infectious febrile syndrome requiring high-dose corticosteroid. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGvHD) were 47.1%. Eight patients who had GvHD prophylaxis with post-transplant cyclophosphamide (PTCy) had less frequent aGvHD (grade II-IV, 14.6% versus 58.8%; P = 0.086). The 1 year overall survival (OS), relapse/progression, and non-relapse mortality rates were 81.3%, 27.9%, and 8.4%. In post-allo-HCT setting, the median interval from allo-HCT to the first administration was 589 days. The overall and complete response rates were 75% and 40%. At 100 days after anti-PD-1 therapy, the cumulative incidences of grade II-IV aGvHD, moderate-to-severe chronic GvHD, and grade 3-4 immune-related toxicity were 15.0%, 30.0%, and 30.0%. While the 1 year relapse/progression rate was 47.4%, the 1 year OS probability was 89.7%. In conclusion, immune-related complications were frequent despite modifications of GvHD prophylaxis or anti-PD-1 mAb dosing. In anti-PD-1-mAb-pretreated patients, PTCy-based GvHD prophylaxis may be effective.

Reply to authors.
Isao Yokota, Kentaro Sakamaki, Peter Y Shane, Takanori Teshima
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 73, 11, e3986-e3987, 2020年10月26日, ［国際誌］
英語, 研究論文（学術雑誌）

多種動物に反応する異好抗体により複数の試薬で偽陽性を呈した1症例　　　　　　　　　　　　　　　
中野 恵一, 安田 慶子, 西田 睦, 杉田 純一, 豊嶋 崇徳
臨床化学, 49, Suppl.1, 194, 194, (一社)日本臨床化学会, 2020年10月
日本語

Myeloablative intravenous busulfan-containing regimens for allo-HSCT in AML or MDS patients over 54 years old: combined results of three phase II studies
Naoyuki Uchida, Kana Matsumoto, Toru Sakura, Michihiro Hidaka, Toshihiro Miyamoto, Tetsuya Eto, Yoshinobu Maeda, Tohru Murayama, Naohito Fujishima, Goichi Yoshimoto, Kunihiko Morita, Junji Kishimoto, Takanori Teshima, Shuichi Taniguchi, Takuya Yamashita, Shin-ichiro Mori, Koichi Akashi, Mine Harada
International Journal of Hematology, 112, 4, 510, 523, Springer Science and Business Media LLC, 2020年10月, ［査読有り］
研究論文（学術雑誌）

Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy‐associated hepatitis in Japan
Takashi Kitagataya, Goki Suda, Kazunori Nagashima, Takehiko Katsurada, Koji Yamamoto, Megumi Kimura, Osamu Maehara, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Yoshito Komatsu, Hiroo Hata, Satoshi Takeuchi, Takashige Abe, Jun Sakakibara‐Konishi, Takanori Teshima, Akihiro Homma, Naoya Sakamoto
Journal of Gastroenterology and Hepatology, 35, 10, 1782, 1788, Wiley, 2020年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data. RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis. CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.

Short-term treatment with imetelstat sensitizes hematopoietic malignant cells to a genotoxic agent via suppression of the telomerase-mediated DNA repair process
Daisuke Hidaka, Masahiro Onozawa, Naohiro Miyashita, Shota Yokoyama, Masao Nakagawa, Daigo Hashimoto, Takanori Teshima
Leukemia & Lymphoma, 61, 11, 2722, 2732, Informa UK Limited, 2020年09月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Imetelstat is a specific and competitive inhibitor of telomerase enzymatic activity. We demonstrated that imetelstat could interfere with the DNA repair process and enhance the effect of DNA damaging agents using hematological tumor cell lines. Short-term administration of imetelstat enhanced growth suppression by anticancer agents and radiation. It also upregulated γH2AX expression induced by irradiation. Immunofluorescence staining showed that both human telomerase reverse transcriptase (hTERT) and γH2AX were upregulated and co-localized in the nucleus of peripheral blood mononuclear cells after irradiation, suggesting that hTERT was involved in the DNA-DSB repair process. Imetelstat enhanced growth inhibitory effect of cytotoxic agents in short-term culture without shortening of telomeres, indicating that this effect was attributed by telomere length independent mechanism. Our results suggest that the combination of short-term treatment with imetelstat and cytotoxic agent is a promising strategy to treat a wide variety of hematopoietic malignancies.

臍帯血移植後のドナー由来細胞にモノソミー7を認めたAMLの一症例　　　　　　　　　　　　　　　
佐藤 かおり, 小栗 聡, 市川 絢子, 藤澤 真一, 西田 睦, 杉田 純一, 小野澤 真弘, 豊嶋 崇徳
日本医学検査学会抄録集, 69回, 399, 399, (一社)日本臨床衛生検査技師会, 2020年09月
日本語

Feasibility and efficacy of low‐dose pegfilgrastim for CD34 + cell mobilization in lymphoma
Hideki Goto, Daisuke Hidaka, Satoshi Yamamoto, Koji Hayasaka, Rie Michimata, Ikuko Kagawa, Kana Sunagoya, Hiroaki Iijima, Eiko Hayase, Souichi Shiratori, Kohei Okada, Junichi Sugita, Masahiro Onozawa, Daigo Hashimoto, Kaoru Kahata, Katsuya Fujimoto, Tomoyuki Endo, Chikara Shimizu, Takanori Teshima
Journal of Clinical Apheresis, 35, 5, 413, 419, Wiley, 2020年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Pegfilgrastim has equivalent efficacy to daily granulocyte colony-stimulating factor (G-CSF) in enhancing neutrophil recovery after chemotherapy, but data on its use for peripheral blood stem cell (PBSC) mobilization are limited. We evaluated the safety and efficacy of CD34+ PBSC mobilization by low-dose (3.6 mg) pegfilgrastim after chemotherapy in patients with malignant lymphoma. STUDY DESIGN AND METHODS: Twenty patients with malignant lymphoma were enrolled in this study. Cytotoxic chemotherapy was started on day 1, and 3.6 mg of pegfilgrastim was subcutaneously administered on day 7. CD34+ cells were counted in the peripheral blood daily from days 11 to 14 using a flow cytometric analysis. RESULTS: In 19 of the 20 patients (95%), the CD34+ cell counts in the peripheral blood exceeded 10 × 106/L, with a mean value of 20.3 on day 11, 38.0 on day 12, 40.3 on day 13, and 40.1 on day 14. Older age was associated with lower maximum CD34+ cell mobilization. The most frequent adverse events associated with pegfilgrastim were back pain, nausea, appetite loss, and lactate dehydrogenase elevation. CONCLUSION: Our data indicated that a single dose of 3.6 mg pegfilgrastim on day 7 after chemotherapy safely and effectively mobilized CD34+ cells.

Efficacy and safety of tisagenlecleucel in Japanese adult patients with relapsed/refractory diffuse large B-cell lymphoma
Hideki Goto, Shinichi Makita, Koji Kato, Kota Tokushige, Taizo Fujita, Koichi Akashi, Koji Izutsu, Takanori Teshima
International Journal of Clinical Oncology, 25, 9, 1736, 1743, Springer Science and Business Media LLC, 2020年09月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）,

Tisagenlecleucel demonstrated a high rate of durable response in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in the pivotal global phase 2 JULIET study. Here, we report the efficacy and safety of tisagenlecleucel in the Japanese subgroup.




JULIET (NCT02445248) is a single-arm, open-label, multicenter, phase 2 study involving adult patients with r/r DLBCL who either relapsed after or were ineligible for autologous stem cell transplant. Primary endpoint was best overall response rate (ORR; complete response [CR] + partial response [PR]) as judged by an independent review committee.




In Japan, of 17 patients enrolled, 9 were infused with tisagenlecleucel and completed ≥ 3 months of follow-up. Best ORR was 77.8% (7/9; 95% confidence interval, 40.0–97.2), with 5 patients (55.6%) in CR and 2 (22.2%) in PR. Cytokine release syndrome (CRS) occurred in 6 patients (66.7%), with grade 3 CRS in 2 patients (Penn grading scale). Two patients received tocilizumab. Two deaths (22.2%) occurred more than 30 days after tisagenlecleucel infusion due to disease progression, neither of which were related to tisagenlecleucel.




Tisagenlecleucel showed a high best ORR with a manageable safety profile, thus offering a new treatment option in selected Japanese patients with r/r DLBCL.

Comparison of SARS-CoV-2 detection in nasopharyngeal swab and saliva
Sumio Iwasaki, Shinichi Fujisawa, Sho Nakakubo, Keisuke Kamada, Yu Yamashita, Tatsuya Fukumoto, Kaori Sato, Satoshi Oguri, Keisuke Taki, Hajime Senjo, Junichi Sugita, Kasumi Hayasaka, Satoshi Konno, Mutsumi Nishida, Takanori Teshima
Journal of Infection, 81, 2, e145, e147, Elsevier BV, 2020年08月, ［査読有り］
研究論文（学術雑誌）

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide
Annie Im, Armin Rashidi, Tao Wang, Michael Hemmer, Margaret L. MacMillan, Joseph Pidala, Madan Jagasia, Steven Pavletic, Navneet S. Majhail, Daniel Weisdorf, Hisham Abdel-Azim, Vaibhav Agrawal, A. Samer Al-Homsi, Mahmoud Aljurf, Medhat Askar, Jeffery J. Auletta, Asad Bashey, Amer Beitinjaneh, Vijaya Raj Bhatt, Michael Byrne, Jean-Yves Cahn, Mitchell Cairo, Paul Castillo, Jan Cerny, Saurabh Chhabra, Hannah Choe, Stefan Ciurea, Andrew Daly, Miguel Angel Diaz Perez, Nosha Farhadfar, Shahinaz M. Gadalla, Robert Gale, Siddhartha Ganguly, Usama Gergis, Rabi Hanna, Peiman Hematti, Roger Herzig, Gerhard C. Hildebrandt, Deepesh P. Lad, Catherine Lee, Leslie Lehmann, Lazaros Lekakis, Rammurti T. Kamble, Mohamed A. Kharfan-Dabaja, Pooja Khandelwal, Rodrigo Martino, Hemant S. Murthy, Taiga Nishihori, Tracey A. O'Brien, Richard F. Olsson, Sagar S. Patel, Miguel-Angel Perales, Tim Prestidge, Muna Qayed, Rizwan Romee, Hélène Schoemans, Sachiko Seo, Akshay Sharma, Melhem Solh, Roger Strair, Takanori Teshima, Alvaro Urbano-Ispizua, Marjolein Van der Poel, Ravi Vij, John L. Wagner, Basem William, Baldeep Wirk, Jean A. Yared, Steve R. Spellman, Mukta Arora, Betty K. Hamilton
Biology of Blood and Marrow Transplantation, 26, 8, 1459, 1468, Elsevier BV, 2020年08月, ［査読有り］
研究論文（学術雑誌）

Lymphocyte‐monocyte ratio (LMR) can predict bendamustine therapeutic efficacy in low‐grade B‐cell lymphoma
Joji Shimono, Koh Izumiyama, Shinichi Ito, Yutaka Tsutsmi, Takeshi Kondo, Yasutaka Kakinoki, Takanori Teshima
International Journal of Laboratory Hematology, 42, 4, 431, 438, Wiley, 2020年08月, ［査読有り］
研究論文（学術雑誌）

Effect of graft-versus-host disease on outcomes after pediatric single cord blood transplantation
Junya Kanda, Katsutsugu Umeda, Koji Kato, Makoto Murata, Junichi Sugita, Souichi Adachi, Katsuyoshi Koh, Maiko Noguchi, Hiroaki Goto, Nao Yoshida, Maho Sato, Yuhki Koga, Tsukasa Hori, Yuko Cho, Atsushi Ogawa, Masami Inoue, Yoshiko Hashii, Yoshiko Atsuta, Takanori Teshima
Bone Marrow Transplantation, 55, 7, 1430, 1437, Springer Science and Business Media LLC, 2020年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The effect of GVHD on transplant outcomes after unrelated cord blood transplantation (UCBT) is not yet fully understood. Pediatric patients aged 0-15 years with acute leukemia or myelodysplastic syndrome who underwent their first UCBT (n = 740) were selected from the Japanese registry. Fifty percent of the patients received a UCB unit containing more than 5.0 × 107/kg total nucleated cells. The occurrence of grade III-IV acute GVHD was associated with a higher risk of non-relapse mortality (NRM, hazard ratio [HR] 4.07, P < 0.001) compared with no acute GVHD. Grade I-II acute GVHD was not associated with NRM. The occurrence of grade I-II or grade III-IV acute GVHD was not associated with a relapse risk. These findings showed that grade I-II acute GVHD carried no survival benefit and grade III-IV acute GVHD had an adverse effect (HR 1.68, P = 0.007). The occurrence of limited chronic GVHD was associated with a low risk of overall mortality (HR 0.60, P = 0.045). Severe acute GVHD should be prevented because of its association with high overall mortality and NRM in pediatric single UCBT. Mild acute GVHD provides no overall benefit. Mild chronic GVHD may be beneficial for survival.

Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8
Takahide Ara, Daigo Hashimoto, Eiko Hayase, Clara Noizat, Ryo Kikuchi, Yuta Hasegawa, Kana Matsuda, Shoko Ono, Yoshihiro Matsuno, Ko Ebata, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Emi Yokoyama, Keitaro Matsuo, Junichi Sugita, Masahiro Onozawa, Ryu Okumura, Kiyoshi Takeda, Takanori Teshima
Science Translational Medicine, 12, 550, eaaw0720, eaaw0720, American Association for the Advancement of Science (AAAS), 2020年07月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Graft-versus-host disease (GVHD) and infection are major obstacles to successful allogeneic hematopoietic stem cell transplantation (HSCT). Intestinal goblet cells form the mucus layers, which spatially segregate gut microbiota from host tissues. Although it is well known that goblet cell loss is one of the histologic features of GVHD, effects of their loss in pathophysiology of GVHD remain to be elucidated. In mouse models of allogeneic HSCT, goblet cells in the colon were significantly reduced, resulting in disruption of the inner mucus layer of the colon and increased bacterial translocation into colonic mucosa. Pretransplant administration of interleukin-25 (IL-25), a growth factor for goblet cells, protected goblet cells against GVHD, prevented bacterial translocation, reduced plasma concentrations of interferon-γ (IFN-γ) and IL-6, and ameliorated GVHD. The protective role of IL-25 was dependent on Lypd8, an antimicrobial molecule produced by enterocytes in the colon that suppresses motility of flagellated bacteria. In clinical colon biopsies, low numbers of goblet cells were significantly associated with severe intestinal GVHD, increased transplant-related mortality, and poor survival after HSCT. Goblet cell loss is associated with poor transplant outcome, and administration of IL-25 represents an adjunct therapeutic strategy for GVHD by protecting goblet cells.

Efficacy of a novel SARS-CoV-2 detection kit without RNA extraction and purification.
Tatsuya Fukumoto, Sumio Iwasaki, Shinichi Fujisawa, Kasumi Hayasaka, Kaori Sato, Satoshi Oguri, Keisuke Taki, Sho Nakakubo, Keisuke Kamada, Yu Yamashita, Satoshi Konno, Mutsumi Nishida, Junichi Sugita, Takanori Teshima
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 98, 16, 17, Elsevier BV, 2020年06月26日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for the diagnosis of coronavirus disease 2019 (COVID-19) and preventing the spread of the virus. A novel detection kit - the 2019 Novel Coronavirus Detection Kit (nCoV-DK) - halves the detection time by eliminating the steps of RNA extraction and purification. We evaluated the concordance between the nCoV-DK and direct PCR. The virus was detected in 53/71 specimens (74.6%) by direct PCR and in 55/71 specimens (77.5%) by nCoV-DK; the overall concordance rate was 94.4%: 95.2% for nasopharyngeal swab, 95.5% for saliva, and 85.7% for sputum. The nCoV-DK test effectively detects SARS-CoV-2 in all types of sample including saliva, while reducing the time required for detection, labor, and the risk of human error.

Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT
Rohtesh S. Mehta, Shernan G. Holtan, Tao Wang, Michael T. Hemmer, Stephen R. Spellman, Mukta Arora, Daniel R. Couriel, Amin M. Alousi, Joseph Pidala, Hisham Abdel-Azim, Vaibhav Agrawal, Ibrahim Ahmed, A. Samer Al-Homsi, Mahmoud Aljurf, Joseph H. Antin, Medhat Askar, Jeffery J. Auletta, Vijaya Raj Bhatt, Lynette Chee, Saurabh Chhabra, Andrew Daly, Zachariah DeFilipp, James Gajewski, Robert Peter Gale, Usama Gergis, Peiman Hematti, Gerhard C. Hildebrandt, William J. Hogan, Yoshihiro Inamoto, Rodrigo Martino, Navneet S. Majhail, David I. Marks, Taiga Nishihori, Richard F. Olsson, Attaphol Pawarode, Miguel Angel Diaz, Tim Prestidge, Hemalatha G. Rangarajan, Olle Ringden, Ayman Saad, Bipin N. Savani, Hélène Schoemans, Sachiko Seo, Kirk R. Schultz, Melhem Solh, Thomas Spitzer, Jan Storek, Takanori Teshima, Leo F. Verdonck, Baldeep Wirk, Jean A. Yared, Jean-Yves Cahn, Daniel J. Weisdorf
Journal of Clinical Oncology, 38, 18, 2062, 2076, American Society of Clinical Oncology (ASCO), 2020年06月20日, ［査読有り］
研究論文（学術雑誌）, There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]–bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor.

We report composite end points of graft-versus-host disease (GVHD)–free relapse-free survival (GRFS) and chronic GVHD (cGVHD)–free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant.

In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group.

Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.

High metabolic heterogeneity on baseline 18FDG-PET/CT scan as a poor prognostic factor for newly diagnosed diffuse large B-cell lymphoma
Hajime Senjo, Kenji Hirata, Koh Izumiyama, Koichiro Minauchi, Eriko Tsukamoto, Kazuo Itoh, Minoru Kanaya, Akio Mori, Shuichi Ota, Daigo Hashimoto, Takanori Teshima
Blood Advances, 4, 10, 2286, 2296, American Society of Hematology, 2020年05月26日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）,
Metabolic heterogeneity (MH) can be measured using 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT), and it indicates an inhomogeneous tumor microenvironment. High MH has been shown to predict a worse prognosis for primary mediastinal B-cell lymphoma, whereas its prognostic value in diffuse large B-cell lymphoma (DLBCL) remains to be determined. In the current study, we investigated the prognostic values of MH evaluated in newly diagnosed DLBCL. In the training cohort, 86 patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone–like chemotherapies were divided into low-MH and high-MH groups using receiver operating characteristic analysis. MH was not correlated with metabolic tumor volume of the corresponding lesion, indicating that MH was independent of tumor burden. At 5 years, overall survivals were 89.5% vs 61.2% (P = .0122) and event-free survivals were 73.1% vs 51.1% (P = .0327) in the low- and high-MH groups, respectively. A multivariate Cox-regression analysis showed that MH was an independent predictive factor for overall survival. The adverse prognostic impacts of high MH were confirmed in an independent validation cohort with 64 patients. In conclusion, MH on baseline 18FDG-PET/CT scan predicts treatment outcomes for patients with newly diagnosed DLBCL.

Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease
Robert Zeiser, Nikolas von Bubnoff, Jason Butler, Mohamad Mohty, Dietger Niederwieser, Reuven Or, Jeff Szer, Eva M. Wagner, Tsila Zuckerman, Bruyère Mahuzier, Judith Xu, Celine Wilke, Kunal K. Gandhi, Gérard Socié
New England Journal of Medicine, 382, 19, 1800, 1810, Massachusetts Medical Society, 2020年05月07日, ［査読有り］
研究論文（学術雑誌）

Histological and magnified endoscopic evaluation of villous atrophy in gastrointestinal graft-versus-host disease
Kana Matsuda, Shoko Ono, Ikko Tanaka, Masaki Inoue, Sayoko Kinowaki, Marin Ishikawa, Momoko Tsuda, Keiko Yamamoto, Yuichi Shimizu, Shuichiro Takahashi, Eiko Hayase, Daigo Hashimoto, Takanori Teshima, Naoya Sakamoto
Annals of Hematology, 99, 5, 1121, 1128, Springer Science and Business Media LLC, 2020年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIM:  To measure histological villous atrophy and to clarify the diagnostic accuracy of endoscopic villous atrophy in gastrointestinal graft-versus-host disease. METHODS:  Data for patients who underwent upper and/or lower endoscopic examinations after hematopoietic stem cell transplantation were retrospectively collected. In study 1, group A included 56 patients in whom GI-GVHD was histologically confirmed and group B included 60 patients in whom GI-GVHD was not histologically confirmed. Group C included 59 patients before HSCT. The lengths of villi and crypts in the duodenum and terminal ileum were histologically measured. In study 2, the diagnostic accuracies of villous atrophy of the duodenum and of the terminal ileum using magnifying endoscopy were evaluated. RESULTS:  In study 1, the lengths of villi and the villi/crypt (V/C) ratios of the duodenum and terminal ileum in group A were significantly smaller than those in the other groups (p < 0.05). V/C ratio was moderately correlated with clinical severity, histological grades, and endoscopic grades in the terminal ileum. In study 2, the diagnostic accuracies of magnified images for villous atrophy were 83.8% in the duodenum and 94.9% in the terminal ileum. CONCLUSION:  Magnifying endoscopy enables evaluation of villous atrophy and is useful for optical biopsy of GVHD.

Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis.
Emi Yokoyama, Daigo Hashimoto, Eiko Hayase, Takahide Ara, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Takahiro Tateno, Yuta Hasegawa, Xuanzhong Chen, Takanori Teshima
Bone marrow transplantation, 55, 4, 787, 795, 2020年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Posttransplant high-dose cyclophosphamide (PTCY) has been increasingly used as graft-versus-host disease (GVHD) prophylaxis after HLA-haploidentical or matched hematopoietic stem cell transplantation (SCT). However, PTCY alone is insufficient and requires additional immunosuppressants such as calcineurin inhibitors. In the current study, we evaluated effects of a novel GVHD prophylaxis with PTCY in combination with short-term KRP203, a selective agonist of sphingosine-1-phosphate receptor 1 that regulates egress of lymphocytes from the secondary lymphoid organs (SLOs) in mice. Short-term oral administration of KRP203 alone induced apoptosis of donor T cells in the SLOs and ameliorated GVHD. Administration of KRP203 significantly preserved graft-versus-leukemia effects compared to cyclosporin. A combination of KRP203 on days 0 to +4 and PTCY on day +3 synergistically suppressed donor T-cell migration into the intestine and skin, and ameliorated GVHD more potently than PTCY alone. A combination of short-term KRP203 and PTCY is a promising novel calcineurin-free GVHD prophylaxis in HLA-haploidentical SCT.

Rosai-Dorfman disease: earlier spontaneous regression of skin lesions relative to nasal, pharyngeal, and bone lesions
Kazumasa Sato, Hideyuki Ujiie, Shinichi Nakazato, Mika Watanabe, Erika Watanabe, Teruki Yanagi, Yuji Nakamaru, Dai Takagi, Ryuta Arai, Tomohiro Onodera, Takeshi Kondo, Takanori Teshima, Hiroshi Shimizu
European Journal of Dermatology, 30, 2, 182, 183, John Libbey Eurotext, 2020年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Reduced dose of MTX for GVHD prophylaxis promotes engraftment and decreases non-relapse mortality in umbilical cord blood transplantation.
Souichi Shiratori, Hiroyuki Ohigashi, Shuichiro Takahashi, Takahide Ara, Hideki Goto, Masao Nakagawa, Junichi Sugita, Masahiro Onozawa, Kaoru Kahata, Tomoyuki Endo, Daigo Hashimoto, Takanori Teshima
Annals of hematology, 99, 3, 591, 598, Springer Science and Business Media LLC, 2020年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Although a combination of calcineurin inhibitor and methotrexate (MTX) is used for graft-versus-host disease (GVHD) prophylaxis in umbilical cord blood transplantation (CBT), optimal dose of MTX for CBT remains to be determined.We conducted a retrospective study to evaluate the safety and efficacy of standard-dose MTX (St-MTX, 15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6) and mini-dose MTX (Mini-MTX, 5 mg/m2 on days 1, 3 and 6) for GVHD prophylaxis in patients who underwent single unit CBT against hematological malignancies.Thirty-two and 26 patients received St-MTX and Mini-MTX, respectively. Cumulative incidence of neutrophil engraftment was significantly higher in the Mini-MTX group than in the St-MTX group (88.5% vs 65.6%, P = 0.00448). Cumulative incidences of grade II to IV and grade III to IV of acute graft-versus-host disease (GVHD) were 34.4% and 6.2% in the St-MTX group, and 34.6% and 7.7% in the Mini-MTX group with no statistical significance. One-year non-relapse mortality (NRM) was significantly lower in the Mini-MTX group compared to the St-MTX group (31.2% vs 3.8%, P = 0.00938), whereas relapse rate was not different between the groups. Multivariate analysis also indicated that Mini-MTX significantly improved engraftment (HR, 0.5359; 95% CI, 0.3082 to 0.9318; P = 0.0270) and reduced NRM (HR, 0.117; 95% CI, 0.0151 to 0.9067; P = 0.040).Our study suggests that GVHD prophylaxis using Mini-MTX in CBT is feasible and associated with improvement of engraftment and reduction in NRM.

Loss of nivolumab binding to T cell PD-1 predicts relapse of Hodgkin lymphoma.
Reiki Ogasawara, Daigo Hashimoto, Junichi Sugita, Fumihiko Yamawaki, Tomoaki Naka, Tomoko Mitsuhashi, Shuichiro Takahashi, Naohiro Miyashita, Kohei Okada, Masahiro Onozawa, Yoshihiro Matsuno, Takanori Teshima
International journal of hematology, 111, 3, 475, 479, 2020年03月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Nivolumab is effective in the treatment of classical Hodgkin lymphoma that relapsed after allogeneic hematopoietic stem cell transplantation (SCT) with the risk of graft-versus-host disease; however, the optimal time and dose of nivolumab administration remain to be investigated. Nivolumab binding to PD-1 masks flowcytometric detection of PD-1 by the anti-PD-1 monoclonal antibody EH12.1. Using this method, we monitored nivolumab binding on T cells after nivolumab treatment in a patient with classical Hodgkin lymphoma relapsed after allogeneic SCT. Nivolumab was effective while prolonged nivolumab binding was evident, but restoration of PD-1 staining predicted tumor relapse. Flowcytometric monitoring of nivolumab binding on T cells could be a promising biomarker for predicting tumor relapse and determining the timing of nivolumab administration.

Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation
Jonathan U. Peled, Antonio L.C. Gomes, Sean M. Devlin, Eric R. Littmann, Ying Taur, Anthony D. Sung, Daniela Weber, Daigo Hashimoto, Ann E. Slingerland, John B. Slingerland, Molly Maloy, Annelie G. Clurman, Christoph K. Stein-Thoeringer, Kate A. Markey, Melissa D. Docampo, Marina Burgos da Silva, Niloufer Khan, André Gessner, Julia A. Messina, Kristi Romero, Meagan V. Lew, Amy Bush, Lauren Bohannon, Daniel G. Brereton, Emily Fontana, Luigi A. Amoretti, Roberta J. Wright, Gabriel K. Armijo, Yusuke Shono, Míriam Sanchez-Escamilla, Nerea Castillo Flores, Ana Alarcon Tomas, Richard J. Lin, Lucrecia Yáñez San Segundo, Gunjan L. Shah, Christina Cho, Michael Scordo, Ioannis Politikos, Kasumi Hayasaka, Yuta Hasegawa, Boglarka Gyurkocza, Doris M. Ponce, Juliet N. Barker, Miguel-Angel Perales, Sergio A. Giralt, Robert R. Jenq, Takanori Teshima, Nelson J. Chao, Ernst Holler, Joao B. Xavier, Eric G. Pamer, Marcel R.M. van den Brink
New England Journal of Medicine, 382, 9, 822, 834, Massachusetts Medical Society, 2020年02月27日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).

Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma
Richard T. Maziarz, Edmund K. Waller, Ulrich Jaeger, Isabelle Fleury, Joseph McGuirk, Harald Holte, Samantha Jaglowski, Stephen J. Schuster, Michael R. Bishop, Jason R. Westin, Stephan Mielke, Takanori Teshima, Veronika Bachanova, Stephen R. Foley, Peter Borchmann, Gilles A. Salles, Jie Zhang, Ranjan Tiwari, Lida B. Pacaud, Qiufei Ma, Constantine S. Tam
Blood Advances, 4, 4, 629, 637, American Society of Hematology, 2020年02月25日, ［査読有り］
研究論文（学術雑誌）, The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the HRQoL assessments at baseline, including 57 patients who eventually achieved CR or partial response (PR). Further, 30 and 21 patients in clinical response who completed assessments at baseline also completed assessments at months 12 and 18, respectively. Patients who achieved CR or PR sustained HRQoL improvement in all FACT scores at all time points. SF-36 instruments showed improvement above the minimal clinically important differences on 5 of 8 subscales. Long-term follow-up in the phase 2 JULIET study demonstrated that patients with r/r DLBCL who respond to tisagenlecleucel therapy had sustained, clinically meaningful improvements in HRQoL. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

MT Seminar トロポニン測定のピットフォール
中野 恵一, 眞船 直樹, 安田 慶子, 西田 睦, 杉田 純一, 豊嶋 崇徳
Medical Technology, 48, 2, 193, 197, 医歯薬出版(株), 2020年02月
日本語, <要点>・トロポニンの測定値は臨床所見と乖離する可能性がある。・トロポニンTとIの検査結果は一定の相関関係があるが、両者の測定値が大きく異なる症例が存在する。・自施設の測定キットの特異性を理解しておくことが重要である。(著者抄録)

不規則抗体スクリーニング試薬0.8%セルスクリーンJ-Alba-を用い不規則抗体の早期検出が可能であった2症例
増田 裕弥, 伊藤 誠, 櫻澤 貴代, 魚住 諒, 渡邊 千秋, 西田 睦, 高橋 秀一郎, 杉田 純一, 豊嶋 崇徳
日本輸血細胞治療学会誌, 66, 1, 57, 57, (一社)日本輸血・細胞治療学会, 2020年02月
日本語

新生児におけるcisAB型の血液型検査反応性と発育に伴う抗原量の変化に関する検討
櫻澤 貴代, 高橋 秀一郎, 渡邊 千秋, 伊藤 誠, 魚住 諒, 増田 裕弥, 早坂 光司, 西田 睦, 杉田 純一, 豊嶋 崇徳
日本輸血細胞治療学会誌, 66, 1, 31, 35, (一社)日本輸血・細胞治療学会, 2020年02月, ［査読有り］
日本語, cisA2B3型はオモテ検査での抗A、抗Bの反応が弱く、血漿中に抗Bが認められる反応態度であるが、新生児におけるcisA2B3型の反応態度に関する報告は少ない。今回、cisA2B3型が疑われる新生児の血液型反応態度と成長に伴う血液型抗原量の変化について検討した。症例は日齢0日の新生児、ABO血液型検査はカラム凝集法にてオモテ検査のみ施行し、抗A:2+、抗B:0となった。母親が血清学的検査でcisA2B3型と疑われていたことから、児の血液型精査、母児のABO遺伝子タイピング、血液型抗原量を測定した。児の赤血球の抗B吸着解離試験よりB抗原が検出され、ABO遺伝子タイピングでは母児共にcisAB01/O01と判定された。血液型抗原量は母親と比較して児のA、B抗原量は低く、特にB抗原量が著しく低かった。1歳11ヵ月時に再検査したところ、児のB抗原量は出生時よりも増加し、血漿中から抗Bが検出された。新生児のcisAB型では通常の血液型検査では検出できないB抗原量であるため、血液型判定に際しcisAB型を疑う場合はABO遺伝子タイピングや血液型抗原量の測定が有用であることが示唆された。(著者抄録)

Salvage Transplantation with Cord Blood for Graft Rejection of Peripheral Blood Stem Cells due to Donor Specific Antibody
Maria Regina Pelobello de Leon, Shuichiro Takahashi, Masahiro Onozawa, Makoto Ito, Manabu Nakano, Hajime Senjo, Masahiro Chiba, Hiroyuki Ohigashi, Emi Yokoyama, Junichi Sugita, Daigo Hashimoto, Takanori Teshima
BLOOD CELL THERAPY / The official journal of APBMT, 3, 3, 74, 77, Asia-Pacific Blood and Marrow Transplantation Group, 2020年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various kinds of hematological malignancies and disorders. Recently, HLA-haploidentical stem cell transplantation with post-transplantation cyclophosphamide (PTCy-haplo HSCT) has been widely performed due to its safety and favorable immune recovery. However, graft rejection remains an obstacle to PTCy-haplo HSCT. Donor specific antibody (DSA) is considered to be a major factor of graft rejection of haplo HSCT. We herein present a case of graft rejection after PTCy haplo-HSCT due to DSA induced by pretransplant platelet transfusion after donor selection. The patient was dependent on platelet transfusion and had not received cytotoxic chemotherapy because he was diagnosed as myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable. We retrospectively confirmed the level of DSA just before the first transplantation and found that it was dramatically elevated, which was enough to cause graft rejection. We successfully performed cord blood transplantation of the HLA that was not the target of DSA, as salvage transplantation without any desensitization. This case illustrates that we have to confirm the presence of DSA immediately before the haplo-HSCT, particularly in high risk patients who are dependent on platelet transfusion and have no cytotoxic chemotherapy before HSCT.

A Novel Strategy for SARS-CoV-2 Mass-Screening Using Quantitative Antigen Testing of Saliva
Isao Yokota, Peter Y. Shane, Kazufumi Okada, Yokota Unoki, Yichi Yang, Sumio Iwasaki, Shinichi Fujisawa, Mutsumi Nishida, Takanori Teshima
SSRN Electronic Journal, Elsevier BV, 2020年, ［査読有り］
研究論文（学術雑誌）

Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease
Satomi Matsuoka, Daigo Hashimoto, Masanori Kadowaki, Hiroyuki Ohigashi, Eiko Hayase, Emi Yokoyama, Yuta Hasegawa, Takahiro Tateno, Xuanzhong Chen, Kazutoshi Aoyama, Hideyo Oka, Masahiro Onozawa, Kiyoshi Takeda, Koichi Akashi, Takanori Teshima
Haematologica, 105, 1, 226, 234, Ferrata Storti Foundation (Haematologica), 2020年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Myeloid differentiation factor 88 (MyD88) signaling has a crucial role in activation of both innate and adoptive immunity. MyD88 transduces signals via Toll-like receptor and interleukin-1 receptor superfamily to the NFκB pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. The MyD88/interleukin-1 receptor-associated kinase 4 pathway plays an important role, not only in innate immunity, but also T-cell immunity; however, its role in donor T cells on the pathophysiology of graft-versus-host disease (GvHD) remains to be elucidated. We addressed this issue by using MyD88-deficient T cells in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-SCT). While MyD88-deficient and wild-type T cells proliferated equivalently after transplantation, MyD88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe GvHD compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly ameliorated GvHD after allo-SCT. These results thus demonstrate that donor T-cell MyD88/interleukin-1 receptor-associated kinase 4 pathway is a novel therapeutic target against GvHD after allo-SCT.

Localization of BCR-ABL to Stress Granules Contributes to Its Oncogenic Function.
Sayaka Kashiwagi, Yoichiro Fujioka, Takeshi Kondo, Aya O Satoh, Aiko Yoshida, Mari Fujioka, Hitoshi Sasajima, Maho Amano, Takanori Teshima, Yusuke Ohba
Cell structure and function, 44, 2, 195, 204, 2019年12月26日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The oncogenic tyrosine kinase BCR-ABL activates a variety of signaling pathways and plays a causative role in the pathogenesis of chronic myelogenous leukemia (CML); however, the subcellular distribution of this chimeric protein remains controversial. Here, we report that BCR-ABL is localized to stress granules and that its granular localization contributes to BCR-ABL-dependent leukemogenesis. BCR-ABL-positive granules were not colocalized with any markers for membrane-bound organelles but were colocalized with HSP90a, a component of RNA granules. The number of such granules increased with thapsigargin treatment, confirming that the granules were stress granules. Given that treatment with the ABL kinase inhibitor imatinib and elimination of the N-terminal region of BCR-ABL abolished granule formation, kinase activity and the coiled-coil domain are required for granule formation. Whereas wild-type BCR-ABL rescued the growth defect in IL-3-depleted Ba/F3 cells, mutant BCR-ABL lacking the N-terminal region failed to do so. Moreover, forced tetramerization of the N-terminus-deleted mutant could not restore the growth defect, indicating that granule formation, but not tetramerization, through its N-terminus is critical for BCR-ABL-dependent oncogenicity. Our findings together provide new insights into the pathogenesis of CML by BCR-ABL and open a window for developing novel therapeutic strategies for this disease.Key words: BCR-ABL, subcellular localization, stress granule.

A prospective observational study of immune reconstitution following transplantation with post‐transplant reduced‐dose cyclophosphamide from HLA ‐haploidentical donors
Hirohisa Nakamae, Kazuki Fujii, Satoru Nanno, Hiroshi Okamura, Takahiko Nakane, Hideo Koh, Yasuhiro Nakashima, Mika Nakamae, Asao Hirose, Takanori Teshima, Masayuki Hino
Transplant International, 32, 12, 1322, 1332, Wiley, 2019年12月, ［査読有り］
研究論文（学術雑誌）

Carbapenem inactivation method(CIM)を応用したESBLおよびAmpCの同時検出法の開発　　　　　　　　　　　　　　　
岩崎 澄央, 福元 達也, 早坂 かすみ, 西田 睦, 杉田 純一, 豊嶋 崇徳
日本臨床微生物学会雑誌, 30, Suppl.1, 284, 284, (一社)日本臨床微生物学会, 2019年12月
日本語

Simplified Carbapenem inactivation method(sCIM)を応用したESBLおよびAmpCの同時検出法の開発　　　　　　　　　　　　　　　
福元 達也, 岩崎 澄央, 早坂 かすみ, 西田 睦, 杉田 純一, 豊嶋 崇徳
日本臨床微生物学会雑誌, 30, Suppl.1, 284, 284, (一社)日本臨床微生物学会, 2019年12月
日本語

Ibrutinib Caused Mediastinal Emphysema and Pneumothorax in the Treatment of a Patient with Mantle Cell Lymphoma
Yutaka Tsutsumi, Takahiro Sekine, Shinichi Ito, Satomi Matsuoka, Takanori Teshima
Drug Safety - Case Reports, 6, 1, 3, 3, Springer Science and Business Media LLC, 2019年12月, ［査読有り］
研究論文（学術雑誌）

Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT
Maddalena Noviello, Francesco Manfredi, Eliana Ruggiero, Tommaso Perini, Giacomo Oliveira, Filippo Cortesi, Pantaleo De Simone, Cristina Toffalori, Valentina Gambacorta, Raffaella Greco, Jacopo Peccatori, Monica Casucci, Giulia Casorati, Paolo Dellabona, Masahiro Onozawa, Takanori Teshima, Marieke Griffioen, Constantijn J. M. Halkes, J. H. F. Falkenburg, Friedrich Stölzel, Heidi Altmann, Martin Bornhäuser, Miguel Waterhouse, Robert Zeiser, Jürgen Finke, Nicoletta Cieri, Attilio Bondanza, Luca Vago, Fabio Ciceri, Chiara Bonini
Nature Communications, 10, 1, 1065, 1065, Springer Science and Business Media LLC, 2019年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (TSCM) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1+Eomes+T-bet-) BM-TSCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.

Lactose drives Enterococcus expansion to promote graft-versus-host disease.
C K Stein-Thoeringer, K B Nichols, A Lazrak, M D Docampo, A E Slingerland, J B Slingerland, A G Clurman, G Armijo, A L C Gomes, Y Shono, A Staffas, M Burgos da Silva, S M Devlin, K A Markey, D Bajic, R Pinedo, A Tsakmaklis, E R Littmann, A Pastore, Y Taur, S Monette, M E Arcila, A J Pickard, M Maloy, R J Wright, L A Amoretti, E Fontana, D Pham, M A Jamal, D Weber, A D Sung, D Hashimoto, C Scheid, J B Xavier, J A Messina, K Romero, M Lew, A Bush, L Bohannon, K Hayasaka, Y Hasegawa, M J G T Vehreschild, J R Cross, D M Ponce, M A Perales, S A Giralt, R R Jenq, T Teshima, E Holler, N J Chao, E G Pamer, J U Peled, M R M van den Brink
Science (New York, N.Y.), 366, 6469, 1143, 1149, 2019年11月29日, ［国際誌］
英語, 研究論文（学術雑誌）, Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

Using a machine learning algorithm to predict acute graft-versus-host disease following allogeneic transplantation.
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26日, ［査読有り］, ［国際誌］
英語, 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.

妊娠後期に診断された発作性夜間ヘモグロビン尿症に対してeculizumabを導入した1例　　　　　　　　　　　　　　　
小島 圭祐, 荒 隆英, 遠藤 知之, 高橋 承吾, 米田 和樹, 横山 翔大, 笠原 耕平, 白鳥 聡一, 後藤 秀樹, 中川 雅夫, 森川 守, 山本 準也, 豊嶋 崇徳
臨床血液, 60, 11, 1583, 1583, (一社)日本血液学会-東京事務局, 2019年11月
日本語

ART開始後に縮小傾向を認めたEBV-associated smooth muscle tumor合併AIDSの一例　　　　　　　　　　　　　　　
荒 隆英, 遠藤 知之, 後藤 秀樹, 笠原 耕平, 長谷川 裕太, 横山 翔大, 高桑 恵美, 松野 吉宏, 橋野 聡, 豊嶋 崇徳
日本エイズ学会誌, 21, 4, 426, 426, (一社)日本エイズ学会, 2019年11月
日本語

Clinical efficacy and safety of first-line nilotinib therapy and evaluation of the clinical utility of the FRET-based drug sensitivity test.
Takeshi Kondo, Mari Fujioka, Shinichi Fujisawa, Kaori Sato, Masumi Tsuda, Takuto Miyagishima, Akio Mori, Hiroshi Iwasaki, Yasutaka Kakinoki, Satoshi Yamamoto, Yoshihito Haseyama, Seisho Ando, Motohiro Shindo, Shuichi Ota, Mitsutoshi Kurosawa, Yusuke Ohba, Takanori Teshima
International journal of hematology, 110, 4, 482, 489, 2019年10月, ［査読有り］, ［国内誌］
英語, Nilotinib is widely used for primary treatment of patients with chronic myelogenous leukemia (CML). We previously reported that use of an FRET-based drug sensitivity test at diagnosis efficiently predicts the response to treatment with imatinib or dasatinib. Here, we conducted a phase-II study to evaluate the efficacy and safety of nilotinib treatment and identify useful biomarkers, including results of the FRET-based drug sensitivity test, for predicting treatment response. Data from 42 patients were used in the analysis. Major molecular response (MMR), MR4, and MR4.5 rates at 12 months were 64.3, 42.9, and 28.6%, respectively. Grade 3/4 non-hematologic adverse events occurred in 11 patients (26.2%). The dose intensity of nilotinib (> 76.44%) and halving time (HT, < 13.312 days) were identified as significant factors for MMR at 12 months. However, when we focused on patients whose dose intensity of nilotinib was > 76.44%, the FRET-based drug sensitivity test became a predictive factor of MR4 achievement at 12 months. Our study reconfirmed the efficacy and safety of nilotinib treatment in CML patients. Moreover, our results suggest that the FRET-based drug sensitivity test is an independent predictor for achievement of MR4 in patients treated with a sufficient dose intensity of nilotinib.

北海道大学病院における血液培養陽性検体でのDISK法による薬剤中間報告の有用性　　　　　　　　　　　　　　　
福元 達也, 岩崎 澄央, 早坂 かすみ, 西田 睦, 杉田 純一, 豊嶋 崇徳
臨床病理, 67, 補冊, 144, 144, (一社)日本臨床検査医学会, 2019年10月
日本語

Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial
Usmani SZ, Schjesvold F, Oriol A, Karlin L, Cavo M, Rifkin RM, Yimer HA, LeBlanc R, Takezako N, McCroskey RD, Lim ABM, Suzuki K, Kosugi H, Grigoriadis G, Avivi I, Facon T, Jagannath S, Lonial S, Ghori RU, Farooqui MZH, Marinello P, San-Miguel J, KEYNOTE, Investigators
Lancet Haematol, 6, 9, e448, e458, 2019年09月, ［査読有り］

Break Apart FISH Probeで転座判定に苦慮したKMT2A-MLLT10 mRNA陽性AMLの一症例
小栗 聡, 佐藤 かおり, 市川 絢子, 藤澤 真一, 原 和也, 杉山 未奈子, 寺下 友佳代, 長 祐子, 井口 晶裕, 杉田 純一, 西田 睦, 豊嶋 崇徳, 真部 淳
日本染色体遺伝子検査学会雑誌, 37, 2, 47, 47, 日本染色体遺伝子検査学会, 2019年09月
日本語

G-bandで非典型転座様式を示しDEK-NUP214 mRNA検出が核型決定に有用であったAMLの一症例
佐藤 かおり, 小栗 聡, 市川 絢子, 藤澤 真一, 西田 睦, 高橋 秀一郎, 杉田 純一, 豊嶋 崇徳
日本染色体遺伝子検査学会雑誌, 37, 2, 48, 48, 日本染色体遺伝子検査学会, 2019年09月
日本語

脾臓への放射線照射が奏功した脾機能亢進症の1例　　　　　　　　　　　　　　　
岩崎 愛美, 安田 耕一, 遠藤 知之, 大東 寛幸, 清水 伸一, 鬼丸 力也, 豊嶋 崇徳, 白土 博樹
日本医学放射線学会秋季臨床大会抄録集, 55回, S518, S518, (公社)日本医学放射線学会, 2019年09月
日本語

Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation
Ayman Saad, Lawrence Lamb, Tao Wang, Michael T. Hemmer, Stephen Spellman, Daniel Couriel, Amin Alousi, Joseph Pidala, Hisham Abdel-Azim, Vaibhav Agrawal, Mahmoud Aljurf, Amer M. Beitinjaneh, Vijaya Raj Bhatt, David Buchbinder, Michael Byrne, Jean-Yves Cahn, Mitchell Cairo, Paul Castillo, Saurabh Chhabra, Miguel Angel Diaz, Shatha Farhan, Yngvar Floisand, Hadar A. Frangoul, Shahinaz M. Gadalla, James Gajewski, Robert Peter Gale, Manish Gandhi, Usama Gergis, Betty Ky Hamilton, Peiman Hematti, Gerhard C. Hildebrandt, Rammurti T. Kamble, Abraham S. Kanate, Pooja Khandelwal, Aleksandr Lazaryan, Margaret MacMillan, David I. Marks, Rodrigo Martino, Parinda A. Mehta, Taiga Nishihori, Richard F. Olsson, Sagar S. Patel, Muna Qayed, Hemalatha G. Rangarajan, Ran Reshef, Olle Ringden, Bipin N. Savani, Harry C. Schouten, Kirk R. Schultz, Sachiko Seo, Brian C. Shaffer, Melhem Solh, Takanori Teshima, Alvaro Urbano-Ispizua, Leo F. Verdonck, Ravi Vij, Edmund K. Waller, Basem William, Baldeep Wirk, Jean A. Yared, Lolie C. Yu, Mukta Arora, Shahrukh Hashmi
Biology of Blood and Marrow Transplantation, 25, 9, 1875, 1883, Elsevier BV, 2019年09月, ［査読有り］
研究論文（学術雑誌）

Resolved versus Active Chronic Graft-versus-Host Disease: Impact on Post-Transplantation Quality of Life
Saiko Kurosawa, Takuhiro Yamaguchi, Kumi Oshima, Atsumi Yanagisawa, Takahiro Fukuda, Heiwa Kanamori, Takehiko Mori, Satoshi Takahashi, Tadakazu Kondo, Akio Kohno, Koichi Miyamura, Yukari Umemoto, Takanori Teshima, Shuichi Taniguchi, Takuya Yamashita, Yoshihiro Inamoto, Yoshinobu Kanda, Shinichiro Okamoto, Yoshiko Atsuta
Biology of Blood and Marrow Transplantation, 25, 9, 1851, 1858, Elsevier BV, 2019年09月, ［査読有り］
研究論文（学術雑誌）

Inferior Outcomes with Cyclosporine and Mycophenolate Mofetil after Myeloablative Allogeneic Hematopoietic Cell Transplantation
Betty K. Hamilton, Ying Liu, Michael T. Hemmer, Navneet Majhail, Olle Ringden, Dennis Kim, Luciano Costa, Robert Stuart, Amin Alousi, Joseph A. Pidala, Daniel R. Couriel, Mahmoud Aljurf, Joseph H. Antin, Christopher Bredeson, Jean-Yves Cahn, Mitchell Cairo, Sung Won Choi, Christopher Dandoy, Robert Peter Gale, Usama Gergis, Peiman Hematti, Yoshihiro Inamoto, Rammurti T. Kamble, Margaret MacMillan, David I. Marks, Eneida Nemecek, Taiga Nishihori, Ayman Saad, Bipin N. Savani, Jeff Schriber, Sachiko Seo, Gérard Socié, Takanori Teshima, Leo F. Verdonck, Edmund K. Waller, Mona Wirk, Stephen R. Spellman, Mukta Arora, Saurabh Chhabra
Biology of Blood and Marrow Transplantation, 25, 9, 1744, 1755, Elsevier BV, 2019年09月, ［査読有り］
研究論文（学術雑誌）

Clinical significance of end-diastolic opening of pulmonary valve in a case complicating left ventricular systolic dysfunction.
Hisao Nishino, Hiroyuki Iwano, Sanae Kaga, Mutsumi Nishida, Koji Akizawa, Takanori Teshima, Toshihisa Anzai
Journal of echocardiography, 19, 1, 53, 55, 2019年08月03日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

IgG4による抗IgE作用の生理的意義解析 IgG4-IgE複合体がIgE測定値に与える影響　　　　　　　　　　　　　　　
中野 恵一, 眞船 直樹, 安田 慶子, 西田 睦, 杉田 純一, 豊嶋 崇徳
臨床化学, 48, Suppl.1, 282, 282, (一社)日本臨床化学会, 2019年08月
日本語

Anagrelide Modulates Proplatelet Formation Resulting in Decreased Number and Increased Size of Platelets.
Naohiro Miyashita, Masahiro Onozawa, Shota Yokoyama, Daisuke Hidaka, Koji Hayasaka, Shinji Kunishima, Takanori Teshima
HemaSphere, 3, 4, e268, 2019年08月, ［国際誌］
英語, 研究論文（学術雑誌）, We retrospectively evaluated 48 essential thrombocythemia (ET) patients who were treated in our institute (male/female, 14/34, median age, 61.5 years). In 14 patients treated with anagrelide (ANA), the degree of platelet count reduction (median, -56.6%) was strongly correlated with increase of mean platelet volume (MPV) (median, +11.7%) (R = 0.777). This correlation was not observed in ET patients treated with hydroxycarbamide alone (R = 0.245). The change in size of platelets strongly suggested that ANA affected the final process of platelet production. Thus, we hypothesized that ANA modifies the process by which platelets are released from proplatelets. To verify the association in an in vitro setting, we compared MEG-01 cells treated with PMA ± ANA. The number of platelet-like particles (PLPs) was decreased (P < 0.05) and the size of PLPs estimated by using flow cytometry was significantly increased when MEG-01 cells were treated with PMA + ANA (P < 0.05 vs PMA alone), recapitulating the clinical findings. The cytoplasmic protrusions extending from MEG-01 cells were shorter and thicker and the number of proplatelets was decreased when MEG-01 cells were treated with PMA + ANA (P < 0.01 vs PMA alone). Western blotting analysis showed that ANA treatment resulted in increased phosphorylation of MLC2 and reduced phosphorylation of focal adhesion kinase (FAK). The morphological change of proplatelets were reversed by blebbistatin, a specific inhibitor of myosin II. These findings indicated that ANA modulates the FAK-RhoA-ROCK-MLC2-myosine IIA pathway and suppresses proplatelet maturation, leading to a decrease in platelet count and increase in MPV.

Safety and efficacy of amnion-derived mesenchymal stem cells (AM01) in patients with steroid-refractory acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: a study protocol for a phase I/II Japanese trial.
Kenichi Yamahara, Akiko Hamada, Toshihiro Soma, Rika Okamoto, Masaya Okada, Satoshi Yoshihara, Kyoko Yoshihara, Kazuhiro Ikegame, Hiroya Tamaki, Katsuji Kaida, Takayuki Inoue, Yuko Ohsugi, Hiroki Nishikawa, Hiroshi Hayashi, Yoichi M Ito, Hiroaki Iijima, Shunsuke Ohnishi, Daigo Hashimoto, Toshiyuki Isoe, Takanori Teshima, Hiroyasu Ogawa, Norihiro Sato, Yoshihiro Fujimori
BMJ open, 9, 7, e026403, 2019年07月09日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Regenerative medicine and cell therapies have been gaining much attention among clinicians. Therapeutic infusion of mesenchymal stromal cells (MSCs) is now a leading investigational strategy for the treatment of acute graft-versus-host disease (aGVHD). Bone marrow MSCs are approved for manufacture and marketing as a cell therapy for aGVHD. Our non-clinical studies confirmed that human amnion-derived MSCs had immunomodulatory activity equal to or higher than that of human bone marrow MSCs. This study will aim to evaluate the safety and efficacy of amnion-derived MSCs (AM01) in patients with steroid-refractory aGVHD. METHODS AND ANALYSIS: This study will be a multicentre, single-arm, open-label trial (an interventional study). This clinical trial will begin with a low-dose group, and when safety has been confirmed in at least three cases in the low-dose group, treatment will begin for the high-dose group, for which the safety will also be verified. The primary endpoint is to assess the safety of intravenous infusion therapy of AM01 within 24 hours after intravenous infusion of AM01. The secondary endpoint is to explore the efficacy of intravenous infusion therapy with AM01. ETHICS AND DISSEMINATION: The institutional review boards of all participating hospitals approved this study protocol (latest V3.3.0, 3 August 2018). Final data will be publicly announced. A report releasing the study results will be submitted for publication to an appropriate peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000029945.

Validation of US evaluation of ulcerative colitis activity
Satomi Omotehara, Mutsumi Nishida, Kenji Kinoshita, Reizo Onishi, Aki Onodera, Mitsuhisa Suya, Toru Hasegawa, Daiki Mitsumori, Takehiko Katsurada, Takanori Teshima
Ultrasound in Medicine & Biology, 45, 7, 1537, 1544, Elsevier BV, 2019年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study was aimed at validating the inter-rater grading agreement for assessing disease activity in patients with established ulcerative colitis (UC) using transabdominal ultrasonography (US) versus colonoscopy (CS). Fifty-seven patients underwent US and CS at four facilities. UC disease activity was assessed using the original US grading system and CS Matts classification. Initially, the US and CS grades were assessed at each examining facility, and still images and movie clips were re-assessed at the central facility. Grading agreement between the examining and central facilities was evaluated. Grading agreement for US and CS were 0.75 and 0.72 in all segments and 0.82 and 0.70 in the maximum grade of each patient, respectively (all p < 0.001). US grading agreement was "almost perfect" for the maximum grade and "moderate" to "substantial" for other assessments. The inter-rater US grading agreement was good and not inferior to that of CS for evaluating UC disease activity.

Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas
Keisuke Kataoka, Hiroaki Miyoshi, Seiji Sakata, Akito Dobashi, Lucile Couronné, Yasunori Kogure, Yasuharu Sato, Kenji Nishida, Yuka Gion, Yuichi Shiraishi, Hiroko Tanaka, Kenichi Chiba, Yosaku Watatani, Nobuyuki Kakiuchi, Yusuke Shiozawa, Tetsuichi Yoshizato, Kenichi Yoshida, Hideki Makishima, Masashi Sanada, Masahiro Onozawa, Takanori Teshima, Yumiko Yoshiki, Tadao Ishida, Kenshi Suzuki, Kazuyuki Shimada, Akihiro Tomita, Motohiro Kato, Yasunori Ota, Koji Izutsu, Ayako Demachi-Okamura, Yoshiki Akatsuka, Satoru Miyano, Tadashi Yoshino, Philippe Gaulard, Olivier Hermine, Kengo Takeuchi, Koichi Ohshima, Seishi Ogawa
Leukemia, 33, 7, 1687, 1699, Springer Science and Business Media LLC, 2019年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3'-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.

新生児のcis A2B3型の判定にABO遺伝子タイピングが有用であった1例
上床 貴代, 渡邊 千秋, 伊藤 誠, 魚住 諒, 林 泰弘, 早坂 光司, 秋沢 宏次, 早瀬 英子, 豊嶋 崇徳
日本輸血細胞治療学会誌, 65, 3, 652, 652, (一社)日本輸血・細胞治療学会, 2019年06月
日本語

抗Dによる胎児・新生児溶血性疾患で胎児輸血が必要となった1症例
魚住 諒, 渡邊 千秋, 伊藤 誠, 上床 貴代, 林 泰弘, 早坂 光司, 馬詰 武, 早瀬 英子, 秋沢 宏次, 豊嶋 崇徳
日本輸血細胞治療学会誌, 65, 3, 652, 652, (一社)日本輸血・細胞治療学会, 2019年06月
日本語

新生児に対する輸血回数と曝露ドナー数の検討
林 泰弘, 渡邊 千秋, 猪股 百華, 伊藤 誠, 上床 貴代, 魚住 諒, 秋沢 宏次, 早瀬 英子, 豊嶋 崇徳
日本輸血細胞治療学会誌, 65, 3, 653, 654, (一社)日本輸血・細胞治療学会, 2019年06月
日本語

Myasthenia gravis after allogeneic bone marrow transplantation: A case report and literature review
Yutaka Tsutsumi, Takashi Kamiishi, Ryo Kikuchi, Shinichi Ito, Satomi Matsuoka, Takanori Teshima
Hematology/Oncology and Stem Cell Therapy, 12, 2, 110, 114, Elsevier BV, 2019年06月, ［査読有り］
研究論文（学術雑誌）

GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia
Rohtesh S. Mehta, Shernan G. Holtan, Tao Wang, Michael T. Hemmer, Stephen R. Spellman, Mukta Arora, Daniel R. Couriel, Amin M. Alousi, Joseph Pidala, Hisham Abdel-Azim, Ibrahim Ahmed, Mahmoud Aljurf, Medhat Askar, Jeffery J. Auletta, Vijaya Bhatt, Christopher Bredeson, Saurabh Chhabra, Shahinaz Gadalla, James Gajewski, Robert Peter Gale, Usama Gergis, Peiman Hematti, Gerhard C. Hildebrandt, Yoshihiro Inamoto, Carrie Kitko, Pooja Khandelwal, Margaret L. MacMillan, Navneet Majhail, David I. Marks, Parinda Mehta, Taiga Nishihori, Richard F. Olsson, Attaphol Pawarode, Miguel Angel Diaz, Tim Prestidge, Muna Qayed, Hemalatha Rangarajan, Olle Ringden, Ayman Saad, Bipin N. Savani, Sachiko Seo, Ami Shah, Niketa Shah, Kirk R. Schultz, Melhem Solh, Thomas Spitzer, Jeffrey Szer, Takanori Teshima, Leo F. Verdonck, Kirsten M. Williams, Baldeep Wirk, John Wagner, Jean A. Yared, Daniel J. Weisdorf
Blood Advances, 3, 9, 1441, 1449, American Society of Hematology, 2019年05月14日, ［査読有り］
研究論文（学術雑誌）,
We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy–requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen–mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P &lt; .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation–based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P &lt; .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.

HIV診療がカウンセラーのチーム医療への姿勢に与える影響の解析 2015・2016年度HIV医療体制班アンケート調査から
石田 陽子, 横幕 能行, 中川 雄真, 小松 賢亮, 渡邊 愛祈, 木村 聡太, 松岡 亜由子, 豊嶋 崇徳, 小島 賢一
日本エイズ学会誌, 21, 2, 111, 117, (一社)日本エイズ学会, 2019年05月, ［査読有り］
日本語, 2015・2016年度HIV医療体制班のアンケート調査結果から、HIV診療がカウンセラーのチーム医療への姿勢に与える影響について解析した。その結果、チーム医療を重視する姿勢は、HIV臨床経験年数とは有意な相関を認めたが、他領域での経年年数とは有意な相関がみられなかった。全てのカウンセラーが患者支援と多職種連携の両方を重視していたが、HIV臨床経験年数が長い者ほどマネジメントの視点やチーム力の向上を重視する傾向がみられた。また、カウンセラーの雇用形態が患者への支援に影響する可能性が示された。

Clinicopathological features of HCV-positive splenic diffuse large B cell lymphoma.
Joji Shimono, Hiroaki Miyoshi, Fumiko Arakawa, Kyohei Yamada, Takeshi Sugio, Kohta Miyawaki, Tetsuya Eto, Takuto Miyagishima, Koji Kato, Koji Nagafuji, Koichi Akashi, Takanori Teshima, Koichi Ohshima
Annals of hematology, 98, 5, 1197, 1207, 2019年05月, ［査読有り］, ［国際誌］
英語, The hepatitis C virus (HCV) is a single-stranded RNA virus which is thought to be involved in the onset of B cell lymphoma. HCV-positive diffuse large B cell lymphoma (DLBCL) has been reported to clinically manifest in extranodal lesions (e.g., in the liver, spleen, and stomach). Here, we investigated HCV-positive and -negative primary splenic DLBCL (p-spDLBCL) and non-primary splenic DLBCL (ordinary DLBCL). Furthermore, to examine HCV lymphomagenesis, RNA in situ hybridization (ISH), RT-PCR (reverse-transcription polymerase chain reaction), and NS3 immunostaining of HCV viral nonstructural proteins were performed. HCV-positive p-spDLBCL patients presented fewer B symptoms (asymptomatic) and better performance status, with elevated presence of splenic macronodular lesions and more germinal center B cell (GCB) sub-group cases than HCV-negative p-spDLBCL patients. However, HCV-positive ordinary DLBCL patients were found to have more non-GCB sub-group cases than HCV-negative ordinary DLBCL patients. HCV-positive DLBCL patients showed 20.6% (7/34) NS3 positivity, 16.7% (1/6) HCV-RNA in situ positivity, and 22.2% (2/9) detection of HCV-RNA in tumor tissue by RT-PCR. Splenic samples were found to have a higher frequency of HCV detection than lymph node samples, thus suggesting that HCV may be closely related to lymphomagenesis, especially in splenic lymphoma.

Ocular instillation of vitamin A–coupled liposomes containing HSP47 siRNA ameliorates dry eye syndrome in chronic GVHD
Hiroyuki Ohigashi, Daigo Hashimoto, Eiko Hayase, Shuichiro Takahashi, Takahide Ara, Tomohiro Yamakawa, Junichi Sugita, Masahiro Onozawa, Masao Nakagawa, Takanori Teshima
Blood Advances, 3, 7, 1003, 1010, American Society of Hematology, 2019年04月09日, ［査読有り］
研究論文（学術雑誌）, Chronic graft-versus-host disease (GVHD) profoundly affects the quality of life of long-term survivors of allogeneic hematopoietic stem cell transplantation (SCT). The eyes are frequently involved, and dry eye syndrome is the most common manifestation of ocular chronic GVHD. We explored the role of heat shock protein 47 (HSP47) in ocular GVHD and developed a novel antifibrotic topical therapy using vitamin A–coupled liposomes containing HSP47 small interfering RNA (siRNA) against HSP47 (VA-lip HSP47). In a mouse model of chronic GVHD, infiltration of HSP47+ fibroblasts and massive fibrosis surrounding the lacrimal ducts were observed after allogeneic SCT, leading to impaired tear secretion. After ocular instillation, VA-lip HSP47 was distributed to the lacrimal glands, knocked down HSP47 expression in fibroblasts, reduced collagen deposition, and restored tear secretion after allogeneic SCT. Ocular instillation of VA-lip HSP47 also ameliorated established lacrimal gland fibrosis and dry eye syndrome. VA-lip HSP47 eye drops are a promising prophylactic and therapeutic option against dry eye syndrome in chronic GVHD.

A pitfall of serum troponin assay; an estrangement of cardiac troponin T and I　　　　　　　　　　　　　　　
Keiichi Nakano, Naoki Mafune, Keiko Yasuda, Koji Akizawa, Junichi Sugita, Takanori Teshima
Japanese Journal of Clinical Chemistry, 48, 2, 130, 136, Japanese Journal of Clinical Chemistry, 2019年04月01日
日本語, 研究論文（学術雑誌）, The molecules of the troponin consist of three subunits called T, I and C. Cardiac troponin T and I which had a specific amino acid sequence have been used for a high sensitive marker of the detection of the myocardium damage. This allowed to establish several monoclonal antibodies used widely in a clinical field We had an opportunity to measure cardiac troponin T and I simultaneously in the serum of the patients with myocardial diseases. With the case, both values of the cardiac troponin almost showed the positive correlation. However, we met with the case that cardiac troponin values showed marked change independently. As for this kind of estrangement, we revealed that a competitive inhibition gets up for troponin between an autoantibody in patient's serum and an antibody used in assay. As for the care, assays of cardiac troponin T and I must be performed with the possibility of association of this estrangement as a pitfall of the assay.

生物由来原料基準を満たす国産ウシ血小板溶解物「NeoSERA」を原材料とする羊膜由来間葉系幹細胞の細胞製剤化
山原 研一, 浜田 彰子, 黒田 将子, 池本 純子, 吉原 享子, 吉原 哲, 岡田 昌也, 橋本 大吾, 相馬 俊裕, 豊嶋 崇徳, 藤盛 好啓
日本輸血細胞治療学会誌, 65, 2, 476, 476, (一社)日本輸血・細胞治療学会, 2019年04月
日本語

超音波診断をググッとあげる!こんな時どう考える? できる技師のスキルアップ術
工藤 悠輔, 西田 睦, 澁谷 斉, 豊嶋 崇徳
超音波検査技術, 44, Suppl., S105, S105, (一社)日本超音波検査学会, 2019年04月
日本語

免疫チェックポイント阻害薬関連大腸炎3例の超音波所見　　　　　　　　　　　　　　　
表原 里実, 西田 睦, 長島 一哲, 桂田 武彦, 村中 徹人, 小松 嘉人, 澁谷 斉, 秋沢 宏次, 杉田 純一, 豊嶋 崇徳
超音波医学, 46, Suppl., S650, S650, (公社)日本超音波医学会, 2019年04月
日本語

初回治療から18年後に生じた多臓器進展を伴うホジキンリンパ腫の一剖検例　　　　　　　　　　　　　　　
五味川 龍, 杉野 弘和, 白鳥 聡一, 石田 雄介, 王 磊, 畑中 佳奈子, 松野 吉宏, 豊嶋 崇徳, 田中 伸哉
日本病理学会会誌, 108, 1, 453, 453, (一社)日本病理学会, 2019年04月
日本語

Gene Polymorphism of Tacrolimus-Metabolizing Enzymes Associated With Impaired Absorption of Tacrolimus Following Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report
S. Matsuoka, Y. Tsutsumi, R. Kikuchi, S. Ito, T. Teshima
Transplantation Proceedings, 51, 3, 998, 1001, Elsevier BV, 2019年04月, ［査読有り］
研究論文（学術雑誌）

Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation
Cristina Toffalori, Laura Zito, Valentina Gambacorta, Michela Riba, Giacomo Oliveira, Gabriele Bucci, Matteo Barcella, Orietta Spinelli, Raffaella Greco, Lara Crucitti, Nicoletta Cieri, Maddalena Noviello, Francesco Manfredi, Elisa Montaldo, Renato Ostuni, Matteo M. Naldini, Bernhard Gentner, Miguel Waterhouse, Robert Zeiser, Jurgen Finke, Maher Hanoun, Dietrich W. Beelen, Ivana Gojo, Leo Luznik, Masahiro Onozawa, Takanori Teshima, Raynier Devillier, Didier Blaise, Constantijn J. M. Halkes, Marieke Griffioen, Matteo G. Carrabba, Massimo Bernardi, Jacopo Peccatori, Cristina Barlassina, Elia Stupka, Dejan Lazarevic, Giovanni Tonon, Alessandro Rambaldi, Davide Cittaro, Chiara Bonini, Katharina Fleischhauer, Fabio Ciceri, Luca Vago
Nature Medicine, 25, 4, 603, 611, Springer Science and Business Media LLC, 2019年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-γ or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.

Quantitative detection of IKZF1 deletion by digital PCR in patients with acute lymphoblastic leukemia.
Junichi Hashiguchi, Masahiro Onozawa, Kohei Okada, Toraji Amano, Kanako C Hatanaka, Hiroshi Nishihara, Norihiro Sato, Takanori Teshima
International journal of laboratory hematology, 41, 2, e38-e40, e40, 2019年04月, ［査読有り］, ［国際誌］
英語

関節エコーで診るリウマチ性疾患の病態と治療戦略 技師による関節エコーの現状と展望　　　　　　　　　　　　　　　
西田 睦, 澁谷 斉, 豊嶋 崇徳
日本リウマチ学会総会・学術集会プログラム・抄録集, 63回, 192, 192, (一社)日本リウマチ学会, 2019年03月
日本語

Myeloablative and reduced-intensity conditioning in HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide
Junichi Sugita, Yusuke Kagaya, Toshihiro Miyamoto, Yasuhiko Shibasaki, Koji Nagafuji, Shuichi Ota, Tatsuo Furukawa, Miho Nara, Koichi Akashi, Shuichi Taniguchi, Mine Harada, Keitaro Matsuo, Takanori Teshima
Bone Marrow Transplantation, 54, 3, 432, 441, Springer Science and Business Media LLC, 2019年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We conducted two parallel prospective, multicenter, phase II studies to evaluate the safety and efficacy of HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) following myeloablative conditioning (MAC, n = 50) and reduced-intensity conditioning (RIC, n = 77). Event-free survival (EFS) at 1-year as for primary endpoint was 64% and 43% in the MAC and RIC groups, respectively. Neutrophil engraftment was achieved in 98% and 94% in the MAC and RIC groups, respectively. The incidences of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 18% and 8% in the MAC group, and 14% and 5% in the RIC group, respectively. Those of all grade and moderate to severe chronic GVHD at 2-year were 36% and 20% in the MAC group, and 27% and 20% in the RIC group, respectively. Overall survival (OS), EFS, nonrelapse mortality, and relapse rate at 2-year were 68%, 54%, 10%, and 36% in the MAC group, and 44%, 35%, 20%, and 45% in the RIC group, respectively. Notably, 83% and 86% of patients who survived without relapse stopped immunosuppressant at 2-year in the MAC and RIC groups, respectively. Our results indicate that both MAC and RIC are valid options for PTCy-haploPBSCT for adults with hematological malignancies.

Serum level of soluble interleukin‐2 receptor is positively correlated with metabolic tumor volume on 18 F‐FDG PET/CT in newly diagnosed patients with diffuse large B‐cell lymphoma
Hajime Senjo, Minoru Kanaya, Koh Izumiyama, Koichiro Minauchi, Kenji Hirata, Akio Mori, Makoto Saito, Masanori Tanaka, Hiroaki Iijima, Eriko Tsukamoto, Kazuo Itoh, Shuichi Ota, Masanobu Morioka, Daigo Hashimoto, Takanori Teshima
Cancer Medicine, 8, 3, 953, 962, Wiley, 2019年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphoma. High total metabolic tumor volume (TMTV) calculated using 18 F-FDG PET/CT images at diagnosis predicts poor prognosis of patients with DLBCL. However, high cost and poor access to the imaging facilities hamper wider use of 18 F-FDG PET/CT. In order to explore a surrogate marker for TMTV, we evaluated the correlation between the serum levels of soluble interleukin-2 receptor (sIL-2R) and TMTV in 64 patients with DLBCL, and the results were verified in an independent validation cohort of 86 patients. Serum levels of sIL-2R were significantly correlated with TMTV. ROC analysis revealed that the cutoff value of TMTV ≥150 cm3 or sIL-2R ≥ 1300 U/mL could predict failure to achieve EFS24 with areas under the curve (AUC) 0.706 and 0.758, respectively. Each of TMTV ≥150 cm3 and sIL-2R ≥1300 U/mL was significantly associated with worse 5-year overall survival and event-free survival. Importantly, each of sIL-2R <1300 U/mL or TMTV <150 cm3 identified patients with favorable prognosis among NCCN-IPI high-intermediate and high-risk group. Serum level of sIL-2R represents a convenient surrogate marker to estimate metabolic tumor burden measured by 18 F-FDG PET/CT that can predict treatment outcomes of patients with DLBCL.

UTILITY OF LISS AS AN AUTOANTIBODY ADSORPTION METHOD FOR DETECTION OF COEXISTING ALLOANTIBODIES IN PATIENTS WITH AUTOANTIBODIES
Takayo Uwatoko, Chiaki Watanabe, Makoto Ito, Ryo Uozumi, Yasuhiro Hayashi, Shuichiro Takahashi, Naohiro Miyashita, Souichi Shiratori, Daigo Hashimoto, Junichi Sugita, Eiko Hayase, Koji Akizawa, Takanori Teshima
Japanese Journal of Transfusion and Cell Therapy, 65, 1, 98, 102, Japan Society of Transfusion Medicine and Cell Therapy, 2019年02月28日
研究論文（学術雑誌）

A role for IL-34 in osteolytic disease of multiple myeloma
Muhammad Baghdadi, Kozo Ishikawa, Sayaka Nakanishi, Tomoki Murata, Yui Umeyama, Takuto Kobayashi, Yosuke Kameda, Hiraku Endo, Haruka Wada, Bjarne Bogen, Satoshi Yamamoto, Keisuke Yamaguchi, Ikumi Kasahara, Hiroshi Iwasaki, Mutsumi Takahata, Makoto Ibata, Shuichiro Takahashi, Hideki Goto, Takanori Teshima, Ken-ichiro Seino
Blood Advances, 3, 4, 541, 551, American Society of Hematology, 2019年02月26日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Multiple myeloma (MM) is a hematological malignancy that grows in multiple sites of the axial skeleton and causes debilitating osteolytic disease. Interleukin-34 (IL-34) is a newly discovered cytokine that acts as a ligand of colony-stimulating factor-1 (CSF-1) receptor and can replace CSF-1 for osteoclast differentiation. In this study, we identify IL-34 as an osteoclastogenic cytokine that accelerates osteolytic disease in MM. IL-34 was found to be expressed in the murine MM cell line MOPC315.BM, and the expression of IL-34 was enhanced by stimulation with proinflammatory cytokines or by bone marrow (BM) stromal cells. MM-cell–derived IL-34 promoted osteoclast formation from mouse BM cells in vitro. Targeting Il34 by specific small interfering RNA impaired osteoclast formation in vitro and attenuated osteolytic disease in vivo. In BM aspirates from MM patients, the expression levels of IL-34 in CD138+ populations vary among patients from high to weak to absent. MM cell–derived IL-34 promoted osteoclast formation from human CD14+ monocytes, which was reduced by a neutralizing antibody against IL-34. Taken together, this study describes for the first time the expression of IL-34 in MM cells, indicating that it may enhance osteolysis and suggesting IL-34 as a potential therapeutic target to control pathological osteoclastogenesis in MM patients.

自己抗体保有患者の同種抗体検出におけるLISSを用いた自己抗体吸着法の有用性の検討
上床 貴代, 渡邊 千秋, 伊藤 誠, 魚住 諒, 林 泰弘, 高橋 秀一郎, 宮下 直洋, 白鳥 聡一, 橋本 大吾, 杉田 純一, 早瀬 英子, 秋沢 宏次, 豊嶋 崇徳
日本輸血細胞治療学会誌, 65, 1, 98, 102, (一社)日本輸血・細胞治療学会, 2019年02月, ［査読有り］
日本語, <背景>自己抗体保有患者は自己抗体の他に同種抗体を保有する頻度が多いため、共存する同種抗体の検出が重要となる。ポリエチレングリコール(PEG)吸着法は自己抗体吸着法として一般的に用いられているが、低力価の同種抗体も吸着されると指摘する報告がある。海外では低イオン強度溶液(low ionic strength solution;LISS)を用いた自己抗体吸着法(以下LISS吸着法)も短時間での自己抗体吸着において有用であるという報告があるが本邦では一般的ではない。今回我々はLISS吸着法が同種抗体の検出に有用であった3症例を経験したので報告する。<方法>自己抗体を保有する3患者においてLISS吸着法を行った。3ヵ月以内に輸血歴のない患者は自己赤血球を用い、輸血歴のある患者は患者とRh、Kidd、Diego同型の酵素処理した他家赤血球を用いて自己抗体の吸着を行い、上清で同種抗体の検索を行った。<結果>3例共にLISS吸着法にて同種抗体が検出された。<考察>LISS吸着法は自己抗体の吸着および、共存する同種抗体の検出において有用であると考えられた。(著者抄録)

Impacts of thymoglobulin in patients with acute leukemia in remission undergoing allogeneic HSCT from different donors.
Manabu Wakamatsu, Seitaro Terakura, Kazuteru Ohashi, Takahiro Fukuda, Yukiyasu Ozawa, Heiwa Kanamori, Masashi Sawa, Naoyuki Uchida, Shuichi Ota, Akiko Matsushita, Yoshinobu Kanda, Hirohisa Nakamae, Tatsuo Ichinohe, Koji Kato, Makoto Murata, Yoshiko Atsuta, Takanori Teshima
Blood advances, 3, 2, 105, 115, 2019年01月22日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Antithymocyte globulin (ATG) is widely used to reduce acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD). To clarify the different impacts of ATG for conditioning across different donor types, we retrospectively analyzed patients with acute leukemia (n = 6617) who underwent hematopoietic stem cell transplantation between 2008 and 2015 with ATG (n = 279) or without ATG (n = 6338). Because thymoglobulin is the only ATG drug approved for GVHD prophylaxis in Japan since September 2008, we included thymoglobulin alone in the present analysis. The survivors' median follow-up time was 1081 days. Patients were categorized into 5 groups: cord blood (CB; n = 1915), matched related donor (n = 1772), 1-antigen mismatched related donor (1-MMRD; n = 225), matched unrelated donor (MUD; n = 1742), and 1-allele mismatched unrelated donor (1-MMUD; n = 963). In multivariate analysis, ATG decreased overall survival (hazard ratio [HR], 1.403; P = .054) and GVHD-free/relapse-free survival (GRFS) (HR, 1.458; P = .053) in association with increased nonrelapse mortality (NRM) (HR, 1.608; P =03) with CB, whereas it improved GRFS (HR, 0.515; P < .01) and decreased grades II to IV aGVHD (HR, 0.576; P < .01), extensive cGVHD (HR, 0.460; P = .02), and NRM (HR, 0.545; P = .03) with 1-MMUD. ATG did not impact survival with 1-MMRD and MUD. The use of ATG in conditioning is beneficial due to the reduction in acute/chronic GVHD without increasing NRM or disease relapse only in 1-MMUD transplantation. On the other hand, ATG is not recommended for CB transplantation.

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Stephen J. Schuster, Michael R. Bishop, Constantine S. Tam, Edmund K. Waller, Peter Borchmann, Joseph P. McGuirk, Ulrich Jäger, Samantha Jaglowski, Charalambos Andreadis, Jason R. Westin, Isabelle Fleury, Veronika Bachanova, S. Ronan Foley, P. Joy Ho, Stephan Mielke, John M. Magenau, Harald Holte, Serafino Pantano, Lida B. Pacaud, Rakesh Awasthi, Jufen Chu, Özlem Anak, Gilles Salles, Richard T. Maziarz
New England Journal of Medicine, 380, 1, 45, 56, Massachusetts Medical Society, 2019年01月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. METHODS: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. RESULTS: A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found. CONCLUSIONS: In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).

Phase I study of ibrutinib in Japanese patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma.
Hirohiko Shibayama, Takanori Teshima, Ilseung Choi, Kiyohiko Hatake, Naohiro Sekiguchi, Nozomi Yoshinari
Journal of clinical and experimental hematopathology : JCEH, 59, 4, 179, 186, 2019年, ［国内誌］
英語, 研究論文（学術雑誌）, This phase I study evaluated the safety and efficacy of single-agent ibrutinib in Japanese patients with treatment-naïve chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (aged 20-69 years and ineligible for chemotherapy using fludarabine or cyclophosphamide, or aged ≥70 years). Eight patients received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was safety; secondary endpoints included the overall response rate (ORR). At the time of final analysis (August 22, 2018), eight patients (all with CLL; median age, 68.5 years) had received ibrutinib for a median of 32.2 months (range, 10.4-35.9); all patients had discontinued study treatment, with 50.0% of patients switching to marketing-approved ibrutinib as subsequent anticancer therapy. All patients had ≥1 adverse event (AE); the most common AEs included a decreased platelet count, upper respiratory tract infection, increased lymphocyte count, diarrhea, nasopharyngitis, peripheral edema and rash. Four patients (50.0%) had a total of eight grade ≥3 AEs, most commonly lung infection and decreased neutrophil count. Eight serious AEs were reported in four patients (50.0%); these included a case of muscle hemorrhage (grade 3), decreased neutrophil count (grade 4) that led to dose reduction and one case of fatal cardiac arrest. The ORR was 87.5% (7/8 patients [exact 95% confidence interval 47.3-99.7]). One patient had a complete response, six had a partial response and one had a partial response with lymphocytosis. Ibrutinib had an acceptable safety profile and high ORR in Japanese patients with treatment-naïve CLL.

Comparative Analysis of Calcineurin Inhibitor–Based Methotrexate and Mycophenolate Mofetil–Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation
Saurabh Chhabra, Ying Liu, Michael T. Hemmer, Luciano Costa, Joseph A. Pidala, Daniel R. Couriel, Amin M. Alousi, Navneet S. Majhail, Robert K. Stuart, Dennis Kim, Olle Ringden, Alvaro Urbano-Ispizua, Ayman Saad, Bipin N. Savani, Brenda Cooper, David I. Marks, Gerard Socie, Harry C. Schouten, Helene Schoemans, Hisham Abdel-Azim, Jean Yared, Jean-Yves Cahn, John Wagner, Joseph H. Antin, Leo F. Verdonck, Leslie Lehmann, Mahmoud D. Aljurf, Margaret L. MacMillan, Mark R. Litzow, Melhem M. Solh, Muna Qayed, Peiman Hematti, Rammurti T. Kamble, Ravi Vij, Robert J. Hayashi, Robert P. Gale, Rodrigo Martino, Sachiko Seo, Shahrukh K. Hashmi, Taiga Nishihori, Takanori Teshima, Usama Gergis, Yoshihiro Inamoto, Stephen R. Spellman, Mukta Arora, Betty K. Hamilton
Biology of Blood and Marrow Transplantation, 25, 1, 73, 85, Elsevier BV, 2019年01月, ［査読有り］
研究論文（学術雑誌）

Impact of graft-versus-host disease on relapse and survival after allogeneic stem cell transplantation for pediatric leukemia.
Motohiro Kato, Mio Kurata, Junya Kanda, Koji Kato, Daisuke Tomizawa, Kazuko Kudo, Nao Yoshida, Kenichiro Watanabe, Hiroyuki Shimada, Jiro Inagaki, Katsuyoshi Koh, Hiroaki Goto, Keisuke Kato, Yuko Cho, Yuki Yuza, Atsushi Ogawa, Keiko Okada, Masami Inoue, Yoshiko Hashii, Takanori Teshima, Makoto Murata, Yoshiko Atsuta
Bone marrow transplantation, 54, 1, 68, 75, 2019年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Graft-versus-host disease (GVHD) occasionally leads to morbidity and mortality but is thought to reduce the risk of relapses in patients with a hematological malignancy. However, information on the effect of GVHD in pediatric leukemia is limited. Using a nationwide registry, we retrospectively analyzed 1526 children who underwent allogeneic stem cell transplantation for leukemia. Grades 0-I acute GVHD were associated with a higher relapse rate at three years after transplantation, at 25.4 and 24.3%, respectively, than grades II, III, or IV acute GVHD at 18.9%, 21.2%, and 2.6%, respectively. In contrast, the overall survival curve of the grades 0 and I GVHD groups (79.0% and 79.5%, respectively) approximated that of the grade II GVHD group (76.3%), and the probability of survival was worst in the severe GVHD groups (66.9% for grade III and 42.5% for grade IV). Chronic GVHD also reduced the relapse risk but conferred no survival advantage. Acute lymphoblastic leukemia was more sensitive to acute GVHD than acute myeloid leukemia (AML) while AML was more sensitive to chronic GVHD. Our study reproduced the preventive effects of GVHD against pediatric leukemia relapses but failed to demonstrate a significant survival advantage.

サイトカインリッチな成牛多血小板血漿由来血清「NeoSERA」を用いた高品質羊膜MSCの製剤化と急性GVHD・クローン病向け医師主導治験
山原 研一, 浜田 彰子, 黒田 将子, 岡田 昌也, 吉原 哲, 大西 俊介, 相馬 俊裕, 豊嶋 崇徳, 小川 啓恭, 藤盛 好裕
日本内分泌学会雑誌, 94, 4, 1573, 1573, (一社)日本内分泌学会, 2018年12月
日本語

Human Herpes Virus-6-Associated Encephalitis/Myelitis Mimicking Calcineurin Inhibitor-Induced Pain Syndrome in Allogeneic Stem Cell Transplantation Recipients
Goichi Yoshimoto, Yasuo Mori, Koji Kato, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Kenjiro Kamezaki, Akihiko Numata, Takahiro Maeda, Katsuto Takenaka, Hiromi Iwasaki, Takanori Teshima, Koichi Akashi, Toshihiro Miyamoto
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 24, 12, 2540, 2548, ELSEVIER SCIENCE INC, 2018年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor-induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve-related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve-related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P=.049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P= .036), whereas there was no significant difference among the latter 2 groups (P= .889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve-related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication. (C) 2018 American Society for Blood and Marrow Transplantation.

Intestinal Lymphatic Endothelial Cells Produce R-Spondin3
Reiki Ogasawara, Daigo Hashimoto, Shunsuke Kimura, Eiko Hayase, Takahide Ara, Shuichiro Takahashi, Hiroyuki Ohigashi, Kosuke Yoshioka, Takahiro Tateno, Emi Yokoyama, Ko Ebata, Takeshi Kondo, Junichi Sugita, Masahiro Onozawa, Toshihiko Iwanaga, Takanori Teshima
Scientific Reports, 8, 1, 10719, 10719, Springer Science and Business Media LLC, 2018年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The R-Spondin (R-Spo) family regulates WNT signaling and stimulates the proliferation and differentiation of intestinal stem cells (ISCs). R-Spo plays a critical role in maintaining intestinal homeostasis, but endogenous producers of R-Spo in the intestine remain to be investigated. We found that R-Spo3 was the major R-Spo family member produced in the intestine and it was predominantly produced by CD45-CD90+CD31+ lymphatic endothelial cells (LECs) in the lamina propria of the intestinal mucosa. Transcriptome analysis demonstrated that LECs highly expressed R-Spo receptor, Lgr5, suggesting an autocrine stimulatory loop in LECs. LECs were significantly reduced in number, and their R-Spo3 production was impaired in intestinal graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. The impaired production of R-Spo3 in the intestine may be a novel mechanism of delayed tissue repair and defective mucosal defense in intestinal GVHD. We demonstrate a novel role of intestinal LECs in producing R-Spondin3 to maintain intestinal homeostasis.

未来の造血幹細胞移植
豊嶋 崇徳
日本輸血細胞治療学会誌, 64, 6, 675, 680, 2018年12月, ［査読有り］

Wilms Tumor 1 Expression at Diagnosis Correlates With Genetic Abnormalities and Polymorphism But Is Not Independently Prognostic in Acute Myelogenous Leukemia: A Hokkaido Leukemia Net Study
Daisuke Hidaka, Masahiro Onozawa, Junichi Hashiguchi, Naohiro Miyashita, Kohei Kasahara, Shinichi Fujisawa, Eiko Hayase, Kohei Okada, Souichi Shiratori, Hideki Goto, Junichi Sugita, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Tomoyuki Endo, Satoshi Yamamoto, Yutaka Tsutsumi, Yoshihito Haseyama, Takahiro Nagashima, Akio Mori, Shuichi Ota, Hajime Sakai, Toshimichi Ishihara, Kiyotoshi Imai, Takuto Miyagishima, Yasutaka Kakinoki, Mitsutoshi Kurosawa, Hajime Kobayashi, Hiroshi Iwasaki, Chikara Shimizu, Takeshi Kondo, Takanori Teshima
Clinical Lymphoma Myeloma and Leukemia, 18, 11, e469, e479, Elsevier BV, 2018年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The prognostic effect of Wilms tumor 1 (WT1) expression at the diagnosis of acute myelogenous leukemia (AML) has been controversial. The aim of the present study was to determine the correlations of WT1 expression at the diagnosis of AML with established prognostic alterations. PATIENTS AND METHODS: We analyzed diagnostic bone marrow samples from 252 patients. WT1 expression, single nucleotide polymorphism (SNP) in the WT1 gene (rs16754), and Fms-like tyrosine kinase receptor-3 internal tandem duplication (FLT3-ITD) mutation were analyzed for all patients. The nucleophosmin 1 (NPM1) mutation and CCAAT/enhancer-binding protein-α (CEBPA) double mutation were analyzed for cytogenetically normal (CN)-AML. The KIT mutation was analyzed for core-binding factor AML. RESULTS: Within the cytogenetically favorable prognosis group, WT1 expression in AML with inv(16) or t(15;17) was significantly greater than that in AML with t(8;21). In cases with CN-AML, FLT3-ITD and NPM1 mutations both correlated with greater expression of WT1, and the CEBPA double mutation was related to lower WT1 expression. The existence of both FLT3-ITD and NPM1 mutations showed synergistically greater expression of WT1 in CN-AML. SNP in the WT1 gene (rs16754) was significantly associated with lower expression of WT1. The WT1 levels were not prognostic factors in the total cohort or any cytogenetic group or stratified by SNP status. CONCLUSION: Because WT1 expression has correlated with known prognostic factors, the prognostic effect of WT1 levels could be misunderstood depending on the distribution of the collaborative mutations in each cohort. We have concluded that the prognostic significance of WT1 at the diagnosis of AML is weak compared with the other established prognostic factors.

Synchronous case of follicular lymphoma and Langerhans cell sarcoma in the same lymph node
Joji Shimono, Hiroaki Miyoshi, Fumiko Arakawa, Hideyuki Abe, Takuto Miyagishima, Jun Akiba, Takanori Teshima, Koichi Ohshima
Pathology International, 68, 11, 614, 617, Wiley, 2018年11月, ［査読有り］
研究論文（学術雑誌）

Analysis of GNA13 Protein in Follicular Lymphoma and its Association With Poor Prognosis.
Joji Shimono, Hiroaki Miyoshi, Noriaki Yoshida, Takeharu Kato, Kensaku Sato, Takeshi Sugio, Kohta Miyawaki, Daisuke Kurita, Yuya Sasaki, Keisuke Kawamoto, Yoshitaka Imaizumi, Koji Kato, Koji Nagafuji, Koichi Akashi, Masao Seto, Takanori Teshima, Koichi Ohshima
The American journal of surgical pathology, 42, 11, 1466, 1471, 2018年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, GNA13 is a G protein involved in modulating tumor proliferative capacity, infiltration, metastasis, and migration. Genomic alteration of GNA13 was frequently observed in follicular lymphoma (FL). In this study, we examined 167 cases of FL by immunostaining of GNA13 using tissue microarray to evaluate the clinical significance. There were 26 GNA13-positive cases (15.6%) and 141 GNA13-negative cases (84.4%). GNA13-positive cases had a higher incidence of early progression of disease for which disease progression was recognized within 2 years compared with GNA13-negative cases (P=0.03). There were no significant differences in other clinicopathologic factors including histological grade, BCL2-IGH translocation, immunohistochemical phenotype, and Follicular Lymphoma International Prognostic Index. In addition, overall survival and progression-free survival were poorer in GNA13-positive cases than in GNA13-negative cases (P=0.009 and 0.005, respectively). In multivariate analysis, GNA13 positivity was found to be a poor prognostic factor for overall survival and progression-free survival. Thus, GNA13 protein expression was an independent prognostic factor and may affect disease progression in FL.

Hematogones Predict Better Outcome in Allogeneic Hematopoietic Stem Cell Transplantation Irrespective of Graft Sources
Takashi Ishio, Junichi Sugita, Takahiro Tateno, Daisuke Hidaka, Eiko Hayase, Souichi Shiratori, Kohei Okada, Hideki Goto, Masahiro Onozawa, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Katsuya Fujimoto, Tomoyuki Endo, Takeshi Kondo, Takanori Teshima
Biology of Blood and Marrow Transplantation, 24, 10, 1990, 1996, Elsevier BV, 2018年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Benign precursors of B lymphocytes, termed hematogones, are observed in the regenerative state of hematopoiesis following chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have demonstrated that expansion of hematogones correlates with better clinical outcomes after allo-HSCT. We retrospectively analyzed the association between hematogones and clinical outcomes in 309 consecutive patients who underwent allo-HSCT, which is the largest population-based cohort reported so far. The incidence of hematogones was significantly higher in complete remission (CR) patients at the time of transplantation than in non-CR patients, after myeloablative conditioning than after reduced-intensity conditioning, with tacrolimus-based graft-versus-host disease (GVHD) prophylaxis than with cyclosporine-based prophylaxis, and with disease other than malignant lymphoma (all P < .05). Patients with hematogones developed less acute GVHD and infections than did those without them (P < .05). Emergence of hematogones was associated with superior GVHD-free relapse-free survival and lower nonrelapse mortality, and was an independent prognostic factor for overall survival, irrespective of donor sources.

Essential role of IFN-γ in T cell–associated intestinal inflammation
Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E. Selsted, André J. Ouellette
JCI Insight, 3, 18, e121886, e121886, American Society for Clinical Investigation, 2018年09月20日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Paneth cells contribute to small intestinal homeostasis by secreting antimicrobial peptides and constituting the intestinal stem cell (ISC) niche. Certain T cell-mediated enteropathies are characterized by extensive Paneth cell depletion coincident with mucosal destruction and dysbiosis. In this study, mechanisms of intestinal crypt injury have been investigated by characterizing responses of mouse intestinal organoids (enteroids) in coculture with mouse T lymphocytes. Activated T cells induced enteroid damage, reduced Paneth cell and Lgr5+ ISC mRNA levels, and induced Paneth cell death through a caspase-3/7-dependent mechanism. IFN-γ mediated these effects, because IFN-γ receptor-null enteroids were unaffected by activated T cells. In mice, administration of IFN-γ induced enteropathy with crypt hyperplasia, villus shortening, Paneth cell depletion, and modified ISC marker expression. IFN-γ exacerbated radiation enteritis, which was ameliorated by treatment with a selective JAK1/2 inhibitor. Thus, IFN-γ induced Paneth cell death and impaired regeneration of small intestinal epithelium in vivo, suggesting that IFN-γ may be a useful target for treating defective mucosal regeneration in enteric inflammation.

Autologous haematopoietic stem cell transplantation for Japanese patients with systemic sclerosis: Long-term follow-up on a phase II trial and treatment-related fatal cardiomyopathy
Hiroyuki Nakamura, Toshio Odani, Shinsuke Yasuda, Atsushi Noguchi, Yuichiro Fujieda, Masaru Kato, Kenji Oku, Toshiyuki Bohgaki, Junichi Sugita, Tomoyuki Endo, Takanori Teshima, Tatsuya Atsumi
Modern Rheumatology, 28, 5, 879, 884, Oxford University Press (OUP), 2018年09月03日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: The objective of this study is to elucidate the efficacy and safety of autologous haematopoietic stem cell transplantation (HSCT) for Japanese patients with systemic sclerosis (SSc). METHODS: A phase II clinical trial included SSc patients diagnosed within the last three years having at least one of the following clinical features: diffuse skin sclerosis with modified Rodman total thickness skin score (mRSS) ≥ 15, refractory digital ulcer or interstitial lung disease (ILD). HSCT were performed after conditioning using cyclophosphamide. RESULTS: Fourteen patients were enrolled and underwent HSCT. Median follow-up period was 137 months. Overall survival or event-free survival rate was 93% or 40% at 10 years, respectively. Eight patients (57%) achieved more than a 50% decrease in mRSS from baseline within six months after HSCT. Six patients (43%) required additional immunosuppressive treatments due to progression of diffuse skin sclerosis and/or ILD during follow-up period. Adverse events related to HSCT occurred in six patients (43%). Severe cardiomyopathy occurred in two patients, and one of them had a fatal course. CONCLUSION: HSCT is a feasible treatment bringing favourable results to more than half of our patients with SSc. Careful selection of the patients is essential for whom benefited from HSCT, considering the risk-benefit balance of the treatment.

骨髄バンクを介したコーディネート期間短縮に向けた開始ドナー人数増加(5人→10人)トライアル(Trial to increase the initial numbers of donor candidates for the donor coordination of JMDP)　　　　　　　　　　　　　　　
平川 経晃, 田島 絹子, 大橋 一輝, 豊嶋 崇徳, 大西 康, 小澤 幸泰, 加藤 剛二, 日野 雅之, 前田 嘉信, 嶋田 明, 宮本 敏浩, 白土 基明, 山口 公平, 福田 隆浩
臨床血液, 59, 9, 1630, 1630, (一社)日本血液学会-東京事務局, 2018年09月
日本語

成人急性リンパ性白血病におけるIKZF1欠失およびCRLF2発現の解析(Analysis of IKZF1 deletion and CRLF2 expression in adult patients with acute lymphoblastic leukemia)　　　　　　　　　　　　　　　
橋口 淳一, 小野澤 真弘, 藤澤 真一, 高橋 秀一郎, 宮下 直洋, 早瀬 英子, 白鳥 聡一, 後藤 秀樹, 杉田 純一, 中川 雅夫, 橋本 大吾, 加畑 馨, 遠藤 知之, 山本 聡, 堤 豊, 長谷山 美仁, 永嶋 貴博, 盛 暁生, 太田 秀一, 宮城島 拓人, 柿木 康孝, 黒澤 光俊, 岩崎 博, 近藤 健, 豊嶋 崇徳
臨床血液, 59, 9, 1648, 1648, (一社)日本血液学会-東京事務局, 2018年09月
英語

日本人未治療CLL/SLL患者を対象としたIbrutinibの第I相試験(Phase 1 study of ibrutinib in Japanese patients with treatment-naive CLL/SLL)　　　　　　　　　　　　　　　
豊嶋 崇徳, 柴山 浩彦, 崔 日承, 畠 清彦, 関口 直宏, 吉成 望
臨床血液, 59, 9, 1526, 1526, (一社)日本血液学会-東京事務局, 2018年09月
英語

KEYNOTE185 未治療多発性骨髄腫を対象としたLen/dex±pembrolizumab第3相試験(日本人解析含む)(KEYNOTE185: Randomized phase 3 study of Len/dex±pembrolizumab in untreated MM: including JPN subset)　　　　　　　　　　　　　　　
小杉 浩史, 竹迫 直樹, 松本 守生, 飯田 真介, 石川 隆之, 近藤 恭夫, 安藤 潔, 張 高明, 三木 浩和, 松村 到, 角南 一貴, 豊嶋 崇徳, 岩崎 浩己, 大西 康, 木崎 昌弘, 伊豆津 宏二, 丸山 大, 飛内 賢正, 鈴木 憲史
臨床血液, 59, 9, 1610, 1610, (一社)日本血液学会-東京事務局, 2018年09月
英語

The association between the incidence of intestinal graft-vs-host disease and antibiotic use after allogeneic hematopoietic stem cell transplantation
Daisuke Hidaka, Eiko Hayase, Souichi Shiratori, Yuta Hasegawa, Takashi Ishio, Takahiro Tateno, Kohei Okada, Hideki Goto, Junichi Sugita, Masahiro Onozawa, Masao Nakagawa, Kaoru Kahata, Tomoyuki Endo, Daigo Hashimoto, Takanori Teshima
Clinical Transplantation, 32, 9, e13361, e13361, Wiley, 2018年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Intestinal microbiota plays an important role in the regulation of allogeneic immune reaction after allogeneic hematopoietic stem cell transplantation (allo-SCT). Intestinal graft-vs-host disease (GVHD) is one of the major causes of mortality after allo-SCT and often complicated with intestinal dysbiosis. Recent studies suggest that antibiotic-induced dysbiosis is a risk factor for intestinal GVHD. We retrospectively evaluated the impacts of antibiotic use on the incidence of intestinal GVHD occurring before day 100 after allo-SCT. Among 213 patients who underwent allo-SCT, 200 patients achieving engraftment were analyzed. Antibiotics were classified into carbapenem, quinolone, penicillin, cephem, and glycopeptide. Among 128 patients who developed acute GVHD, intestinal GVHD developed in 36 patients. Patients with intestinal GVHD received significantly longer administration of carbapenem and glycopeptide compared to those without it in periengraftment period. In multivariate analysis, use of carbapenem for greater than 7 days was associated with an increased risk of intestinal GVHD. However, use of antibiotics for greater than 7 days was not associated with poor overall survival and high nonrelapse mortality. Long use of carbapenem in periengraftment period may be a risk for intestinal GVHD. Prospective studies are required to validate our findings.

北海道HIV透析ネットワークの構築とその有効性の検討
遠藤 知之, センテノ田村 恵子, 渡部 恵子, 後藤 秀樹, 宮下 直洋, 荒 隆英, 笠原 耕平, 橋野 聡, 豊嶋 崇徳
日本エイズ学会誌, 20, 3, 199, 205, (一社)日本エイズ学会, 2018年08月, ［査読有り］
日本語, 北海道透析療法学会と連携し、HIV感染者の受け入れが可能な透析施設をあらかじめ登録する「北海道HIV透析ネットワーク」を設置した。平成29年12月末までに、ネットワークには全道で42施設の登録が得られた。北海道内で維持透析を必要としたHIV感染者は、透析ネットワーク構築前後でそれぞれ4例ずつであった。維持透析施設確保までに要した期間は、ネットワーク構築前は、エイズ拠点病院でそのまま透析となった1例以外は、2ヵ月、12ヵ月と長く、透析施設が確保できず、体調が悪くなったときのみ拠点病院で緊急透析を行っていた症例もあった。自宅から透析施設までの距離も3kmから30kmとなっており、車で1時間かけて透析施設に通っていた症例もあった。透析ネットワーク構築後は、1例は、透析施設自体がない地域に居住していたため、自宅での腹膜透析となったが、他の3例はいずれも相談を行った即日維持透析受け入れの承諾が得られた。自宅から透析施設までの距離は最長で3kmで、通院に要する時間も30分以内となった。さらに、旅行者の一時透析の受け入れ相談例が1件あり、その症例に対しても即日透析受け入れの承諾が得られた。

Disseminated fusariosis emerged from prolonged local genital infection after cord blood transplantation
Kohei Okada, Tomoyuki Endo, Daigo Hashimoto, Tomoyuki Saga, Takahide Ara, Reiki Ogasawara, Atsushi Yasumoto, Makoto Ibata, Mutsumi Takahata, Akio Shigematsu, Takeshi Kondo, Yasunori Muraosa, Toshifumi Nomura, Hiromi Kanno-Okada, Satoshi Hashino, Shinya Tanaka, Katsuhiko Kamei, Takanori Teshima
Journal of Infection and Chemotherapy, 24, 8, 660, 663, Elsevier B.V., 2018年08月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Disseminated fusariosis (DF) is a rare life threatening fungal infection in immunocompromised hosts. We herein report a case of a fatal DF mimicking varicella zoster virus (VZV) infection that was emerged from a localized genital infection during cord blood transplantation (CBT) in a patient with severe aplastic anemia (SAA). The patient developed an ulcer following small painful vesicles mimics herpes simplex virus infection (HSV) on the glans penis before CBT, but a Fusarium species was identified. Despite administration of voriconazole, liposomal amphotericin B and granulocyte transfusion, the lesion was extended to extensive skin looked like VZV infection and the patients died after CBT. Massive fusarium infiltration was detected in multiple organs at autopsy. A genetic analysis of the mold identified Fusarium solani after his death. It should be noted that in patients with fusarium infection, localized and disseminated lesions of fusarium infection sometimes mimic HSV and VZV infections, which hampers an early diagnosis.

Safety, tolerability and pharmacokinetics of shorter duration of infusion of obinutuzumab in Japanese patients with B-cell non-Hodgkin lymphoma: final results of the phase II GATS study
Ken Ohmachi, Kiyoshi Ando, Tomohiro Kinoshita, Kyoya Kumagai, Kiyohiko Hatake, Takayuki Ishikawa, Takanori Teshima, Koji Kato, Koji Izutsu, Eisuke Ueda, Kiyohiko Nakai, Hiroshi Kuriki, Kensei Tobinai
Japanese Journal of Clinical Oncology, 48, 8, 736, 742, Oxford University Press (OUP), 2018年08月01日, ［査読有り］
研究論文（学術雑誌）

AMLにおけるWT1発現量と染色体・遺伝子異常の関連　　　　　　　　　　　　　　　
日高 大輔, 小野澤 真弘, 橋口 淳一, 宮下 直洋, 笠原 耕平, 藤澤 真一, 早瀬 英子, 岡田 耕平, 白鳥 聡一, 後藤 秀樹, 杉田 純一, 中川 雅夫, 加畑 馨, 橋本 大吾, 遠藤 知之, 山本 聡, 堤 豊, 長谷山 美仁, 永嶋 貴博, 盛 暁生, 太田 秀一, 酒井 基, 石原 敏道, 今井 陽俊, 宮城島 拓人, 柿木 康孝, 黒澤 光俊, 小林 一, 岩崎 博, 清水 力, 近藤 健, 豊嶋 崇徳
臨床血液, 59, 7, 964, 964, (一社)日本血液学会-東京事務局, 2018年07月
日本語

Development of a Fluorescence in Situ Hybridization Probe for Detecting IKZF1 Deletion Mutations in Patients with Acute Lymphoblastic Leukemia
Junichi Hashiguchi, Masahiro Onozawa, Satoshi Oguri, Shinichi Fujisawa, Masahisa Tsuji, Kohei Okada, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Takeshi Kondo, Chikara Shimizu, Takanori Teshima
Journal of Molecular Diagnostics, 20, 4, 446, 454, Elsevier B.V., 2018年07月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Intragenic deletion of IKZF1 is a recurrent genomic alteration in acute lymphoblastic leukemia. The deletions are mediated by illegitimate variable(diversity)joining recombination via cryptic recombination signal sequences (RSSs). We developed a fluorescence in situ hybridization (FISH) probe set that can detect any type of IKZF1 deletion, including the commonly deleted exon 4 to 7 region. The probe set consists of a designed probe for the commonly deleted region (Cy3
red) and a bacterial artificial chromosomes clone probe for detecting the 3′ flanking region (Spectrum Green). Intact IKZF1 showed a fusion signal, and the deleted allele showed loss of the red signal (0R1G1F). The FISH probes worked correctly for human leukemic cell lines and clinical samples. One case showed an atypical break-apart signal (1R1G1F). Inverse PCR of the case revealed rearrangement of the excised IKZF1 fragment into a legitimate RSS site at Ig κ on chromosome 2, suggesting a pathogenic role of this recombination-activating gene 1/2-mediated event. In this study, we established FISH probe detecting IKZF1 deletion in a quick, quantitative, and cost-effective manner, and the results provided a novel insight into B-cell receptor editing by rearrangement of a cryptic RSS-mediated genomic fragment in acute lymphoblastic leukemia pathology.

Pretreatment evaluation of fluorescence resonance energy transfer-based drug sensitivity test for patients with chronic myelogenous leukemia treated with dasatinib.
Takeshi Kondo, Mari Fujioka, Masumi Tsuda, Kazunori Murai, Kohei Yamaguchi, Takuto Miyagishima, Motohiro Shindo, Takahiro Nagashima, Kentaro Wakasa, Nozomu Fujimoto, Satoshi Yamamoto, Masakatsu Yonezumi, Souichi Saito, Shinji Sato, Kazuei Ogawa, Takaaki Chou, Reiko Watanabe, Yuichi Kato, Shuichiro Takahashi, Yoshiaki Okano, Joji Yamamoto, Masatsugu Ohta, Hiroaki Iijima, Koji Oba, Satoshi Kishino, Junichi Sakamoto, Yoji Ishida, Yusuke Ohba, Takanori Teshima
Cancer science, 109, 7, 2256, 2265, 2018年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The ΔFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the ΔFRET value and molecular response, a threshold of the ΔFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with ΔFRET value ≥0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with ΔFRET value <0.31. These results suggest that the FRET-based drug sensitivity test at diagnosis can predict early and deep molecular responses. This study is registered with UMIN Clinical Trials Registry (UMIN000006358).

The Microbiome and Hematopoietic Cell Transplantation: Past, Present, and Future
Tessa M. Andermann, Jonathan U. Peled, Christine Ho, Pavan Reddy, Marcie Riches, Rainer Storb, Takanori Teshima, Marcel R.M. van den Brink, Amin Alousi, Sophia Balderman, Patrizia Chiusolo, William B. Clark, Ernst Holler, Alan Howard, Leslie S. Kean, Andrew Y. Koh, Philip L. McCarthy, John M. McCarty, Mohamad Mohty, Ryotaro Nakamura, Katy Rezvani, Brahm H. Segal, Bronwen E. Shaw, Elizabeth J. Shpall, Anthony D. Sung, Daniela Weber, Jennifer Whangbo, John R. Wingard, William A. Wood, Miguel-Angel Perales, Robert R. Jenq, Ami S. Bhatt
Biology of Blood and Marrow Transplantation, 24, 7, 1322, 1340, Elsevier BV, 2018年07月, ［査読有り］
研究論文（学術雑誌）

Extracorporeal photopheresis with TC-V in Japanese patients with steroid-resistant chronic graft-versus-host disease
Shinichiro Okamoto, Takanori Teshima, Mizuha Kosugi-Kanaya, Kaoru Kahata, Naomi Kawashima, Jun Kato, Takehiko Mori, Yukiyasu Ozawa, Koichi Miyamura
International Journal of Hematology, 108, 3, 1, 8, Springer Tokyo, 2018年06月29日, ［査読有り］
英語, 研究論文（学術雑誌）, There are few established therapies for chronic graft-versus-host disease (cGVHD) refractory to first-line treatment with steroids. We evaluated the efficacy and safety of extracorporeal photopheresis (ECP) with a third-generation TC-V device in Japanese patients with cGVHD. Fifteen patients with steroid-resistant or -intolerant cGVHD after allogeneic hematopoietic stem cell transplantation participated in this multicenter open-label study. Extracorporeal photopheresis was conducted on days 1–3, week 1
days 1–2, weeks 2–12
and days 1–2, weeks 16, 20, and 24. The composite primary endpoint consisted of evaluation of response and changes in steroid dose 24 weeks after ECP initiation. Secondary endpoints included response over time, concomitant drug dose, quality of life, and safety. Twelve patients completed scheduled ECP therapy
eight (66.7%) showed a response at week 24. In all 15 patients, the mean (± standard deviation) steroid dose decreased 0.115 ± 0.230 mg/kg/day from screening to week 24. Five serious, potentially treatment-related adverse events (heart failure, thrombosis in the device, pneumonia, edema, and wheezing) occurred
none were fatal. This study confirmed that ECP using the TC-V device was effective, with an acceptable toxicity profile. Further studies in larger cohorts are clearly warranted to determine its optimal use in Japanese patients with cGVHD.

体外診断薬開発のための慢性骨髄性白血病におけるBCR-ABL活性測定用改良型FRETバイオセンサー　　　　　　　　　　　　　　　
大場 雄介, 近藤 健, 豊嶋 崇徳
臨床薬理の進歩, 39, 18, 26, (公財)臨床薬理研究振興財団, 2018年06月, ［査読有り］
日本語, アミノ酸置換および核外移行シグナル(NES)の導入により、切断抵抗性が向上した改良型Picklesバイオセンサーを開発したので報告した。フェルスター共鳴エネルギー移動(FRET)に基づくバイオセンサーPickles 2.31のために開発されたオリジナルのプロトコールでは、評価対象細胞をCFPとYFPの蛍光強度比に従って選択する。この基準に従ってPickles 2.31とPickles 2.34 NESの特性を比較したところ、薬剤処理の有無にかかわらず基準を満たす細胞の数が5%から25%増加した。さらに、実際の薬効評価指標であるFRET効率(FRET/CFP蛍光強度比)についても単一細胞レベルで評価した。以前の報告において使用した定義では、FRET効率が2.04より高い細胞は有意に高いBCR-ABL活性を示す。この基準によれば、改良型バイオセンサーはコントロールサンプル中に四つのFRET-high細胞を検出できるが、プロトタイプでは2.04以上の細胞は一つしか検出されなかった。この増加は分析対象細胞数の増加が検出能の向上に寄与した結果と考えられた。

Re-infection of Toxoplasma gondii after HSCT presenting lymphadenopathy resembling recurrence of lymphoma
Junichi Hashiguchi, Masahiro Onozawa, Tomoaki Naka, Kanako C. Hatanaka, Souichi Shiratori, Junichi Sugita, Katsuya Fujimoto, Yoshihiro Matsuno, Takanori Teshima
Transplant Infectious Disease, 20, 3, e12892, Blackwell Publishing Inc., 2018年06月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Toxoplasma gondii (T. gondii) reactivation is one of the fatal complications after hematopoietic stem cell transplantation (HSCT)
however, re-infection has not been reported. Here, we report a case of mycosis fungoides in which cervical lymphadenopathy developed after HSCT. Initially, recurrent lymphoma was suspected. However, biopsy of the lymph node showed typical histology of toxoplasmosis and serology showed re-infection of T. gondii. Toxoplasmosis needs to be differentiated for cases with lymphoadenopthy after HSCT.

Graft-versus-host disease in recipients of male unrelated donor compared with parous female sibling donor transplants
Anita J. Kumar, Soyoung Kim, Michael T. Hemmer, Mukta Arora, Stephen R. Spellman, Joseph A. Pidala, Daniel R. Couriel, Amin M. Alousi, Mahmoud D. Aljurf, Jean-Yves Cahn, Mitchell S. Cairo, Corey S. Cutler, Shatha Farhan, Usama Gergis, Gregory A. Hale, Shahrukh K. Hashmi, Yoshihiro Inamoto, Rammurti T. Kamble, Mohamed A. Kharfan-Dabaja, Margaret L. MacMillan, David I. Marks, Hideki Nakasone, Maxim Norkin, Muna Qayed, Olle Ringden, Harry C. Schouten, Kirk R. Schultz, Melhem M. Solh, Takanori Teshima, Alvaro Urbano-Ispizua, Leo F. Verdonck, Robert Peter Gale, Betty K. Hamilton, Navneet S. Majhail, Alison W. Loren
Blood Advances, 2, 9, 1022, 1031, American Society of Hematology, 2018年05月08日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）,
Compared with parous female sibling donors, male URDs confer more aGVHD in all patients and more cGVHD in females. There was no difference in survival, relapse, or transplant mortality between recipients of parous female sibling or male URD grafts.

Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease
Shuichiro Takahashi, Daigo Hashimoto, Eiko Hayase, Reiki Ogasawara, Hiroyuki Ohigashi, Takahide Ara, Emi Yokoyama, Ko Ebata, Satomi Matsuoka, Geoffrey R. Hill, Junichi Sugita, Masahiro Onozawa, Takanori Teshima
Blood, 131, 18, 2074, 2085, American Society of Hematology, 2018年05月03日, ［査読有り］
英語, 研究論文（学術雑誌）, Graft-versus-host disease (GVHD) is the major complication after allogeneic stem cell transplantation (SCT). Emerging evidence indicates that GVHD leads to injury of intestinal stem cells. However, it remains to be investigated whether skin stem cells could be targeted in skin GVHD. Lgr51 hair follicle stem cells (HFSCs) contribute to folliculogenesis and have a multipotent capacity to regenerate all epithelial cells in repair. We studied the fate of Lgr51 HFSCs after SCT and explored the novel treatment to protect Lgr51 HFSCs against GVHD using murine models of SCT. We found that GVHD reduced Lgr51 HFSCs in association with impaired hair regeneration and wound healing in the skin after SCT. Topical corticosteroids, a standard of care for a wide range of skin disorders including GVHD, damaged HFSCs and failed to improve skin homeostasis, despite of their anti-inflammatory effects. In contrast, JAK1/2 inhibitor ruxolitinib significantly ameliorated skin GVHD, protected Lgr51 HFSCs, and restored hair regeneration and wound healing after SCT. We, for the first time, found that GVHD targets Lgr51 HFSCs and that topical ruxolitinib represents a novel strategy to protect skin stem cells and maintain skin homeostasis in GVHD.

担癌患者の精査加療中、偶発的に病理組織診断された慢性リンパ性白血病/リンパ球性リンパ腫の3例
岡田 宏美, 清水 亜衣, 桑原 健, 大塚 拓也, 高桑 恵美, 岡田 耕平, 白鳥 聡一, 遠藤 知之, 豊嶋 崇徳, 三橋 智子, 松野 吉宏
日本リンパ網内系学会会誌, 58, 111, 111, (一社)日本リンパ網内系学会, 2018年05月
日本語

Cecum ulcer is a reliable endoscopic finding in cytomegalovirus colitis concomitant with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
Kana Matsuda, Shoko Ono, Marin Ishikawa, Shuichi Miyamoto, Satoshi Abiko, Momoko Tsuda, Keiko Yamamoto, Takahiko Kudo, Yuichi Shimizu, Eiko Hayase, Daigo Hashimoto, Takanori Teshima, Yoshihiro Matsuno, Naoya Sakamoto
Annals of Hematology, 97, 5, 877, 883, Springer Verlag, 2018年05月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Although graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), cytomegalovirus (CMV) reactivation also occurs in patients after allo-HSCT and these conditions often clinically overlap. The aim of this study was to determine reliable endoscopic findings of CMV colitis in patients with gastrointestinal graft-versus-host-disease (GI-GVHD). Patients after allo-HSCT who were histologically confirmed to have GI-GVHD with or without CMV colitis and patients with an immunosuppressive condition were retrospectively analyzed. We divided the patients into three groups: GI-GVHD with CMV colitis (group A), GI-GVHD without CMV colitis (group B), and CMV colitis without undergoing allo-HSCT (group C). From medical records, the involved colorectal areas and endoscopic findings according to the groups were compared. A total of 70 patients were divided into three groups (group A: n = 19, group B: n = 28, group C: n = 23). Mucosal injuries in groups A and C frequently occurred in the cecum including ileocecal valves. On the other hand, there were no abnormal lesions on ileocecal valves in group B. Furthermore, ulcer lesions were more frequently observed in groups A and C than in group B (p <
0.001). The sensitivity and specificity of mucosal injuries in the cecum for prediction of CMV colitis were 89.5 and 76.5%, respectively, and mucosal injuries in the cecum were more reliable findings than CMV antigenemia. Ulcer lesions in the cecum are reliable endoscopic findings for CMV colitis in patients with GI-GVHD after allo-HSCT.

Clinicopathological analysis of polyploid diffuse large B-cell lymphoma
Joji Shimono, Hiroaki Miyoshi, Junichi Kiyasu, Tomohiko Kamimura, Tetsuya Eto, Takuto Miyagishima, Koji Nagafuji, Masao Seto, Takanori Teshima, Koichi Ohshima
PLOS ONE, 13, 4, e0194525, e0194525, Public Library of Science (PLoS), 2018年04月11日, ［査読有り］
研究論文（学術雑誌）

A novel heterozygous ITGB3 p.T720del inducing spontaneous activation of integrin αIIbβ3 in autosomal dominant macrothrombocytopenia with aggregation dysfunction
Naohiro Miyashita, Masahiro Onozawa, Koji Hayasaka, Takahiro Yamada, Ohsuke Migita, Kenichiro Hata, Kohei Okada, Hideki Goto, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Takeshi Kondo, Shinji Kunishima, Takanori Teshima
Annals of Hematology, 97, 4, 629, 640, Springer Science and Business Media LLC, 2018年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We identified a novel heterozygous ITGB3 p.T720del mutation in a pedigree with macrothrombocytopenia exhibiting aggregation dysfunction. Platelet aggregation induced by ADP and collagen was significantly reduced, while ristocetin aggregation was normal. Integrin αIIbβ3 was partially activated in a resting status, but platelet expression of αIIbβ3 was downregulated. Functional analysis using a cell line showed spontaneous phosphorylation of FAK in αIIb/β3 (p.T720del)-transfected 293T cells in suspension conditions. Abnormal cytoplasmic protrusions, membrane ruffling, and cytoplasmic localization of αIIbβ3 were observed in αIIb/β3 (p.T720del)-transfected CHO cells. Such morphological changes were reversed by treatment with an FAK inhibitor. These findings imply spontaneous, but partial, activation of αIIbβ3 followed by phosphorylation of FAK as the initial mechanism of abnormal thrombopoiesis. Internalization and decreased surface expression of αIIbβ3 would contribute to aggregation dysfunction. We reviewed the literature of congenital macrothrombocytopenia associated with heterozygous ITGA2B or ITGB3 mutations. Reported mutations were highly clustered at the membrane proximal region of αIIbβ3, which affected the critical interaction between αIIb R995 and β3 D723, resulting in a constitutionally active form of the αIIbβ3 complex. Macrothrombocytopenia caused by a heterozygous activating mutation of ITGA2B or ITGB3 at the membrane proximal region forms a distinct entity of rare congenital thrombocytopenia.

Prospective randomization of post-remission therapy comparing autologous peripheral blood stem cell transplantation versus high-dose cytarabine consolidation for acute myelogenous leukemia in first remission
Toshihiro Miyamoto, Koji Nagafuji, Tomoaki Fujisaki, Naoyuki Uchida, Kosei Matsue, Hideho Henzan, Ryosuke Ogawa, Ken Takase, Takatoshi Aoki, Michihiro Hidaka, Takanori Teshima, Shuichi Taniguchi, Koichi Akashi, Mine Harada, For the Japan Study Group for Cell Therapy and Transplantation (JSCT)
International Journal of Hematology, 107, 4, 468, 477, Springer Tokyo, 2018年04月01日, ［査読有り］
英語, 研究論文（学術雑誌）, We prospectively compared outcomes of autologous stem cell transplantation (ASCT) versus high-dose cytarabine (HiDAC) consolidation as post-remission therapy for favorable- and intermediate-risk acute myelogenous leukemia (AML) in first complete remission (CR1). Two-hundred-forty patients under 65 years with AML-M1, M2, M4, or M5 subtypes were enrolled. After induction, 153 patients did not undergo randomization, while the remaining 87 who achieved CR1 were prospectively randomized to HiDAC (n = 45) or ASCT arm (n = 42). In the HiDAC arm, 43 patients completed three cycles of HiDAC, whereas in ASCT arm 22 patients completed two cycles of consolidation consisting of intermediate-dose cytarabine plus mitoxantrone or etoposide followed by ASCT. The three-year disease-free survival (DFS) rate was 41% in HiDAC and 55% in ASCT arm (p = 0.25). Three-year overall survival (OS) rates were 77 and 68% (p = 0.67). Incidence of relapse was 54 and 41% (p = 0.22). There was no significant difference in nonrelapse mortality between two arms (p = 0.88). Patients in the ASCT arm tended to have higher DFS rates and lower relapse rates than patients in HiDAC
however, there was no significant improvement in OS in patients with favorable- and intermediate-risk AML in CR1. Patients with AML are not benefited by the intensified chemotherapy represented by ASCT.

Vitamin A–coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease
Tomohiro Yamakawa, Hiroyuki Ohigashi, Daigo Hashimoto, Eiko Hayase, Shuichiro Takahashi, Miyono Miyazaki, Kenjiro Minomi, Masahiro Onozawa, Yoshiro Niitsu, Takanori Teshima
Blood, 131, 13, 1476, 1485, American Society of Hematology, 2018年03月29日, ［査読有り］
英語, 研究論文（学術雑誌）, Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/801 macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti–colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP471 myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD
macrophage production of transforming growth factor b mediates fibroblast differentiation to HSP471 myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP471 myofibroblasts without inducing immunosuppression.

Overcoming HLA Barrier in Hematopoietic Stem Cell Transplantation
Takanori Teshima
Nihon Naika Gakkai Zasshi, 107, 3, 579, 585, Japanese Society of Internal Medicine, 2018年03月10日, ［査読有り］
日本語, 研究論文（学術雑誌）

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells
Nimitha R. Mathew, Francis Baumgartner, Lukas Braun, David O'Sullivan, Simone Thomas, Miguel Waterhouse, Tony A. Müller, Kathrin Hanke, Sanaz Taromi, Petya Apostolova, Anna L. Illert, Wolfgang Melchinger, Sandra Duquesne, Annette Schmitt-Graeff, Lena Osswald, Kai-Li Yan, Arnim Weber, Sonia Tugues, Sabine Spath, Dietmar Pfeifer, Marie Follo, Rainer Claus, Michael Lübbert, Christoph Rummelt, Hartmut Bertz, Ralph Wäsch, Johanna Haag, Andrea Schmidts, Michael Schultheiss, Dominik Bettinger, Robert Thimme, Evelyn Ullrich, Yakup Tanriver, Giang Lam Vuong, Renate Arnold, Philipp Hemmati, Dominik Wolf, Markus Ditschkowski, Cordula Jilg, Konrad Wilhelm, Christian Leiber, Sabine Gerull, Jörg Halter, Claudia Lengerke, Thomas Pabst, Thomas Schroeder, Guido Kobbe, Wolf Rösler, Soroush Doostkam, Stephan Meckel, Kathleen Stabla, Stephan K. Metzelder, Sebastian Halbach, Tilman Brummer, Zehan Hu, Joern Dengjel, Björn Hackanson, Christoph Schmid, Udo Holtick, Christof Scheid, Alexandros Spyridonidis, Friedrich Stölzel, Rainer Ordemann, Lutz P. Müller, Flore Sicre-De-Fontbrune, Gabriele Ihorst, Jürgen Kuball, Jan E. Ehlert, Daniel Feger, Eva-Maria Wagner, Jean-Yves Cahn, Jacqueline Schnell, Florian Kuchenbauer, Donald Bunjes, Ronjon Chakraverty, Simon Richardson, Saar Gill, Nicolaus Kröger, Francis Ayuk, Luca Vago, Fabio Ciceri, Antonia M. Müller, Takeshi Kondo, Takanori Teshima, Susan Klaeger, Bernhard Kuster, Dennis H. Kim, Daniel Weisdorf, Walter Van Der Velden, Daniela Dörfel, Wolfgang Bethge, Inken Hilgendorf, Andreas Hochhaus, Geoffroy Andrieux, Melanie Börries, Hauke Busch, John Magenau, Pavan Reddy, Myriam Labopin, Joseph H. Antin, Andrea S. Henden, Geoffrey R. Hill, Glen A. Kennedy, Merav Bar, Anita Sarma, Donal McLornan, Ghulam Mufti, Betul Oran, Katayoun Rezvani, Omid Shah, Robert S. Negrin, Arnon Nagler, Marco Prinz, Andreas Burchert, Andreas Neubauer, Dietrich Beelen, Andreas Mackensen, Nikolas Von Bubnoff, Wolfgang Herr, Burkhard Becher, Gerard Socié, Michael A. Caligiuri, Eliana Ruggiero, Chiara Bonini, Georg Häcker, Justus Duyster, Jürgen Finke, Erika Pearce, Bruce R. Blazar, Robert Zeiser
Nature Medicine, 24, 3, 282, 291, Nature Publishing Group, 2018年03月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD + leukemia cells. This synergized with the allogeneic CD8 + T cell response, leading to long-term survival in six mouse models of FLT3-ITD + AML. Sorafenib-related IL-15 production caused an increase in CD8 + CD107a + IFN-3 + T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD + AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 + T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma
M. Fujisawa, M. Sakata-Yanagimoto, S. Nishizawa, D. Komori, P. Gershon, M. Kiryu, S. Tanzima, K. Fukumoto, T. Enami, M. Muratani, K. Yoshida, S. Ogawa, K. Matsue, N. Nakamura, K. Takeuchi, K. Izutsu, K. Fujimoto, T. Teshima, H. Miyoshi, P. Gaulard, K. Ohshima, S. Chiba
Leukemia, 32, 3, 694, 702, Nature Publishing Group, 2018年03月01日, ［査読有り］
英語, 研究論文（学術雑誌）, Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.

T-cell depletion effects of low-dose antithymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation
Souichi Shiratori, Mizuha Kosugi-Kanaya, Eiko Hayase, Kohei Okada, Hideki Goto, Junichi Sugita, Masahiro Onozawa, Masao Nakagawa, Kaoru Kahata, Daigo Hashimoto, Tomoyuki Endo, Takeshi Kondo, Takanori Teshima
Transplant Immunology, 46, 21, 22, Elsevier BV, 2018年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

潜伏感染III型のEBウイルスが発症に寄与したと思われる膿胸関連リンパ腫の1例
千丈 創, 盛 暁生, 金谷 穣, 泉山 康, 岡田 耕平, 竹薮 公洋, 飛岡 弘敏, 斉藤 誠, 田中 雅則, 豊嶋 崇徳, 森岡 正信
日本老年医学会雑誌, 55, 1, 143, 147, (一社)日本老年医学会, 2018年01月, ［査読有り］
日本語, 膿胸関連リンパ腫(pyothorax-associated lymphoma;PAL)は、結核性胸膜炎や肺結核症に対する人工気胸術後の患者が、数十年後に膿胸腔に隣接して発症する悪性リンパ腫である。人工気胸術は1950年代から施行されなくなっており、膿胸関連リンパ腫患者は今後減少していくと考える。今回、われわれは人工気胸術から67年後に発症し、潜伏感染III型EBウイルスの関連が強く示唆されたPALの1例を経験した。人工気胸術の既往がある患者に胸部症状が認められる場合、依然として膿胸関連リンパ腫を念頭に入れる必要があることを示す貴重な症例として、文献的考察を加えて報告する。症例は84歳男性。1950年に肺結核に対し人工気胸術を施行された。2017年2月中旬より右胸部痛が出現し、近医を受診した。胸部単純写真にて浸潤影を認め、胸部単純CTで右胸壁、右肺底部、下大静脈背側に腫瘤陰影を認めた。18FDG-PETで同部に一致して高集積を認めた。このため右胸壁腫瘤に対しCTガイド下で経皮生検を施行し、病理組織学的にびまん性大細胞型B細胞性リンパ腫(Diffuse large B-cell Lymphoma;DLBCL)と診断された。3月某日に精査加療目的で当院入院した。入院時血液検査で血清EBV-DNAが33,000copies/mlと著明に高値であり、腫瘤検体に対する追加の免疫染色でEBNA-2陽性の腫瘍細胞をびまん性に認め、LMP-1陽性の腫瘍細胞を少数認めたことから、EBウイルス潜伏感染III型による膿胸関連リンパ腫の診断に至った。DLBCLに対しR-THP-COP、BRによる化学療法を施行し、血清EBV-DNAの著明な減少を認めたが、全身状態の悪化から治療継続困難となり、化学療法を中止し緩和的治療へと変更した。(著者抄録)

Pyothorax-associated lymphoma with the expression of epstein-barr virus latent genes
Hajime Senjo, Akio Mori, Minoru Kanaya, Koh Izumiyama, Kohei Okada, Kimihiro Takeyabu, Hirotoshi Tobioka, Makoto Saito, Masanori Tanaka, Takanori Teshima, Masanobu Morioka
Japanese Journal of Geriatrics, 55, 1, 143, 147, Japan Geriatrics Society, 2018年, ［査読有り］
日本語, 研究論文（学術雑誌）, An 84-year-old man, who had received artificial pneumothorax for pulmonary tuberculosis 67 years previously, complained of severe chest pain. Chest CT revealed chronic pyothorax with multiple heterogeneously enhanced cavity lesions in the wall of the right intrathoracic space. 18FDG-PET revealed that the lesions showed an abnormal uptake. CT-guided biopsy was performed and he was diagnosed with pyothorax-associated lymphoma (PAL)
the histological diagnosis was diffuse large B cell lymphoma (DLBCL). Furthermore, immunohistochemical staining revealed that the tumor cells were positive for EBNA-2 and LMP-1, suggesting that the latent gene products of Epstein-Barr virus were associated with the development of PAL. The patient was treated with chemotherapy, including rituximab
however, the treatment was discontinued due to the development of severe delirium after chemotherapy. We should keep in mind that elderly patients with a long history of chronic pyothorax are at risk of developing malignant lymphoma. We report the present case with a brief review of the literature.

Novel Ultrasonographic Scoring System of Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation
Mutsumi Nishida, Kaoru Kahata, Eiko Hayase, Akio Shigematsu, Megumi Sato, Yusuke Kudo, Satomi Omotehara, Takahito Iwai, Junichi Sugita, Hitoshi Shibuya, Chikara Shimizu, Takanori Teshima
Biology of Blood and Marrow Transplantation, 24, 9, 1896, 1900, Elsevier Inc., 2018年, ［査読有り］
英語, 研究論文（学術雑誌）, Sinusoidal obstruction syndrome (SOS)/hepatic veno-occlusive disease (VOD) is a well-documented complication after hematopoietic stem cell transplantation (HSCT). Transabdominal ultrasonography (US) enables the visualization of blood flow abnormalities and is therefore useful for the diagnosis of SOS/VOD. We herein prospectively evaluated accuracy of a novel US diagnostic scoring system of SOS/VOD based on US findings. We carried out US in 106 patients on day 14 and when SOS/VOD was suspected after allogeneic HSCT. Among 106 patients, 10 patients (9.4%) were diagnosed as SOS/VOD by Baltimore or Seattle criteria. According to univariate analysis of 17 US findings (US-17 screening), we established a novel scoring system (HokUS-10) consisting of 10 parameters, such as gallbladder wall thickening, ascites, and blood flow signal in the paraumbilical vein. The sensitivity and specificity were 100% and 95.8%, respectively. Diagnostic performance of the HokUS-10 was significantly better than US-17 screening. In 4 of 10 patients US detection of SOS/VOD preceded to clinical diagnosis. The HokUS-10 scoring system is useful in the diagnosis of SOS/VOD
however, our results should be validated in other cohorts.

Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma
Joji Shimono, Hiroaki Miyoshi, Takeharu Kato, Takeshi Sugio, Kohta Miyawaki, Tomohiko Kamimura, Takuto Miyagishima, Tetsuya Eto, Yoshitaka Imaizumi, Koji Kato, Koji Nagafuji, Koichi Akashi, Masao Seto, Takanori Teshima, Koichi Ohshima
Oncotarget, 9, 2, 1717, 1725, Impact Journals LLC, 2018年, ［査読有り］
英語, 研究論文（学術雑誌）, Hepatitis C virus (HCV) is a single-stranded RNA virus that not only affects hepatocytes, by B cells as well. It is thought that HCV is involved in the onset of B-cell lymphoma. The clinicopathological characteristics of HCV-positive diffuse large B-cell lymphoma (DLBCL) and HCV-positive splenic marginal zone lymphoma (SMZL) are known, but there has been no report on HCV-positive follicular lymphoma (FL). In this study, the clinicopathological characteristics of HCV-positive FL were examined in 263 patients with FL who were classified into a HCV-positive group with HCV antibody and negative groups without one. The number of patients with HCV-positive FL and HCV-negative FL was 10 (3.8%) and 253 (96.2%), respectively. The patients with HCV-positive FL commonly had more than one region of lymphadenopathy, Ann Arbor stage III/IV, hemoglobin <
120 g/l, elevated lactate dehydrogenase level, and highrisk categorization of Follicular Lymphoma International Prognostic Index (FLIPI) than in patients with HCV-negative FL. Overall survival and progression-free survival were poorer in patients with HCV-positive FL than in those with HCV-negative FL (p <
0.0001 and 0.006, respectively). Also, multivariate analysis revealed that positive HCV antibody was a poor prognostic factor of OS. In conclusion, HCV-positive FL has unique clinical features and may have a great impact on the overall survival of affected patients.

脳死肝移植時のフィブリノゲン製剤使用による術中出血量と輸血使用量に関する検討
上床 貴代, 後藤 了一, 渡邊 千秋, 秋沢 宏次, 嶋村 剛, 清水 力, 豊嶋 崇徳, 早瀬 英子, 加畑 馨, 橋本 大吾, 伊藤 誠, 魚住 諒, 林 泰弘, 杉田 純一, 腰塚 靖之
日本輸血細胞治療学会誌, 64, 5, 641, 648, 一般社団法人 日本輸血・細胞治療学会, 2018年, ［査読有り］
日本語, <p>＜背景＞肝移植患者は，凝固障害によりしばしば大量出血をきたし，大量の輸血製剤が必要となる．肝移植時のフィブリノゲン製剤の使用で輸血使用量が減少したとの報告があり¹⁾，当院でも2012年より脳死肝移植でのフィブリノゲン製剤の使用を導入した．今回，脳死肝移植でのフィブリノゲン製剤の使用による術中出血量と輸血使用量について検討した．＜対象＞2001年2月から2016年8月の間に当院で脳死肝移植を施行した成人44例を対象とし，フィブリノゲン製剤非投与群25例，投与群19例で術中出血量，輸血使用量の比較検討を行った．また，術中出血量が循環血液量を超えた症例33例（非投与群16例，投与群17例）で同様に検討を行った．＜結果＞全症例での比較では両群で術中出血量，輸血使用量に有意差は認めなかった．循環血液量以上の出血を来した33例でサブ解析を施行したところ，投与群で術中出血量が有意に減少した．輸血使用量は投与群において濃厚血小板の使用量が有意に減少し，赤血球液，新鮮凍結血漿は減少傾向が認められた．＜結論＞脳死肝移植ではフィブリノゲン製剤の使用により大量出血を抑制し，輸血使用量を削減できると考えられた．</p>

Long-Lasting Graft-Derived Donor T Cells Contribute to the pathogenesis of Chronic Graft-versus-Host Disease in Mice
Mizuha Kosugi-Kanaya, Satoshi Ueha, Jun Abe, Shigeyuki Shichino, Francis H. W. Shand, Teppei Morikawa, Makoto Kurachi, Yusuke Shono, Naoto Sudo, Ai Yamashita, Fumiko Suenaga, Akihiro Yokoyama, Wang Yong, Masahiro Imamura, Takanori Teshima, Kouji Matsushima
FRONTIERS IN IMMUNOLOGY, 8, 8, 1842, FRONTIERS MEDIA SA, 2017年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Chronic graft-versus-host disease (cGVHD) is a major complication in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Graft-derived T cells (T-G) have been implicated in the induction of cGVHD; however, the extent of their contribution to the pathogenesis of cGVHD remains unclear. Using a mouse model of cGVHD, we demonstrate that T-G predominate over hematopoietic stem cell-derived T cells generated de novo (T-HSC) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting T-G, in particular CD8(+) T-G, not only displayed an exhausted or senescent phenotype but also contained a substantial proportion of cells that had the potential to proliferate and produce inflammatory cytokines. Host antigens indirectly presented by donor HSC-derived hematopoietic cells were involved in the maintenance of T-G in the reconstituted host. Selective depletion of T-G in the chronic phase of disease resulted in the expansion of THSC and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, THSC depletion caused activation of T-G and resulted in a lethal T-G-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting T-G in cGVHD.

R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease
Eiko Hayase, Daigo Hashimoto, Kiminori Nakamura, Clara Noizat, Reiki Ogasawara, Shuichiro Takahashi, Hiroyuki Ohigashi, Yuki Yokoi, Rina Sugimoto, Satomi Matsuoka, Takahide Ara, Emi Yokoyama, Tomohiro Yamakawa, Ko Ebata, Takeshi Kondo, Rina Hiramine, Tomoyasu Aizawa, Yoshitoshi Ogura, Tetsuya Hayashi, Hiroshi Mori, Ken Kurokawa, Kazuma Tomizuka, Tokiyoshi Ayabe, Takanori Teshima
JOURNAL OF EXPERIMENTAL MEDICINE, 214, 12, 3507, 3518, ROCKEFELLER UNIV PRESS, 2017年12月, ［査読有り］
英語, 研究論文（学術雑誌）, The intestinal microbial ecosystem is actively regulated by Paneth cell-derived antimicrobial peptides such as alpha-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant a-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of a-defensins. Administration of R-Spo1 or recombinant a-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host-microbiota cross talk toward therapeutic benefits.

Clinicopathological features of primary splenic follicular lymphoma
Joji Shimono, Hiroaki Miyoshi, Tomohiko Kamimura, Tetsuya Eto, Takuto Miyagishima, Yuya Sasaki, Daisuke Kurita, Keisuke Kawamoto, Koji Nagafuji, Masao Seto, Takanori Teshima, Koichi Ohshima
ANNALS OF HEMATOLOGY, 96, 12, 2063, 2070, SPRINGER, 2017年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Follicular lymphoma (FL) is a low-grade lymphoma that is usually characterized by generalized lymphadenopathy. Extranodal invasion by FL generally involves the bone marrow, skin, and duodenum; splenic infiltration often occurs in the advanced stages. However, primary splenic FL is very rare. Hence, few studies have been performed on splenic FL, and its clinicopathological features have not been established. This study aimed to investigate the clinicopathological features of primary splenic FL, as compared to nodal FL. We analyzed 17 patients diagnosed with primary splenic FL and 153 control patients with systemic FL. Hepatitis C virus (HCV)-positive status was significantly more common in patients with splenic FL than in the control patients (p = 0.02). Ann Arbor stage III or IV (p = 0.0003) and high-risk FLIPI (Follicular Lymphoma International Prognostic Index) (p = 0.03) were significantly less common in patients with splenic FL than in the control patients; however, the overall and progression-free survival curves were not significantly different between the groups. Among the 17 patients with splenic FL, the progression-free survival was significantly worse in patients who underwent splenectomy without receiving postoperative chemotherapy than in those who did (p = 0.03). These results suggest that primary splenic FL should be considered different from systemic FL; accordingly, its management should also be conducted differently.

Efficacy and prognosis of antiviral therapy on hepatitis C following treatment of lymphoma in HCV-positive diffuse large-cell lymphoma
Yutaka Tsutsumi, Chie Nakayama, Koki Kamada, Ryo Kikuchi, Daiki Kudo, Shinichi Ito, Satomi Matsuoka, Souichi Shiratori, Yoshiya Yamamoto, Hirohito Naruse, Takanori Teshima
ANNALS OF HEMATOLOGY, 96, 12, 2057, 2061, SPRINGER, 2017年12月, ［査読有り］
英語, 研究論文（学術雑誌）, The purpose of this study is to study the usefulness of post-remission antiviral therapy in cases of HCV-RNA-positive diffuse large-cell lymphoma. Antiviral therapy against HCV was performed after remission using CHOP or CHOP-like chemotherapy in combination with rituximab in five successive cases of HCV-RNA-positive diffuse large-cell lymphoma. The control groups consisted of a group of HCV-RNA-positive diffuse large-cell lymphoma cases prior to this trial (control 1), and a group of cases that tested negative for HIV, HCV, and HBV (control 2). All the cases were in remission at the time of initial treatment. There were no significant differences between the three groups in terms of age, sex, treatment, stage, or International Prognosis Index (IPI). When HCV antiviral therapy was performed after treatment for diffuse large-cell lymphoma, we observed no recurrence or deaths, and the 2-year overall survival and progression-free survival rates were significantly greater than those in the control 1 group (P = 0.0246). It is possible that a better prognosis can be achieved by performing HCV antiviral therapy after achieving remission in cases of HCV-RNA-positive diffuse large-cell lymphoma through the use of R-CHOP or similar treatments.

Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: Evaluation of drug-drug interactions mediated by organic anion transporter 3
Katsuya Narumi, Yu Sato, Masaki Kobayashi, Ayako Furugen, Kumiko Kasashi, Takehiro Yamada, Takanori Teshima, Ken Iseki
BIOPHARMACEUTICS & DRUG DISPOSITION, 38, 9, 501, 508, WILEY, 2017年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Methotrexate (MTX) is an antifolate agent used in the treatment of numerous types of cancer, and eliminated by active tubular secretion via organic anion transporter 3 (OAT3). Gastric antisecretory drugs, such as proton pump inhibitors (PPIs) and histamine H-2 receptor antagonists, are widely used among patients with cancer in clinical practice. The aim of the present study was to analyse the potential drug-drug interactions between MTX and gastric antisecretory drugs in high-dose MTX (HD-MTX) therapy. The impact of PPIs on the plasma MTX concentration on 73cycles of HD-MTX therapy was analysed retrospectively in 43 patients. Also investigated was the involvement of OAT3 in PPI-MTX drug interaction in an in vitro study using human OAT3 expressing HEK293 cells. In a retrospective study, patients who received a PPI had significantly higher MTX levels at 48h (0.38 vs. 0.15mol l(-1), respectively, p=0.000018) and 72h (0.13 vs. 0.05mol l(-1), respectively, p=0.0002) compared with patients who did not receive a PPI (but received famotidine). Moreover, in vitro experiments demonstrated that PPIs (esomeprazole, lansoprazole, omeprazole and rabeprazole) inhibited hOAT3-mediated uptake of MTX in a concentration-dependent manner (IC50 values of 0.40-5.5 m), with a rank order of lansoprazole > esomeprazole > rabeprazole > omeprazole. In contrast to PPIs, famotidine showed little inhibitory effect on hOAT3-mediated MTX uptake. These results demonstrated that co-administration of PPI, but not famotidine, could result in a pharmacokinetic interaction that increases the plasma MTX levels, at least in part, via hOAT3 inhibition.

Transcriptome analysis reveals PDGF signaling-dependent regulation of myelofibrosis in murine chronic graft-versus-host diseases
Shigeyuki Shichino, Satoshi Ueha, Naoto Sudo, Mizuha Kosugi-Kanaya, Francis H. W. Shand, Teppei Morikawa, Shin-ichi Hashimoto, Takanori Teshima, Kouji Matsushima
CYTOKINE, 100, 108, 108, ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2017年12月, ［査読有り］
英語

同種造血幹細胞移植を施行したCSF3R T613I変異陽性非定型慢性骨髄性白血病　　　　　　　　　　　　　　　
原田 晋平, 岡田 耕平, 日高 大輔, 早瀬 英子, 後藤 秀樹, 橋本 大吾, 加畑 馨, 遠藤 知之, 豊嶋 崇徳
臨床血液, 58, 11, 2299, 2299, (一社)日本血液学会-東京事務局, 2017年11月
日本語

Quality of Life after Allogeneic Hematopoietic Cell Transplantation According to Affected Organ and Severity of Chronic Graft-versus-Host Disease
Saiko Kurosawa, Kumi Oshima, Takuhiro Yamaguchi, Atsumi Yanagisawa, Takahiro Fukuda, Heiwa Kanamori, Takehiko Mori, Satoshi Takahashi, Tadakazu Kondo, Akio Kohno, Koichi Miyamura, Yukari Umemoto, Takanori Teshima, Shuichi Taniguchi, Takuya Yamashita, Yoshihiro Inamoto, Yoshinobu Kanda, Shinichiro Okamoto, Yoshiko Atsuta
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 23, 10, 1749, 1758, ELSEVIER SCIENCE INC, 2017年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Knowing the impact of chronic graft-versus-host disease (GVHD) on quality of life (QoL) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by GVHD type and severity is critical for providing care to transplant survivors. We conducted a cross-sectional questionnaire study to examine the relationship between patient reported QoL as measured by the Medical Outcomes Study 36-Item Short-Form Health Survey, Functional Assessment of Cancer Therapy-Bone Marrow Transplant, and visual analogue scale (VAS) and chronic GVHD defined by the National Institutes of Health (NIH) criteria. Recipients of allo-HCT for hematologic disease between 1995 and 2009 aged 16 years at transplant and >= 20 years at the time of the survey who were relapse-free were eligible. A total of 1140 pairs of patient and physician questionnaires were included in the analysis. By NIH global severity score, QoL scores in all aspects were significantly lower in patients with higher global and organ-specific severity grades, independent of background variables. Compared with patients without GVHD symptoms, those with mild symptoms had impaired physical and general QoL according to global severity score and organ-specific scores except for the genital tract. Mild symptoms in the lungs, gastrointestinal tract, and joints and fascia were associated with clinically meaningful deterioration of physical QoL. VAS scores provided by physicians were generally higher than those provided by patients. Differences between scores reported by patients and physicians were larger for patients with no or mild GVHD symptoms. Our findings based on more than 1000 long-term survivors after HCT enabled us to identify a target of care, informing survivorship care protocols to improve post-transplantation QoL. (C) 2017 American Society for Blood and Marrow Transplantation.

JAK阻害剤を用いたGVHD治療
豊嶋 崇徳
日本造血細胞移植学会雑誌, 6, 4, 146, 151, 2017年10月, ［査読有り］

GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia
S. Terakura, Y. Kuwatsuka, S. Yamasaki, A. Wake, J. Kanda, Y. Inamoto, S. Mizuta, T. Yamaguchi, N. Uchida, Y. Kouzai, N. Aotsuka, H. Ogawa, H. Kanamori, K. Nishiwaki, S. Miyakoshi, M. Onizuka, I. Amano, T. Fukuda, T. Ichinohe, Y. Atsuta, M. Murata, T. Teshima
BONE MARROW TRANSPLANTATION, 52, 9, 1261, 1267, NATURE PUBLISHING GROUP, 2017年09月, ［査読有り］
英語, 研究論文（学術雑誌）, To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/mu L was significantly better in the MMF+ group (relative risk (RR), 1.55; P < 0.001: RR, 1.34; P = 0.003, respectively). In multivariate analyses, the risk of grade II-IV and III-IV acute GvHD was significantly higher in the MMF+ group than in the MTX+ group (RR, 1.75; P < 0.001: RR, 1.97; P = 0.004, respectively). In disease-specific analyses of AML, the risk of relapse of high-risk disease was significantly lower in the MMF+ group (RR, 0.69; P = 0.009), whereas no significant difference was observed in the risk of relapse-free and overall survival in high-risk disease. In patients with standard-risk disease, no significant differences were noted in the risk of relapse or survival between the MTX+ and MMF+ groups. Collectively, these results suggest that MMF-containing prophylaxis may be preferable in RIC-UCBT, particularly for high-risk disease.

Clinicopathological analysis of primary splenic diffuse large B-cell lymphoma
Joji Shimono, Hiroaki Miyoshi, Junichi Kiyasu, Kensaku Sato, Tomohiko Kamimura, Tetsuya Eto, Takuto Miyagishima, Koji Nagafuji, Takanori Teshima, Koichi Ohshima
BRITISH JOURNAL OF HAEMATOLOGY, 178, 5, 719, 727, WILEY, 2017年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Splenic infiltration is often seen in diffuse large B-cell lymphoma (DLBCL). However, primary splenic DLBCL is rare and studies on its clinicopathological features are limited. We assessed 66 cases of primary splenic DLBCL and 309 control DLBCL, not otherwise specified. Hepatitis C virus antibody prevalence, B symptoms, poor performance status and CD5 positivity differed significantly between the primary splenic DLBCL and control DLBCL groups. Primary splenic DLBCL cases were classified histopathologically into two groups [white pulp pattern (n = 46), red pulp pattern (n = 20)]. Survival analysis showed no difference in overall survival between the primary splenic DLBCL and the control group, but the former had a more favourable progression-free survival. In the examination of primary splenic DLBCL, the white pulp pattern was statistically associated with a lower performance status (2-4), and a lower CD5 positivity than the red pulp pattern. In the survival analysis, the red pulp pattern demonstrated poorer overall survival. Multivariate analysis of overall survival in primary splenic DLBCL cases identified CD5 positivity as an indicator of poor prognosis. Classifying primary splenic DLBCL into white and red pulp patterns was useful in terms of clinicopathological features and overall survival.

IgA型ALアミロイドーシスに線状IgA皮膚症を併発した1例　　　　　　　　　　　　　　　
山口 泰之, 氏家 英之, 大東 寛幸, 岩田 浩明, 村松 憲, 清水 宏, 遠藤 知之, 豊嶋 崇徳
日本皮膚科学会雑誌, 127, 9, 2111, 2111, (公社)日本皮膚科学会, 2017年08月
日本語

北海道HIV福祉サービスネットワークの構築
富田 健一, 白坂 るみ, 遠藤 知之, 渡部 恵子, 武内 阿味, 坂本 玲子, センテノ田村 恵子, 石田 陽子, 豊嶋 崇徳
日本エイズ学会誌, 19, 3, 180, 184, (一社)日本エイズ学会, 2017年08月, ［査読有り］
日本語, HIV陽性者に困難なく福祉サービス提供を行うために、「北海道福祉サービスネットワーク」を構築し、有効な手段を検討した。対象施設は、北海道内の福祉事業所(高齢者領域のサービス事業所、障がい領域のサービス事業所、領域を問わずサービス提供を行う保険外の事業所)とした。北海道ブロック各拠点病院HIV担当ソーシャルワーカーが、HIV陽性者に対して理解があると感じられる福祉事業所に登録依頼を行った。その結果、407件の登録が得られ、HIV陽性者へのサービス提供の経験のある福祉事業所の登録割合が92.3%と最も高かった。これは、サービス提供を行うことで、それまで未知であったHIV感染者に対する漠然とした不安や戸惑いが払拭されたものと考えられた。一方、登録を断った事業所については、施設長・責任者の賛同が得らないことを理由にあげられることから、施設長や責任者に対して、HIVに関する正しい知識を説明するなど、直接的にアプローチすることが有効と考えた。行政(北海道保健福祉部)から、ネットワークへの登録依頼文書を配布した987法人からは、2週間以内に17件の社会福祉法人、87件の福祉事業所からの登録が得られた。2週間という短期間で、多くの登録を得られたことは、行政との連携がきわめて有効と考えられた。

Diffuse large B-cell lymphoma with a bulky mass in the cranial vault
Minoru Kanaya, Tomoyuki Endo, Daigo Hashimoto, Shogo Endo, Ryo Takemura, Kohei Okada, Kanako C. Hatanaka, Yoshihiro Matsuno, Takanori Teshima
INTERNATIONAL JOURNAL OF HEMATOLOGY, 106, 2, 147, 148, SPRINGER JAPAN KK, 2017年08月, ［査読有り］
英語, 研究論文（学術雑誌）

Disseminated toxoplasmosis after hematopoietic stem cell transplantation showing unusual magnetic resonance images
Takahiro Tateno, Masahiro Onozawa, Junichi Hashiguchi, Takashi Ishio, Sayaka Yuzawa, Satomi Matsuoka, Mizuha Kosugi-Kanaya, Kohei Okada, Souichi Shiratori, Hideki Goto, Taichi Kimura, Junichi Sugita, Masao Nakagawa, Daigo Hashimoto, Kaoru Kahata, Katsuya Fujimoto, Tomoyuki Endo, Takeshi Kondo, Shinya Tanaka, Satoshi Hashino, Takanori Teshima
TRANSPLANT INFECTIOUS DISEASE, 19, 4, e12720, WILEY, 2017年08月, ［査読有り］
英語, 研究論文（学術雑誌）, We herein report a patient who had disseminated toxoplasmosis after hematopoietic stem cell transplantation showing atypical clinical presentation and neuroimaging. Parkinsonism symptoms such as muscle rigidity, bradykinesia, tremor, and postural instability were initial manifestations. Magnetic resonance imaging showed diffuse symmetrical lesions of bilateral basal ganglia lacking ringed enhancement. Post-mortem analysis revealed multiple tachyzoites of Toxoplasma gondii in the basal ganglia, mid brain, cerebellum, and cardiac muscle.

Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway
Soung-Min Lee, Ha Young Park, Young-Sill Suh, Eun Hye Yoon, Juyang Kim, Won Hee Jang, Won-Sik Lee, Sae-Gwang Park, Il-Whan Choi, Inhak Choi, Sun-Woo Kang, Hwayoung Yun, Takanori Teshima, Byungsuk Kwon, Su-Kil Seo
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114, 29, E5881, E5890, NATL ACAD SCIENCES, 2017年07月, ［査読有り］
英語, 研究論文（学術雑誌）, The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4(+) T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-gamma-dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-gamma gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-gamma-independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-gamma expression was suppressed by FK506. Finally, L-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4(+) T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.

Risk factors of human herpesvirus 6 encephalitis/myelitis after allogeneic hematopoietic stem cell transplantation
Naohiro Miyashita, Tomoyuki Endo, Masahiro Onozawa, Daigo Hashimoto, Takeshi Kondo, Katsuya Fujimoto, Kaoru Kahata, Junichi Sugita, Hideki Goto, Toshihiro Matsukawa, Satoshi Hashino, Takanori Teshima
TRANSPLANT INFECTIOUS DISEASE, 19, 3, e12682, WILEY, 2017年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Human herpesvirus 6 (HHV-6) encephalitis/myelitis is now a well-known complication after allogeneic stem cell transplantation (allo-HSCT), particularly after cord blood transplantation (CBT). In this study, we evaluated the risk factors of HHV-6 encephalitis/myelitis.
Methods: We evaluated 253 patients who received allo-HSCT from 2007 to 2015 at our institute. HHV-6 encephalitis/myelitis was defined as HHV-6 DNA detection in the cerebrospinal fluid or peripheral blood by polymerase chain reaction in the presence of typical manifestations without other concurrent condition that led to the manifestations.
Results: HHV-6 encephalitis/myelitis occurred in 11 patients (4.5%) (9 encephalitis, 3.7%; 2 myelitis, 0.8%). Multivariate analysis showed that CBT, mycophenolate mofetil (MMF) for graft-versus-host disease prophylaxis, history of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and engraftment syndrome (ES) were significantly associated with incidence of HHV-6 encephalitis/myelitis (P=.025, P=.017, P=.017, and P=.014, respectively).
Conclusion: Although it has been shown that CBT, ES, and history of allo-HSCT are risk factors for HHV-6 encephalitis/myelitis, our study demonstrated MMF is also a risk factor for the disease.

MALDI-TOF MS in post-transplant bloodstream infections: reliable identification of causative bacteria in the neutropenic phase
M. Kanaya, Y. Hayashi, D. Hashimoto, T. Endo, J. Sugita, H. Ohigashi, J. Hashiguchi, T. Matsukawa, S. Matsuoka, M. Kosugi-Kanaya, H. Goto, M. Onozawa, K. Kahata, K. Fujimoto, T. Kondo, K. Akizawa, H. Shibuya, C. Shimizu, T. Teshima
BONE MARROW TRANSPLANTATION, 52, 5, 778, 780, NATURE PUBLISHING GROUP, 2017年05月, ［査読有り］
英語, 研究論文（学術雑誌）

Linear IgA Bullous Dermatosis Associated with Immunoglobulin Light-chain Amyloidosis
Yasuyuki Yamaguchi, Hideyuki Ujiie, Hiroyuki Ohigashi, Hiroaki Iwata, Ken Muramatsu, Tomoyuki Endou, Takanori Teshima, Hiroshi Shimizu
ACTA DERMATO-VENEREOLOGICA, 97, 4, 528, 529, ACTA DERMATO-VENEREOLOGICA, 2017年04月, ［査読有り］
英語

Late onset toxic epidermal necrolysis induced by mogamulizumab, an anti-CC chemokine receptor 4 antibody for the treatment of adult T-cell leukaemia/lymphoma.
Souichi Shiratori, Hiroyuki Ohhigashi, Shinichi Ito, Kazuhiro Kudo, Maki Adachi, Toshiyuki Minamimoto, Junji Kato, Yasue Osai, Yutaka Tsutsumi, Takanori Teshima
Hematological oncology, 35, 1, 138, 140, 2017年03月, ［国際誌］
英語

Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation
J. Kanda, Y. Morishima, S. Terakura, A. Wake, N. Uchida, S. Takahashi, Y. Ono, Y. Onishi, H. Kanamori, N. Aotsuka, Y. Ozawa, H. Ogawa, T. Sakura, K. Ohashi, T. Ichinohe, K. Kato, Y. Atsuta, T. Teshima, M. Murata
LEUKEMIA, 31, 3, 663, 668, NATURE PUBLISHING GROUP, 2017年03月, ［査読有り］
英語, 研究論文（学術雑誌）, The effect of graft-versus-host disease (GVHD) on transplant outcomes after unrelated cord blood transplantation (UCBT) has not been fully elucidated. We analyzed the impact of acute and chronic GVHD on outcomes in adult patients with acute leukemia or myelodysplastic syndrome who underwent their first UCBT (n= 2558). The effect of GVHD on outcomes was analyzed after adjusting for other significant variables. The occurrence of GVHD was treated as a time-dependent covariate. The occurrence of grade 1-2 or 3-4 acute GVHD was significantly associated with a lower relapse rate. Grade 3-4 acute GVHD was associated with a higher risk of non-relapse and overall mortality than no acute GVHD, whereas grade 1-2 acute GVHD was associated with a lower risk of non-relapse and overall mortality than no acute GVHD. Limited or extensive chronic GVHD was significantly associated with a lower relapse rate. Limited chronic GVHD was associated with a lower overall and non-relapse mortality than no chronic GVHD. In conclusion, mild acute or chronic GVHD was associated not only with a low risk of relapse but also with a low risk of non-relapse mortality, and provides a survival benefit in UCBT.

GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes
Y-B Chen, T. Wang, M. T. Hemmer, C. Brady, D. R. Couriel, A. Alousi, J. Pidala, A. Urbano-Ispizua, S. W. Choi, T. Nishihori, T. Teshima, Y. Inamoto, B. Wirk, D. I. Marks, H. Abdel-Azim, L. Lehmann, L. Yu, M. Bitan, M. S. Cairo, M. Qayed, R. Salit, R. P. Gale, R. Martino, S. Jaglowski, A. Bajel, B. Savani, H. Frangoul, I. D. Lewis, J. Storek, M. Askar, M. A. Kharfan-Dabaja, M. Aljurf, O. Ringden, R. Reshef, R. F. Olsson, S. Hashmi, S. Seo, T. R. Spitzer, M. L. MacMillan, A. Lazaryan, S. R. Spellman, M. Arora, C. S. Cutler
BONE MARROW TRANSPLANTATION, 52, 3, 400, 408, NATURE PUBLISHING GROUP, 2017年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (>= 18 years) = 810, double (< 18 years) = 594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil
S. Terakura, A. Wake, Y. Inamoto, M. Murata, R. Sakai, T. Yamaguchi, S. Takahashi, N. Uchida, Y. Onishi, K. Ohashi, Y. Ozawa, H. Kanamori, H. Yamaguchi, T. Fukuda, T. Ichinohe, M. Takanashi, Y. Atsuta, T. Teshima
BONE MARROW TRANSPLANTATION, 52, 3, 423, 430, NATURE PUBLISHING GROUP, 2017年03月, ［査読有り］
英語, 研究論文（学術雑誌）, In order to examine GvHD prophylaxis in umbilical cord blood transplantation (UCBT) in more detail, we compared transplant outcomes after UCBT for acute leukemia among GvHD prophylaxes using registry data. We selected patients transplanted with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 1516 first myeloablative UCBT between 2000 and 2012 (Cyclosporine A (CyA) plus MTX, 824, Tacrolimus (Tac) plus MTX, 554, Tac plus MMF, 138) were included. With adjusted analyses, Tac plus MMF showed a significantly higher risk for grade II-IV and III-IV acute GvHD than CyA or Tac plus MTX. Although NRM was similar, Tac plus MMF showed a significantly lower risk of relapse than CyA or Tac plus MTX. A significant difference was observed in the risk of overall mortality (OM) between the MTX-containing group and MMF-containing group. In patients with standard-risk disease, there was no significant difference in the risk of OM in any GvHD prophylaxis. However, in patients with advanced-risk disease, Tac plus MMF showed a significantly lower risk of OM. Therefore, MTX-containing prophylaxis is preferred in UCBT for standard-risk disease, whereas MMF-containing prophylaxis is preferred for advanced-risk disease. A prospective study to identify optimal GvHD prophylaxis for UCBT is warranted.

Graft-versus-host disease targets ovary and causes female infertility in mice
Sonoko Shimoji, Daigo Hashimoto, Hidetsugu Tsujigiwa, Kohta Miyawaki, Koji Kato, Shuichiro Takahashi, Reiki Ogasawara, Takashi Jiromaru, Hiromi Iwasaki, Toshihiro Miyamoto, Koichi Akashi, Takanori Teshima
BLOOD, 129, 9, 1216, 1225, AMER SOC HEMATOLOGY, 2017年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). Although pretransplant conditioning regimen has been appreciated as a cause of ovarian failure, increased application of reduced-intensity conditioning allowed us to revisit other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell-mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. Histological evaluation of the ovaries after SCT demonstrated donor T-cell infiltration in close proximity to apoptotic granulosa cells in the ovarian follicles, resulting in impaired follicular hormone production and maturation of ovarian follicles. Mating experiments showed that female recipients of allogeneic SCT deliver significantly fewer newborns than recipients of syngeneic SCT. GVHD-mediated ovary insufficiency and infertility were independent of conditioning. Pharmacologic GVHD prophylaxis protected the ovary from GVHD and preserved fertility. These results demonstrate for the first time that GVHD targets the ovary and impairs ovarian function and fertility and has important clinical implications in young female transplant recipients with nonmalignant diseases, in whom minimally toxic regimens are used. (Blood. 2017; 129(9): 1216-1225)

Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities
Makoto Ibata, Junko Iwasaki, Yoichiro Fujioka, Koji Nakagawa, Stephanie Darmanin, Masahiro Onozawa, Daigo Hashimoto, Yusuke Ohba, Shigetsugu Hatakeyama, Takanori Teshima, Takeshi Kondo
CANCER SCIENCE, 108, 2, 200, 207, WILEY, 2017年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Fusion tyrosine kinases play a crucial role in the development of hematological malignancies. FIP1L1-PDGFRA is a leukemogenic fusion kinase that causes chronic eosinophilic leukemia. As a constitutively active kinase, FIP1L1-PDGFRA stimulates downstream signaling molecules, leading to cellular proliferation and the generation of an anti-apoptotic state. Contribution of the N-terminal FIP1L1 portion is necessary for FIP1L1-PDGFRA to exert its full transforming activity, but the underlying mechanisms have not been fully characterized. We identified PIAS1 as a FIP1L1-PDGFRA association molecule by yeast two-hybrid screening. Our analyses indicate that the FIP1L1 portion of FIP1L1-PDGFRA is required for efficient association with PIAS1. As a consequence of the association, FIP1L1-PDGFRA phosphorylates PIAS1. Moreover, the kinase activity of FIP1L1-PDGFRA stabilizes PIAS1. Therefore, PIAS1 is one of the downstream targets of FIP1L1-PDGFRA. Moreover, we found that PIAS1, as a SUMO E3 ligase, sumoylates and stabilizes FIP1L1-PDGFRA. In addition, suppression of PIAS1 activity by a knockdown experiment resulted in destabilization of FIP1L1-PDGFRA. Therefore, FIP1L1-PDGFRA and PIAS1 form a positive cross-talk through their enzymatic activities. Suppression of sumoylation by ginkgolic acid, a small molecule compound inhibiting a SUMO E1-activating enzyme, also destabilizes FIP1L1-PDGFRA, and while the tyrosine kinase inhibitor imatinib suppresses FIP1L1-PDGFRA-dependent cell growth, ginkgolic acid or siRNA of PIAS1 has a synergistic effect with imatinib. In conclusion, our results suggest that sumoylation by PIAS1 is a potential target in the treatment of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.

Prior history of HLA-mismatched stem cell transplantation is a risk factor for graft failure in HLA-haploidentical transplantation
J. Sugita, T. Miyamoto, N. Kawashima, N. Hatsumi, N. Anzai, H. Kaneko, M. Nara, K. Minauchi, M. Harada, T. Teshima
BONE MARROW TRANSPLANTATION, 52, 2, 323, 325, NATURE PUBLISHING GROUP, 2017年02月, ［査読有り］
英語, 研究論文（学術雑誌）

Low-dose thymoglobulin as second-line treatment for steroid-resistant acute GvHD: an analysis of the JSHCT
M. Murata, K. Ikegame, Y. Morishita, H. Ogawa, K. Kaida, H. Nakamae, T. Ikeda, T. Nishida, M. Inoue, T. Eto, K. Kubo, T. Sakura, T. Mori, N. Uchida, T. Ashida, Y. Matsuhashi, Y. Miyazaki, T. Ichinohe, Y. Atsuta, T. Teshima
Bone Marrow Transplant, 52, 2, 252, 257, NATURE PUBLISHING GROUP, 2017年02月, ［査読有り］
英語, 研究論文（学術雑誌）, A nationwide retrospective study for the clinical outcomes of 99 patients who had received thymoglobulin at a median total dose of 2.5 mg/kg (range, 0.5-18.5 mg/kg) as a second-line treatment for steroid-resistant acute GvHD was conducted. Of the 92 evaluable patients, improvement (complete or partial response) was observed in 55 patients (60%). Multivariate analysis demonstrated that male sex and grade III and IV acute GvHD were associated with a lower improvement rate, whereas thymoglobulin dose (<2.0, 2.0-3.9 and 4.0 mg/kg) was NS. Factors associated with significantly higher nonrelapse mortality included higher patient age (50 years), grade IV acute GvHD, no improvement of GvHD and higher dose of thymoglobulin (hazard ratio, 2.55; 95% confidence interval, 1.34-4.85; P=0.004 for 2.0-3.9 mg/kg group and 1.79; 0.91-3.55; P=0.093 for 4.0 mg/kg group). Higher dose of thymoglobulin was associated with a higher incidence of bacterial infections, CMV antigenemia and any additional infection. Taken together, low-dose thymoglobulin at a median total dose of 2.5 mg/kg provides a comparable response rate to standard-dose thymoglobulin reported previously, and <2.0 mg/kg thymoglobulin is re

Unilateral conjunctival infiltration of Adult T-cell leukemia/lymphoma. Case report and literature review
Joji Shimono, Shigeki Kaino, Kohei Okada, Kazuo Oshimi, Yusuke Ishida, Tatsuro Takahashi, Takuto Miyagishima, Takanori Teshima
Journal of Clinical and Experimental Hematopathology, 57, 3, 143, 146, Japanese Society for Lymphoreticular Tissue Research, 2017年, ［査読有り］
研究論文（学術雑誌）

Improved FRET Biosensor for the Measurement of BCR-ABL Activity in Chronic Myeloid Leukemia Cells
Mika Horiguchi, Mari Fujioka, Takeshi Kondo, Yoichiro Fujioka, Xinxin Li, Kosui Horiuchi, Aya O. Satoh, Prabha Nepal, Shinya Nishide, Asuka Nanbo, Takanori Teshima, Yusuke Ohba
CELL STRUCTURE AND FUNCTION, 42, 1, 15, 26, JAPAN SOC CELL BIOLOGY, 2017年, ［査読有り］
英語, 研究論文（学術雑誌）, Although the co-development of companion diagnostics with molecular targeted drugs is desirable, truly efficient diagnostics are limited to diseases in which chromosomal translocations or overt mutations are clearly correlated with drug efficacy. Moreover, even for such diseases, few methods are available to predict whether drug administration is effective for each individual patient whose disease is expected to respond to the drug(s). We have previously developed a biosensor based on the principle of Forster resonance energy transfer to measure the activity of the tyrosine kinase BCR-ABL and its response to drug treatment in patient-derived chronic myeloid leukemia cells. The biosensor harbors CrkL, one of the major substrates of BCR-ABL, and is therefore named Pickles after phosphorylation indicator of CrkL en substrate. The efficacy of this technique as a clinical test has been demonstrated, but the number of cells available for analysis is limited in a case-dependent manner, owing to the cleavage of the biosensor in patient-derived leukemia cells. Here, we describe an improved biosensor with an amino acid substitution and a nuclear export signal being introduced. Of the two predicted cleavage positions in CrkL, the mutations inhibited one cleavage completely and the other cleavage partially, thus collectively increasing the number of cells available for drug evaluation. This improved version of the biosensor holds promise in the future development of companion diagnostics to predict responses to tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

Clinical features of diffuse large B-cell lymphoma with polyploidy
Joji Shimono, Hiroaki Miyoshi, Masao Seto, Takanori Teshima, Koichi Ohshima
PATHOLOGY INTERNATIONAL, 67, 1, 17, 23, WILEY-BLACKWELL, 2017年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Polyploidy, defined as more than two sets of homologous chromosomes, is found in a variety of malignant tumors and is thought to be related to disease pathogenesis. However, there have been no studies that have investigated polyploidy in diffuse large B-cell lymphoma (DLBCL). Here we reviewed clinicopathological features of 16 cases of DLBCL with polypoidy, which was defined as DLBCL with either neartetraploid or greater number of chromosomes as detected by the G-band method. The frequency of polyploid DLBCL was 2.9 % (16/544), including 15 near-tetraploid and one nearpentaploid case.
CD5, CD30 and EBER positive cases were 13 % (2/16), 13 % (2/16) and 6 % (1/16), respectively. Bcl2 positive cases were 75 % (12/16).
The numbers of huge and multinucleated cells were higher in polyploid than in non-polyploid DLBCL (P = 0.0029 and P < 0.0001, respectively). Clinical features of polyploid DLBCL included reduced infiltration of extranodal sites (2/15, 13 %) and major lymph node infiltration. Of seven cases that received chemotherapy, six responded to treatment and survived. Our results suggest that polyploid DLBCL represents a clinicopathologically characteristic group of DLBCL. This knowledge can be useful for informing more personalized and targeted management of DLBCL patients.

Comparison of cyclosporine and tacrolimus combined with mycophenolate mofetil in prophylaxis for graft-versus-host disease after reduced-intensity umbilical cord blood transplantation
Toshihiro Miyamoto, Shuichiro Takashima, Koji Kato, Ken Takase, Goichi Yoshimoto, Shuro Yoshida, Hideho Henzan, Koichi Osaki, Tomohiko Kamimura, Hiromi Iwasaki, Tetsuya Eto, Takanori Teshima, Koji Nagafuji, Koichi Akashi
INTERNATIONAL JOURNAL OF HEMATOLOGY, 105, 1, 92, 99, SPRINGER JAPAN KK, 2017年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Umbilical cord blood transplantation with a reduced-intensity conditioning regimen (RIC-UCBT) is used increasingly in patients who have comorbid organ functions and lack human leukocyte antigen-identical donors. We compared the outcomes in 35 patients who received mycophenolate mofetil plus cyclosporine (MMF/CSP, n = 17) or MMF plus tacrolimus (MMF/TAC, n = 18) for graft-versus-host disease (GVHD) prophylaxis after RIC-UCBT. Cumulative incidence of neutrophil engraftment was 94 and 89 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.34). The incidence of pre-engraftment immune reaction did not differ between the MMF/CSP (41 %) and MMF/TAC (39 %, p = 1.00) groups; however, patients in the MMF/TAC group tended to have a lower incidence of grade II-IV acute GVHD than those in MMF/CSP group (28 vs 53 %, p = 0.11). Overall survival (OS) at 1 year was 43 and 60 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.39). Progression-free survival, non-relapse mortality, and relapse rate were comparable between the two groups (p = 0.76, 0.59, and 0.88, respectively). In multivariate analyses, MMF/TAC GVHD prophylaxis was closely associated with improved OS, but not with incidence of engraftment and acute GVHD. These results suggest that more intensive GVHD prophylaxis with MMF/TAC decreased acute GVHD without affecting other clinical outcomes, resulting in improved OS after RIC-UCBT.

Graft-versus-host disease in the ovary potentially causes female infertility after allogeneic hematopoietic stem cell transplantation.
Shimoji S, Hashimoto D, Teshima T
[Rinsho ketsueki] The Japanese journal of clinical hematology, 58, 7, 827, 834, 2017年, ［査読有り］

日本骨髄バンクドナーの2回骨髄提供に関する検討
折原 勝己, 吾郷 浩厚, 奥山 美樹, 落合 亮一, 澤 正史, 田野﨑 隆二, 玉井 佳子, 豊嶋 崇徳, 中尾 康夫, 日野 雅之, 宮﨑 泰司, 神田 善伸, 金森 平和
日本造血細胞移植学会雑誌, 6, 2, 108, 114, (一社)日本造血細胞移植学会, 2017年, ［査読有り］
日本語, 研究論文（学術雑誌）, 日本骨髄バンクを介して2回の骨髄提供を行ったドナー820人を解析した。骨髄穿刺部の痛みの程度は変わりなく，痛みの持続日数および日常生活への復帰日数は2回目で短かった。骨髄採取時間，骨髄採取量，総細胞数，細胞濃度，細胞数/患者体重の1回目 : 2回目の平均値は，74分 : 78分，821mL: 848mL，160×10＾8個 : 139×10＾8個，2.0×10＾7個/mL: 1.7×10＾7個/mL，3.0×10＾8個/kg: 2.7×10＾8個/kgであった。2回目提供の骨髄移植では造血回復の遅延がみられ，標準リスクの患者群では生存率の低下がみられた。

Ruxolitinib treatment for GvHD in patients with myelofibrosis
Y. Mori, K. Ikeda, T. Inomata, G. Yoshimoto, N. Fujii, H. Ago, T. Teshima
BONE MARROW TRANSPLANTATION, 51, 12, 1584, 1587, NATURE PUBLISHING GROUP, 2016年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Jak1/2 inhibitor ruxolitinib is a promising agent for treating steroid-refractory GvHD after allogeneic hematopoietic stem cell transplantation (SCT) to produce quick and durable responses. However, optimal dose and tapering schedule of ruxolitinib remain to be determined. Discontinuation of ruxolitinib in myelofibrosis often induces 'withdrawal syndrome' characterized by acute relapse of the disease, but this issue is not well addressed in the treatment of GvHD. Four patients with GvHD (one acute and three chronic) after SCT for myelofibrosis were treated with ruxolitinib. Low-dose ruxolitinib at 5 mg/day was safe and effective, but one of two patients treated at 10 mg/day of ruxolitinib was complicated with severe cytopenia. Withdrawal syndrome developed in one patient, who died of recurrence of GvHD shortly after discontinuation of ruxolitinib. Slow tapering or maintenance with low-dose ruxolitinib inhibited GvHD flare. Our experience calls attention that initiation at low-dose of ruxolitinib may be safe and careful tapering schedule is required to avoid withdrawal syndrome in patients with GvHD after SCT for myelofibrosis.

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups
Yoshihiro Inamoto, Fumihiko Kimura, Junya Kanda, Junichi Sugita, Kazuhiro Ikegame, Hideki Nakasone, Yasuhito Nannya, Naoyuki Uchida, Takahiro Fukuda, Kosuke Yoshioka, Yukiyasu Ozawa, Ichiro Kawano, Yoshiko Atsuta, Koji Kato, Tatsuo Ichinohe, Masami Inoue, Takanori Teshima
HAEMATOLOGICA, 101, 12, 1592, 1602, FERRATA STORTI FOUNDATION, 2016年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Graft-versus-host disease-free relapse-free survival, which is defined as the absence of grade III-IV acute graft-versus-host disease, systemically treated chronic graft-versus-host disease, relapse, and death, is a novel, meaningful composite end point for clinical trials. To characterize risk factors and differences in graft-versus-host disease-free relapse-free survival according to a variety of graft sources, we analyzed 23,302 patients with hematologic malignancy that had a first allogeneic transplantation from 2000 through 2013 using the Japanese national transplant registry database. The 1-year graft-versus-host disease-free relapse-free survival rate was 41% in all patients. The rate was higher after bone marrow transplantation than after peripheral blood stem cell transplantation due to the lower risks of III-IV acute and chronic graft-versus-host disease. The rate was highest after HLA-matched sibling bone marrow transplantation. The rate after single cord blood transplantation was comparable to that after HLA-matched unrelated bone marrow transplantation among patients aged 20 years or under, and was comparable or better than other alternative graft sources among patients aged 21 years or over, due to the low risk of chronic graft-versus-host disease. Other factors associated with better graft-versus-host disease-free relapse-free survival include female patients, antithymocyte globulin prophylaxis (for standard-risk disease), recent years of transplantation, sex combinations other than from a female donor to a male patient, the absence of prior autologous transplantation, myeloablative conditioning, negative cytomegalovirus serostatus, and tacrolimus-based prophylaxis. These results provide important information to guide the choice of graft sources and are benchmarks for future graft-versus-host disease prophylaxis studies.

Successful T-cell Replete Hematopoietic Stem Cell Boost Without Conditioning for Late Graft Failure
Y. Tsutsumi, T. Tateno, S. Ito, S. Shiratori, T. Teshima
TRANSPLANTATION PROCEEDINGS, 48, 9, 3225, 3226, ELSEVIER SCIENCE INC, 2016年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Late graft failure is a rare but significant complication after allogeneic stem cell transplantation, which is often complicated by severe infections. We report a case of late graft failure, which was successfully treated with a T-cell replete hematopoietic stem cell boost without conditioning that induced rapid engraftment and relieved the patient of infection. Discontinuation of immunosuppressants and nilotinib administration suppressed the host cells. Achieving full donor chimerism allowed us to administer a peripheral blood stem cell boost without conditioning.

Evaluation of Short-Term Ruxolitinib Tapering Strategy Before Allogeneic Stem Cell Transplantation for Primary Myelofibrosis Through the Transition of Serum Cytokines and Growth Factors
Souichi Shiratori, Takahiro Tateno, Shinichi Ito, Yutaka Tsutsumi, Takanori Teshima
Transplantation Direct, 2, 8, e95, e95, Ovid Technologies (Wolters Kluwer Health), 2016年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）

Reduced-dose methotrexate in combination with tacrolimus was associated with rapid engraftment and recovery from oral mucositis without affecting the incidence of GVHD
Toshihiro Matsukawa, Daigo Hashimoto, Junichi Sugita, Seitarou Nakazawa, Takae Matsushita, Haruhiko Kashiwazaki, Hideki Goto, Masahiro Onozawa, Kaoru Kahata, Katsuya Fujimoto, Tomoyuki Endo, Takeshi Kondo, Satoshi Hashino, Yutaka Yamazaki, Takanori Teshima
INTERNATIONAL JOURNAL OF HEMATOLOGY, 104, 1, 117, 124, SPRINGER JAPAN KK, 2016年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic stem cell transplantation is a curable treatment for hematological diseases. Graft-versus-host disease (GVHD) causes morbidity and mortality after HSCT. Methotrexate (MTX) is used for GVHD prophylaxis, but its appropriate dose remains unclear. In the present study, we compared the efficacy and toxicity of 15-10-10 MTX (day +1: 15 mg/m(2); days +3 and +6: 10 mg/m(2)) with 10-7-7 MTX (day +1: 10 mg/m(2); day +3 and +6: 7 mg/m(2)) in combination with tacrolimus. The cumulative incidence rates of grades II-IV acute GVHD, grades III-IV acute GVHD and chronic GVHD in the 15-10-10 MTX and 10-7-7 MTX groups did not differ to a statistically significant extent. The median time for neutrophil engraftment in the 15-10-10 MTX group was 16 days (range, 11-31 days), while that in the 10-7-7 group was 15 days (range, 12-19 days) (P = 0.024). Moreover, the median time for platelet recovery was significantly shorter in the 10-7-7 MTX group (22 days; range, 13-49 days) than that in the 15-10-10 MTX group (27 days; range, 9-405 days) (P = 0.027). The duration of oral mucositis was significantly shorter in the patients who received a reduced dose of MTX (median, 4.5 vs 13.0 days; P = 0.013). In conclusion, GVHD prophylaxis with a reduced dose of MTX was associated with earlier engraftment and earlier recovery from mucositis in comparison to a standard dose of MTX, without affecting the incidence of GVHD.

Soluble DNAM-1, as a Predictive Biomarker for Acute Graft-Versus-Host Disease
Minoru Kanaya, Kazuko Shibuya, Rei Hirochika, Miyoko Kanemoto, Kazuteru Ohashi, Masafumi Okada, Yukiko Wagatsuma, Yukiko Cho, Hiroshi Kojima, Takanori Teshima, Masahiro Imamura, Hisashi Sakamaki, Akira Shibuya
PLOS ONE, 11, 6, e0154173, PUBLIC LIBRARY SCIENCE, 2016年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I-IV) and sgrade II-IV aGVHD in patients with high maximal serum levels of sDNAM-1 (>= 30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD.

Ceramide-CD300f binding suppresses experimental colitis by inhibiting ATP-mediated mast cell activation
Toshihiro Matsukawa, Kumi Izawa, Masamichi Isobe, Mariko Takahashi, Akie Maehara, Yoshinori Yamanishi, Ayako Kaitani, Ko Okumura, Takanori Teshima, Toshio Kitamura, Jiro Kitaura
GUT, 65, 5, 777, U777, BMJ PUBLISHING GROUP, 2016年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective Extracellular ATP mediates mast cell-dependent intestinal inflammation via P2X7 purinoceptors. We have previously shown that CD300f (also called the leucocyte mono-immunoglobulin-like receptor 3 (LMIR3)) suppresses immunoglobulin E-dependent and mast cell-dependent allergic responses by binding to ceramide. The aim of the present study was to clarify the role of ceramide-LMIR3 interaction in the development of IBD.
Design The dextran sodium sulfate (DSS)-induced colitis model was used in wild-type (WT), LMIR3(-/-), mast cell-deficient KitW-sh/W-sh, KitW-sh/W-shLMIR3(-/-) or KitW-sh/W-sh mice engrafted with WT or LMIR3(-/-) bone marrow-derived mast cells (BMMCs). The severity of colitis was determined by clinical and histological criteria. Lamina propria cell populations were assessed by flow cytometry. Production of chemical mediators from lamina propria cells was measured by real-time reverse transcription PCR. Production of chemical mediators from ATP-stimulated BMMCs in the presence or absence of ceramide was measured by ELISA. The severity of DSS-induced colitis was assessed in mice given either an Fc fusion protein containing an extracellular domain of LMIR3, and anticeramide antibody, or ceramide liposomes.
Results LMIR3 deficiency exacerbated DSS-induced colitis in mice. KitW-sh/W-sh mice harbouring LMIR3(-/-) mast cells exhibited more severe colitis than those harbouring WT mast cells. Ceramide-LMIR3 interaction inhibited ATP-stimulated activation of BMMCs. DSS-induced colitis was aggravated by disrupting the ceramide-LMIR3 interaction, whereas it was suppressed by treating with ceramide liposomes.
Conclusions LMIR3-deficient colonic mast cells were pivotal in the exacerbation of DSS-induced colitis in LMIR3(-/-) mice. Ceramide liposomes attenuated DSS-induced colitis by inhibiting ATP-mediated activation of colonic mast cells through ceraimide-LMIR3 binding.

Allogeneic unrelated bone marrow transplantation from older donors results in worse prognosis in recipients with aplastic anemia
Y. Arai, T. Kondo, H. Yamazaki, K. Takenaka, J. Sugita, T. Kobayashi, Y. Ozawa, N. Uchida, K. Iwato, N. Kobayashi, Y. Takahashi, K. Ishiyama, T. Fukuda, T. Ichinohe, Y. Atsuta, T. Mori, T. Teshima, T. Japan, Society for, Hematopoietic Cell
Haematologica, 101, 5, 644, 652, FERRATA STORTI FOUNDATION, 2016年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Allogeneic bone marrow transplantation is an essential therapy for acquired aplastic anemia and prognosis has recently improved. However, engraftment failure and graft-versus-host disease are potential fatal complications. Various risk factors for poor prognosis have been identified, such as patient age and human-leukocyte antigen disparity, but the relationship between donor age and prognosis is still unknown. Therefore, we performed a cohort study to compare the prognosis of unrelated bone marrow transplantation from younger and older donors using the registry database in Japan. We evaluated 427 patients (age 16-72 years) with aplastic anemia who underwent bone marrow transplantation from younger (</=39 years, n=281) or older (>/=40 years, n=146) unrelated donors. Overall survival of the older donor group was significantly inferior to that of the younger donor group (adjusted hazard ratio 1.64; 95% confidence interval 1.15-2.35; P<0.01). The incidence of fatal infection was significantly higher in the older donor group (13.7% vs. 7.5%; P=0.03). Primary engraftment failure and acute graft-versus-host disease were significantly more frequent in the older donor group (9.7% vs. 5.0%;

HLA半合致移植の現状と展望
藤本勝也, 杉田純一, 豊嶋崇徳
臨床血液, 57, 3, 288, 297, 2016年04月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, HLA-haploidentical hematopoietic stem cell transplantation from related donors has gained attention as an alternative treatment for patients who do not have HLA-identical siblings and lack the time to search for HLA-matched unrelated donors due to availability for nearly all individuals. As a key factor in the success of this approach is depletion of donor T cells, HLA-haploidentical transplantation has rapidly gained acceptance worldwide with the development of three platforms: 1) CD34-positive cell selection using CliniMACS®; 2) the conditioning regimen with anti-thymocyte globulin; and 3) a recently-developed, post-transplant cyclophosphamide regimen. Since the high efficacy of T-cell-depletion provides both sufficient suppression of GVHD and a high risk of opportunistic infection, there is an urgent need to strengthen the prevention of viral infections. On the other hand, conditioning with ATG and the post-transplant cyclophosphamide regimen are becoming the strategies mainly used in haploidentical transplantation because of high practicability and low risk of infection, though these platforms necessitate other drugs for GVHD prophylaxis due to the low efficacy of T cell depletion. Together with progress in these platforms, outcomes of haploidentical transplantation are comparable to outcomes of HLA-matched transplants. Currently, HLA-haploidentical transplantation is increasingly being recognized as a novel breakthrough in hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome
Souichi Shiratori, Katsuya Fujimoto, Machiko Nishimura, Kanako C. Hatanaka, Mizuha Kosugi-Kanaya, Kohei Okada, Junichi Sugita, Akio Shigematsu, Daigo Hashimoto, Tomoyuki Endo, Takeshi Kondo, Riichiro Abe, Satoshi Hashino, Yoshihiro Matsuno, Hiroshi Shimizu, Takanori Teshima
HEMATOLOGICAL ONCOLOGY, 34, 1, 9, 16, WILEY-BLACKWELL, 2016年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Advanced-stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced-intensity conditioning (RIC) regimen, is a promising treatment for advanced-stage MF/SS. We performed RIC-HSCT in nine patients with advanced MF/SS. With a median follow-up period of 954days after HSCT, the estimated 3-year overall survival was 85.7% (95% confidence interval, 33.4-97.9%) with no non-relapse mortality. Five patients relapsed after RIC-HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft-versus-lymphoma effect and down-staging' effect from advanced stage to early stage by HSCT improve the prognosis of advanced-stage MF/SS. These results suggest that RIC-HSCT is an effective treatment for advanced MF/SS. Copyright (c) 2014 John Wiley & Sons, Ltd.

Reprint of: Acute Graft-versus-Host Disease: Novel Biological Insights
Takanori Teshima, Pavan Reddy, Robert Zeiser
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 22, 3, S3, S8, ELSEVIER SCIENCE INC, 2016年03月, ［査読有り］
英語, Graft-versus-host disease (GVHD) continues to be a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recent insights into intestinal homeostasis and uncovering of new pathways and targets have greatly reconciled our understanding of GVHD pathophysiology and will reshape contemporary GVHD prophylaxis and treatment. Gastrointestinal (GI) GVHD is the major cause of mortality. Emerging data indicate that intestinal stem cells (ISCs) and their niche Paneth cells are targeted, resulting in dysregulation of the intestinal homeostasis and microbial ecology. The microbiota and their metabolites shape the immune system and intestinal homeostasis, and they may alter host susceptibility to GVHD. Protection of the ISC niche system and modification of the intestinal microbiota and metabolome to restore intestinal homeostasis may, thus, represent a novel approach to modulate GVHD and infection. Damage to the intestine plays a central role in amplifying systemic GVHD by propagating a proinflammatory cytokine milieu. Molecular targeting to inhibit kinase signaling may be a promising approach to treat GVHD, ideally via targeting the redundant effect of multiple cytokines on immune cells and enterocytes. In this review, we discuss insights on the biology of GI GVHD, interaction of microflora and metabolome with the hosts, identification of potential new target organs, and identification and targeting of novel T cell signaling pathways. Better understanding of GVHD biology will, thus, pave a way to develop novel treatment strategies with great clinical benefits. (c) 2016 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.

Impact of age on outcomes of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in elderly patients with acute myeloid leukemia
Jun Aoki, Heiwa Kanamori, Masatsugu Tanaka, Satoshi Yamasaki, Takahiro Fukuda, Hiroyasu Ogawa, Koji Iwato, Kazuteru Ohashi, Hirokazu Okumura, Makoto Onizuka, Yoshitomo Maesako, Takanori Teshima, Naoki Kobayashi, Yasuo Morishima, Makoto Hirokawa, Yoshiko Atsuta, Shingo Yano, Akiyoshi Takami
AMERICAN JOURNAL OF HEMATOLOGY, 91, 3, 302, 307, WILEY-BLACKWELL, 2016年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Previous studies have repeatedly reported that increasing age is a significant risk factor for worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among patients with acute myeloid leukemia (AML). However, more recent studies reported conflicting results regarding the association between age and outcomes in elderly patients. Therefore, we conducted a large-scale, nationwide retrospective study to examine the impact of age on outcomes of allo-HSCT with reduced intensity conditioning (RIC) for AML patients who were older than 50 years. Of the 757 patients, 89 patients (11.8%) were 50-54, 249 patients (32.9%) were 55-59, 301 patients (39.8%) were 60-64 and 118 patients (15.6%) were 65 years old. The 3-year overall survival (OS) (47.8, 45.2, 37.9, and 36.6% for patients aged 50-54, 55-59, 60-64, and 65 years, respectively, P=0.24) and nonrelapse mortality (NRM) (24.0, 22.8, 29.2, and 27.6% for patients aged 50-54, 55-59, 60-64, and 65 years, respectively, P=0.49) were not significantly different among the four age groups. Multivariate analysis revealed that increased age had no significant effect on OS or NRM after adjusting for covariates. These results suggested that advanced patient age is not a contraindication for RIC allo-HSCT in elderly AML patients. Am. J. Hematol. 91:302-307, 2016. (c) 2015 Wiley Periodicals, Inc.

5-Azacytidine partially restores CD20 expression in follicular lymphoma that lost CD20 expression after rituximab treatment: A case report
Yutaka Tsutsumi, Hiroyuki Ohigashi, Shinichi Ito, Souichi Shiratori, Takanori Teshima
Journal of Medical Case Reports, 10, 1, 27, BioMed Central Ltd., 2016年02月02日, ［査読有り］
英語, 研究論文（学術雑誌）, Background: The loss of CD20 protein expression after a rituximab-containing regimen is one of the resistance mechanisms in non-Hodgkin's lymphoma. Recently, it was reported that 5-azacitidine administration upregulates the expression of CD20 in CD20-negative B-cell acute lymphoblastic leukemia. Here we report a similar upregulation in a patient with follicular lymphoma who was treated with 5-azacitidine against secondary myelodysplastic syndrome. Case presentation: A 69-year-old Japanese woman with follicular lymphoma with treatment-related myelodysplastic syndrome was negative for the CD20 antibody at the time of her relapse. After treatment of 5-azacytidine for her myelodysplastic syndrome, CD20 expression was upregulated in the follicular lymphoma cells in her peripheral blood. We also observed follicular lymphoma cell stimulation in her peripheral blood due to 5-azacytidine. Conclusions: Although partial, CD20 expression was upregulated after treatment with 5-azacitidine. However, CD20 expression was not re-upregulated after a second administration of 5-azacitidine and we also observed the risk of lymphoma cell stimulation due to 5-azacitidine.

オーバービュー
豊嶋 崇徳
臨床血液, 57, 3, 270, 270, 一般社団法人 日本血液学会, 2016年
日本語

Cord Blood Transplantation Following Reduced-intensity Conditioning for Adult-onset Inherited Hemophagocytic Lymphohistiocytosis
Takuro Kuriyama, Koji Kato, Keiji Sakamoto, Masayasu Hayashi, Shuichiro Takashima, Yasuo Mori, Katsuto Takenaka, Hiromi Iwasaki, Takanori Teshima, Naoki Harada, Koji Nagafuji, Toshihiro Miyamoto, Koichi Akashi
INTERNAL MEDICINE, 55, 6, 667, 671, JAPAN SOC INTERNAL MEDICINE, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, Inherited hemophagocytic lymphohistiocytosis (HLH) is a genetic anomaly disorder in which abnormally activated cytotoxic T lymphocytes cannot induce the apoptosis of target cells and antigen-presenting cells, leading to hemophagocytosis, pancytopenia, and a variety of symptoms such as a high fever. The present patient with adult-onset HLH developed refractory disease despite receiving immunosuppressive treatments. He underwent a reduced-intensity conditioning (RIC) regimen that comprised antithymocyte globulin (ATG) followed by cord blood transplantation (RIC-CBT). He achieved and maintained a complete donor type. The incorporation of ATG into RIC-CBT may prevent graft failure and control hemophagocytosis, however, further efforts are necessary to reduce infectious complications.

Cytogenetically Unrelated Clones in Acute Myeloid Leukemia Showing Different Responses to Chemotherapy
Kohei Kasahara, Masahiro Onozawa, Naohiro Miyashita, Emi Yokohata, Miho Yoshida, Minoru Kanaya, Mizuha Kosugi-Kanaya, Ryo Takemura, Shojiro Takahashi, Junichi Sugita, Akio Shigematsu, Mutsumi Takahata, Shinichi Fujisawa, Daigo Hashimoto, Katsuya Fujimoto, Tomoyuki Endo, Takeshi Kondo, Takanori Teshima
Case Reports in Hematology, 2016, 1, 5, Hindawi Limited, 2016年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We report a case of acute myeloid leukemia (AML) with two cytogenetically unrelated clones. The patient was a 45-year-old male who was diagnosed with acute monoblastic leukemia (AMoL). Initial G-band analysis showed 51,XY,+6,+8,inv(9)(p12q13)c,+11,+13,+19[12]/52,idem,+Y[8], but G-band analysis after induction therapy showed 45,XY,-7,inv(9)(p12q13)c[19]/46,XY,inv(9)(p12q13)c[1]. Retrospective FISH analysis revealed a cryptic monosomy 7 clone in the initial AML sample. The clone with multiple trisomies was eliminated after induction therapy and never recurred, but a clone with monosomy 7 was still detected in myelodysplastic marrow with a normal blast percentage. Both clones were successfully eliminated after related peripheral blood stem cell transplantation, but the patient died of relapsed AML with monosomy 7. We concluded that one clone was de novo AMoL with chromosome 6, 8, 11, 13, and 19 trisomy and that the other was acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) with chromosome 7 monosomy showing different responses to chemotherapy. Simultaneous onset of cytogenetically unrelated hematological malignancies that each have a different disease status is a rare phenomenon but is important to diagnose for a correct understanding of the disease status and for establishing an appropriate treatment strategy.

Determination of prognosis of Philadelphia chromosome-negative myeloproliferative neoplasms with a simple clinical examination: Retrospective analysis of 71 patients in a single institution
SHINICHI ITO, YUTAKA TSUTSUMI, HIROYUKI OHIGASHI, SOUICHI SHIRATORI, TAKANORI TESHIMA
Molecular and Clinical Oncology, 4, 1, 51, 57, Spandidos Publications, 2016年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF), are clonal hematopoietic diseases. A single-institution retrospective analysis was performed, including 71 MPN patients diagnosed at the Hakodate Municipal Hospital between April, 2001 and April, 2014, and certain clinical characteristics were identified as effective prognostic factors. The patients were categorized by risk factor scoring based on age, number of abnormal blood cell lineages and splenomegaly at diagnosis, and the association between this categorization and prognosis was analyzed using a statistical procedure. The effect of Janus kinase 2 (JAK2) V617F mutation on prognosis was also investigated. The MPN patients were consolidated into three risk groups based on the margin of intergroup survival differences: i) Score 1-2 (n=23), ii) score 3 (n=24) and iii) score 4-5 (n=24). MPN patients with scores of 4 or 5 exhibited poorer overall survival (OS) compared with those with lower scores (P<0.001). In addition, there were significant differences in event-free survival (EFS) among scoring groups (P=0.0059). PV and ET had a better prognosis compared with PMF, although this analysis suggested that PV and ET patients with scores of 4 or 5 may have a poorer prognosis in terms of OS (P=0.0052) and EFS (P=0.022) and should be closely followed up. We observed no significant prognostic effect of the JAK2V167F mutation for OS (P=0.28) or EFS (P=0.17). Our results suggested that a simple scoring system based on age, blood cell counts and presence of splenomegaly at diagnosis may be used for the long-term prognosis of MPN patients.

Unplanned discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia
YUTAKA TSUTSUMI, SHINICHI ITO, HIROYUKI OHIGASHI, SOUICHI SHIRATORI, TAKANORI TESHIMA
Molecular and Clinical Oncology, 4, 1, 89, 92, Spandidos Publications, 2016年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, This study was conducted to investigate the outcomes of patients with chronic myeloid leukemia (CML) who discontinued tyrosine kinase inhibitor (TKI) treatment. A single-center retrospective analysis was performed, including 46 chronic-phase (CP) CML patients who achieved complete molecular response (CMR) with TKIs. TKI treatment was discontinued in 13 patients based on their requests. The BCR-ABL transcript levels were monitored in the peripheral blood by quantitative polymerase chain reaction analysis following treatment discontinuation. Of the 13 patients who discontinued TKI treatment, 7 remained in CMR, with a median follow-up of 26 months (range, 10-60 months). The remaining 6 patients lost CMR following TKI discontinuation; 2 of these patients achieved a second CMR following re-administration of TKIs, 2 patients spontaneously achieved CMR and 2 remained in complete hematological response (CHR) without TKI treatment with a median follow-up of 29.5 months (range, 10-52 months). In conclusion, the survival of patients who lost CMR following TKI discontinuation may not be affected, even without re-administration of TKIs. Vigilant observation is recommended for such patients. The limitations of this study included the small patient sample, retrospective design and patient heterogeneity. Therefore, the results must be interpreted with caution.

Pharmacokinetics and dose adjustment of etoposide administered in a medium-dose etoposide, cyclophosphamide and total body irradiation regimen before allogeneic hematopoietic stem cell transplantation.
Yuki Tazawa, Akio Shigematsu, Kumiko Kasashi, Junichi Sugita, Tomoyuki Endo, Takeshi Kondo, Takanori Teshima, Ken Iseki, Mitsuru Sugawara, Yoh Takekuma
Journal of pharmaceutical health care and sciences, 2, 18, 18, 18, 2016年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We investigated the pharmacokinetics of etoposide (ETP) to reduce the inter-individual variations of ETP concentrations in patients with acute leukemia who underwent allogeneic hematopoietic stem cell transplantation. We also carried out an in vivo study using rats to verify the dose adjustment. METHODS: This study included 20 adult patients. ETP was administered intravenously at a dose of 15 mg/kg once daily for 2 days (total dose: 30 mg/kg) combined with standard conditioning of cyclophosphamide and total body irradiation. In an in vivo study using rats, ETP was administered intravenously at a dose of 15 mg/kg or an adjusted dose. The ETP plasma concentration was determined by using HPLC. The pharmacokinetic parameters were estimated by using a 1-compartment model. RESULTS: The peak concentration (Cmax) of ETP and the area under the plasma concentration-time curve (AUC) of ETP differed greatly among patients (range of Cmax, 51.8 - 116.5 μg/mL; range of AUC, 870 - 2015 μg · h/mL). A significant relationship was found between Cmax and AUC (R = 0.85, P < 0.05). Distribution volume (Vd) was suggested to be one of the factors of inter-individual variation in plasma concentration of ETP in patients (range of Vd, 0.13 - 0.27 L/kg), and correlated with Alb and body weight (R = 0.56, P < 0.05; R = 0.40, P < 0.05 respectively). We predicted Vd of rats by body weight of rats (with normal albumin levels and renal function), and the dose of ETP was adjusted using predicted Vd. In the dose adjustment group, the target plasma ETP concentration was achieved and the variation of plasma ETP concentration was decreased. CONCLUSION: The results suggested that inter-individual variation of plasma concentration of ETP could be reduced by predicting Vd. Prediction of Vd is effective for reducing individual variation of ETP concentration and might enable a good therapeutic effect to be achieved.

組織幹細胞システム保護による次世代型造血幹細胞移植　　　　　　　　　　　　　　　
豊嶋 崇徳
上原記念生命科学財団研究報告集, 29, 1, 4, (公財)上原記念生命科学財団, 2015年12月
日本語, マウスの同種骨髄移植のモデルにおいて、移植前処置としての全身放射線照射やGVHDと、腸幹細胞傷害、Paneth細胞傷害がどのように発生するのか検討した。腸幹細胞は移植前処置である全身放射線照射による傷害のため一時的に消失するが、GVHDを発症しない場合はニッチであるPaneth細胞が保たれるため、腸幹細胞は回復可能であった。GVHDを発症した場合は、全身放射線照射による腸幹細胞傷害後にアロ反応性T細胞によるPaneth細胞傷害が加わり、ニッチの傷害により腸幹細胞は回復できず陰窩のアポトーシスをきたした。Paneth細胞が保たれるnon-GVHD群と比較して、著明なPaneth細胞の減少をきたしたGVHD群では腸内細菌叢の異常を認めた。造血幹細胞移植においてPaneth細胞は腸幹細胞の保護と腸内細菌叢の維持の二つの点で非常に大きな役割を担っていた。

Effects of conditioning intensity in allogeneic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia
Shuichiro Takashima, Toshihiro Miyamoto, Tomohiko Kamimura, Goichi Yoshimoto, Shuro Yoshida, Hideho Henzan, Ken Takase, Koji Kato, Yoshikiyo Ito, Yuju Ohno, Koji Nagafuji, Tetsuya Eto, Takanori Teshima, Koichi Akashi
INTERNATIONAL JOURNAL OF HEMATOLOGY, 102, 6, 689, 696, SPRINGER JAPAN KK, 2015年12月, ［査読有り］
英語, 研究論文（学術雑誌）, We retrospectively analyzed the outcomes of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) who underwent first allogeneic stem cell transplantation (allo-SCT) at complete remission (CR) with myeloablative conditioning (MAC, n = 31) or reduced-intensity conditioning (RIC, n = 15) between 2001 and 2012. All the patients had received tyrosine kinase inhibitor (TKI)-based chemotherapy prior to allo-SCT. Overall survival (OS) rates (57 vs 63 %, p = 0.53), leukemia-free survival rates (50 vs 65 %, p = 0.29), and non-relapse mortality rates (39 vs 35 %, p = 0.62) at 2 years were similar between the MAC and RIC groups. The minimal residual disease (MRD) status evaluated by sensitive polymerase chain reaction prior to allo-SCT did not influence the OS rate (77 vs 54 %, p = 0.28) and leukemia-free survival rate (69 vs 51 %, p = 0.48), irrespective of the conditioning intensity. Our data suggest that the RIC regimen may represent a sufficient intensity of therapeutic pre-transplant conditioning for patients with Ph(+)ALL who have maintained a hematological CR with TKI-combined chemotherapy.

Occurrence of adverse events caused by valganciclovir as pre-emptive therapy for cytomegalovirus infection after allogeneic stem cell transplantation is reduced by low-dose administration
M. Takahata, S. Hashino, M. Nishio, J. Sugita, A. Shigematsu, M. Onozawa, K. Fujimoto, T. Endo, T. Kondo, J. Tanaka, M. Imamura, T. Teshima
TRANSPLANT INFECTIOUS DISEASE, 17, 6, 810, 815, WILEY-BLACKWELL, 2015年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Background. Pre-emptive therapy with valganciclovir (VGCV) has become the standard therapy for preventing cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HSCT). The effectiveness of low-dose VGCV (900 mg per day) has been shown to be equal to that of standard-dose VGCV (900 mg twice daily); however, individualized optimal dosing and toxicity of VGCV have not been reported.
Methods. We conducted a retrospective study to evaluate the optimal dose of VGCV as pre-emptive therapy for preventing CMV infection by comparing the frequency of adverse events (AEs) and clinical efficacy in a low-dose VGCV group with those in a standard-dose VGCV group. Thirty-eight patients who were administered VGCV because of CMV antigenemia after HSCT were analyzed.
Results. Neutropenia (standard-dose group: 33%, low-dose group: 15%, P = 0.26) and thrombocytopenia (standard-dose group: 39%, low-dose group: 15%, P = 0.14) were frequent AEs of VGCV, and a significantly higher frequency of overall AEs was detected in the standard-dose group than in the low-dose group (P < 0.01). In comparison of dosage based on weight, dosage of VGCV > 27 mg/kg was closely related to onset of AEs (P = 0.04).
Conclusions. Low-dose VGCV was not inferior in clinical efficacy, including clearance rate of CMV antigenemia and incidence of consequent CMV disease, to standard-dose VGCV as was previously reported. Initial low-dose VGCV for pre-emptive CMV therapy markedly reduces hematologic toxicity and has clinical efficacy equivalent to that of standard-dose VGCV. It is therefore reasonable for patients, except for noticeably overweight patients, to be given initial low-dose VGCV.

Sustained CD4 and CD8 lymphopenia after rituximab maintenance therapy following bendamustine and rituximab combination therapy for lymphoma
Yutaka Tsutsumi, Shinichi Ito, Hiroyuki Ohigashi, Naohiro Miyashita, Joji Shimono, Souichi Shiratori, Takanori Teshima
LEUKEMIA & LYMPHOMA, 56, 11, 3216, 3218, TAYLOR & FRANCIS LTD, 2015年11月, ［査読有り］
英語

Decreased secretion of Paneth cell α-defensins in graft-versus-host disease
Y. Eriguchi, K. Nakamura, D. Hashimoto, S. Shimoda, N. Shimono, K. Akashi, T. Ayabe, T. Teshima
Transplant Infectious Disease, 17, 5, 702, 706, 2015年10月01日
英語, 研究論文（学術雑誌）, Background: Intestinal microbial ecology is actively regulated by Paneth cell-derived antimicrobial peptides, α-defensins. Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (SCT). We previously demonstrated that Paneth cells are targeted by GVHD, and their expression of antimicrobial peptide α-defensins is impaired, leading to a loss of physiological diversity among the microflora and development of bloodstream infection. Herein, we evaluated whether fecal levels of α-defensins could be surrogate marker of intestinal dysbiosis. Methods: We directly measured α-defensin cryptdin-1 (Crp1) in fecal pellets of mice with GVHD by using a novel enzyme-linked immunosorbent assay. Results: Fecal levels of Crp1 were significantly decreased in mice with GVHD but unchanged in mice without GVHD after SCT. These were correlated with intestinal flora diversity. Conclusion: We demonstrate a link between reduced secretion of Paneth cell α-defensins and dysbiosis of intestinal flora in GVHD. Fecal levels of α-defensins could be surrogate markers for intestinal microbial homeostasis.

Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia
Yoshihiro Inamoto, Mary E. D. Flowers, Tao Wang, Alvaro Urbano-Ispizua, Michael T. Hemmer, Corey S. Cutler, Daniel R. Couriel, Amin M. Alousi, Joseph H. Antin, Robert Peter Gale, Vikas Gupta, Betty K. Hamilton, Mohamed A. Kharfan-Dabaja, David I. Marks, Olle T. H. Ringden, Gerard Socie, Melhem M. Solh, Goerguen Akpek, Mitchell S. Cairo, Nelson J. Chao, Robert J. Hayashi, Taiga Nishihori, Ran Reshef, Ayman Saad, Ami Shah, Takanori Teshima, Martin S. Tallman, Baldeep Wirk, Stephen R. Spellman, Mukta Arora, Paul J. Martin
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 21, 10, 1776, 1782, ELSEVIER SCIENCE INC, 2015年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia, Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia. (C) 2015 American Society for Blood and Marrow Transplantation.

HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide after Busulfan-Containing Reduced-Intensity Conditioning
Junichi Sugita, Naomi Kawashima, Tomoaki Fujisaki, Kazuhiko Kakihana, Shuichi Ota, Keitaro Matsuo, Toshihiro Miyamoto, Koichi Akashi, Shuichi Taniguchi, Mine Harada, Takanori Teshima
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 21, 9, 1646, 1652, ELSEVIER SCIENCE INC, 2015年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic stem cell transplantation (allo-SCT) using post-transplant cyclophosphamide (PTCy) is increasingly performed. We conducted a multicenter phase II study to evaluate the safety and efficacy of PTCy-based HLA-haploidentical peripheral blood stem cell transplantation (PTCy-haploPBSCT) after busulfan-containing reduced-intensity conditioning. Thirty-one patients were enrolled; 61% patients were not in remission and 42% patients had a history of prior allo-SCT Neutrophil engraftment was achieved in 87% patients with a median of 19 days. The cumulative incidence of grades II to IV and III to IV acute graft-versus-host disease (GVHD) and chronic GVHD at 1 year were 23%, 3%, and 15%, respectively. No patients developed severe chronic GVHD. Day 100 nonrelapse mortality (NRM) rate was 19.4%. Overall survival, relapse, and disease-free survival rates were 45%, 45%, and 34%, respectively, at 1 year. Subgroup analysis showed that patients who had a history of prior allo-SCT had lower engraftment, higher NRM, and lower overall survival than those not receiving a prior allo-SCT. Our results suggest that PTCy-haploPBSCT after busulfan-containing reduced-intensity conditioning achieved low incidences of acute and chronic GVHD and NRM and stable donor engraftment and low NRM, particularly in patients without a history of prior allo-SCT. (C) 2015 American Society for Blood and Marrow Transplantation.

Preserved in vivo reconstitution ability of PBSCs cryopreserved for a decade at -80 °C.
Shima T, Iwasaki H, Yamauchi T, Kadowaki M, Kiyosuke M, Mochimaru T, Takenaka K, Miyamoto T, Akashi K, Teshima T
Bone Marrow Transplant., 50, 9, 1195, 1200, NATURE PUBLISHING GROUP, 2015年09月, ［査読有り］
英語, 研究論文（学術雑誌）, PBSC products for auto- and allografting can be cryopreserved in liquid nitrogen with controlled-rate freezing until their use. Alternatively, they can be stored at - 80 degrees C in a mechanical chest freezer, but it remains to be clarified whether PBSCs can be stored for the long term. We evaluated viability and functions of PBSCs cryopreserved for more than 10 years with this simplified method. Although recovery rate and viability of CD34(+) cells were significantly decreased, myeloid differentiation potential and in vivo reconstitution and self-renewal potential of CD34(+) cells in a xenogeneic engraftment assay were maintained for more than 10 years. These results indicate that PBSCs can be stored at -80 degrees C for years. Although accumulation of clinical engraftment data is required to confirm our results, this simplified cryopreservation will thus meet the increasing worldwide demand for PBSC transplantation in a region with limited resources.

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know
M. Ogata, T. Fukuda, T. Teshima
BONE MARROW TRANSPLANTATION, 50, 8, 1030, 1036, NATURE PUBLISHING GROUP, 2015年08月
英語, Human herpesvirus-6 (HHV-6) encephalitis following allogeneic hematopoietic cell transplantation is a serious and often fatal complication accompanying reactivation of HHV-6B. Incidence varies among studies, but is reportedly 0-11.6% after bone marrow or PBSC transplantation and 4.9-21.4% after umbilical cord blood transplantation, typically around 2-6 weeks post transplant. Symptoms are characterized by memory loss, loss of consciousness and seizures. Magnetic resonance imaging (MRI) typically shows bilateral signal abnormalities in the limbic system. This complication is considered to represent acute encephalitis caused by direct virally induced damage to the central nervous system, but our understanding of the etiologies and pathogenesis is still limited. The mortality rate attributable to this pathology remains high, and survivors are often left with serious sequelae such as impaired memory and epilepsy. Despite the poor prognosis, no validated treatments or preventative measures have been established. Establishment of preventative strategies represents an important challenge. This article reviews the current knowledge of the clinical features, incidence, pathogenesis and treatment of HHV-6 encephalitis, and discusses issues needing clarification in the future to overcome this serious complication.

Ultrasonographic evaluation of gastrointestinal graft-versus-host disease after hematopoietic stem cell transplantation
Mutsumi Nishida, Akio Shigematsu, Megumi Sato, Yusuke Kudo, Satomi Omotehara, Tatsunori Horie, Takahito Iwai, Tomoyuki Endo, Akihiro Iguchi, Hitoshi Shibuya, Kanako Hatanaka, Chikara Shimizu, Takanori Teshima
CLINICAL TRANSPLANTATION, 29, 8, 697, 704, WILEY-BLACKWELL, 2015年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Gastrointestinal graft-versus-host disease (GI-GVHD) is a major and life-threatening complication of hematopoietic stem cell transplantation (HSCT). This study evaluated the efficacy of ultrasonography (US) for assessing and monitoring GI-GVHD. GI tract was evaluated by US in 81 patients. US findings were positive in 43 patients, including 11 false positive, and negative in 38 patients. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of US for the diagnosis of GI-GVHD were 100%, 78%, 74%, 100%, and 86%, respectively. Diffuse wall thickening of the ileum was the most frequent finding in patients with GI-GVHD. Severity of GI-GVHD was correlated with the thickness of internal low echoic layer of the wall, the echogenicity of mesenteric fat tissue, and the intensity of Doppler signaling. We classified US findings of GI-GVHD into four USgrades. There was a significant correlation between clinical stage of GI-GVHD and the US grade. These ultrasonographic abnormalities were improved with clinical improvement of GI-GVHD upon treatment. Thus, US is an effective and efficient non-invasive means of identifying the extent and severity of GI-GVHD and monitoring response to treatment.

PolyI:C-Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector-Mediated Tumor Elimination In Vivo
Ryo Takemura, Hiromi Takaki, Seiji Okada, Hiroaki Shime, Takashi Akazawa, Hiroyuki Oshiumi, Misako Matsumoto, Takanori Teshima, Tsukasa Seya
CANCER IMMUNOLOGY RESEARCH, 3, 8, 902, 914, AMER ASSOC CANCER RESEARCH, 2015年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Double-stranded RNA directly acts on fibroblast and myeloid lineages to induce necroptosis as in TNF alpha. Here, we investigated whether this type of cell death occurred in cancer cells in response to polyinosinic-polycytidylic acid (polyI:C) and the pan-caspase inhibitor z-Val-Ala-Asp fluromethyl ketone (zVAD). We found that the colon cancer cell line CT26 is highly susceptible to necroptosis, as revealed by staining with annexin V/propidium iodide. CT26 cells possess RNA sensors, TLR3 and MDA5, which are upregulated by interferon (IFN)-inducing pathways and linked to receptor-interacting protein kinase (RIP) 1/3 activation via TICAM-1 or MAVS adaptor, respectively. Although exogenously added polyI: C alone marginally induced necroptosis in CT26 cells, a combined regimen of polyI: C and zVAD induced approximately 50% CT26 necroptosis in vitro without secondary effects of TNF alpha or type I IFNs. CT26 necroptosis depended on the TLR3-TICAM-1-RIP3 axis in the tumor cells to produce reactive oxygen species, but not on MDA5, MAVS, or the caspases/inflammasome activation. However, the RNA-derived necroptosis was barely reproduced in vivo in a CT26 tumor-implanted Balb/c mouse model with administration of polyI: C+zVAD. Significant shrinkage of CT26 tumors was revealed only when polyI: C (100 mg) was injected intraperitoneally and zVAD (1 mg) subcutaneously into tumor-bearing mice that were depleted of cytotoxic T lymphocytes and natural killer cells. The results were confirmed with immune-compromised mice with no lymphocytes. Although necroptosis-induced tumor growth retardation appears mechanistically complicated and dependent on the injection routes of polyI: C and zVAD, anti-caspase reagent directed to tumor cells will make RNA adjuvant immunotherapy more effective by modulating the formation of the tumoricidal microenvironment and dendritic cell-inducing antitumor immune system.

Key players in intestinal GVHD
Daigo Hashimoto, Takanori Teshima
[Rinshō ketsueki] The Japanese journal of clinical hematology, 56, 807, 814, 2015年07月01日
Acute graft versus host disease (GVHD) is a potentially life threatening complication after allogeneic hematopoietic stem cell transplantation. The gut is one of the most frequently affected organs in GVHD. Intestinal GVHD is often resistant to current therapies for GVHD and greatly affects the nutritional status of patients. Recent advances in understanding the biology of the intestinal immune system have revealed the significance of mechanical and chemical barriers involving the intestinal mucosa and intestinal microflora in the pathophysiology of GVHD. These barriers and flora are tightly regulated by key populations such as intestinal stem cells, Paneth cells, innate lymphoid cells, and macrophages. Recent findings for these key players in the process of intestinal GVHD are reviewed in this article.

Late onset toxic epidermal necrolysis induced by mogamulizumab, an anti-CC chemokine receptor 4 antibody for the treatment of adult T-cell leukaemia/lymphoma.
Shiratori S, Ohigashi H, Ito S, Kudo K, Adachi M, Minamimoto T, Kato J, Osai Y, Tsutsumi Y, Teshima T
Hematol Oncol., 2015年07月, ［査読有り］

Decreased secretion of Paneth cell α-defensin in graft-versus-host disease.
Eriguchi Y, Nakamura K, Hashimoto D, Shimoda S, Shimono N, Akashi K, Ayabe T, Teshima T
Transpl Infect Dis., 2015年07月, ［査読有り］

初発の非胚中心B細胞様びまん性大細胞型B細胞性リンパ腫患者を対象としたブルトン型チロシンキナーゼ(BTK)阻害薬PCI-32765(ibrutinib)の国際共同第III相試験
頼 晋也, 豊嶋 崇徳, 福原 規子, 飛内 賢正, 畠 清彦, 下山 達, 安藤 潔, 内田 俊樹, 永井 宏和, 谷脇 雅史, 柴山 浩彦, 中前 博久, 松村 到, 石川 隆之, 一戸 辰夫, 加藤 光次, 日高 道弘
日本リンパ網内系学会会誌, 55, 108, 108, (一社)日本リンパ網内系学会, 2015年06月, ［査読有り］
日本語

JAK阻害剤によるGVHDの制御
豊嶋崇徳
血液内科, 70, 5, 656, 660, 科学評論社, 2015年05月, ［査読有り］
日本語

Upregulation of microRNA-126-5p is associated with drug resistance to cytarabine and poor prognosis in AML patients
YOSHIHIKO SHIBAYAMA, TAKESHI KONDO, HIROKI OHYA, SHIN-ICHI FUJISAWA, TAKANORI TESHIMA, KEN ISEKI
Oncology Reports, 33, 5, 2176, 2182, Spandidos Publications, 2015年05月, ［査読有り］
英語, 研究論文（学術雑誌）, MicroRNAs (miRs) have been shown to negatively regulate gene expression by binding to mRNAs, and they play an important role in various physiological processes and malignancies. A previous study identified mature miR-126-3p as an onco-microRNA that is generated from the pre-microRNA, miR-126. Although miR-126 also generates mature miR-126-5p, its function is less clear. In the present study, the relationship between miR-126-5p/3p expression levels and overall survival in 109 patients with acute myeloid leukemia (AML) who received intensive therapy were evaluated. Higher expression levels above the median value of miR-126-5p/3p were correlated with a poorer overall survival. The hazard ratio and 95% confidence intervals (95% CI) for the higher expression group relative to the lower expression group of miR-126-5p/3p were 2.098 (95% CI: 1.075-4.228) and 1.958 (95% CI: 1.001-3.927), respectively. An interaction was not observed between the hazard ratios of miR-126-5p and miR-126-3p (p=0.73). Transfection of the mimic miR-126-5p into the AML cell line, KG-1, resulted in a decrease in the sensitivity to cytarabin and the expression level of Klotho mRNA as well as the elevation in the phosphorylation of Akt. The results of the present study demonstrated that higher expression levels of miR-126-5p/3p in patients with AML resulted in a poorer prognosis. Furthermore, miR-126-5p elevated the phosphorylation of Akt.

Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.
Youko Suehiro, Atsuhiko Hasegawa, Tadafumi Iino, Amane Sasada, Nobukazu Watanabe, Masao Matsuoka, Ayako Takamori, Ryuji Tanosaki, Atae Utsunomiya, Ilseung Choi, Tetsuya Fukuda, Osamu Miura, Shigeo Takaishi, Takanori Teshima, Koichi Akashi, Mari Kannagi, Naokuni Uike, Jun Okamura
Br. J. Haematol., 169, 3, 356, 367, WILEY, 2015年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease alt

α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice.
Uryu H, Hashimoto D, Kato K, Hayase E, Matsuoka S, Ogasawara R, Takahashi S, Maeda Y, Iwasaki H, Miyamoto T, Saijo S, Iwakura Y, Hill GR, Akashi K, Teshima T
Blood., 125, 19, 3014, 3023, AMER SOC HEMATOLOGY, 2015年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for various hematopoietic disorders. Graft-versus-host disease (GVHD) and infections are the major obstacles of HSCT, and their close relationship has been suggested. Although roles of bacterial and viral infections in the pathophysiology of GVHD are well described, impacts of fungal infection on GVHD remain to be elucidated. In mouse models of GVHD, injection of a-mannan (Mn), a major component of fungal cell wall, or heat-killed Candida albicans exacerbated GVHD, particularly in the lung. Mn-induced donor T-cell polarization toward Th17 and lung-specific chemokine environment in GVHD led to accumulation of Th17 cells in the lung. The detrimental effects of Mn on GVHD depended on donor IL-17A production and host C-type lectin receptor Dectin-2. These results suggest a previously unrecognized link between pulmonary GVHD and fungal infection after allogeneic HSCT.

The primacy of IL-6 in IPS?
Takanori Teshima
Blood, 125, 15, 2320, 2322, American Society of Hematology, 2015年04月09日, ［査読有り］
研究論文（学術雑誌）

Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation
H. Nakasone, T. Fukuda, J. Kanda, T. Mori, S. Yano, T. Kobayashi, K. Miyamura, T. Eto, H. Kanamori, K. Iwato, N. Uchida, S. Mori, T. Nagamura-Inoue, T. Ichinohe, Y. Atsuta, T. Teshima, M. Murata
BONE MARROW TRANSPLANTATION, 50, 4, 559, 565, NATURE PUBLISHING GROUP, 2015年04月, ［査読有り］
英語, 研究論文（学術雑誌）, The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (P<0.001). In a multivariate analysis, TBI-MAC, but not no-TBI MAC, was significantly associated with an increased risk of aGVHD 2-4 (hazard ratio (HR) 1.33, P<0.01), whereas TBI-RIC was associated with an increased risk of GVHD 3-4 (HR 1.36, P = 0.048). TBI-MAC and TBI-RIC were significantly associated with skin and gastrointestinal aGVHD. Subgroup analyses demonstrated that not only TBI-MAC, but also TBI-RIC, was significantly associated with aGVHD 2-4 in older patients. Furthermore, high-dose TBI only had an adverse impact on aGVHD 2-4 in HLA-matched HCT. Impacts of intensity and TBI on aGVHD differ by patient backgrounds, and this difference should be considered to establish a risk-adapted strategy for the prevention of aGVHD.

Analysis of the influence of dabigatran on coagulation factors and inhibitors
Y. Tsutsumi, J. Shimono, H. Ohhigashi, S. Ito, S. Shiratori, T. Teshima
INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, 37, 2, 225, 230, WILEY-BLACKWELL, 2015年04月, ［査読有り］
英語, 研究論文（学術雑誌）, IntroductionDabigatran is an oral intake thrombin inhibitor for preventive administration against stroke accompanied by atrial fibrillation. Although dabigatran causes prolonged activated partial thromboplastin time (APTT), the effect of dabigatran on each coagulation factor and coagulation factor inhibitor remains to be investigated. Our aim was to analyze the influence of dabigatran on coagulation factors and coagulation factor inhibitors.
MethodsWe administered dabigatran to 40 patients. In 26 of these 40, we analyzed the activity of several coagulation factors and their inhibitors. We used Fisher's exact test to determine statistical significance.
ResultsThe activities of many coagulation factors changed during the dabigatran therapy. Factor II levels decreased in all patients showing prolongation of partial thromboplastin (PT) and APTT. The antifactor VIII inhibitor was positive in the majority of patients with prolonged PT and APTT, while activities of protein C, protein S, and antifactor IX inhibitor were not associated with PT and APTT prolongation.
ConclusionDabigatran affects the activities of many coagulation factors, including factors II, V, VIII, and IX, as well as the antifactor VIII inhibitor.

CD155 Regulates Regulatory T Cell Population and Attenuates Acute Graft-Versus-Host Disease
Minoru Kanaya, Kazuko Shibuya, Fumie Abe, Takanori Teshima, Akira Shibuya
Biology of Blood and Marrow Transplantation, 21, 2, S335, S335, Elsevier BV, 2015年02月, ［査読有り］
研究論文（学術雑誌）

Ceramide-CD300f binding suppresses experimental colitis by inhibiting ATP-mediated mast cell activation.
Matsukawa T, Izawa K, Isobe M, Takahashi M, Maehara A, Yamanishi Y, Kaitani A, Okumura K, Teshima T, Kitamura T, Kitaura J
Gut., 2015年02月, ［査読有り］

Increasing Incidence of Chronic Graft-versus-Host Disease in Allogeneic Transplantation: A Report from the Center for International Blood and Marrow Transplant Research
Sally Arai, Mukta Arora, Tao Wang, Stephen R. Spellman, Wensheng He, Daniel R. Courie, Alvaro Urbano-Ispizua, Corey S. Cutler, Andrea A. Bacigalupo, Minoo Battiwallaw, Mary E. Flowers, Mark B. Juckett, Stephanie J. Lee, Alison W. Loren, Thomas R. Klumpp, Susan E. Prockup, Olle E. T. H. Ringden, Bipin N. Savani, Gerard Socie, Kirk R. Schultz, Thomas Spitzer, Takanori Teshima, Christopher N. Bredeson, David A. Jacobsohn, Robert J. Hayashi, William R. Drobyski, Haydar A. Frangoul, Gorgiin Akpek, Vincent T. Ho, Victor A. Lewis, Robert Peter Gale, John Koreth, Nelson J. Chao, Mahmoud D. Aljurf, Brenda W. Cooper, Mary J. Laughlin, Jack W. Hsu, Peiman Hematti, Leo F. Verdonck, Melhelm M. Solh, Maxim Norkin, Vijay Reddy, Jose A. Perez-Simon, Nandita Khera, Ian D. Lewis, Yoshiko Atsuta, Richard F. Olsson, Wael Saber, Edmund K. Waller, Didier Blaise, Joseph A. Pidala, Paul J. Martin, Prakash Satwani, Martin Bornhauser, Yoshihiro Inamoto, Daniel J. Weisdorf, Mary M. Horowitz, Steven Z. Pavletic
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 21, 2, 266, 274, ELSEVIER SCIENCE INC, 2015年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P <.0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research. (C) 2015 American Society for Blood and Marrow Transplantation.

血液腫瘍治療薬.　　　　　　　　　　　　　　　
藤本勝也, 豊嶋崇徳
医薬ジャーナル増刊号「新薬展望2015」, 51, S-1, 180, 189, 2015年

移植後シクロホスファミドを用いたHLA半合致移植の現状と課題.
杉田純一, 小杉瑞葉, 豊嶋崇徳
日本造血細胞移植学会雑誌, 4, 1, 9, 22, The Japan Society for Hematopoietic Stem Cell Transplantation, 2015年01月
英語, 研究論文（学術雑誌）, 近年，移植後シクロホスファミドを用いたhuman leukocyte antigen（HLA）半合致骨髄移植において，良好な生着とgraft-versus-host disease（GVHD）抑制効果が得られることが示された。その機序として，選択的にアロ応答性T細胞を排除すること，制御性T細胞を温存することが考えられている。GVHD，非再発死亡は低いが，再発率が高い点が問題であり，再発率の低下や拒絶の減少を目的として，末梢血幹細胞や骨髄破壊的前処置を用いた移植において本法が試みられている。さらに移植後シクロホスファミドは血液悪性疾患のみならず非腫瘍性血液疾患に対する同種移植後にも適用されている。近年ではHLA一致移植への使用も報告され，カルシニューリン阻害剤を使用しない新たなGVHD予防法のプラットフォームとして期待される。

抗がん剤の副作用と支持療法-より適切な抗がん剤の安全使用をめざして-　　　　　　　　　　　　　　　
小野澤真弘, 豊嶋崇徳
日本臨床, 73, suppl2, 623, 627, 2015年

非血縁者間同種末梢血幹細胞移植の今後の展開.　　　　　　　　　　　　　　　
重松明男, 豊嶋崇徳
医学のあゆみ, 253, 2, 187, 188, 2015年

造血幹細胞移植における腸幹細胞、ニッチシステムと腸内細菌.無菌生物　　　　　　　　　　　　　　　
豊嶋 崇徳
無菌生物, 45, 1, 43, 47, 日本無菌生物ノートバイオロジー学会, 2015年
日本語, 造血幹細胞移植の成績向上には移植片対宿主病(graft-versus-host disease:GVHD)と感染症の制御が重要な課題である。われわれは腸管GVHDでは、腸幹細胞・ニッチシステムが標的となることを見出した。またパネート細胞の障害により、内因性抗菌ペプチドの産生が低下し、腸内細菌叢の多様性が消失し、この菌交代現象により優勢となった細菌がGVHDにより破綻した粘膜バリアから侵入し敗血症が発症する。感染症は自然免疫を活性化しGVHDを増悪させ、GVHDと感染症にクロストークが存在する可能性が示唆された。このようにGVHDとは組織幹細胞・ニッチシステムが標的となることによって、生体の恒常性の維持のメカニズムの破綻が、その病態と難治化に関与しているものと考えられた。組織幹細胞・ニッチシステムの保護、生体のホメオスタシス維持を目指した新たな治療の開発が待たれる。(著者抄録)

腸内細菌叢がGVHDにもたらす影響　　　　　　　　　　　　　　　
早瀬英子, 豊嶋崇徳
Keynote R・A : rheumatic & autoimmune diseases, 3, 1, 24, 28, 2015年01月

白血病・リンパ腫の治療：過去から未来へ　　　　　　　　　　　　　　　
豊嶋 崇徳
北海道医報, 1156, 1, 31, 35, 2015年01月

CD4/CD8 Double-negative T-cell Lymphoma: A Variant of Primary Cutaneous CD8(+) Aggressive Epidermotropic Cytotoxic T-cell Lymphoma?
Toshinari Miyauchi, Riichiro Abe, Yusuke Morita, Maki Adachi, Keiko Shiba, Yohei Hamade, Nan Saito, Machiko Nishimura, Makoto Ibata, Kohei Okada, Akio Shigematsu, Tomoyuki Endo, Kazuhiro Kawai, Takanori Teshima, Hiroshi Shimizu
ACTA DERMATO-VENEREOLOGICA, 95, 8, 1024, 1025, ACTA DERMATO-VENEREOLOGICA, 2015年, ［査読有り］
英語, 研究論文（学術雑誌）

Human Herpesvirus-6 Pneumonitis around the Engraftment of Cord Blood Transplantation following Foscarnet Prophylaxis in a Patient with Acute Leukemia
Takashi Ishio, Tomoyuki Endo, Kohei Okada, Akio Shigematsu, Satoshi Hashino, Takanori Teshima
Case Reports in Hematology, 2015, 1, 5, Hindawi Limited, 2015年, ［査読有り］
研究論文（学術雑誌）, Human herpesvirus-6 (HHV-6) reactivation is sometimes observed in immunocompromised patients, especially after allogeneic stem cell transplantation. The complications of HHV-6 reactivation in this setting are mainly recognized as HHV-6 encephalitis. We herein report the case of a patient who developed HHV-6 pneumonitis after cord blood transplantation (CBT). A 35-year-old male underwent CBT for T-cell/myeloid mixed phenotype acute leukemia and achieved neutrophil engraftment on day 31. He had received foscarnet as prophylaxis for HHV-6 reactivation. A computed tomography (CT) scan to evaluate the leukemic tumor showed bilateral interstitial pneumonitis on day 33, although he had no respiratory symptoms. The findings of the CT scan were consistent with those of HHV-6 pneumonitis that were reported previously. HHV-6 DNA, but no other pathogens, was detected in his bronchoalveolar lavage (BAL) fluid. The patient was successfully treated with a therapeutic dose of foscarnet. This case indicates that performing a CT scan around the time of neutrophil engraftment can play an important role in detecting the early phase of HHV-6 pneumonia, and BAL should be considered if features consistent with HHV-6 pneumonitis are observed in patients with a risk of HHV-6 reactivation.

当院におけるHIV 感染者のビタミンDの検討
遠藤知之, 藤本勝也, 南昭子, 吉田美穂, 竹村龍, 渡部恵子, 坂本玲子, 武内阿味, 近藤健, 橋野聡, 清水力, 豊嶋崇徳
日本エイズ学会誌, 17, 1, 30, 35, (一社)日本エイズ学会, 2015年, ［査読有り］
日本語, HIV感染者におけるビタミンDの充足率を把握し、骨密度低下と因果関係を評価した。方法は著者らの施設へ通院中のHIV患者118例(男性115例、女性3例、年齢24〜73歳、平均年齢43歳)を対象に、血清25水酸化ビタミンD[25(OH)D]を測定、そのうち100例でDXA法による骨塩量測定検査を行った。その結果、1)血清25(OH)Dの平均値は18.5±11.0ng/mlであり、ビタミンD不足(20〜29ng/dl)は24例(20.3%)、ビタミンD欠乏(20ng/dl以下)が79例(67.0%)にみられた。更にビタミンD高度欠乏(10ng/ml以下)は26例(22.0%)にみられ、ビタミンD正常(30ng/ml以上)は15例(12.7%)に過ぎなかった。2)100例におけるDXA法による骨塩定量測定では骨減少症は27例(27.0%)、骨粗鬆症は8例(8%)であった。3)このことからビタミンDの充足度と骨密度には有意な相関は認められなかったが、抗HIV療法を受けている症例では未治療の症例と比較して有意に骨密度が低下していた。4)多くのHIV患者でビタミンDが不足・欠乏していたが、骨密度低下の要因としてはビタミンD欠乏より抗HIV薬の影響が大きいと考えられた。以上より、HIV患者にビスホスフォネートを投与する際にはビタミンDの評価を行い、ビタミンDが低下・欠乏している症例に対するビタミンDの補充も必要と考えられた。

Primary Bone Lymphoma: A Clinical Analysis of 17 Patients in a Single Institution
Eiko Hayase, Mitsutoshi Kurosawa, Hiroaki Suzuki, Kohei Kasahara, Tomohiro Yamakawa, Masakatsu Yonezumi, Sachiko Suzuki, Takanori Teshima
ACTA HAEMATOLOGICA, 134, 2, 80, 85, KARGER, 2015年, ［査読有り］
英語, 研究論文（学術雑誌）, Primary bone lymphoma (PBL) comprises less than 1% of all malignant lymphomas. Because few studies of PBL have been conducted in Japan, the characteristics of Japanese patients with PBL have not been fully elucidated. We retrospectively analyzed 17 patients diagnosed with PBL at our institution between 2001 and 2011. Median patient age was 60 years. Eleven patients had diffuse large B-cell lymphoma and 2 patients had T-cell lymphoma histology. The spine was the most frequently involved site at the time of presentation. There were 11 patients with stage IV disease and 11 patients with high or high-intermediate risk according to the International Prognostic Index (IPI). Thirteen patients achieved complete response (CR) after initial treatment. At a median follow-up of 31 months, the 3-year overall survival (OS) and progression free survival were 63.5 and 49.9%, respectively. Localized disease, low or low-intermediate IPI, and CR after initial treatment were associated with a good outcome in patients with PBL and significantly associated with a better OS. Spine involvement and T/NK-cell phenotype are more frequent in Japanese than in Caucasian patients with PBL. (C) 2015 S. Karger AG, Basel

Ultra-high level of serum soluble interleukin-2 receptor at diagnosis predicts poor outcome for angioimmunoblastic T-cell lymphoma
Souichi Shiratori, Mizuha Kosugi-Kanaya, Akio Shigematsu, Hajime Kobayashi, Satoshi Yamamoto, Naoki Kobayashi, Hiroshi Iwasaki, Akio Mori, Yasuyuki Kunieda, Yutaka Tsutsumi, Mitsutoshi Kurosawa, Yasutaka Kakinoki, Tomoyuki Endo, Takeshi Kondo, Satoshi Hashino, Takanori Teshima
LEUKEMIA & LYMPHOMA, 56, 9, 2592, 2597, TAYLOR & FRANCIS LTD, 2015年, ［査読有り］
英語, 研究論文（学術雑誌）, Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma and displays an aggressive clinical course with poor outcome. To identify prognostic factors for AITL, we retrospectively analyzed 36 patients with AITL. The median age was 74 years with 83% of the patients having advanced stage. Eighty-three percent received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like chemotherapies, resulting in an overall response rate of 63%. With a median follow-up of 9 years, the estimated overall survival at 5 years was 33.3%. Median serum level of soluble interleukin-2 receptor (sIL-2R) was 5615 U/mL at diagnosis, and over 10 000 U/mL of sIL-2R was identified as a significant poor prognostic factor, independent of the International Prognostic Index, Prognostic Index for peripheral T-cell lymphoma and Prognostic index for AITL (hazard ratio [HR], 4.42; 95% confidence interval [ CI], 1.49-13.11; log-rank, p < 0.01). Our study shows that an ultra-high level of serum sIL-2R at diagnosis is a significant poor prognostic biomarker for AITL.

PolyI:C and mouse survivin artificially embedding human 2B peptide induce a CD4+T cell response to autologous survivin in HLA-A*2402 transgenic mice
Jun Kasamatsu, Shojiro Takahashi, Masahiro Azuma, Misako Matsumoto, Akiko Morii-Sakai, Masahiro Imamura, Takanori Teshima, Akari Takahashi, Yoshihiko Hirohashi, Toshihiko Torigoe, Noriyuki Sato, Tsukasa Seya
IMMUNOBIOLOGY, 220, 1, 74, 82, ELSEVIER GMBH, URBAN & FISCHER VERLAG, 2015年01月, ［査読有り］
英語, 研究論文（学術雑誌）, CD4(+) T cell effectors are crucial for establishing antitumor immunity. Dendritic cell maturation by immune adjuvants appears to facilitate subset-specific CD4(+) T cell proliferation, but the adjuvant effect for CD4 T on induction of cytotoxic T lymphocytes (CTLs) is largely unknown. Self-antigenic determinants with low avidity are usually CD4 epitopes in mutated proteins with tumor-associated class I-antigens (TAAs). In this study, we made a chimeric version of survivin, a target of human CTLs. The chimeric survivin, where human survivin-2B containing a TAA was embedded in the mouse survivin frame (MmSVN2B), was used to immunize HLA-A-2402/K-b-transgenic (HLA24(b)-Tg) mice. Subcutaneous administration of MmSVN2B or xenogeneic human survivin (control HsSNV2B) to HLA24(b)-Tg mice failed to induce an immune response without co-administration of an RNA adjuvant polyI:C, which was required for effector induction in vivo. Although HLA-A-2402/K-b presented the survivin-2B peptide in C57BL/6 mice, 2B-specific tetramer assays showed that no CD8(+) T CTLs specific to survivin-2B proliferated above the detection limit in immunized mice, even with polyI:C treatment. However, the CD4(+) T cell response, as monitored by IFN-gamma, was significantly increased in mice given polyI:C+ MmSVN2B. The Th1 response and antibody production were enhanced in the mice with polyI:C. The CD4 epitope responsible for effector function was not Hs/MmSNV(13-27), a nonconserved region between human and mouse survivin, but region 53-67, which was identical between human and mouse survivin. These results suggest that activated, self-reactive CD4(+) helper T cells proliferate in MmSVN2B + polyI:C immunization and contribute to Thl polarization followed by antibody production, but hardly participate in CTL induction. (C) 2014 Elsevier GmbH. All rights reserved.

Allogeneic hematopoietic cell transplantation for mycosis fungoides and Sezary syndrome
M. J. Lechowicz, H. M. Lazarus, J. Carreras, G. G. Laport, C. S. Cutler, P. H. Wiernik, G. A. Hale, D. Maharaj, R. P. Gale, P. A. Rowlings, C. O. Freytes, A. M. Miller, J. M. Vose, R. T. Maziarz, S. Montoto, D. G. Maloney, P. N. Hari
BONE MARROW TRANSPLANTATION, 49, 11, 1360, 1365, NATURE PUBLISHING GROUP, 2014年11月, ［査読有り］
英語, 研究論文（学術雑誌）, We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P = 0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free.

[Case Report; Primary central nervous system lymphoma mimicking progressive multifocal leukoencephalopathy in a patient with acquired immune deficiency syndrome].
Yamakawa T, Fujimoto K, Ebata K, Iwasaki J, Takahashi S, Shiratori S, Sugita J, Kondo T, Nishio M, Teshima T
Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 103, 10, 2578, 2580, 2014年10月, ［査読有り］

Hepatitis B virus (HBV) reverse seroconversion (RS) can be prevented even in non-responders to hepatitis B vaccine after allogeneic stem cell transplantation: long-term analysis of intervention in RS with vaccine for patients with previous HBV infection
M. Takahata, S. Hashino, M. Onozawa, A. Shigematsu, J. Sugita, K. Fujimoto, T. Endo, T. Kondo, J. Tanaka, M. Imamura, T. Teshima
TRANSPLANT INFECTIOUS DISEASE, 16, 5, 797, 801, WILEY-BLACKWELL, 2014年10月, ［査読有り］
英語, 研究論文（学術雑誌）, BackgroundReactivation of hepatitis B virus (HBV) infection, reverse seroconversion (RS), is a serious complication after allogeneic stem cell transplantation (alloHSCT). We previously conducted a post-transplant hepatitis B vaccine intervention trial and demonstrated the vaccine efficacy in preventing HBV-RS. This report is an update of the hepatitis B vaccine study.
MethodsIn this trial, 21 patients were enrolled and received a standard 3-dose regimen of hepatitis B vaccine after discontinuation of immunosuppressants, whereas 25 transplant recipients with previous HBV infection did not receive the vaccine and served as controls.
ResultsNone of the 21 patients in the vaccine group developed HBV-RS and 12 controls developed HBV-RS in median follow-up periods of 60months (range 13-245). HBV vaccine resulted in a positive value of hepatitis B surface antibody (HBsAb) titer in 9 patients, while HBsAb remained negative in 12 patients. Presence of a high titer of HBsAb before vaccination was associated with conversion into HBsAb positivity after vaccination.
ConclusionThese results demonstrated the long-term effects of HBV vaccine for preventing HBV-RS after alloHSCT. Of note, no HBV-RS occurred, even in patients who did not achieve conversion into HBsAb positivity after vaccination.

FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia
Junko Iwasaki, Takeshi Kondo, Stephanie Darmanin, Makoto Ibata, Masahiro Onozawa, Daigo Hashimoto, Naoya Sakamoto, Takanori Teshima
ANNALS OF HEMATOLOGY, 93, 9, 1473, 1481, SPRINGER, 2014年09月, ［査読有り］
英語, 研究論文（学術雑誌）, FIP1-like 1 (FIP1L1) is associated with two leukemogenic fusion genes: FIP1L1-retinoic acid receptor alpha (RARA) and FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA). Analyses of a series of deletion mutants revealed that the FIP1 motif in FIP1L1-RARA plays a pivotal role in its homodimerization and transcriptional repressor activity. However, in FIP1L1-PDGFRA, the C-terminal PDGFRA portion possesses the ability of forming a homodimer by itself, making FIP1L1 dispensable for constitutive activation of this kinase. Both the full-length and the C-terminal PDGFRA portion of FIP1L1-PDGFRA could transform the IL-3-dependent hematopoietic cell line, BAF-B03. Moreover, when either the full-length or the C-terminal PDGFRA portion of FIP1L1-PDGFRA was introduced in these cells, they grew in the absence of IL-3. The cells having the C-terminal PDGFRA portion of FIP1L1-PDGFRA, however, were partially IL-3 dependent, whereas the cells having the full-length FIP1L1-PDGFRA became completely IL-3 independent for their growth. Taken together, these results show that FIP1L1 differentially contributes to the pathogenesis of distinct types of leukemia.

Essential requirements for setting up a stem cell processing laboratory
T. Leemhuis, D. Padley, C. Keever-Taylor, D. Niederwieser, T. Teshima, F. Lanza, C. Chabannon, P. Szabolcs, A. Bazarbachi, M. B. C. Koh
BONE MARROW TRANSPLANTATION, 49, 8, 1098, 1105, NATURE PUBLISHING GROUP, 2014年08月, ［査読有り］
英語, 研究論文（学術雑誌）, The Graft Processing subcommittee of the Worldwide Network for Blood and Marrow Transplantation wrote this guideline to assist physicians and laboratory technologists with the setting up of a cell processing laboratory (CPL) to support a hematopoietic stem cell transplant program, thereby facilitating the start-up of a transplant program in a new location and improving patient access to transplantation worldwide. This guideline describes the minimal essential features of designing such a laboratory and provides a list of equipment and supply needs and staffing recommendations. It describes the typical scope of services that a CPL is expected to perform, including product testing services, and discusses the basic principles behind the most frequent procedures. Quality management (QM) principles specific to a CPL are also discussed. References to additional guidance documents that are available worldwide to assist with QM and regulatory compliance are also provided.

Combination of bortezomib, thalidomide, and dexamethasone (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients
Shuichiro Takashima, Toshihiro Miyamoto, Masanori Kadowaki, Yoshikiyo Ito, Takatoshi Aoki, Ken Takase, Takahiro Shima, Goichi Yoshimoto, Koji Kato, Tsuyoshi Muta, Motoaki Shiratsuchi, Katsuto Takenaka, Hiromi Iwasaki, Takanori Teshima, Tomohiko Kamimura, Koichi Akashi
INTERNATIONAL JOURNAL OF HEMATOLOGY, 100, 2, 159, 164, SPRINGER JAPAN KK, 2014年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of bortezomib, thalidomide, and dexamethasone (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of bortezomib at a dose of 1.3 mg/m(2) and dexamethasone at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral thalidomide at a dose of 100 mg/day. Grade 3-4 neutropenia and thrombocytopenia were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. Peripheral neuropathy was common (63 %), but severe grade 3-4 peripheral neuropathy was not observed. Very good partial response or better response (a parts per thousand yenVGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from < VGPR before consolidation therapy to a parts per thousand yenVGPR after consolidation therapy (p = 0.041). The VTD regimen may be safe and effective as a consolidation therapy in the treatment of MM in Japanese population.

チゲサイクリンとコリスチンの併用が奏功した多剤耐性アシネトバクター・バウマニによるカテーテル関連血流感染症の1例　　　　　　　　　　　　　　　
山田武宏, 白鳥聡一, 杉田純一, 藤本勝也, 豊嶋崇徳, 福元達也, 岩崎澄央, 秋沢宏治
日本化学療法学会雑誌, 62, 4, 501, 505, (公社)日本化学療法学会, 2014年07月, ［査読有り］
日本語, 34歳男性、慢性骨髄性白血病のため骨髄移植を10年前に施行され、外来にて免疫抑制療法を継続中であった。肺炎のため入院し、levofloxacin等の投与でいったん軽快したものの、その後40.5℃の高熱およびCRPの上昇を認めた。血液培養とカテーテル先端より多剤耐性Acinetobacter baumannii(multidrug-resistant Acinetobacter baumannii;MDRAB)が分離され、カテーテル関連血流感染症と診断された。tigecycline(TGC)とcolistin(CL)の併用療法を開始したところ、翌日の血液培養で菌は陰性化し、患者の体温は平熱に復した。投与開始10日目にCRPは正常値となった。CLには重篤な腎機能障害が知られているが、治療経過中にCLのトラフ血中濃度を測定することにより安全に使用することができた。MDRAB敗血症は重篤な転帰にいたる場合が多く、TGCに加えCLを使用することで、より確実な効果を期待できるものと考えられた。(著者抄録)

JAK inhibitors: a home run for GVHD patients?
Takanori Teshima
Blood, 123, 24, 3691, 3693, American Society of Hematology, 2014年06月12日, ［査読有り］
研究論文（学術雑誌）

High Level of Serum Soluble Interleukin-2 Receptor at Transplantation Predicts Poor Outcome of Allogeneic Stem Cell Transplantation for Adult T Cell Leukemia
Akio Shigematsu, Naoki Kobayashi, Hiroshi Yasui, Motohiro Shindo, Yasutaka Kakinoki, Kyuhei Koda, Satoshi Iyama, Hiroyuki Kuroda, Yutaka Tsutsumi, Masahiro Imamura, Takanori Teshima
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 20, 6, 801, 805, ELSEVIER SCIENCE INC, 2014年06月, ［査読有り］
英語, 研究論文（学術雑誌）, The prognosis for adult T cell leukemia/lymphoma (ATL) is very poor, and only allogeneic hematopoietic stem cell transplantation (allo-SCT) has been considered to be a curative treatment for ATL. In this study, we retrospectively analyzed data for patients who had received allo-SCT for ATL in Hokkaido, the northernmost island of Japan, to determine prognostic factors. Fifty-six patients with a median age of 57 years received allo-SCT. Twenty-eight (50.0%) patients had acute type and 22 (46.4%) had lymphoma type. Twenty-three (41.1%) patients received allo-SCT in complete remission (CR), whereas the others were in non-CR. Seventeen (30.4%) patients received myeloablative conditioning and the others received reduced-intensity conditioning. With a median follow-up period of 48 months (range, 17 to 134 months), 1-year overall survival (OS) and 5-year OS rates were 55.4% and 46.1%, respectively. The survival curve reached a plateau at 22 months after stem cell transplantation (SCT). Male sex, high level of serum soluble interleukin-2 receptor (sIL-2R) at SCT, and non-CR at SCT were determined to be significant risk factors for OS. A high level of sIL-2R at SCT was a risk factor for poor OS in patients with non-CR at SCT by univariate analysis (P = .02), and it remained significant after adjustment by sex (hazard ratio, 2.73 [95% confidence interval, 1.07 to 7.90]). A high level of sIL-2R at SCT was also determined to be a risk factor for disease progression (P = .02). This region-wide study showed encouraging results for survival after allo-SCT for ATL and demonstrated for the first time that a high level of sIL-2R at SCT predicts worse SCT outcome. (C) 2014 American Society for Blood and Marrow Transplantation.

Stenotrophomonas maltophilia infection during allogeneic hematopoietic stem cell transplantation: a single-center experience
Souichi Shiratori, Kentaro Wakasa, Kohei Okada, Junichi Sugita, Koji Akizawa, Akio Shigematsu, Daigo Hashimoto, Katsuya Fujimoto, Tomoyuki Endo, Takeshi Kondo, Chikara Shimizu, Satoshi Hashino, Takanori Teshima
CLINICAL TRANSPLANTATION, 28, 6, 656, 661, WILEY, 2014年06月, ［査読有り］
英語, 研究論文（学術雑誌）, To examine risk factors for Stenotrophomonas maltophilia (S.maltophilia) infection during allogeneic hematopoietic stem cell transplantation (allo-HSCT), we retrospectively analyzed 259 patients who underwent allo-HSCT. Not only S.maltophilia infection but also S.maltophilia colonization was associated with mortality during allo-HSCT. Among 52 episodes in 39 patients in whom S.maltophilia was detected, documented infection developed in 33 episodes (25 patients). The onset of S.maltophilia infection in the period from the conditioning regimen to engraftment was associated with a high mortality rate. Breakthrough S.maltophilia infection developed in 24% of the patients during prophylactic administration of fluoroquinolones, to which S.maltophilia is sensitive. Reinsertion of a central venous catheter (CVC) immediately after removal was suggested to be a risk for persistent S.maltophilia infection in the period of neutropenia. Our results indicated that (i) onset of S.maltophilia infection in the period from the conditioning therapy to engraftment and (ii) removal and immediate reinsertion of a CVC as treatment after the onset of S.maltophilia infection are possible risk factors for S.maltophilia-related mortality during allo-HSCT.

臍帯血移植における移植片対宿主病(GVHD)　　　　　　　　　　　　　　　
高畑むつみ, 豊嶋崇徳
医学のあゆみ, 249, 7, 587, 592, 2014年05月

Bone Marrow Graft-versus-Host Disease: Evaluation of Its Clinical Impact on Disrupted Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation
Yusuke Shono, Souichi Shiratori, Mizuha Kosugi-Kanaya, Satoshi Ueha, Junichi Sugita, Akio Shigematsu, Takeshi Kondo, Daigo Hashimoto, Katsuya Fujimoto, Tomoyuki Endo, Mitsufumi Nishio, Satoshi Hashino, Yoshihiro Matsuno, Kouji Matsushima, Junji Tanaka, Masahiro Imamura, Takanori Teshima
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 20, 4, 495, 500, ELSEVIER SCIENCE INC, 2014年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Idiopathic cytopenias are frequently observed in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported the effect of graft-versus-host disease (GVHD) on bone marrow (BM) in murine models, indicating that the osteoblast injury mediated by donor T cells was associated with bone marrow suppression and delayed immune reconstitution. In this study, we prospectively evaluated the relevance of these findings in 51 patients. Patients with chronic GVHD manifested the loss of osteoblasts, contributing to cytopenic symptoms (P =.0427 compared with patients without cytopenic symptoms). The loss of osteoblasts was significantly associated with the extensive type of chronic GVHD (P =.012), and flow cytometric analyses revealed lower numbers of CD19(+) B cells and a significantly increased CD4 to CD8 ratio (P.0002) in these patients. Our data, for the first time to our knowledge, summarize the detailed analyses of the effect of GVHD on BM in the clinical allo-HSCT patients. (c) 2014 American Society for Blood and Marrow Transplantation.

Comparison of bortezomib, cyclophosphamide, and dexamethasone (VCD) induction with bortezomib and dexamethasone (BD) induction for newly diagnosed symptomatic multiple myeloma
Takashima S, Miyamoto T, Kamimura T, Yoshimoto G, Kato K, Ito Y, Muta T, Matsushima T, Shiratsuchi M, Tanimoto K, Takenaka K, Iwasaki H, Teshima T, Akashi K
International Journal of Myeloma, 4, 1, 7, 12, 2014年03月, ［査読有り］

造血幹細胞移植後GVHDと消化管傷害　　　　　　　　　　　　　　　
早瀬英子, 橋本大吾, 豊嶋崇徳
最新医学, 69, 3, 503, 507, 2014年03月

移植後GVHDの分子病態と治療
豊嶋 崇徳
血液内科, 68, 3, 291, 297, 2014年03月

ビンクリスチンによる麻痺性イレウスに引き続き posterior reversible encephalopathy syndrome を発症したT細胞性リンパ芽球性リンパ腫
早瀬英子, 杉田純一, 藤本勝也, 江端浩, 山川知宏, 吉田美穂, 竹村龍, 岩﨑純子
臨床血液, 55, 2, 249, 253, (一社)日本血液学会-東京事務局, 2014年02月, ［査読有り］
日本語, [症例報告]

北海道内のHIV感染症患者におけるHBV・HCV重複感染の現状 -拠点病院・診療施設アンケート調査結果-
藤本勝也, 遠藤知之, 吉田美穂, 竹村龍, 近藤健, 橋野聡, 須田剛生, 中馬誠, 後藤了一, センテノ田村恵子, 渡部恵子, 大野稔子, 石田禎夫, 大竹孝明, 宮城島拓人, 小林一, 堤豊, 三宅高義, 北川浩彦, 佐藤典宏, 豊嶋崇徳
日本エイズ学会誌, 16, 1, 18, 27, (一社)日本エイズ学会, 2014年02月, ［査読有り］
日本語, 北海道内のエイズ診療拠点病院と診療施設を対象として、HBVおよびHCV重複感染症に関するアンケート調査を実施し、その現状について分析した。アンケートの回収率は84%であった。HIV感染症患者総数は295名で、うちHBV重複感染例は22名(8%)、HCV重複感染例は34名(12%)で、すべて男性であった。HBV重複感染例では全例がテノフォビルまたはラミブジンを含む抗HIV療法を継続中で、86%が非活動性肝炎の状態を維持していた。HCV重複感染例では56%が抗HCV療法を施行され、うち32%が持続的ウイルス陰性化を達成していたが、41%が肝硬変に進行していた。重複感染例のうち71%は何らかの肝疾患以外の慢性合併症を有し、38%が2つ以上の合併症を認めた。HBV重複感染例に比べ、HCV重複感染例では高血圧の合併率が有意に高かった。以上の結果から、より有効で安全な抗HCV療法の導入、肝硬変例に対する肝移植を視野に入れた診療体制の整備、肝臓以外の慢性合併症の管理の重要性が示唆された。

Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease
Haruko Sugiyama, Yoshinobu Maeda, Hisakazu Nishimori, Yoshiko Yamasuji, Ken-ichi Matsuoka, Nobuharu Fujii, Eisei Kondo, Katsuji Shinagawa, Takehiro Tanaka, Kengo Takeuchi, Takanori Teshima, Mitsune Tanimoto
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 20, 2, 183, 191, ELSEVIER SCIENCE INC, 2014年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Chronic graft-versus-host disease (GVHD) remains a major late complication of allogeneic bone marrow transplantation (BMT). In a previous study, impaired thymic negative selection of the recipients permitted the emergence of pathogenic T cells that cause chronic GVHD using MHC class II-deficient (H2-Ab1 KO) B6 into OH model and CD4(+) T cells isolated from chronic GVHD mice caused chronic GVHD when administered into the secondary recipients. In this study, we evaluated the kinetics of regulatory T cell (Treg) reconstitution in wild type B6 into C3H model. After myeloablative conditioning, host Tregs disappeared rapidly, followed by expansion of Tregs derived from the donor splenic T cell inoculum. However, the donor splenic T cell derived Treg pool contracted gradually and was almost completely replaced by newly generated donor bone marrow (BM)-derived Tregs in the late post-transplantation period. Next, we compared the effects of cyclosporine (CSA) and mammalian target of rapamycin (mTOR) inhibitors on Treg reconstitution. Administration of CSA significantly impaired Treg reconstitution in the spleen and thymus. In contrast, BM-derived Treg reconstitution was not impaired in mTOR inhibitor-treated mice. Histopathological examination indicated that mice treated with GSA, but not mTOR inhibitors, showed pathogenic features of chronic GVHD on day 120. Mice treated with CSA until day 60, but not mTOR inhibitors, developed severe chronic GVHD followed by adoptive transfer of the pathogenic CD4(+) T cells isolated from H2-Ab1 KO into C3H model. These findings indicated that long-term use of CSA impairs reconstitution of BM-derived Tregs and increases the liability to chronic GVHD. The choice of immunosuppression, such as calcineurin inhibitor-free GVHD prophylaxis with mTOR inhibitor, may have important implications for the control of chronic GVHD after BMT. (C) 2014 American Society for Blood and Marrow Transplantation.

“No effect of humanized CCR monoclonal antibody (Mogamulizumab) on treatment-resistant adult T-cell leukemia with meningeal infiltration.”
Tsutsumi Y, Shimono J, Miyashita N, Teshima T
Leuk Lymphoma (letter), 55, 2, 457, 459, INFORMA HEALTHCARE, 2014年02月, ［査読有り］
英語, [症例報告]

[Control of graft-versus-host disease].
Sugita J, Teshima T
[Rinsho ketsueki] The Japanese journal of clinical hematology, 55, 2, 170, 176, 2, 2014年02月, ［査読有り］
日本語

[Posterior reversible encephalopathy syndrome following paralytic ileus caused by vincristine in a patient with T cell lymphoblastic lymphoma].
Eiko Hayase, Junichi Sugita, Katsuya Fujimoto, Ko Ebata, Tomohiro Yamakawa, Miho Yoshida, Ryo Takemura, Junko Iwasaki, Shojiro Takahashi, Souichi Shiratori, Takeshi Kondo, Junji Tanaka, Takanori Teshima
[Rinsho ketsueki] The Japanese journal of clinical hematology, 55, 2, 249, 53, 2014年02月, ［国内誌］
日本語, 研究論文（学術雑誌）, A 22-year-old woman presented with high fever, chest tightness and cough in January 20XX. Since CT scans revealed an anterior mediastinal mass, percutaneous needle biopsies of the mass were performed and she was diagnosed with T-cell lymphoblastic lymphoma (T-LBL). After the immunophenotype of lymphocytes in her pleural effusion had been identified, she received CHOP therapy because her dyspnea worsened, and induction therapy for acute lymphoblastic leukemia was subsequently performed after confirmation of her diagnosis as T-LBL. During this induction therapy, she developed paralytic ileus. One week thereafter, she suddenly exhibited visual disturbance, headache and nausea. Her cerebrospinal fluid was normal. Magnetic resonance imaging showed symmetrical high signal intensities on T2-weighted and fluid-attenuated inversion recovery images, and low signal intensities on T1-weighted images in the cortical and subcortical white matter of the posterior parietal and occipital lobes. Based on these findings, she was diagnosed as having posterior reversible encephalopathy syndrome (PRES). During chemotherapy for hematologic malignancies, some patients with PRES reportedly develop paralytic ileus or tumor lysis syndrome. PRES should be considered in patients with neurological abnormalities following such complications during chemotherapy.

Graft-versus-host disease制御
杉田純一, 豊嶋崇徳
臨床血液, 55, 2, 170, 176, 2014年02月

Impact of Conditioning Intensity with or without Total Body Irradiation on Acute Graft-Versus-Host Disease and Clinical Outcomes
Hideki Nakasone, Takahiro Fukuda, Junya Kanda, Takehiko Mori, Takanori Teshima, Shingo Yano, Naoyuki Uchida, Kazuhiko Kakihana, Tetsuya Eto, Shin-Ichiro Mori, Tokiko Nagamura, Tatsuo Ichinohe, Yoshiko Atsuta, Makoto Murata
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 20, 2, S275, S276, ELSEVIER SCIENCE INC, 2014年02月
英語, 研究論文（学術雑誌）

Epstein-Barr Virus-Associated Smooth Muscle Tumors After Bone Marrow Transplantation
Eiko Hayase, Katsuya Fujimoto, Tomoko Mitsuhashi, Yutaka Hatanaka, Miho Yoshida, Ryo Takemura, Junko Iwasaki, Souichi Shiratori, Junichi Sugita, Takeshi Kondo, Junji Tanaka, Masahiro Imamura, Yoshihiro Matsuno, Takanori Teshima
TRANSPLANTATION, 97, 1, E1, +, LIPPINCOTT WILLIAMS & WILKINS, 2014年01月, ［査読有り］
英語

Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning
M. Koyama, D. Hashimoto, K. Nagafuji, T. Eto, Y. Ohno, K. Aoyama, H. Iwasaki, T. Miyamoto, G. R. Hill, K. Akashi, T. Teshima
BONE MARROW TRANSPLANTATION, 49, 1, 110, 115, NATURE PUBLISHING GROUP, 2014年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Graft rejection remains a major obstacle in allogeneic hematopoietic SCT following reduced-intensity conditioning (RIC-SCT), particularly after cord blood transplantation (CBT). In a murine MHC-mismatched model of RIC-SCT, primary graft rejection was associated with activation and expansion of donor-reactive host T cells in peripheral blood and BM early after SCT. Donor-derived dendritic cells are at least partly involved in host T-cell activation. We then evaluated if such an expansion of host T cells could be associated with graft rejection after RIC-CBT. Expansion of residual host lymphocytes was observed in 4/7 patients with graft rejection at 3 weeks after CBT, but in none of the 17 patients who achieved engraftment. These results suggest the crucial role of residual host T cells after RIC-SCT in graft rejection and expansion of host T cells could be a marker of graft rejection. Development of more efficient T cell-suppressive conditioning regimens may be necessary in the context of RIC-SCT.

Effect of combination therapy of tigecycline and colistin against a case of catheter-related bloodstream infection by multidrug-resistant Acinetobacter baumannii　　　　　　　　　　　　　　　
Takehiro Yamada, Souichi Shiratori, Junichi Sugita, Katsuya Fujimoto, Takanori Teshima, Tatsuya Fukumoto, Sumio Iwasaki, Koji Akizawa, Katsuya Narumi, Nobuhisa Ishiguro, Ken Iseki
Japanese Journal of Chemotherapy, 62, 4, 501, 505, Japan Society of Chemotherapy, 2014年
日本語, 研究論文（学術雑誌）, A 34-year-old man who had undergone bone marrow transplantation 10 years previously due to chronic leukemia was being administered an immunosuppressant on an outpatient basis. He was admitted to hospital due to pneumonia and levofloxacin was administered intravenously. His symptoms improved temporarily, but severe fever and elevation of CRP occurred. Multidrug-resistant Acinetobacter baumannii(MDRAB) was detected from his catheter tip, so a diagnosis of catheter-related bloodstream infection of MDRAB was made. Tigecycline treatment concomitant with colistin was started. MDRAB was not detected in a blood culture the day after initiation of therapy, and body temperature decreased to the normal level. The CRP level became normal 10 days after the initiation of tigecycline and colistin treatment. Colistin is known for its severe renal toxicity: however, we monitored its trough blood level, enabling us to use it safely during therapy. Since MDRAB infection often results in sepsis, combination treatment of tigecycline and colistin may be more effective for this condition.

消化管GVHD（graft-versus-host disease）に対する経口ベクロメタゾン製剤の有用性の検討
久保田 康生, 鳴海 克哉, 笠師 久美子, 山田 武宏, 岡田 耕平, 重松 明男, 豊嶋 崇徳, 井関 健
医療薬学, 40, 5, 291, 296, 一般社団法人日本医療薬学会, 2014年
日本語, Graft-versus-host diseases (GVHD) are the main complications after stem cell transplantations. The use of systemic steroids remains the standard for first-line treatment of such complications despite the severe adverse side effects such as the risk of opportunistic infections, glucose intolerance, and bone demineralization. Many of the adverse side effects associated with systemic steroids can be avoided through the use of beclomethasone dipropionate (BDP) as BDP is promptly metabolized in the liver after absorption from the intestines. The BDP is an activated form of steroid that exerts a strong anti-inflammatory action and may be expected to have an effect on gastrointestinal GVHD (GI-GVHD).
This retrospective study verified such an effect for 29 cases diagnosed with alimentary GI-GVHD from June 2008 to July 2013 in order to clarify an effective case. The BDP was administered to 21 patients with acute GVHD and 8 patients with chronic GVHD. The GI-GVHD improved in 20 patients and the condition worsened with 9 patients. The BDP was also effective with acute and chronic GI-GVHD. With lighter conditions of the disease at the time of the BDP internal administration, it was more effective. In 15 cases where systemic steroids were administered there were no new infections. It may be concluded that BDP is an effective medication for GI-GVHD when administered at an early stage.

The Use of Oral Beclomethasone Dipropionate in the Treatment of Gastrointestinal Graft-versus-host Disease: The Experience of the Fukuoka Blood and Marrow Transplantation (BMT) Group
Shuichiro Takashima, Tetsuya Eto, Motoaki Shiratsuchi, Michihiro Hidaka, Yasuo Mori, Koji Kato, Kenjiro Kamezaki, Seido Oku, Hideho Henzan, Ken Takase, Takamitsu Matsushima, Katsuto Takenaka, Hiromi Iwasaki, Toshihiro Miyamoto, Koichi Akashi, Takanori Teshima
INTERNAL MEDICINE, 53, 12, 1315, 1320, JAPAN SOC INTERNAL MEDICINE, 2014年, ［査読有り］
英語, 研究論文（学術雑誌）, Objective We examined the therapeutic strategies for treating mild gastrointestinal (GI) graft-versus-host disease (GVHD) using oral beclomethasone dipropionate (BDP) in 15 Japanese patients based on the donor source. The primary objective was to determine the efficacy and toxicity of oral BDP combined with/without low-dose prednisone (PSL).
Methods Oral BDP was administered with 1 mg/kg/d of PSL in patients undergoing bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT; n=11), and the dose of PSL was tapered off after 22 days. Oral BDP alone was administered in patients undergoing cord blood stem cell transplantation (CBSCT; n=4). The primary endpoint was the rate of treatment success on day 49, as measured according to the improvement or complete resolution of GI symptoms without additional treatment. The secondary endpoints included treatment-related toxicity according to the National Cancer Institute Common Toxicity Criteria version 3.0, the rate of treatment discontinuation due to toxicity, the rate of relapse of acute GVHD by day 100 and the incidence of bacterial, fungal or viral infection, including cytomegalovirus (CMV) antigenemia.
Results Treatment success was achieved in seven of the 11 (64%) patients undergoing BMT or PBSCT and in all four patients (100%) undergoing CBSCT. Subsequent adverse events included herpes zoster infection, catheter-associated sepsis and CMV enteritis; all affected patients responded well to treatment.
Conclusion The use of a risk-stratified treatment strategy with oral BDP depending on the stem cell source is effective in patients with mild GI-GVHD.

Successful Treatment of Invasive Zygomycosis Based on a Prompt Diagnosis Using Molecular Methods in a Patient with Acute Myelogenous Leukemia
Junichiro Yuda, Koji Kato, Yoshikane Kikushige, Kiyofumi Ohkusu, Makiko Kiyosuke, Keiji Sakamoto, Seido Oku, Noriko Miyake, Masako Kadowaki, Tadafumi Iino, Kazuki Tanimoto, Katsuto Takenaka, Hiromi Iwasaki, Toshihiro Miyamoto, Nobuyuki Shimono, Takanori Teshima, Koichi Akashi
INTERNAL MEDICINE, 53, 10, 1087, 1091, JAPAN SOC INTERNAL MEDICINE, 2014年, ［査読有り］
英語, 研究論文（学術雑誌）, Zygomycosis is a lethal and invasive mold infection that is often associated with hematological malignancies. The keys for successful treatment include making a rapid diagnosis and appropriately administering antifungal agents. We herein report the early diagnosis of a case of zygomycosis in a patient with acute myeloid leukemia using a deoxyribonucleic acid sequence analysis. We successfully performed allogeneic hematopoietic stem cell transplantation with the use of high-dose liposomal amphotericin B and granulocyte transfusion.

Hepatitis B virus reactivation with rituximab-containing regimen
Yutaka Tsutsumi, Yoshiya Yamamoto, Joji Shimono, Hiroyuki Ohhigashi, Takanori Teshima
World Journal of Hepatology, 5, 11, 612, 620, 2013年11月
英語, Rituximab is recognized as a useful drug for the treatment of B-cell non-Hodgkin's lymphoma and its use has been extended to such diseases as idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, chronic rheumatoid arthritis and ANCA-associated vasculitides. One serious complication associated with its use is the reactivation of hepatitis B virus and the search for methods to prevent this occurrence has resulted in the rapid accumulation of knowledge. In this review, we discuss case analyses from our department and other groups and outline the current knowledge on the topic and the remaining issues. © 2013 Baishideng Publishing Group Co., Limited.

Reduced-intensity conditioning followed by cord blood transplantation in a patient with refractory folliculotropic mycosis fungoides
Takashi Nakaike, Koji Kato, Seido Oku, Masayasu Hayashi, Yoshikane Kikushige, Mika Kuroiwa, Katsuto Takenaka, Hiromi Iwasaki, Toshihiro Miyamoto, Takanori Teshima, Koichi Ohshima, Koichi Akashi
International Journal of Hematology, 98, 4, 491, 495, 2013年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Advanced-stage mycosis fungoides (MF) has a generally poor prognosis. Allogeneic hematopoietic stem cell transplantation improves the outcome of advanced-stage MF. Recently, cord blood has been used as an alternative stem cell source
however, there are few reports of MF patients treated using cord blood transplantation. Here, we report a rare case of refractory folliculotropic MF, which was treated with reduced-intensity conditioning followed by cord blood transplantation. © 2013 The Japanese Society of Hematology.

Clinical outcomes of allogeneic stem cell transplantation for relapsed or refractory follicular lymphoma: A retrospective analysis by the Fukuoka Blood and Marrow Transplantation Group
Yoshikiyo Ito, Toshihiro Miyamoto, Tomohiko Kamimura, Ken Takase, Hideho Henzan, Yasuo Sugio, Koji Kato, Yuju Ohno, Tetsuya Eto, Takanori Teshima, Koichi Akashi
International Journal of Hematology, 98, 4, 463, 471, 2013年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic stem cell transplantation (allo-SCT) is considered the only curative treatment for relapsed or refractory follicular lymphoma (FL), but it has a high treatment-related mortality rate. Only a few reports, however, have described the efficacy of allo-SCT for FL in the Japanese population. We retrospectively analyzed the outcome of allo-SCT in 30 patients with FL. Seventeen (56.7 %) patients were chemorefractory, whereas 13 (43.3 %) were chemosensitive. An estimated 2-year overall survival rate (OS) and relapse rate of all patients was 46.7 and 20.0 %, respectively. There were no significant differences in the estimated 2-year OS rate between patients who received myeloablative conditioning and those who received reduced-intensity conditioning (P = 0.98), and among the recipients of related bone marrow (BM)/peripheral blood stem cell, unrelated BM and umbilical cord blood (P = 0.20). In patients who were either chemosensitive or chemorefractory at allo-SCT, the 2-year OS rate was 69.2 and 29.4 % (P = 0.06). Patients with mild-to-moderate acute GVHD had better 2-year PFS rate compared with patients who had severe acute GVHD (P = 0.01), but not better PFS compared with patients who had no acute GVHD (P = 0.12). Our results suggest that the graft-versus-lymphoma effects of allo-SCT may provide survival benefits even in patients with chemorefractory FL. © 2013 The Japanese Society of Hematology.

Reciprocal Expression of Enteric Antimicrobial Proteins in Intestinal Graft-Versus-Host Disease
Yoshihiro Eriguchi, Hidetaka Uryu, Kiminori Nakamura, Sonoko Shimoji, Shuichiro Takashima, Hiromi Iwasaki, Toshihiro Miyamoto, Nobuyuki Shimono, Daigo Hashimoto, Koichi Akashi, Tokiyoshi Ayabe, Takanori Teshima
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 19, 10, 1525, 1529, ELSEVIER SCIENCE INC, 2013年10月, ［査読有り］
英語, 研究論文（学術雑誌）, We recently demonstrated that expression of alpha-defensins, the major antimicrobial peptides produced by Paneth cells, was severely suppressed in mice with graft-versus-host disease (GVHD). In this study, we found that antibacterial lectin, regenerating islet-derived III gamma (RegIII gamma) was upregulated in villous enterocytes, thus demonstrating the reciprocal control of enteric antimicrobial proteins in GVHD. Upregulation of RegIII gamma was mediated by a mechanism independent upon radiation-induced intestinal tract damage. MyD88-mediated signaling in intestinal epithelium was required for RegIII gamma upregulation in GVHD and antibiotic therapy downregulated RegIII gamma expression. These results suggest that MyD88-mediated sensing of the intestinal microbes disregulated in GVHD induces RegIII gamma upregulation in GVHD and argue a role for RegIII gamma in the pathogenesis of GVHD. (C) 2013 American Society for Blood and Marrow Transplantation.

抗癌剤治療をしている患者さんへのインフルエンザワクチン接種について教えて下さい　　　　　　　　　　　　　　　
藤本勝也, 豊嶋崇徳
インフルエンザ, 14, 3, 32, 2013年10月

基礎・臨床医学融合の最前線としての造血幹細胞移植　　　　　　　　　　　　　　　
豊嶋 崇徳
細胞, 45, 11, 2, 4, 2013年10月

血球トラフィッキングとGVHD　　　　　　　　　　　　　　　
橋本大吾, 豊嶋崇徳
血液フロンティア, 23, 10, 59, 70, 2013年10月

Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration
Kazutoshi Aoyama, Asim Saha, Jakub Tolar, Megan J. Riddle, Rachelle G. Veenstra, Patricia A. Taylor, Rune Blomhoff, Angela Panoskaltsis-Mortari, Christopher A. Klebanoff, Gerard Socie, David H. Munn, William J. Murphy, Jonathan S. Serody, LeShara M. Fulton, Takanori Teshima, Roshantha A. Chandraratna, Ethan Dmitrovsky, Yanxia Guo, Randolph J. Noelle, Bruce R. Blazar
BLOOD, 122, 12, 2125, 2134, AMER SOC HEMATOLOGY, 2013年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen-presenting cells and differentiate into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A-metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RAR alpha (dnRAR alpha) showed markedly diminished lethality. The dnRAR alpha transgenic T cells showed reduced Th1 differentiation and alpha 4 beta 7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4(+) T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties.

Combination of high-dose melphalan and bortezomib as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma
Toshihiro Miyamoto, Goichi Yoshimoto, Tomohiko Kamimura, Tsuyoshi Muta, Shuichiro Takashima, Yoshikiyo Ito, Motoaki Shiratsuchi, Ilseung Choi, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Yasushi Takamatsu, Takanori Teshima, Koichi Akashi
International Journal of Hematology, 98, 3, 337, 345, 2013年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Bortezomib and melphalan have synergistic effects against multiple myeloma (MM) cells. We conducted a pilot study on the combination of bortezomib and high-dose melphalan (Bor-HDM) as a conditioning regimen followed by autologous stem cell transplant (ASCT) in 17 Japanese patients with newly diagnosed MM, in comparison with a historical control of patients who received high-dose melphalan (HDM) only followed by ASCT. Nine patients received a single dose of bortezomib 1.3 mg/m2 on day -1 in combination with melphalan 100 mg/m2 on days -3 and -2 (Bor1-HDM), and eight received two doses of bortezomib 1.3 mg/m2 on days -4 and -1 (Bor2-HDM) in combination with HDM. Engraftment of autologous peripheral blood stem cells and regimen-related toxicities (RRT) were comparable among the HDM and Bor-HDM groups. Probability of upgrading from a less than very good partial response (VGPR) to VGPR after ASCT was approximately two times higher in the Bor-HDM group than in the HDM group. However, we observed no significant differences in engraftment, RRT, and response rates between the Bor1-HDM and Bor2-HDM groups. The present study showed that concurrent administration of at least two doses of bortezomib in combination with HDM can be safe in Japanese patients. Additional large prospective randomized trials are required to address the optimal dosages and schedules of bortezomib administration, as well as the efficacy of the Bor-HDM conditioning regimen for ASCT. © 2013 The Japanese Society of Hematology.

Evaluating the association between histological manifestations of cord colitis syndrome with GVHD
S. Shimoji, K. Kato, Y. Eriguchi, K. Takenaka, H. Iwasaki, T. Miyamoto, Y. Oda, K. Akashi, T. Teshima
BONE MARROW TRANSPLANTATION, 48, 9, 1249, 1252, NATURE PUBLISHING GROUP, 2013年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Cord colitis syndrome (CCS) is a recently proposed clinical entity characterized by a persistent diarrheal illness after cord blood transplantation (CBT), which is not caused by GVHD or CMV colitis. CCS is histologically characterized by chronic active colitis with granulomatous inflammation and Paneth cell metaplasia suggesting chronicity. However, the specificity of these pathological features to CCS remains to be validated. We conducted a retrospective study of 49 patients who had diarrhea and underwent diagnostic colonoscopy with biopsy following allogeneic hematopoietic SCT. None of the patients met the clinical criteria for CCS. Chronic active colitis with granulomatous inflammation and Paneth cell metaplasia was present in 12/33 (36%) patients with biopsy-proven GVHD, 4/6 (67%) patients with CMV colitis and 2/15 (13%) patients with nonspecific colitis. In patients with GVHD and/or CMV colitis, these pathological features were present in 4/8 (50%) patients after CBT and in 11/26 (42%) patients undergoing BMT or PBSCT. These results demonstrate that chronic active colitis with granuloma and Paneth cell metaplasia is not only a specific feature of CCS but also is present in GVHD and CMV colitis, irrespective of stem cell source.

Efficacy and Safety of Aprepitant in Allogeneic Hematopoietic Stem Cell Transplantation
Mayako Uchida, Koji Kato, Hiroaki Ikesue, Kimiko Ichinose, Hiromi Hiraiwa, Asako Sakurai, Tsuyoshi Muta, Katsuto Takenaka, Hiromi Iwasaki, Toshihiro Miyamoto, Takanori Teshima, Motoaki Shiratsuchi, Kimitaka Suetsugu, Kenichiro Nagata, Nobuaki Egashira, Koichi Akashi, Ryozo Oishi
PHARMACOTHERAPY, 33, 9, 893, 901, WILEY-BLACKWELL, 2013年09月, ［査読有り］
英語, 研究論文（学術雑誌）, STUDY OBJECTIVE To evaluate the efficacy and safety of aprepitant added to standard antiemetic regimens used in high-dose chemotherapy for allogeneic hematopoietic stem cell transplantation (allo-HSCT).
DESIGN Retrospective medical record review.
SETTING Hematology ward of a university hospital in Japan.
PATIENTS Of 88 patients treated with high-dose chemotherapy followed by allo-HSCT, 46 received aprepitant and granisetron as antiemetic therapy (between April 1, 2010, and December 31, 2011), and 42 received granisetron alone (between April 1, 2008, and March 31, 2010).
INTERVENTIONS Patients in both groups received 3 mg of granisetron intravenously 30 minutes before the administration of anticancer drugs. In the aprepitant group, 125 mg of aprepitant was administered orally 60-90 minutes before the administration of the first moderately to highly emetogenic anticancer drug. On the following days, 80 mg of aprepitant was administered orally every morning. The mean administration duration of aprepitant was 3.3 days (range 3-6 days).
MEASUREMENTS AND MAIN RESULTS The primary objective was to evaluate the percentage of patients who achieved complete response (CR; no vomiting and none to mild nausea). The CR rate in the aprepitant group was significantly higher than that in the control group (48% vs 24%, p=0.02). Multivariate analysis showed that nonprophylactic use of aprepitant was associated with failure to achieve CR (odds ratio [OR] 2.92; 95% confidence interval [CI] 1.13-7.99, p=0.03). The frequency of abdominal pain was lower in the aprepitant group (9% vs 25%, p=0.03). Rates of other frequently observed adverse drug events were similar between groups. There was no significant difference in neutrophil engraftment (median 18 vs 17 days), platelet engraftment (median 32 vs 32 days), the incidence of acute graft-versus-host-disease (63% vs 55%, p=0.52), viral infection (74% vs 67%, p=0.49), or 1-year overall survival (63% vs 62%, p=0.90) between the two groups.
CONCLUSIONS The addition of aprepitant to granisetron increases the antiemetic effect without influencing transplantation-related toxicities in allo-HSCT.

Unrelated allogeneic bone marrow-derived mesenchymal stem cells for steroid-refractory acute graft-versus-host disease: a phase I/II study.
Kazuo Muroi, Koichi Miyamura, Kazuteru Ohashi, Makoto Murata, Tetsuya Eto, Naoki Kobayashi, Shuichi Taniguchi, Masahiro Imamura, Kiyoshi Ando, Shunichi Kato, Takehiko Mori, Takanori Teshima, Masaki Mori, Keiya Ozawa
International journal of hematology, 98, 2, 206, 13, 2013年08月, ［査読有り］, ［国内誌］
英語, We conducted a multicenter phase I/II study using mesenchymal stem cells (MSCs) manufactured from the bone marrow of healthy unrelated volunteers to treat steroid-refractory acute graft-versus-host disease (aGVHD). Fourteen patients with hematological malignancies who suffered from grade II (9 patients) or III aGVHD (5) were treated. Affected organs were gut (10 patients), skin (9 patients), and liver (3 patients). Seven patients had two involved organs. The median age was 52. No other second-line agents were given. MSCs were given at a dose of 2 × 10(6) cells/kg for each infusion twice a week for 4 weeks. If needed, patients were continuously given MSCs weekly for an additional 4 weeks. By week 4, 13 of 14 patients (92.9 %) had responded to MSC therapy with a complete response (CR; n = 8) or partial response (PR; n = 5). At 24 weeks, 11 patients (10 with CR and 1 with PR) were alive. At 96 weeks, 8 patients were alive in CR. A total of 6 patients died, attributable to the following: underlying disease relapse (2 patients), breast cancer relapse (1), veno-occlusive disease (1), ischemic cholangiopathy (1), and pneumonia (1). No clear adverse effects associated with MSC infusion were observed. Third party-derived bone marrow MSCs may be safe and effective for patients with steroid-refractory aGVHD.

Autologous peripheral blood stem cell transplantation with granulocyte colony-stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission
Tetsuya Eto, Ken Takase, Toshihiro Miyamoto, Yuju Ohno, Tomohiko Kamimura, Koji Nagafuji, Yasushi Takamatsu, Takanori Teshima, Hisashi Gondo, Shuichi Taniguchi, Koichi Akashi, Mine Harada
INTERNATIONAL JOURNAL OF HEMATOLOGY, 98, 2, 186, 196, SPRINGER JAPAN KK, 2013年08月, ［査読有り］
英語, 研究論文（学術雑誌）, We retrospectively analyzed the outcomes of 81 patients with non-M3 acute myelogenous leukemia (AML) in first complete remission (CR1) who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (Auto-PBSCT) by the Fukuoka Blood and Marrow Transplantation Group between 1989 and 2005. Cytogenetically, 16 patients were defined as good risk, 56 as intermediate risk, and nine as poor risk, following the Southwest Oncology Group criteria. The pre-transplant conditioning regimen consisted of high-dose busulfan, etoposide, and cytarabine (BEA regimen), combined with priming by granulocyte colony-stimulating factor (G-CSF). Disease-free survival (DFS) and overall survival at 5 years were 64.0 % (95 % CI 52.5-73.4) and 66.4 % (95 % CI 54.9-75.6) after Auto-PBSCT at a median follow-up time of 103 months (range 3-240 months), respectively. Two patients died of transplant-related pulmonary complications 6 months after Auto-PBSCT without relapse. The 5-year DFS rates of patients in the genetically good-, intermediate-, and poor-risk groups were 80.8, 64.3, and 33.3 %, respectively, but there was no significant difference statistically among the risk groups (log-rank p = 0.0579). These observations suggest that HDCT supported by Auto-PBSCT with the BEA regimen combined with G-CSF priming is a therapeutic option for postremission therapy of AML in CR1.

A novel filtration method for cord blood processing using a polyester fabric filter
T. Shima, N. Forraz, N. Sato, T. Yamauchi, H. Iwasaki, K. Takenaka, K. Akashi, C. McGuckin, T. Teshima
INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, 35, 4, 436, 446, WILEY-BLACKWELL, 2013年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Introduction: Cord blood (CB) is being increasingly used as a source of hematopoietic stem cells for transplantation to treat diseases of the blood and immune systems, and there is an urgent need to expand CB banking worldwide. CB processing requires costly machinery or a clean room that hampers wider application of CBT particularly in the developing countries.
Methods: We developed a novel filtration system using a nonchemical- coated and nonwoven polyester fabric filter, which traps cells through affinity and does not require centrifugation or potentially toxic chemicals.
Results: Cell processing with the device resulted in minimum cell loss of total cells and CD34(+) cells, without impairing the ability of CD34(+) cells to engraft and differentiate both in vivo and in vitro.
Conclusion: CB processing with this device is simple, cost-effective, and nontoxic without requiring costly equipment will thus facilitate international CB banking, which helps in meeting the increasing worldwide demand for CB for allogeneic hematopoietic stem cell transplantation.

BMT Tandem meetingに参加して　　　　　　　　　　　　　　　
豊嶋 崇徳
血液フロンティア, 23, 6, 822, 824, 2013年06月
日本語, 研究論文（学術雑誌）

HIV感染者における梅毒血清反応と抗カルジオリピン抗体に関する検討
遠藤知之, 藤本勝也, 吉田美穂, 竹村龍, 杉田純一, 重松明男, 近藤健, 橋野聡, 田中淳司, 佐藤典宏, 豊嶋崇徳
日本エイズ学会誌, 15, 2, 113, 118, (一社)日本エイズ学会, 2013年05月, ［査読有り］
日本語, 血清学的に梅毒と診断されたHIV感染者19例(全例男性、平均年齢41歳)を対象に、梅毒治療後の梅毒血性反応(RPR)の推移と抗カルジオリピン抗体(aCL)の有無、HIV-RNA量との関連について後方視的に検討した。その際、RPRが1.0R.U.以上、TPLAが1.0C.O.I以上の場合を血性梅毒反応陽性とし、治療開始後6ヵ月でRPR値が4分の1以下にならなかった場合を血清学的効果不十分とした。1)感染経路は同性間性行為が16例、異性間性行為が3例、AIDS発症者が4例、未発症者が15例であった。2)梅毒治療後は全症例で消失し、RPRの血清学的効果が不十分の症例は19例中10例であった。3)梅毒治療後に血清学的効果が得られた群と不十分であった群を比較したところ、梅毒の効果判定時のHIV-RNAが測定感度以上で測定されていた症例で、梅毒の血清学的効果が不十分と評価された症例と比べ有意に多かった。4)血清学的効果不十分の群では10例中6例がaCL陽性で有意差が認められた。更に梅毒治療前にaCLが陽性であった3例は治療後もRPRが持続陽性であったが、aCLが陰性であった2例は梅毒治療後にRPRが速やかに陰性化していた。5)HIV-RNA量とaCLの関連についてはHIV-RNA量が40コピー未満に十分抑制されていた症例が11例、40コピー以上が8例であった。また、HIV-RNAが測定感度以下でaCLが陰性であった10例中8例はRPRが速やかに陰性化していたが、一方、HIV-RNAの抑制が不十分でaCLが陽性であった5例は全例RPRが持続的に高値となっていた。6)梅毒治療前後のRPRの変化とaCLおよびHIV-RNA量について検討したところ、aCL陽性の群およびHIV-RNAが40copies/mL以上の群で有意にRPR低下率が低くなっていた。

Effectiveness and Safety of Antiemetic Aprepitant in Japanese Patients Receiving High-Dose Chemotherapy Prior to Autologous Hematopoietic Stem Cell Transplantation
Mayako Uchida, Hiroaki Ikesue, Toshihiro Miyamoto, Koji Kato, Kimitaka Suetsugu, Kimiko Ichinose, Hiromi Hiraiwa, Asako Sakurai, Katsuto Takenaka, Tsuyoshi Muta, Hiromi Iwasaki, Takanori Teshima, Motoaki Shiratsuchi, Nobuaki Egashira, Koichi Akashi, Ryozo Oishia
BIOLOGICAL & PHARMACEUTICAL BULLETIN, 36, 5, 819, 824, PHARMACEUTICAL SOC JAPAN, 2013年05月, ［査読有り］
英語, 研究論文（学術雑誌）, For patients receiving high-dose chemotherapy, a 5-hydroxytryptamine 3 receptor antagonist combined with dexamethasone is a standard antiemetic therapy. Despite this prophylactic anti-emetic treatment, many patients still suffer from uncontrollable emesis. In this study, we retrospectively evaluated the antiemetic effectiveness and safety of aprepitant (a neurokinin-1 receptor antagonist) in addition to 5-HT3 antagonist in Japanese patients with hematologic malignancy receiving high-dose chemotherapy prior to autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-six patients received aprepitant and granisetron (the aprepitant group), whereas, 22 patients received granisetron alone (the control group). All patients received 3 mg of granisetron intravenously 30 mm before chemotherapy administration. Patients in the aprepitant group additionally received 125 mg of aprepitant 60-90 min before administration of the first moderately to highly emetogenic chemotherapy. On the next day or thereafter, 80 mg of aprepitant was administered in the morning until the last administration of moderately to highly emetogenic anticancer drugs. The percentage of patients who achieved complete response (CR), defined as no emesis with only grade 1-2 nausea, in the aprepitant group was significantly higher than that in the control group (42% vs. 5%, p=0.003). Logistic regression analysis showed that non-prophylactic use of aprepitant was significantly associated with non-CR. The frequencies of adverse drug events (ADEs) were not significantly different between two groups. In conclusion, the results of this study suggest that the addition of aprepitant to granisetron can improve the antiemetic effect without increasing ADEs in patients receiving high-dose chemotherapy prior to auto-PBSCT.

Protective Roles of Epithelial Cells in the Survival of Adult T-Cell Leukemia/Lymphoma Cells
Yukiko Miyatake, Andre L. A. Oliveira, Mohamed Ali Jarboui, Shuichi Ota, Utano Tomaru, Takanori Teshima, William W. Hall, Masanori Kasahara
AMERICAN JOURNAL OF PATHOLOGY, 182, 5, 1832, 1842, ELSEVIER SCIENCE INC, 2013年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Adult T-cell leukemia/lymphoma (ATL) is a highly invasive and intractable T-cell malignancy caused by human T-cell leukemia virus-1 infection. We demonstrate herein that normal tissue-derived epithelial cells (NECs) exert protective effects on the survival of leukemic cells, which may partially account for high resistance to antileukemic therapies in patients with ATL. Viral gene-silenced, ATL-derived cell Lines (ATL cells) dramatically escaped from histone deacetylase inhibitor-induced apoptosis by direct co-culture with NECs. Adhesions to NECs suppressed p21(Cip1) expression and increased a proportion of resting G0/G1 phase cells in trichostatin A (TSA)-treated ATL cells. ATL cells adhering to NECs down-regulated CD25 expression and enhanced vimentin expression, suggesting that most ATL cells acquired a quiescent state by cell-cell interactions with NECs. ATL cells adhering to NECs displayed highly elevated expression of the cancer stem cell marker CD44. Blockade of CD44 signaling diminished the NEC-conferred resistance of ATL cells to TSA-induced apoptosis. Co-culture with NECs also suppressed the expression of NKG2D Ligands on TSA-treated ATL cells, resulting in decreased natural killer cell-mediated cytotoxicity. Combined evidence suggests that interactions with normal epithelial cells augment the resistance of ATL cells to TSA-induced apoptosis and facilitate immune evasion by ATL cells.

～なぜ、今GVHDなのか～　　　　　　　　　　　　　　　
豊嶋 崇徳
血液フロンティア, 23, 5, 17, 19, 2013年05月
日本語, 研究論文（学術雑誌）

Decrease in Venous Irritation by Adjusting the Concentration of Injected Bendamustine
Hiroyuki Watanabe, Hiroaki Ikesue, Tomoko Tsujikawa, Kenichiro Nagata, Mayako Uchida, Kimitaka Suetsugu, Nobuaki Egashira, Tsuyoshi Muta, Koji Kato, Katsuto Takenaka, Saiji Ohga, Takamitsu Matsushima, Motoaki Shiratsuchi, Toshihiro Miyamoto, Takanori Teshima, Koichi Akashi, Ryozo Oishi
BIOLOGICAL & PHARMACEUTICAL BULLETIN, 36, 4, 574, 578, PHARMACEUTICAL SOC JAPAN, 2013年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Intravenous injection of bendamustine often causes venous irritation and also deteriorates the patient's quality of life. Thus, we evaluated the risk factors associated with venous irritation induced by bendamustine in patients with follicular lymphoma or mantle cell lymphoma. We also evaluated the effectiveness of intervention of changing the preparation procedure for bendamustine. All data were retrospectively collected from the electronic medical record system. In the initial analysis of the total 43 courses of bendamustine therapy, most patients (88%) were administered bendamustine with 250 mL of diluent according to the bendamustine package insert in Japan. The median concentration of bendamustine solution (0.56 mg/mL vs. 0.24 mg/mL) and the incidences of venous irritation (66% vs. 0%, p=0.01) were significantly different between the patients receiving bendamustine at 250 mL and 500 mL of diluent. Based on this result, we proposed changing the final volume of bendamustine dissolution from 250 to 500 mL, which is recommended in other countries. After this intervention, the incidence of venous irritation was significantly reduced from 58 to 20% (p=0.02). The incidence of venous irritation increased in a concentration-dependent manner (<= 0.40 mg/mL: 6%; 0.41-0.60 mg/mL: 62%, p<0.001; >0.60 mg/mL: 75%, p<0.001). We conclude that a high concentration bendamustine solution is a risk factor for venous irritation and that 500 mL of diluent is ideal. To further reduce the incidence of venous irritation, the concentration of bendamustine solution is recommended to be 0.40 mg/mL or less.

骨髄抑制時のエマージェンシー　　　　　　　　　　　　　　　
白鳥聡一, 豊嶋崇徳
成人病と生活習慣病, 43, 4, 533, 538, 2013年04月
日本語, 研究論文（学術雑誌）

Diffuse panbronchiolitis after humanized anti-CCR4 monoclonal antibody therapy for relapsed adult T-cell leukemia/lymphoma
Koji Kato, Toshihiro Miyamoto, Akihiko Numata, Takashi Nakaike, Hideyo Oka, Ayano Yurino, Takuro Kuriyama, Yasuo Mori, Satoshi Yamasaki, Tsuyoshi Muta, Katsuto Takenaka, Hiromi Iwasaki, Takanori Teshima, Koichi Akashi
INTERNATIONAL JOURNAL OF HEMATOLOGY, 97, 3, 430, 432, SPRINGER JAPAN KK, 2013年03月, ［査読有り］
英語, 研究論文（学術雑誌）, We present the case of a 62-year-old Japanese woman with relapsed adult T-cell leukemia/lymphoma (ATLL) who was treated with humanized anti-CCR4 monoclonal antibody (KW-0761). Although this antibody was highly effective against refractory ATLL, 6 months after the final KW-0761 infusion, the patient complained of hypoxia due to diffuse panbronchiolitis. Physicians should remain vigilant to the possibility of such previously unreported late-onset adverse effects associated with KW-0761 therapy.

Diagnosis and evaluation of intestinal graft-versus-host disease after allogeneic hematopoietic stem cell transplantation following reduced-intensity and myeloablative conditioning regimens
Satoshi Yamasaki, Akiko Miyagi-Maeshima, Yasuo Kakugawa, Yoshihiro Matsuno, Fusako Ohara-Waki, Shigeo Fuji, Yuriko Morita-Hoshi, Masakazu Mori, Sung-Won Kim, Shin-ichiro Mori, Takahiro Fukuda, Ryuji Tanosaki, Tadakazu Shimoda, Kensei Tobinai, Daizo Saito, Yoichi Takaue, Takanori Teshima, Yuji Heike
INTERNATIONAL JOURNAL OF HEMATOLOGY, 97, 3, 421, 426, SPRINGER JAPAN KK, 2013年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Colonoscopic evaluation of mucosal tissues after allogeneic hematopoietic stem cell transplantation (HSCT) is very useful in evaluating pathogenesis and diagnosis of intestinal graft-versus-host disease (GVHD). However, information on the timing and sites of biopsies and the immunohistological evaluation of mucosal tissues for diagnosing intestinal GVHD, especially following reduced-intensity (RIC) regimens, remains very limited. A total of 33 patients with histologically proven GVHD after allogeneic HSCT with RIC (n = 23) and myeloablative conditioning (MAC, n = 10) regimens were enrolled in the present study. Colonoscopy was performed due to gastrointestinal symptoms, especially diarrhea and anorexia. Sites of biopsies with the worst histopathological grading were the terminal ileum in 67 % of patients. In the RIC group, the onset of diarrhea prior to colonoscopy examination was later (median: RIC, 57 vs. MAC, 27 days) and the number of patients who developed abdominal pain tended to be higher (RIC, 70 % vs. MAC, 30 %). A lower number of CD4+ cells and a higher ratio of Foxp3+ cells to CD4+ cells were detected in the involved lesions of intestinal GVHD following RIC. These differences in the RIC and MAC groups suggest that regimen-specific therapeutic strategies are required for diagnosing intestinal GVHD.

急性および慢性GVHDの診断とマネジメント　　　　　　　　　　　　　　　
豊嶋 崇徳
血液内科, 66, 3, 392, 398, 2013年03月
日本語, 研究論文（学術雑誌）

造血幹細胞移植の話題 ASH発表演題より
豊嶋 崇徳, 高見 昭良, 谷口 修一, 村田 誠
Therapeutic Research, 34, 3, 259, 266, ライフサイエンス出版(株), 2013年03月, ［査読有り］
日本語

Antiemetic effectiveness and safety of aprepitant in patients with hematologic malignancy receiving multiday chemotherapy
Mayako Uchida, Hiroaki Ikesue, Koji Kato, Kimiko Ichinose, Hiromi Hiraiwa, Asako Sakurai, Katsuto Takenaka, Hiromi Iwasaki, Toshihiro Miyamoto, Takanori Teshima, Nobuaki Egashira, Koichi Akashi, Ryozo Oishi
American Journal of Health-System Pharmacy, 70, 4, 343, 349, 2013年02月15日, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose. Antiemetic effectiveness and safety of aprepitant in patients with hematologic malignancy receiving multiday chemotherapy were evaluated. Methods. All data were retrospectively collected from the Kyushu University Hospital's electronic medical record system. Patients age 20 years or older with hematologic malignancies who received multiday chemotherapy were included in the study. All patients received 3 mg of granisetron i.v. 30 minutes before chemotherapy administration. Patients in the aprepitant group received 125 mg of aprepitant orally 60-90 minutes before administration of the first moderately to highly emetogenic chemotherapy (day 1). On day 2 or thereafter, an 80-mg oral dose of aprepitant was administered in the morning for up to five days. The primary endpoint was the percentage of patients who achieved complete response (CR). Results. A total of 42 patients were treated with aprepitant and granisetron as antiemetic prophylaxis between April and December 2010 (aprepitant group), and 40 patients were treated with only granisetron between March 1, 2009, and March 31, 2010, before the introduction of aprepitant. The percentage of patients who achieved CR in the aprepitant group was significantly higher than that in the control group (p = 0.01). Factors that were significantly associated with non-CR included the prophylactic use of aprepitant and chemotherapies containing ≥4 g/m2/day of cytarabine. The rates of adverse drug events (ADEs) did not significantly differ between groups. Conclusion. The addition of aprepitant to granisetron increased the antiemetic effect without influencing ADEs in patients treated with moderately to highly emetogenic multiday chemotherapy for hematologic malignancies. Copyright © 2013, American Society of Health-System Pharmacists, Inc.

GVHD予防の最前線
杉田純一, 豊嶋崇徳
臨床血液, 54, 2, 156, 166, The Japanese Society of Hematology, 2013年02月
日本語, 研究論文（学術雑誌）

Successful engraftment in hla-mismatched bone marrow transplantation despite the persistence of high-level donor-specific anti-HLA-DR antibody
Souichi Shiratori, Makoto Ito, Maki Yoneoka, Koji Hayasaka, Eiko Hayase, Junko Iwasaki, Junichi Sugita, Akio Shigematsu, Katsuya Fujimoto, Takeshi Kondo, Chikara Shimizu, Takanori Teshima
Transplantation, 96, 5, e34, e35, 2013年, ［査読有り］
英語

多発性骨髄腫患者の末梢血幹細胞採取に対するbortezomibを含む導入療法の影響
牟田毅, 宮本敏浩, 藤崎智明, 大野裕樹, 上村智彦, 平安山知子, 加藤光次, 竹中克斗, 岩崎浩巳, 衛藤徹也, 高松泰, 豊嶋崇徳, 赤司浩一
臨床血液, 54, 1, 109, 116, (一社)日本血液学会-東京事務局, 2013年01月, ［査読有り］
日本語, 多発性骨髄腫に対しbortezomibを含む導入療法が末梢血幹細胞採取へ与える影響を検討した。VAD療法(control群78例)と,bortezomibを含む治療(bortezomib群32例)につき,後方視的に比較した。幹細胞動員のため,control群の83%,bortezomib群の63%でcyclophosphamide(CY)が投与,control群の12%でetoposideが投与された。G-SCF単独投与による採取を受けた症例は,bortezomib群で多かった(5%対38%,P<10-5)。採取された総CD34陽性細胞数はcontrol群で多い結果であった(中央値7.4×106/kg対5.2×106/kg,P=0.004)。しかし,CY投与後の採取例に限ると,CD34陽性細胞数2.0×106/kg以上を達成した割合は両群とも高率であった(control群94%対bortezomib群100%,P=0.3)。従って,bortezomibを含む導入療法はVAD療法と比較して,CY投与にて動員できた症例においては,移植に最低必要なCD34陽性細胞数2.0×106/kg以上を確保することに対して,大きく影響しないことが示された。(著者抄録)

Quantitation of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic hematopoietic stem cell transplantation
Takahiro Shima, Toshihiro Miyamoto, Yoshikane Kikushige, Yasuo Mori, Kenjiro Kamezaki, Ken Takase, Hideho Henzan, Akihiko Numata, Yoshikiyo Ito, Katsuto Takenaka, Hiromi Iwasaki, Tomohiko Kamimura, Tetsuya Eto, Koji Nagafuji, Takanori Teshima, Koji Kato, Koichi Akashi
BLOOD, 121, 5, 840, 848, AMER SOC HEMATOLOGY, 2013年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Transient marrow expansion of normal B-cell precursors, termed hematogones, is occasionally observed after hematopoietic stem cell transplantation (HSCT). To understand the clinical significance of this phenomenon, we enumerated hematogones in 108 consecutive patients who received allogeneic HSCT for the treatment of hematologic malignancies, including acute myelogenous leukemia, advanced myelodysplastic syndromes, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Hematogone quantitation was performed at the time of complete donor engraftment (median day 25 and 32 in patients who received bone marrow and cord blood cell transplants, respectively). Hematogones were polyclonal B cells, and their frequencies correlated positively with blood B-cell numbers, and inversely with donors' but not recipients' age, suggesting that hematogones reflect cell-intrinsic B-cell potential of donor cells. Interestingly, patients developing hematogones that comprised > 5% of bone marrow mononuclear cells constituted a group with significantly prolonged overall survival and relapse-free survival, irrespective of their primary disease or donor cell source. In addition, patients with > 5% hematogones developed severe acute graft-versus-host diseases less frequently, which may contribute toward their improved survival. We therefore conclude that the amount of hematogones at the time of engraftment may be a useful tool in predicting the prognosis of patients treated with allogeneic HSCT. (Blood. 2013; 121(5): 840-848)

Evaluation of the Feasibility and Efficacy of Autologous Stem Cell Transplantation in Elderly Patients with Multiple Myeloma
Tsuyoshi Muta, Toshihiro Miyamoto, Tomoaki Fujisaki, Yuju Ohno, Tomohiko Kamimura, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Tetsuya Eto, Yasushi Takamatsu, Takanori Teshima, Koichi Akashi
INTERNAL MEDICINE, 52, 1, 63, 70, JAPAN SOC INTERNAL MEDICINE, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, Objective The feasibility and efficacy of high-dose melphalan (HD-MEL) followed by autologous hematopoietic stem cell transplantation (auto-SCT) in elderly patients with multiple myeloma (MM) are discussed.
Methods We retrospectively analyzed and compared the results of 25 elderly patients (aged 65-76 years, elderly group) and 63 control patients (aged 51-64 years, control group). Many patients received a vincristine and doxorubicin combined with dexamethasone (VAD) regimen (elderly group: 92%, control group: 78%) with autologous peripheral blood stem cells being harvested after the administration of chemotherapy with high-dose cyclophosphamide (elderly group: 72%, control group: 87%). Ten elderly patients received MEL at a dose of 100-120 mg/m(2), while 15 patients received MEL at a dose of 180-200 mg/m(2).
Results Treatment-related deaths occurred in one elderly patient and two younger patients due to infections. The rate of achieving complete response (CR) or very good partial response (VGPR) was 60% in the elderly group and 83% in the control group. Progression-free survival from auto-SCT in the elderly group was similar to that observed in the control group (median 17.1 vs. 20.8 months, p=0.26), with the median overall survival (OS) from auto-SCT being 40.8 months in the former and 72.5 months in the latter group (p=0.07). When calculated from the beginning of induction treatment, the median OS of the elderly group was 47.0 months and the 3-year OS rate was 81%.
Conclusion The current study provides evidence for the efficacy of auto-SCT in elderly MM patients. A prospective study of auto-SCT in elderly patients using strict eligibility criteria is required to evaluate the prolongation of survival in the era of novel agents.

安全な血液製剤の供給のために　　　　　　　　　　　　　　　
豊嶋 崇徳
血液製剤headline, 9, 3, 2013年
日本語, 研究論文（学術雑誌）

個別化医療―臨床試験におけるバイオーマーカーと標準療法の導入　　　　　　　　　　　　　　　
豊嶋 崇徳
Trends in Hematological Malignancies, 5, 2, 50, 53, 2013年
日本語, 研究論文（学術雑誌）

左副腎原発メトトレキサート関連悪性リンパ腫の一例
亀田啓, 中垣整, 永井聡, 近藤琢磨, 三橋智子, 松野吉宏, 安部崇重, 篠原信雄, 野々村克也, 白鳥聡一, 豊嶋崇徳, 三好秀明, 清水力, 清水力, 渥美達也
日本内分泌学会雑誌, 88, 3, 1034, 2012年12月20日
日本語

Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis
Takuro Kuriyama, Katsuto Takenaka, Kentaro Kohno, Takuji Yamauchi, Shinya Daitoku, Goichi Yoshimoto, Yoshikane Kikushige, Junji Kishimoto, Yasunobu Abe, Naoki Harada, Toshihiro Miyamoto, Hiromi Iwasaki, Takanori Teshima, Koichi Akashi
BLOOD, 120, 19, 4058, 4067, AMER SOC HEMATOLOGY, 2012年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein alpha (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development. (Blood. 2012;120(19):4058-4067)

Low incidence of adenovirus hemorrhagic cystitis following autologous hematopoietic stem cell transplantation in the rituximab era
Yasuo Mori, Toshihiro Miyamoto, Kenjiro Kamezaki, Koji Kato, Yoshikane Kikushige, Shuichiro Takashima, Shingo Urata, Shinji Shimoda, Nobuyuki Shimono, Katsuto Takenaka, Hiromi Iwasaki, Koji Nagafuji, Takanori Teshima, Koichi Akashi
AMERICAN JOURNAL OF HEMATOLOGY, 87, 8, 828, 830, WILEY-BLACKWELL, 2012年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Viral hemorrhagic cystitis (HC) is a frequent complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) but is rare after autologous peripheral blood stem cell transplantation (auto-PBSCT) because immunosuppression is not required in the absence of an allogeneic immune reaction. Recently, auto-PBSCT has been combined with novel anticancer agents targeting specific molecules, such as rituximab; however, these may cause severe immune deficiency and increase the susceptibility of transplant recipients to opportunistic infections. To address this issue, we performed a retrospective analysis of the incidence of viral HC in auto-PBSCT recipients. Of 158 recipients, only 4 cases (2.5%) were diagnosed with viral HC due to adenovirus (ADV), which was significantly less frequent compared with the incidence in allo-HSCT recipients (15.8%). The incidence of HC did not increase with rituximab treatment. This was a single-center retrospective analysis with a small sample size; however, incorporation of rituximab into the treatment of auto-PBSCT recipients did not appear to be a risk factor for developing viral HC.

Validation of pretransplantation assessment of mortality risk score in the outcome of hematopoietic SCT in non-Caucasians
Y. Mori, T. Teshima, K. Kamezaki, K. Kato, K. Takenaka, H. Iwasaki, T. Miyamoto, K. Nagafuji, T. Eto, K. Akashi
BONE MARROW TRANSPLANTATION, 47, 8, 1075, 1081, NATURE PUBLISHING GROUP, 2012年08月, ［査読有り］
英語, 研究論文（学術雑誌）, The Pretransplantation Assessment of Mortality (PAM) score is a risk score for mortality after allogeneic hematopoietic SCT (HSCT). Ethnicity is a genetically determined factor that correlated with immune-mediated outcomes of allogeneic HSCT. We evaluated the predictive value of the PAM score for transplant outcome in 276 Japanese populations in which transplant-related complications occur less frequently than Caucasians. The PAM score effectively risk-stratified these patients for survival; overall survival (OS) at 2 years was 100%, 80.2%, 49.4%, and 13.9% in the categories 1, 2, 3, and 4, respectively, showing a clear distinction of OS by categories (P<0.001). In addition, the PAM score is useful for the prediction of transplant outcomes both in patients with standard-risk underlying diseases and those with high-risk diseases. The PAM score developed in Caucasian populations is thus useful in non-Caucasian populations.

Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of -defensins.
Eriguchi Y, Takashima S, Oka H, Shimoji S, Nakamura K, Uryu H, Shimoda S, Iwasaki H, Shimono N, Ayabe T, Akashi K, Teshima T
Blood, 120, 1, 223, 231, AMER SOC HEMATOLOGY, 2012年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for various hematologic disorders. Graft-versus-host disease (GVHD) and infections are the major complications of SCT, and their close relationship has been suggested. In this study, we evaluated a link between 2 complications in mouse models. The intestinal microbial communities are actively regulated by Paneth cells through their secretion of antimicrobial peptides, alpha-defensins. We discovered that Paneth cells are targeted by GVHD, resulting in marked reduction in the expression of alpha-defensins, which selectively kill noncommensals, while preserving commensals. Molecular profiling of intestinal microbial communities showed loss of physiologic diversity among the microflora and the overwhelming expansion of otherwise rare bacteria Escherichia coli, which caused septicemia. These changes occurred only in mice with GVHD, independently on conditioning-induced intestinal injury, and there was a significant correlation between alteration in the intestinal microbiota and GVHD severity. Oral administration of polymyxin B inhibited outgrowth of E coli and ameliorated GVHD. These results reveal the novel mechanism responsible for shift in the gut flora from commensals toward the widespread prevalence of pathogens and the previously unrecognized association between GVHD and infection after allogeneic SCT. (Blood. 2012;120(1):223-231)

Initial low-dose valganciclovir as a preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients
Katsuto Takenaka, Koji Nagafuji, Ken Takase, Tomohiko Kamimura, Yasuo Mori, Yoshikiyo Ito, Yukiko Nishi, Hideho Henzan, Koji Kato, Naoki Harada, Tetsuya Eto, Toshihiro Miyamoto, Takanori Teshima, Koichi Akashi
INTERNATIONAL JOURNAL OF HEMATOLOGY, 96, 1, 94, 100, SPRINGER TOKYO, 2012年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Preemptive therapy for cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplant (HSCT) patients is effective in decreasing the incidence of CMV disease. Intravenous ganciclovir is a commonly used preemptive therapy, but as we have recently shown, oral valganciclovir (VGC) is a useful alternative. However, the optimal dose of VGC has not been determined. We prospectively evaluated the efficacy and toxicity of an initial low-dose of VGC (900 mg QD) as preemptive therapy in 20 patients with low-level CMV antigenemia following allogeneic HSCT. Patients were screened weekly for CMV pp65 antigenemia after engraftment. Preemptive therapy with VGC (900 mg QD) was initiated if more than two CMV antigen-positive cells per 50,000 leukocytes were detected. CMV antigen-positive cells disappeared from all 20 patients after 14-29 days (median 20 days) of VGC treatment. None of the patients developed CMV disease nor did they require more than the conventional VGC dose (900 mg BID). Neutropenia (< 500/mu L) developed in three patients who required granulocyte-colony-stimulating factor support, but there were no other significant side effects. These observations suggest that the initial dose of VGC in preemptive therapy for CMV can be safely decreased to 900 mg QD for patients with low-level CMV antigenemia.

GVHD-associated immunodeficiency: soil or seed?
Takanori Teshima
Blood, 119, 24, 5618, 5619, American Society of Hematology, 2012年06月14日, ［査読有り］
研究論文（学術雑誌）

Successful treatment by donor lymphocyte infusion of adult T-cell leukemia/lymphoma relapse following allogeneic hematopoietic stem cell transplantation
Tomohiko Kamimura, Toshihiro Miyamoto, Noriaki Kawano, Akihiko Numata, Yoshikiyo Ito, Yong Chong, Koji Nagafuji, Takanori Teshima, Shin Hayashi, Koichi Akashi
INTERNATIONAL JOURNAL OF HEMATOLOGY, 95, 6, 725, 730, SPRINGER TOKYO, 2012年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive hematologic neoplasm that has an extremely poor prognosis; however, this has improved following recent progress in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several clinical studies have shown that discontinuation of immunosuppressant therapy induces durable remission in a significant number of post-transplant relapsed patients, suggesting that ATLL may be susceptible to a graft-versus-leukemia effect. Here, we report two cases with ATLL who received donor lymphocyte infusions (DLIs) for relapse after allo-HSCT; one patient achieved complete remission (CR) after a single DLI, and the other suffered repeated relapses and was treated with chemotherapy and radiotherapy combined with a total of five rounds of DLIs. Both patients presented with exacerbation of the graft-versus-host disease after the DLIs, and remained in CR for 9 and 8 years, respectively. These data support the use of DLIs as an effective therapy to induce durable CR in the treatment of relapsed ATLL. In this study, we review previous reports and discuss the role of DLIs in the treatment of post-transplant relapsed ATLL.

同種抗原による移植片対白血病効果減弱のメカニズム
朝倉 昇司, 橋本 大吾, 高嶋 秀一郎, 杉山 暖子, 前田 嘉信, 赤司 浩一, 谷本 光音, 豊嶋 崇徳
岡山医学会雑誌, 124, 1, 5, 8, 岡山医学会, 2012年04月
日本語

Different Risk Factors Related to Adenovirus- or BK Virus-Associated Hemorrhagic Cystitis following Allogeneic Stem Cell Transplantation
Yasuo Mori, Toshihiro Miyamoto, Koji Kato, Kenjiro Kamezaki, Takuro Kuriyama, Seido Oku, Katsuto Takenaka, Hiromi Iwasaki, Naoki Harada, Motoaki Shiratsuchi, Yasunobu Abe, Koji Nagafuji, Takanori Teshima, Koichi Akashi
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 18, 3, 458, 465, ELSEVIER SCIENCE INC, 2012年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Virus-associated hemorrhagic cystitis (HC) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Although numerous studies have attempted to identify factors that predispose patients to viral HC, its causes remain controversial. We analyzed retrospectively the results of 266 allogeneic HSCTs to identify factors associated with HC. Of this group, 42 patients (15.8%) were diagnosed with viral HC, because of either adenovirus (ADV; n = 26; 9.8%) or BK virus (BKV; n = 16; 6.0%). ADV-HC was frequently associated with T cell purging, and was less common in patients with acute graft-versus-host-disease (GVHD). Conversely, BKV-HC was more frequently observed in patients with excessive immune reactions such as GVHD, preengraftment immune reaction, and hemophagocytic syndrome. These observations indicate that ADV- and BKV-HC may differ significantly in their risk factors and pathogenesis. Profound immune deficiency is more likely to be associated with ADV-HC, whereas immune hyperactivity might play a key role in BKV-HC. Biol Blood Marrow Transplant 18: 458-465 (2012) (C) 2012 American Society for Blood and Marrow Transplantation

Plasma biomarkers of lower gastrointestinal and liver acute GVHD
Andrew C. Harris, James L. M. Ferrara, Thomas M. Braun, Ernst Holler, Takanori Teshima, John E. Levine, Sung W. Choi, Karin Landfried, Koichi Akashi, Mark Vander Lugt, Daniel R. Couriel, Pavan Reddy, Sophie Paczesny
BLOOD, 119, 12, 2960, 2963, AMER SOC HEMATOLOGY, 2012年03月, ［査読有り］
英語, 研究論文（学術雑誌）, The lower gastrointestinal tract (LGI) and liver are the GVHD target organs most associated with treatment failure and nonrelapse mortality. We recently identified regenerating islet-derived 3-alpha (REG3 alpha) as a plasma biomarker of LGI GVHD. We compared REG3 alpha with 2 previously reported GI and liver GVHD diagnostic biomarkers, hepatocyte growth factor (HGF) and cytokeratin fragment 18, in 954 hematopoietic cell transplantation patients. All 3 biomarkers were significantly elevated in LGI GVHD compared with non-GVHD diarrhea; REG3 alpha discerned LGI GVHD from non-GVHD diarrhea better than HGF and cytokeratin fragment 18. Although all 3 biomarkers predicted nonresponse to therapy at day 28 in LGI GVHD patients, only REG3 alpha and HGF concentrations predicted 1-year nonrelapse mortality (P = .01 and P = .02, respectively). Liver GVHD without GI involvement at GVHD onset and non-GVHD liver complications were uncommon; all 3 biomarkers were elevated in liver GVHD, but did not distinguish GVHD from other causes of hyperbilirubinemia. (Blood. 2012;119(12):2960-2963)

特発性血小板減少性紫斑病におけるセファランチン大量療法の有用性 -後方視的多施設共同研究-
高畑むつみ, 橋野聡, 藤本勝也, 遠藤知之, 小林直樹, 黒澤光俊, 岩崎博, 三宅高義, 幸田久平, 前川勲, 笹川裕, 堤豊, 宮城島拓人, 田中淳司, 今村雅寛, 豊嶋崇徳
臨床血液, 53, 12, 1983, 1990, (一社)日本血液学会-東京事務局, 2012年, ［査読有り］
日本語, アルカロイド製剤であるセファランチンは特発性血小板減少性紫斑病(ITP)に対して大量投与することにより血小板増多が認められる例があることが1990年前後に報告され現在も臨床的に用いられている。今回,我々は北海道内の血液診療科を対象にITPに対するセファランチン大量療法の調査を行い,47症例の臨床効果と有害事象の解析を行った。血小板数5万/μl以上の増加を認めた症例は21例(44%)であり,主治医が有用性ありと判断した症例は36例(77%)で有害事象は認めなかった。また,セファランチン単独投与群と副腎皮質ステロイド(PSL)併用投与群の比較を行ったところ,両群で投与前に比べ有意に血小板数増加を認め,群間の有意差は認めなかった。セファランチン大量療法は安全性が高く,単独でも血小板増多を認める例があり,PSLの治療効果が不十分であったり減量中に増悪が見られる症例にはPSLと併用をするなど,ITP治療を行う上で使用を考慮する価値があると考えられた。(著者抄録)

Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17
Hisakazu Nishimori, Yoshinobu Maeda, Takanori Teshima, Haruko Sugiyama, Koichiro Kobayashi, Yoshiko Yamasuji, Sachiyo Kadohisa, Hidetaka Uryu, Kengo Takeuchi, Takehiro Tanaka, Tadashi Yoshino, Yoichiro Iwakura, Mitsune Tanimoto
BLOOD, 119, 1, 285, 295, AMER SOC HEMATOLOGY, 2012年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-gamma-deficient and IL-17-deficient mice as donors. Infusion of IFN-gamma(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-beta expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD. (Blood. 2012; 119(1): 285-295)

GVHDのメカニズムとその克服に向けた細胞療法の展開　　　　　　　　　　　　　　　
豊嶋 崇徳
医学のあゆみ, 240, 5, 460, 464, 2012年
日本語, 研究論文（学術雑誌）

Wntシグナルを標的とした腸管GVHDの制御
豊嶋 崇徳
血液内科, 64, 2, 197, 201, 科学評論社, 2012年
日本語, 研究論文（学術雑誌）

移植片対宿主病(GVHD)のマネジメント　　　　　　　　　　　　　　　
豊嶋 崇徳
がん看護, 17, 3, 354, 356, 2012年
日本語, 研究論文（学術雑誌）

GVHDの成因と治療　　　　　　　　　　　　　　　
豊嶋 崇徳
日本臨床, 70, 2, 264, 268, 2012年
日本語, 研究論文（学術雑誌）

ミニ移植における移植片対宿主病(GVHD)と移植片対白血病(GVL)効果　　　　　　　　　　　　　　　
重松明男, 豊嶋崇徳
血液フロンティア, 22, 10, 23, 30, 2012年
日本語, 研究論文（学術雑誌）

献血者不足とPatient Blood Management　　　　　　　　　　　　　　　
平安山知子, 豊嶋崇徳
医学のあゆみ, 243, 4, 311, 315, 2012年
日本語, 研究論文（学術雑誌）

Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease
James L. M. Ferrara, Andrew C. Harris, Joel K. Greenson, Thomas M. Braun, Ernst Holler, Takanori Teshima, John E. Levine, Sung W. J. Choi, Elisabeth Huber, Karin Landfried, Koichi Akashi, Mark Vander Lugt, Pavan Reddy, Alice Chin, Qing Zhang, Samir Hanash, Sophie Paczesny
BLOOD, 118, 25, 6702, 6708, AMER SOC HEMATOLOGY, 2011年12月, ［査読有り］
英語, 研究論文（学術雑誌）, There are no plasma biomarkers specific for GVHD of the gastrointestinal (GI) tract, the GVHD target organ most associated with nonrelapse mortality (NRM) following hematopoietic cell transplantation (HCT). Using an unbiased, large-scale, quantitative proteomic discovery approach to identify candidate biomarkers that were increased in plasma from HCT patients with GI GVHD, 74 proteins were increased at least 2-fold; 5 were of GI origin. We validated the lead candidate, REG3 alpha, by ELISA in samples from 1014 HCT patients from 3 transplantation centers. Plasma REG3 alpha concentrations were 3-fold higher in patients at GI GVHD onset than in all other patients and correlated most closely with lower GI GVHD. REG3 alpha concentrations at GVHD onset predicted response to therapy at 4 weeks, 1-year NRM, and 1-year survival (P < .001). In a multivariate analysis, advanced clinical stage, severe histologic damage, and high REG3 alpha concentrations at GVHD diagnosis independently predicted 1-year NRM, which progressively increased with higher numbers of onset risk factors present: 25% for patients with 0 risk factors to 86% with 3 risk factors present (P < .001). REG3 alpha is a plasma biomarker of GI GVHD that can be combined with clinical stage and histologic grade to improve risk stratification of patients. (Blood. 2011;118(25):6702-6708)

Th1 and Th17 join forces for acute GVHD
Takanori Teshima
Blood, 118, 18, 4765, 4767, American Society of Hematology, 2011年11月03日, ［査読有り］
研究論文（学術雑誌）

Blood-cell banking for workers at the Fukushima Daiichi nuclear power plant – Authors' reply
Tetsuya Tanimoto, Koichiro Yuji, Naoyuki Uchida, Miwako Hosoda, Yuko Kodama, Takanori Teshima, Shuichi Taniguchi
The Lancet, 378, 9790, 484, 485, Elsevier BV, 2011年08月
英語

Successful allogeneic stem cell transplantation in two patients with acute myelogenous leukaemia and invasive aspergillosis by antifungal combination therapy
Takatoshi Aoki, Toshihiro Miyamoto, Yasuo Mori, Goichi Yoshimoto, Takuji Yamauchi, Kenjiro Kamezaki, Katsuto Takenaka, Hiromi Iwasaki, Naoki Harada, Koji Nagafuji, Nobuyuki Shimono, Takanori Teshima, Koichi Akashi
MYCOSES, 54, 4, E255, E259, WILEY-BLACKWELL, 2011年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Invasive aspergillosis (IA) is an important cause of infectious morbidity and mortality in patients who undergo haematopoietic stem cell transplantation (HSCT). History of IA before allogeneic HSCT is still challenging because of the high risk of recurrence after HSCT. Recent advances in early-stage diagnosis and new, more effective classes of antifungal agents have improved the management of IA in the HSCT recipients. We report two cases with acute myelogenous leukaemia after primary failure of induction chemotherapy with the patients developing pulmonary IA. They responded well to a combination of voriconazole (VCZ) and micafungin, resulting in a remarkable reduction of pulmonary IA lesions at short intervals. Thereafter, antifungal therapy was switched to liposomal amphotericin B (L-AmB), followed by conditioning regimen for allogeneic HSCT, because of the possibility of VCZ altering the metabolism of chemotherapeutic agents and calcineurin inhibitors. Successful engraftment was achieved without severe adverse side-effects or aggravation of IA after HSCT. Combining VCZ with micafungin followed by L-AmB throughout HSCT could be advantageous in stabilising IA in HSCT patients.

Regulatory T cells and IL-17-producing cells in graft-versus-host disease
Takanori Teshima, Yoshinobu Maeda, Katsutoshi Ozaki
IMMUNOTHERAPY, 3, 7, 833, 852, FUTURE MEDICINE LTD, 2011年07月
英語, 研究論文（学術雑誌）, Graft-versus-host disease (GvHD), a major complication following allogeneic hematopoietic stem cell transplantation, is mediated by donor-derived T cells. On activation with alloantigens expressed on host antigen-presenting cells, naive CD4(+) T cells differentiate into T-helper cell subsets of effector T cells expressing distinct sets of transcriptional factors and cytokines. Classically, acute GvHD was suggested to be predominantly related to Th1 responses. However, we now face a completely different and complex scenario involving possible roles of newly identified Th17 cells as well as Tregs in GvHD. Accumulating data from experimental and clinical studies suggest that the fine balance between Th1, Th2, Th17 and Tregs after transplantation may be an important determinant of the severity, manifestation and tissue distribution of GvHD. Understanding the dynamic process of reciprocal differentiation of regulatory and T-helper cell subsets as well as their interactions will be important in establishing novel strategies for preventing and treating GvHD.

Role of autotransplantation in the treatment of acute promyelocytic leukemia patients in remission: Fukuoka BMT Group observations and a literature review
T. Kamimura, T. Miyamoto, K. Nagafuji, A. Numata, H. Henzan, K. Takase, Y. Ito, Y. Ohno, T. Fujisaki, T. Eto, Y. Takamatsu, T. Teshima, H. Gondo, K. Akashi, S. Taniguchi, M. Harada
BONE MARROW TRANSPLANTATION, 46, 6, 820, 826, NATURE PUBLISHING GROUP, 2011年06月, ［査読有り］
英語, We retrospectively analyzed the outcomes of 26 patients with acute promyelocytic leukemia (APL) in the first CR (CR1) or second CR (CR2), who underwent autologous PBSCT (auto-PBSCT) between 1992 and 2008. All patients received all-trans retinoic acid-based induction therapy. After two courses of consolidation chemotherapy, upfront auto-PBSCT was performed in 20 patients in the CR1. Five patients had a high WBC count of more than 10 x 10(9)/L (high risk), while 15 patients had a count of less than 10 x 10(9)/L (low risk) at initial presentation. In addition, six patients, who were considered as low-risk patients at presentation, had a relapse after three cycles of consolidation and 2 years of maintenance therapy, but gained the molecular remission after re-induction and consolidation, and underwent auto-PBSCT in the CR2. In 26 recipients, engraftment was rapid and no TRM was documented. All 20 patients autotransplanted in CR1 were still in CR at a median of 133 months (73-193 months), and six patients who underwent auto-PBSCT in CR2 were also still in CR at a median of 41 months (2-187 months) without maintenance therapy. PML/RAR alpha chimeric mRNA was undetectable in PBSC or BM samples examined before auto-PBSCT. Despite a small number of cases studied, our retrospective observations suggest that auto-PBSCT may be an effective treatment option to continue durable CR in the treatment of high-risk APL. We review previous reports and discuss the role of autotransplantation in the treatment of APL patients in CR. Bone Marrow Transplantation (2011) 46, 820-826; doi: 10.1038/bmt.2010.207; published online 6 September 2010

Analysis of immune reconstitution after autologous CD34(+) stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4(+) T cells
Hiroshi Tsukamoto, Koji Nagafuji, Takahiko Horiuchi, Hiroki Mitoma, Hiroaki Niiro, Yojiro Arinobu, Yasushi Inoue, Kentaro To, Toshihiro Miyamoto, Hiromi Iwasaki, Takanori Teshima, Mine Harada, Koichi Akashi
RHEUMATOLOGY, 50, 5, 944, 952, OXFORD UNIV PRESS, 2011年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Methods. Eleven patients (three males and eight females) with SSc were enrolled. Blood mononuclear cells were harvested after mobilization treatment with CYC and G-CSF. CD34(+) haematopoietic stem/progenitor cell fractions were purified and cryopreserved. Patients were transplanted with > 2 x 10(6)/kg autologous CD34(+) cells after high-dose CYC (50 mg/kg for 4 days) conditioning. Immune reconstitution was evaluated serially by analysing lymphocyte subpopulations for 36 months.
Results. Progressive improvement of skin sclerosis has been observed for 3 years in most of the patients. The serum level of anti-Scl-70, an auto-antibody specific to SSc, was progressively decreased after ASCT. Improvement of skin sclerosis was significantly associated with the change in the serum anti-Scl-70 level after ASCT at 36 months. Serum levels of KL-6 and surfactant protein D, indicators for interstitial pneumonia activity, were also significantly decreased. The number of CD8(+) T cells immediately recovered within a month after ASCT, while the number of CD4(+) T cells remained low for > 36 months post-transplant. The majority of CD4(+) cells were memory but not naive T cells, and regulatory CD4(+) T cells were not recovered. Th1/Th2 ratio was significantly increased after ASCT.
Conclusions. ASCT with purified CD34(+) cells was effective in controlling the disease activity of SSc. Th1/Th2 ratio was significantly increased for at least 3 years after ASCT.

Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation
Daigo Hashimoto, Andrew Chow, Melanie Greter, Yvonne Saenger, Wing-Hong Kwan, Marylene Leboeuf, Florent Ginhoux, Jordi C. Ochando, Yuya Kunisaki, Nico van Rooijen, Chen Liu, Takanori Teshima, Peter S. Heeger, E. Richard Stanley, Paul S. Frenette, Miriam Merad
JOURNAL OF EXPERIMENTAL MEDICINE, 208, 5, 1069, 1082, ROCKEFELLER UNIV PRESS, 2011年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.

Safety of workers at the Fukushima Daiichi nuclear power plant
Tetsuya Tanimoto, Naoyuki Uchida, Yuko Kodama, Takanori Teshima, Shuichi Taniguchi
LANCET, 377, 9776, 1489, 1490, ELSEVIER SCIENCE INC, 2011年04月, ［査読有り］
英語

The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells
Shuichiro Takashima, Masanori Kadowaki, Kazutoshi Aoyama, Motoko Koyama, Takeshi Oshima, Kazuma Tomizuka, Koichi Akashi, Takanori Teshima
JOURNAL OF EXPERIMENTAL MEDICINE, 208, 2, 285, 294, ROCKEFELLER UNIV PRESS, 2011年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.

血小板輸血後に不規則抗体が検出された２症例
吉居真由, 山口恭子, 池松陽子, 江頭貞臣, 豊嶋崇徳, 赤司浩一
日本輸血細胞治療学会誌, 57, 6, 465, 469, 2011年, ［査読有り］
[症例報告]

造血幹細胞移植の新たな感染対策
江里口芳裕, 前原依子, 下野信行, 宮本敏浩, 赤司浩一, 豊嶋崇徳
無菌生物, 41, 1, 45, 47, 日本無菌生物ノートバイオロジー学会, 2011年, ［査読有り］
日本語

Diagnostic Value of Serum Procalcitonin and C-reactive Protein for Infections after Allogeneic Hematopoietic Stem Cell Transplantation versus Nontransplant Setting
Yasuo Mori, Kohta Miyawaki, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Naoki Harada, Toshihiro Miyamoto, Koichi Akashi, Takanori Teshima
INTERNAL MEDICINE, 50, 19, 2149, 2155, JAPAN SOC INTERNAL MEDICINE, 2011年, ［査読有り］
英語, 研究論文（学術雑誌）, Objective Procalcitonin (PCT) has been increasingly used as a biomarker of infection. The purpose of this study was to evaluate its diagnostic value after hematopoietic stem cell transplantation (HSCT), where noninfectious febrile complications such as graft-versus-host disease frequently develop.
Methods We retrospectively analyzed 144 febrile episodes (infections: 82, and noninfections: 62) in adult patients with hematological disorders, including 57 and 87 episodes in HSCT and non-HSCT patients, respectively.
Results Of 57 febrile episodes in HSCT patients, 46 (86%) and 25 (44%) revealed positivity for C-reactive protein (CRP) and PCT, respectively. Among 87 febrile episodes in non-HSCT patients, 81 (93%) and 22 (25%) events showed positive results of CRP and PCT. Both of these biomarkers were associated with infectious episodes in univariate analysis. Multivariate analysis showed that a high cut-off level (>9.5 mg/dL) of CRP was a better indicator for infections than PCT in HSCT patients, while PCT positivity was more diagnostic for infections than any cutoff CRP level in non-HSCT patients.
Conclusion It may be necessary to interpret the results of these biomarkers with different orders of priority in transplant versus nontransplant patients.

GVHDの制御　　　　　　　　　　　　　　　
豊嶋 崇徳
血液フロンティア, 21, 3, 443, 452, 2011年
日本語, 研究論文（学術雑誌）

移植片対宿主病とToll-like receptors
青山一利, 小山幹子, 豊嶋崇徳
臨床免疫・アレルギー科, 55, 5, 566, 571, 科学評論社, 2011年
日本語, 研究論文（学術雑誌）

造血幹細胞移植とウイルス感染症　　　　　　　　　　　　　　　
豊嶋 崇徳
臨床とウイルス, 39, 1, 51, 61, 2011年
日本語, 研究論文（学術雑誌）

Wnt作動薬R-spondin1は腸幹細胞を保護して全身性移植片対宿主病を軽減する　　　　　　　　　　　　　　　
高嶋秀一郎, 豊嶋崇徳
実験医学, 29, 13, 2139, 2142, 2011年
日本語, 研究論文（学術雑誌）

臓器・細胞移植と輸血の現状　　　　　　　　　　　　　　　
豊嶋 崇徳
血液事業, 33, 4, 439, 440, 2011年
日本語, 研究論文（学術雑誌）

造血幹細胞移植後の感染症 ―免疫力ゼロからの闘い―　　　　　　　　　　　　　　　
豊嶋 崇徳
医薬ジャーナル, 47, 11, 2790, 2794, 2011年
日本語, 研究論文（学術雑誌）

造血細胞移植後の免疫不全とその予防治療　　　　　　　　　　　　　　　
豊嶋 崇徳
日本医師会雑誌, 140, 7, 1418, 2011年
日本語, 研究論文（学術雑誌）

TIM-3 Is a Promising Target to Selectively Kill Acute Myeloid Leukemia Stem Cells
Yoshikane Kikushige, Takahiro Shima, Shin-ichiro Takayanagi, Shingo Urata, Toshihiro Miyamoto, Hiromi Iwasaki, Katsuto Takenaka, Takanori Teshima, Toshiyuki Tanaka, Yoshimasa Inagaki, Koichi Akashi
CELL STEM CELL, 7, 6, 708, 717, CELL PRESS, 2010年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. Here we identified T cell immunoglobulin mucin-3 (TIM-3) as a surface molecule expressed on LSCs in most types of AML except for acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). TIM-3(+) but not TIM-3(-) AML cells reconstituted human AML in immunodeficient mice, suggesting that the TIM-3(+) population contains most, if not all, of functional LSCs. We established an anti-human TIM-3 mouse IgG2a antibody having complement-dependent and antibody-dependent cellular cytotoxic activities. This antibody did not harm reconstitution of normal human HSCs, but blocked engraftment of AML after xenotransplantation. Furthermore, when it is administered into mice grafted with human AML, this treatment dramatically diminished their leukemic burden and eliminated LSCs capable of reconstituting human AML in secondary recipients. These data suggest that TIM-3 is one of the promising targets to eradicate AML LSCs.

High Incidence of Human Herpes Virus 6-Associated Encephalitis/Myelitis following a Second Unrelated Cord Blood Transplantation
Yasuo Mori, Toshihiro Miyamoto, Koji Nagafuji, Kenjiro Kamezaki, Asataro Yamamoto, Noriyuki Saito, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Naoki Harada, Yasunobu Abe, Takanori Teshima, Koichi Akashi
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 16, 11, 1596, 1602, ELSEVIER SCIENCE INC, 2010年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Human herpes virus (HHV)6-associated limbic encephalitis and/or myelitis is one of the life-threatening central nervous system complications following allogeneic hematopoietic stem cell transplantation (HSCT). Recent reports have shown significant correlations of these complications with unrelated cord blood transplantation (UCBT). We retrospectively analyzed 228 allogeneic HSCT recipients in our single institution; 13 patients (5.7%) were diagnosed with HHV6-associated encephalitis/myelitis. This complication was documented in 8 of 51 UCBT recipients (15.7%) and 5 of 177 recipients (2.8%) transplanted with bone marrow or peripheral blood stem cells, indicating a higher incidence of this complication occurring in UCBT recipients (P = .0005). In addition, HHV6-associated encephalitis/myelitis occurred more frequently in recipients who underwent 2 or more HSCTs (7 of 59 recipients [11.9%]), compared to those who received only 1 HSCT (6 of 169 recipients [3.6%], P = .018). Of note, the incidence of this complication increased to 28.6% (6 of 21 recipients), when the analysis was restricted to a second or more UCBT recipients. All 13 patients presented preengraftment immune response prior to the onset of encephalitis. Two patients manifested typical symptoms at the onset of HHV6-associated encephalitis/myelitis, such as memory dysfunction, disorientation, and consciousness disturbance. However, 4 patients presented only with dysesthesia and pruritus, described as typical manifestations of patients with calcineurin-inhibitor-induced pain syndrome (CIPS), and the remaining 7 showed both symptoms, indicating that CIPS-like symptoms might be manifestations of HHV6-associated myelitis. Thus, physicians should be alert to this rare but often fatal complication, particularly for those who receive 2 or more HSCTs using UCB.

Altered Effector CD4(+) T Cell Function in IL-21R(-/-) CD4(+) T Cell-Mediated Graft-Versus-Host Disease
Iekuni Oh, Katsutoshi Ozaki, Akiko Meguro, Keiko Hatanaka, Masanori Kadowaki, Haruko Matsu, Raine Tatara, Kazuya Sato, Yoichiro Iwakura, Susumu Nakae, Katsuko Sudo, Takanori Teshima, Warren J. Leonard, Keiya Ozawa
JOURNAL OF IMMUNOLOGY, 185, 3, 1920, 1926, AMER ASSOC IMMUNOLOGISTS, 2010年08月, ［査読有り］
英語, 研究論文（学術雑誌）, We previously showed that transplantation with IL-21R gene-deficient splenocytes resulted in less severe graft-versus-host disease (GVHD) than was observed with wild type splenocytes. In this study, we sought to find mechanism(s) explaining this observation. Recipients of donor CD4(+) T cells lacking IL-21R exhibited diminished GVHD symptoms, with reduced inflammatory cell infiltration into the liver and intestine, leading to prolonged survival. After transplantation, CD4(+) T cell numbers in the spleen were reduced, and MLR and cytokine production by CD4(+) T cells were impaired. These results suggest that IL-21 might promote GVHD through enhanced production of effector CD4(+) T cells. Moreover, we found that CD25 depletion altered neither the impaired MLR in vitro nor the ameliorated GVHD symptoms in vivo. Thus, the attenuated GVHD might be caused by an impairment of effector T cell differentiation itself, rather than by an increase in regulatory T cells and suppression of effector T cells. The Journal of Immunology, 2010, 185: 1920-1926.

Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice
Shoji Asakura, Daigo Hashimoto, Shuichiro Takashima, Haruko Sugiyama, Yoshinobu Maeda, Koichi Akashi, Mitsune Tanimoto, Takanori Teshima
JOURNAL OF CLINICAL INVESTIGATION, 120, 7, 2370, 2378, AMER SOC CLINICAL INVESTIGATION INC, 2010年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell-targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. The T cells that mediate GVL and GVHD are activated by alloantigen presented on host antigen-presenting cells of hematopoietic origin, and it is not well understood how alloantigen expression on non-hematopoietic cells affects GVL activity. Here we show, in mouse models of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation, that alloantigen expression on host epithelium drives donor T cells into apoptosis and dysfunction during GVHD, resulting in a loss of GVL activity. During GVHD, programmed death-1 (PD-1) and PD ligand-1 (PD-L1), molecules implicated in inducing T cell exhaustion, were upregulated on activated T cells and the target tissue, respectively, suggesting that the T cell defects driven by host epithelial alloantigen expression might be mediated by the PD-1/PD-L1 pathway. Consistent with this, blockade of PD-1/PD-L1 interactions partially restored T cell effector functions and improved GVL. These results elucidate a previously unrecognized significance of alloantigen expression on non-hematopoietic cells in GVL and suggest that separation of GVL from GVHD for more effective HSCT may be possible in human patients.

Cord blood stem cell transplantation in a patient with disseminated mucormycosis and acute myelogenous leukemia
T. Aoki, K. Kamezaki, T. Miyamoto, K. Nagafuji, Y. Mori, T. Yamauchi, K. Takenaka, H. Iwasaki, N. Harada, N. Shimono, T. Teshima, K. Akashi
TRANSPLANT INFECTIOUS DISEASE, 12, 3, 277, 279, WILEY-BLACKWELL, 2010年06月, ［査読有り］
英語, T. Aoki, K. Kamezaki, T. Miyamoto, K. Nagafuji, Y. Mori, T. Yamauchi, K. Takenaka, H. Iwasaki, N. Harada, N. Shimono, T. Teshima, K. Akashi. Cord blood stem cell transplantation in a patient with disseminated mucormycosis and acute myelogenous leukemia.Transpl Infect Dis 2010: 12: 277-279. All rights reserved.

High incidence of false-positive Aspergillus galactomannan test in multiple myeloma
Yasuo Mori, Yoji Nagasaki, Kenjiro Kamezaki, Katsuto Takenaka, Hiromi Iwasaki, Naoki Harada, Toshihiro Miyamoto, Yasunobu Abe, Nobuyuki Shimono, Koichi Akashi, Takanori Teshima
AMERICAN JOURNAL OF HEMATOLOGY, 85, 6, 449, 451, WILEY-BLACKWELL, 2010年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Invasive aspergillosis (IA) remains one of the most significant causes of morbidity and mortality in patients with hematological malignancies undergoing chemotherapy and hematopoietic stem cell transplantation (HSCT), mainly due to the difficulty in its early diagnosis. Monitoring of galactomannan (GM) antigen, an exoantigen of Aspergillus, in the blood by sandwich ELISA is a useful and noninvasive method for early diagnosis of IA. The GM test has a sensitivity of 67-100% with a specificity of 81-99% in neutropenic patients and allogeneic transplant recipients [1-3]. Although it has been widely used as a diagnostic criterion for IA [4,5], one of the major limitations of this assay is false-positivity, particularly in pediatric patients [1], patients with graft-versus-host disease (GVHD) [6,7], and those taking dietary GM [8,9] or fungus-derived antibiotics, such as piperacillin-tazobactam (PIPC/TAZ) [10-12].

Peripheral blood stem cell versus bone marrow transplantation from HLA-identical sibling donors in patients with leukemia: a propensity score-based comparison from the Japan Society for Hematopoietic Stem Cell Transplantation registry
Koji Nagafuji, Keitaro Matsuo, Takanori Teshima, Shin-ichiro Mori, Hisashi Sakamaki, Michihiro Hidaka, Hiroyasu Ogawa, Yoshihisa Kodera, Yoshinobu Kanda, Atsuo Maruta, Takehiko Mori, Fumiaki Yoshiba, Tatsuo Ichinohe, Masanobu Kasai, Yoshifusa Takatsuka, Kohmei Kubo, Hiroshi Sao, Yoshiko Atsuta, Ritsuro Suzuki, Takashi Yoshida, Masahiro Tsuchida, Mine Harada
INTERNATIONAL JOURNAL OF HEMATOLOGY, 91, 5, 855, 864, SPRINGER TOKYO, 2010年06月, ［査読有り］
英語, 研究論文（学術雑誌）, We retrospectively analyzed the results of 707 adult patients who underwent myeloablative peripheral blood stem cell transplantation (PBSCT) (n = 365) and myeloablative bone marrow transplantation (BMT) (n = 342) for leukemia from HLA-identical sibling donors between 2000 and 2005 using the propensity score method. The results were obtained from the Japan Society for Hematopoietic Cell Transplantation registry. Multivariate Cox analysis showed that PBSCT was associated with lower overall survival (OS) in standard-risk patients [adjusted hazard ratio (aHR) = 1.83; 95% confidence interval (CI) 1.04-3.23; P = 0.036], but not in high-risk patients (aHR = 1.11; 95% CI 0.76-1.61; P = 0.599). Hematopoietic recovery was significantly faster after PBSCT. The risk of acquiring grade III-IV acute graft-versus-host disease (GVHD) (aHR = 2.23; P = 0.040) and extensive chronic GVHD (aHR = 1.93; P = 0.001) were significantly higher after PBSCT. PBSCT was associated with higher non-relapse mortality in standard-risk patients (aHR = 2.30; 95% CI 1.08-4.88; P = 0.030), but not in high-risk patients (aHR = 1.29; 95% CI 0.65-2.54; P = 0.468). Relapse after transplantation did not differ between PBSCT and BMT either in standard-risk group or in high-risk group (aHR = 1.17; 95% CI 0.55-2.52; P = 0.684 and aHR = 0.81; 95% CI 0.52-1.28; P = 0.370, respectively). In this retrospective analysis, OS was significantly lower after PBSCT in standard-risk patients, but not in high-risk patients. PBSCT was associated with significant risks of grade III-IV acute GVHD and extensive chronic GVHD.

Long-term outcomes of autologous PBSCT for peripheral T-cell lymphoma: retrospective analysis of the experience of the Fukuoka BMT group
A. Numata, T. Miyamoto, Y. Ohno, T. Kamimura, K. Kamezaki, T. Tanimoto, K. Takase, H. Henzan, K. Kato, K. Takenaka, T. Fukuda, N. Harada, K. Nagafuji, T. Teshima, K. Akashi, M. Harada, T. Eto
BONE MARROW TRANSPLANTATION, 45, 2, 311, 316, NATURE PUBLISHING GROUP, 2010年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Peripheral T-cell lymphoma (PTCL) is generally characterized by poor prognosis after conventional chemotherapy compared with aggressive B-cell lymphoma. To elucidate the role of high-dose chemotherapy (HDCT) with auto-SCT, we retrospectively analyzed the outcomes of 39 patients with PTCL who received HDCT and auto-SCT between 1990 and 2005. Eleven patients were histologically typed as angioimmunoblastic, nine as anaplastic large-cell lymphoma, seven as natural killer/T-cell lymphoma and twelve as PTCL unspecified. Clinical conditions at transplantation were complete response (CR) in 27 patients and non-CR in 12 patients. Thirty-two patients received a pre-transplant conditioning regimen (MCEC) comprising ranimustine, carboplatin, etoposide and CY, and seven did other TBI-based regimens. Rapid engraftment was obtained in all cases, and transplant-related death was not seen. An estimated 5-year OS was 62.1% with a median follow-up of 78 months. The 5-year OS was significantly higher in patients transplanted during complete response than in those during other disease status (71.4% vs 27.3%, P = 0.046). HDCT supported by auto-SCT may therefore be effective as consolidation in CR for PTCL treatment. Bone Marrow Transplantation (2010) 45, 311-316; doi:10.1038/bmt.2009.165; published online 13 July 2009

Pulmonary Nocardiosis Developed in a Hematopoietic Stem Cell Transplant Recipient with Bronchiolitis Obliterans
Ruriko Nishida, Yasuo Mori, Hiromi Iwasaki, Takahito Tokuyama, Kenjiro Kamezaki, Yoji Nagasaki, Hideyo Oka, Kohta Miyawaki, Noriyuki Saito, Katsuto Takenaka, Naoki Harada, Toshihiro Miyamoto, Takanori Teshima, Koichi Akashi
INTERNAL MEDICINE, 49, 14, 1441, 1444, JAPAN SOC INTERNAL MEDICINE, 2010年, ［査読有り］
英語, 研究論文（学術雑誌）, The chronic graft-versus-host disease often requires unceasing immunosuppressive therapy (IST), which increases a risk of infectious complications in hematopoietic stem cell transplantation (HSCT) recipients. We report an adult T-cell leukemia/lymphoma case who developed pulmonary nocardiosis, a rare pulmonary complication, after allogeneic HSCT despite administration of the prophylactic trimethoprim-sulfamethoxazole (TMP/STX). The inhaled corticosteroid in addition to systemic IST had been started for bronchiolitis obliterance 4 months prior to nocardiosis development. The patient was successfully treated with an increased dose of TMP/STX combined with meropenem. Transplantation physicians should keep this rare pulmonary complication in mind during sustained IST.

Successful treatment of refractory advanced nasal NK/T cell lymphoma with unrelated cord blood stem cell transplantation incorporating focal irradiation
Yasuo Mori, Takatoshi Aoki, Katsuto Takenaka, Takuji Yamauchi, Asataro Yamamoto, Kenjiro Kamezaki, Hiromi Iwasaki, Naoki Harada, Toshihiro Miyamoto, Koji Nagafuji, Takanori Teshima, Koichi Akashi
INTERNATIONAL JOURNAL OF HEMATOLOGY, 91, 1, 107, 111, SPRINGER TOKYO, 2010年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Nasal natural killer (NK)/T cell lymphoma is a rare disease with a poor prognosis. We report the case of a 52-year-old woman with progressive advanced nasal NK/T cell lymphoma, with local invasiveness and bone marrow involvement, who was successfully treated with unrelated cord blood transplantation (UCBT). The patient was initially refractory to conventional chemotherapy. She was therefore treated with local irradiation, which induced a partial response. The patient then underwent UCBT using a conditioning regimen consisting of cyclophosphamide and total body irradiation. Acute graft-versus-host disease involving the skin was observed, but it was well controlled without systemic administration of corticosteroids. The patient remained in complete remission for 18 months after UCBT. Although the observation period has been relatively short and longer follow-up is needed, our observations suggest that incorporating focal irradiation to conditioning regimen for local control might be an effective treatment option for advanced nasal NK/T cell lymphoma in the setting of UCBT.

日本輸血・細胞治療学会による「輸血業務に関する総合的アンケート調査」における細胞治療に用いる細胞の採取、処理、保管に関する2008年の現状
池田和真, 長村登紀子, 田野崎隆二, 井関徹, 田中朝志, 豊嶋崇徳, 室井一男, 甲斐俊朗, 加藤俊一, 前川平, 佐川公矯, 高橋孝喜, 大戸斉
日本輸血細胞治療学会誌, 56, 5, 639, 644, The Japan Society of Transfusion Medicine and Cell Therapy, 2010年, ［査読有り］
日本語, 2008年実績に対する「輸血に関する総合的アンケート調査」の細胞治療に関する回答結果を報告する．調査は全国の7,857施設を対象とし，3,208（40.8％）から回答があった．輸血部門に専任の看護師がいる施設は53で，細胞の採取を行っている施設数は，自家末梢血幹細胞；108，同種末梢血幹細胞；75，非血縁骨髄；28，血縁骨髄；26，ドナーリンパ球；24，顆粒球；10であった．自家末梢血幹細胞については，48施設で採取が輸血部門で行われ，70施設が手順書を使用し，54施設が作業工程を記録し，59施設が規定のラベルを添付し，52施設が血液製剤に準じた照合を行い，70施設が自施設でフローサイトメトリー解析を行い，63施設が開放系処理に専用クリーン・ベンチを用いていた．処理後と解凍後の無菌検査を行っていると回答したのは7施設と1施設のみであった．成分採血の血管穿刺は82施設で担当診療科医師，成分採血装置のオペレーターは35施設で検査技師，31施設で臨床工学士，細胞の処理，凍結，保管，払出は大半の施設で検査技師により行われていた．検査技師が大きな役割を果たしていること，工程管理と品質管理には課題があることが明らかになった．

造血細胞移植ガイドライン 同種末梢血幹細胞移植のための健常人ドナーからの末梢血幹細胞動員・採取に関するガイドライン
豊嶋崇徳, 日野雅之, 田中淳司, 田野崎隆二, 長藤宏司, 宮村耕一, 小寺良尚, 日本造血細胞移植学会ガイドライン委員会, 日本輸血, 細胞治療学会アフェレーシス安全委員会
造血細胞移植モノグラフ vol.21，日本造血細胞移植学会, 2010年, ［査読有り］

リンパ腫・骨髄腫などにおける造血細胞移植の現状と展望　　　　　　　　　　　　　　　
豊嶋崇徳, 角南一貴, 前田嘉信, 名和由一郎, 平松靖
血液フロンティア, 20, 2, 234, 244, 2010年
日本語, 研究論文（学術雑誌）

造血細胞移植における母子間免疫寛容効果
青山一利, 松岡賢市, 豊嶋崇徳
血液・腫瘍科, 60, 4, 465, 470, 科学評論社, 2010年
日本語, 研究論文（学術雑誌）

骨髄増殖性腫瘍における血小板アフェレーシス　　　　　　　　　　　　　　　
平安山知子, 岩崎浩巳, 豊嶋崇徳, 赤司浩一
日本アフェレーシス学会雑誌, 29, 3, 287, 289, 2010年
日本語, 研究論文（学術雑誌）

造血幹細胞移植における慢性GVHDの発症機序　　　　　　　　　　　　　　　
門脇賢典, 豊嶋崇徳
臨床免疫・アレルギー科, 53, 3, 337, 342, 2010年
日本語, 研究論文（学術雑誌）

Breast milk and transplantation tolerance
Kazutoshi Aoyama, Ken-Ichi Matsuoka, Takanori Teshima
Chimerism, 1, 1, 19, 20, Taylor and Francis Inc., 2010年
英語, 研究論文（学術雑誌）

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation as Immunotherapy for Pancreatic Cancer
Yasunobu Abe, Tetsuhide Ito, Eishi Baba, Koji Nagafuji, Ken Kawabe, Ilseung Choi, Yoshiyuki Arita, Toshihiro Miyamoto, Takanori Teshima, Shuji Nakano, Mine Harada
PANCREAS, 38, 7, 815, 819, LIPPINCOTT WILLIAMS & WILKINS, 2009年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: Advanced unresectable pancreatic cancer has an extremely poor prognosis despite intensive chemotherapy. As a new therapeutic modality, we investigated nonmyeloablative allogeneic hematopoietic stem cell transplantation from a related donor.
Methods: Five patients with chemotherapy-resistant pancreatic cancer received allogeneic peripheral blood stem cell transplantation after a conditioning regimen consisting of low-dose total body irradiation and fludarabine. The prophylaxis for graft-versus-host disease consisted of mycophenolate mofetil and cyclosporine.
Results: The median age of the 5 patients was 54 years, and the median duration from diagnosis to nonmyeloablative allogeneic hematopoietic stem cell transplantation was 10 months. Three of the 5 patients achieved complete donor chimerism of peripheral T cells, at a median time of day 42. Acute graft-versus-host disease developed in 3 patients: grade 2 in 2 patients and grade 1 in 1. Tumor reduction was observed in 2 patients: 1 patient showed disappearance of the pancreatic tumor, and the other patient showed approximately 20% reduction of the tumor. Marked elevation of tumor necrosis factor alpha was observed as the tumor regressed.
Conclusions: Although advanced pancreatic cancer progresses rapidly, some graft-versus-tumor effects and pivotal role of tumor necrosis factor alpha were suggested. To obtain the durable response, patient selection and new strategies become important.

Second unrelated cord blood transplantation using a reduced-intensity conditioning regimen combined with gemtuzumab ozogamicin in patients with relapsed acute myelogenous leukemia
Takuji Yamauchi, Yasuo Mori, Toshihiro Miyamoto, Kenjiro Kamezaki, Takatoshi Aoki, Asataro Yamamoto, Katsuto Takenaka, Hiromi Iwasaki, Naoki Harada, Koji Nagafuji, Takanori Teshima, Koichi Akashi
INTERNATIONAL JOURNAL OF HEMATOLOGY, 90, 3, 416, 420, SPRINGER TOKYO, 2009年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Gemtuzumab ozogamicin (GO) is an effective molecular-targeted agent for CD33-positive acute myelogenous leukemia (AML) patients who are resistant to conventional chemotherapy. Recent prospective trials have revealed the safety and efficacy of GO as part of conditioning following allogeneic bone marrow or peripheral blood stem cell transplantation (SCT). We report here for the first time three AML cases that relapsed after allogeneic SCT and underwent unrelated cord blood transplantation (UCBT) following reduced-intensity conditioning (RIC) comprising fludarabine, melphalan, and low-dose total body irradiation combined with GO. Primary neutrophil engraftment occurred in all cases, while recovery of platelet count was delayed. Only one case of reversible hepatic sinusoidal obstruction syndrome was documented. Non-relapse mortality at day 100 was not documented. Notably, one patient who responded to GO survived for 6 months after UCBT in remission with excellent performance status, while the remaining cases relapsed early. These data suggest that GO may be safely combined with RIC for UCBT after previous allogeneic SCT.

Rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease
Takanori Teshima, Koji Nagafuji, Hideho Henzan, Koichi Miyamura, Ken Takase, Michihiro Hidaka, Toshihiro Miyamoto, Katsuto Takenaka, Koichi Akashi, Mine Harada
INTERNATIONAL JOURNAL OF HEMATOLOGY, 90, 2, 253, 260, SPRINGER TOKYO, 2009年09月, ［査読有り］
英語, 研究論文（学術雑誌）, We prospectively evaluated the safety and efficacy of the anti-CD20 chimeric monoclonal antibody rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Seven patients were treated with 375 mg/m(2) rituximab weekly for 4 consecutive weeks. Rituximab was well tolerated with no severe toxicity observed during treatment. At 1 year, 3 patients showed a partial response to rituximab therapy, 3 had stable disease, and 1 had progressive disease. Rituximab allowed a reduction in the dose of steroids in 4 patients. Responsive manifestations included mild to moderate skin and oral lesions, and immune hemolytic anemia, and thrombocytopenia. Severe manifestations involving the skin, fascia, and eye did not respond to treatment. These observations suggest that rituximab therapy may be effective for select patients with corticosteroid-refractory chronic GVHD that is not advanced.

Infectious complications in patients receiving autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases
K. Kohno, K. Nagafuji, H. Tsukamoto, T. Horiuchi, K. Takase, K. Aoki, H. Henzan, K. Kamezaki, K. Takenaka, T. Miyamoto, T. Teshima, M. Harada, K. Akashi
TRANSPLANT INFECTIOUS DISEASE, 11, 4, 318, 323, WILEY-BLACKWELL PUBLISHING, INC, 2009年08月, ［査読有り］
英語, 研究論文（学術雑誌）, P>Long-term analysis of infectious complication after high-dose immunosuppressive therapy with CD34-selected autologous hematopoietic stem cell transplantation for patients with severe autoimmune diseases (AD) was performed. Theoretically, CD34 selection can reduce the risk of reinfusion of autoreactive lymphocytes. However, it is also associated with a significant reduction in T cells, natural killer cells, and monocytes, which in turn may compromise immune reconstitution, thereby increasing the risk of infection. Moreover, AD compromises host immunity and causes organ damage resulting in dysfunction of the cutaneous or mucosal barrier. In this study, the incidence rate of infections is reported in 14 patients who underwent high-dose (200 mg/kg) cyclophosphamide therapy followed by reinfusion of CD34-selected autologous peripheral blood stem cells. Bacterial complication occurred in 3 of 14 (21%) patients. Cytomegalovirus reactivation and adenovirus hemorrhagic cystitis were observed in 9 (64%) and 2 (14%) patients, respectively. As for late infectious complications, 7 patients (50%) developed dermatomal varicella zoster virus infection. No infection-related mortality was seen in this case series. Because the risk for infections approaches that seen in allogeneic transplant recipients, infection surveillance, diagnostic workup, and prophylactic strategies similar to those applicable to allogeneic recipients are warranted.

Oral valganciclovir as preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients
Katsuto Takenaka, Tetsuya Eto, Koji Nagafuji, Kenjiro Kamezaki, Yayoi Matsuo, Goichi Yoshimoto, Naoki Harada, Maki Yoshida, Hideho Henzan, Ken Takase, Toshihiro Miyamoto, Koichi Akashi, Mine Harada, Takanori Teshima
INTERNATIONAL JOURNAL OF HEMATOLOGY, 89, 2, 231, 237, SPRINGER TOKYO, 2009年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Between March 2007 and January 2008, the safety and efficacy of oral valganciclovir (VGC) preemptive therapy for cytomegalovirus (CMV) infection was evaluated in ten consecutive patients who received allogeneic hematopoietic stem cell transplantation (HSCT). Patients were screened once or twice per week after engraftment using CMV pp65 antigenemia assay. When more than 2 CMV antigen-positive cells per 50,000 leukocytes were detected, preemptive therapy with oral VGC was initiated at a dose of 900 mg twice daily for 3 weeks. Nine patients (90%) completed the 3-week VGC treatment except for one patient who developed febrile neutropenia. There was no other significant toxicity. CMV antigen-positive cells were rapidly decreased in all nine patients and became undetectable by the end of the VGC treatment. None of the patients developed CMV disease. CMV infection relapsed in four of the ten patients (40%) after the VGC treatment. These observations suggest that preemptive therapy with VGC is effective for preventing CMV disease in allogeneic HSCT patients. Further studies with a large number of patients will be necessary to determine the optimal initial- and maintenance-dose of VGC.

Disseminated tuberculosis following second unrelated cord blood transplantation for acute myelogenous leukemia
T. Shima, G. Yoshimoto, T. Miyamoto, S. Yoshida, K. Kamezaki, K. Takenaka, H. Iwasaki, N. Harada, K. Nagafuji, T. Teshima, N. Shimono, K. Akashi
TRANSPLANT INFECTIOUS DISEASE, 11, 1, 75, 77, WILEY-BLACKWELL PUBLISHING, INC, 2009年02月, ［査読有り］
英語, 研究論文（学術雑誌）, T. Shima, G. Yoshimoto, T. Miyamoto, S. Yoshida, K. Kamezaki, K. Takenaka, H. Iwasaki, N. Harada, K. Nagafuji, T. Teshima, N. Shimono, K. Akashi. Disseminated tuberculosis following second unrelated cord blood transplantation for acute myelogenous leukemia.Transpl Infect Dis 2009: 11: 75-77. All rights reserved
Here we report the case of a 43-year-old Japanese woman with acute myelogenous leukemia who underwent 2 unrelated cord blood transplantations (UCBT), terminating in fatal disseminated tuberculosis (TB). The patient did not achieve remission despite intensive chemotherapy, and subsequently underwent UCBT with a standard conditioning regimen. However, engraftment was not achieved. Fifty days after the first UCBT, the patient underwent a second UCBT with a reduced-intensity conditioning regimen. She developed a pre-engraftment immune reaction, which responded well to prednisolone, and engraftment was documented. However, 50 days after the second UCBT, the patient presented with high fever and developed pneumonia despite antibiotic and antifungal treatments. Thereafter, Mycobacterium tuberculosis was detected in blood cultures and specimens of bronchoalveolar lavage, thus indicating disseminated TB. Despite anti-tuberculous treatment, she died on day 85. TB should always be considered as a possible diagnosis when treating febrile immunocompromised patients.

Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells
Motoko Koyama, Daigo Hashimoto, Kazutoshi Aoyama, Ken-ichi Matsuoka, Kennosuke Karube, Hiroaki Niiro, Mine Harada, Mitsune Tanimoto, Koichi Akashi, Takanori Teshima
BLOOD, 113, 9, 2088, 2095, AMER SOC HEMATOLOGY, 2009年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHC-expressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC-T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigen-presenting cells in an antigen-specific T cell-mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation. (Blood. 2009; 113: 2088-2095)

Improved outcome of allogeneic bone marrow transplantation due to breastfeeding-induced tolerance to maternal antigens
Kazutoshi Aoyama, Motoko Koyama, Ken-ichi Matsuoka, Daigo Hashimoto, Tatsuo Ichinohe, Mine Harada, Koichi Akashi, Mitsune Tanimoto, Takanori Teshima
BLOOD, 113, 8, 1829, 1833, AMER SOC HEMATOLOGY, 2009年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Exposure of offspring to noninherited maternal antigens (NIMAs) during pregnancy may have an impact on transplantations performed later in life. Using a mouse model, we recently showed that bone marrow transplantation (BMT) from NIMA-exposed offspring to the mother led to a reduction of graft-versus-host disease (GVHD). Since offspring can also be exposed to NIMAs by breastfeeding after birth, we tested whether breast milk could mediate the tolerogenic NIMA effect. We found that oral exposure to NIMAs by breastfeeding alone was sufficient to reduce GVHD, and that in utero exposure to NIMAs is required for maximum reduction of GVHD. The tolerogenic milk effects disappeared when donor mice were injected with CD25 monoclonal antibodies during the lactation period, suggesting a CD4(+)CD25(+) regulatory T cell dependent mechanism. Our results suggest a previously unknown impact of breastfeeding on the outcome of transplantation. (Blood. 2009;113:1829-1833)

Encephalomyelitis Mimicking Multiple Sclerosis Associated with Chronic Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation
Yayoi Matsuo, Kenjiro Kamezaki, Shoichiro Takeishi, Katsuto Takenaka, Tetsuya Eto, Atsushi Nonami, Toshihiro Miyamoto, Hiromi Iwasaki, Naoki Harada, Koji Nagafuji, Takanori Teshima, Koichi Akashi
INTERNAL MEDICINE, 48, 16, 1453, 1456, JAPAN SOC INTERNAL MEDICINE, 2009年, ［査読有り］
英語, 研究論文（学術雑誌）, We describe a case of encephalomyelitis mimicking multiple sclerosis associated with chronic graft-versus-host disease (GVHD) occurring after allogeneic bone marrow transplanation (BMT) for myelodysplastic syndrome. Immunosuppressive therapy, consisting of a therapeutic dose of cyclosporine A and a maintenance dose of methylprednisolone, was effective in treating symptoms. Although central nervous system GVHD is very rare and remains controversial, presentation of neurological symptoms after allogeneic BMT warrants consideration of GVHD in the differential diagnosis.

造血細胞移植ガイドライン インフルエンザ
豊嶋崇徳, 下野信行, 井上雅美, 日本造血細胞移植学会ガイドライン委員会
造血細胞移植モノグラフvol. 20，日本造血細胞移植学会．名古屋, 2009年, ［査読有り］

The engraftment of transplanted bone marrow-derived cells into the inner ear
Yorihisa Orita, Hidetsugu Tsujigiwa, Kazunori Nishizaki, Takanori Teshima, Junko Yoshinobu, Saeko Orita, Ayako Takeuchi, Yasushi Takeda, Hitoshi Nagatsuka, Noriyuki Nagai
EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY, 266, 1, 59, 63, SPRINGER, 2009年01月, ［査読有り］
英語, 研究論文（学術雑誌）, To investigate whether bone marrow-derived cells (BMC) would migrate and engraft into the sensory epithelium of the inner ear, BMC of green fluorescence protein (GFP) mice were transplanted into lethally irradiated recipient mice. Then the recipient mice were treated with streptomycin and immunohistochemical staining was performed to evaluate the migration and engraftment of donor BMC into the sensory epithelium of the inner ear. Immunohistochemical staining for GFP was found initially in the vascular epithelium and oral mucosa but not in the sensory epithelium of the inner ear. In the case of mouse, BMC may not migrate and be engrafted into the sensory epithelium of the inner ear.

Allogeneic cell therapy from immunized donors with tumor antigen peptide enhances the antitumor effect after cyclophosphamide-using non-myeloablative allogeneic hematopoietic cell transplantation
Masumitsu Hamaguchi, Masatoshi Eto, Yoriyuki Kamiryo, Ario Takeuchi, Masahiko Harano, Katsunori Tatsugami, Takanori Teshima, Mamoru Harada, Yasunobu Yoshikai, Seiji Naito
CANCER SCIENCE, 100, 1, 138, 143, WILEY-BLACKWELL PUBLISHING, INC, 2009年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Non-myeloablative allogeneic stem cell transplantation is an option for the treatment of hematological malignancies as well as solid tumors. We recently proposed a cyclophosphamide-using non-myeloablative cell therapy in which donor lymphocytes infusion (DLI) was carried out after tolerance induction to donor cells. In this study, we tested the possibility that the cyclophosphamide-using cell therapy could be augmented by pre-immunization of donors before DLI. We initially assessed whether or not the cyclophosphamide-using cell therapy could also show antitumor effect against subcutaneously established colon 26 carcinoma. As a tumor antigen-derived peptide for colon 26, we used AH1, an immunodominant H-2L(d)-binding peptide derived from the envelope protein (gp70) of an endogenous murine leukemia virus. The cyclophosphamide-using cell therapy with the DLI from donors which were pre-immunized with the AH1 peptide was compared with that from non-immunized mice. The cyclophosphamide-using cell therapy significantly suppressed subcutaneously established colon 26 carcinoma, and the tumor-rejected mice acquired the tumor-specific protective immunity. When combined with the DLI from donors that were immunized with AH1, antitumor effect of the cyclophosphamide-using cell therapy was significantly augmented. The DLI from tumor peptide-immunized donors showed no influence on donor chimerism and bodyweight of the treated mice, indicating no increased risk of graft-versus-host disease. Tumor-specific cytotoxic T lymphocytes could be generated from tumor-rejected mice. Our results indicate that the cyclophosphamide-using non-myeloablative cell therapy with the DLI from tumor peptide-immunized donors is a useful protocol to augment graft-versus-tumor effect without exacerbation of graft-versus-host disease. (Cancer Sci 2009; 100: 138-143).

急性および慢性GVHDの病態と診断　　　　　　　　　　　　　　　
豊嶋 崇徳
内科, 104, 2, 206, 212, 2009年
日本語, 研究論文（学術雑誌）

同種造血幹細胞移植後のウイルス感染症　　　　　　　　　　　　　　　
豊嶋 崇徳
血液フロンティア, 19, 8, 1264, 1271, 2009年
日本語, 研究論文（学術雑誌）

慢性GVHDのマウスモデル　　　　　　　　　　　　　　　
豊嶋 崇徳
分子細胞治療, 8, 4, 55, 59, 2009年
日本語, 研究論文（学術雑誌）

GVHDにおける樹状細胞の役割　　　　　　　　　　　　　　　
豊嶋 崇徳
血液・腫瘍科, 59, 2, 233, 240, 2009年
日本語, 研究論文（学術雑誌）

造血細胞移植医療の基礎的・臨床的な新たな展開
豊嶋 崇徳
臨床血液, 50, 8, 617, 621, 「臨床血液」編集部, 2009年
日本語, 研究論文（学術雑誌）

同種造血幹細胞移植後の免疫再構築 造血細胞移植後の予防接種ガイドライン
東英一, 池亀和博, 恵美宣彦, 岡村純, 加藤剛二, 坂巻壽, 豊嶋崇徳, 星順隆, 室井一男, 森慎一郎, 矢野邦夫, 矢部普正
臨床血液, 50, 8, 642, 651, 「臨床血液」編集部, 2009年
日本語, 研究論文（学術雑誌）

GVHDとGVL
豊嶋 崇徳
臨床血液, 50, 10, 1407, 1419, 「臨床血液」編集部, 2009年
日本語, 研究論文（学術雑誌）

Additional acquisition of t(1;21)(p32;q22) in a patient relapsing with acute myelogenous leukemia with NUP98-HOXA9
Takatoshi Aoki, Toshihiro Miyamoto, Shuro Yoshida, Asataro Yamamoto, Takuji Yamauchi, Goichi Yoshimoto, Yasuo Mori, Kenjiro Kamezaki, Hiromi Iwasaki, Katsuto Takenaka, Naoki Harada, Koji Nagafuji, Takanori Teshima, Koichi Akashi
INTERNATIONAL JOURNAL OF HEMATOLOGY, 88, 5, 571, 574, SPRINGER TOKYO, 2008年12月, ［査読有り］
英語, 研究論文（学術雑誌）, We report a 29-year-old Japanese male with acute myelogenous leukemia (AML)-M4 with a cryptic t(7;11)(p15;p15), in which a chimeric NUP98-HOXA9 fusion was detected by polymerase chain reaction analysis and a chromosomal analysis showed 46,XY. The patient received intensive chemotherapy and underwent autologous stem cell transplantation, and remission was confirmed by the disappearance of NUP98-HOXA9. However, 6 months after transplantation, the patient relapsed; NUP98-HOXA9 was detected again and karyotypic analysis revealed 46,XY, t(1;21)(p32;q22). Fluorescent in situ hybridization (FISH) analysis using an AML1-ETO translocation dual probe, showed that the 21q22 breakpoint involved AML1 locus. A retrospective FISH analysis showed that t(1;21) was absent at onset. This is the first reported case with AML who had a cryptic t(7;11)(p15;p15), and additionally acquired t(1;21) (p32;q22) at relapse.

Successful treatment of parainfluenza virus 3 pneumonia with oral ribavirin and methylprednisolone in a bone marrow transplant recipient
Takahiro Shima, Goichi Yoshimoto, Atsushi Nonami, Shuro Yoshida, Kenjiro Kamezaki, Hiromi Iwasaki, Katsuto Takenaka, Toshihiro Miyamoto, Naoki Harada, Takanori Teshima, Koichi Akashi, Koji Nagafuji
INTERNATIONAL JOURNAL OF HEMATOLOGY, 88, 3, 336, 340, SPRINGER TOKYO, 2008年10月, ［査読有り］
英語, 研究論文（学術雑誌）, We report a case of severe parainfluenza (PIV) 3 pneumonia in a hematopoietic stem cell transplant recipient that was successfully treated with oral ribavirin and methylprednisolone. A 42-year-old woman diagnosed with acute myelogenous leukemia (FAB M5a) in first complete remission underwent allogeneic bone marrow transplantation from an HLA-matched unrelated donor in May 2006. In July 2007, she developed PIV3 pneumonia. Her respiratory status progressively worsened and she required O(2) inhalation at 6 L/min. After an informed consent was obtained, oral ribavirin was initiated (16 mg/kg per day) for 1 week on July 31. By day 3 of treatment, the high-grade fever had disappeared. However, it recurred after ribavirin was discontinued. In addition, the patient's hypoxia continued to worsen, requiring O(2) inhalation at 9 L/min. To suppress the inflammatory reaction in the lung caused by PIV3 pneumonia, intravenous methylprednisolone (1,000 mg once a day for 3 days) was started along with high-dose oral ribavirin (16 mg/kg per day) on August 11. The patient showed dramatic clinical improvement, and oxygen inhalation was discontinued on September 3. Our case suggests that with concomitant effective anti-viral treatment, corticosteroids may suppress host inflammatory or immune reactions that lead to respiratory failure.

Reduced-intensity unrelated donor bone marrow transplantation for hematologic malignancies
Sung-Won Kim, Keitaro Matsuo, Takahiro Fukuda, Masamichi Hara, Kosei Matsue, Shuichi Taniguchi, Tetsuya Eto, Mitsune Tanimoto, Atsushi Wake, Kazuo Hatanaka, Shinji Nakao, Yoji Ishida, Mine Harada, Atae Utsunomiya, Masahiro Imamura, Yoshinobu Kanda, Kazutaka Sunami, Fumio Kawano, Yoichi Takaue, Takanori Teshima
INTERNATIONAL JOURNAL OF HEMATOLOGY, 88, 3, 324, 330, SPRINGER TOKYO, 2008年10月, ［査読有り］
英語, 研究論文（学術雑誌）, To review a current experience of unrelated bone marrow transplantation (BMT) with reduced-intensity conditioning (RIC) regimens, we conducted a nationwide survey with 77 patients (age, 25-68 years). The backbone RIC regimen was a combination of fludarabine or cladribine, busulfan or melphalan and total body irradiation at 2-4 Gy. Five patients died early, but 71 (92%) achieved initial neutrophil recovery. Thereafter, 36 patients (47%) died of therapy-related complications, 23 (30%) of whom died within day 100. Grades II-IV acute graft-versus-host disease (GVHD) occurred in 34 of the 68 evaluable patients (50%). In a multivariate analysis, a regimen containing antithymocyte globulin (ATG) was significantly associated with a decreased risk of acute GVHD (P = 0.041). Thirty-three patients are currently alive with a median follow-up of 439 days (28-2002 days), with an OS of 50% at 1 year. In conclusion, unrelated BMT with RIC regimens can be a curative treatment in a subset of patients.

ドナーT細胞のToll-like Receptor(TLR)シグナルはGVHDの重症化に関与する　　　　　　　　　　　　　　　
青山 一利, 小山 幹子, 橋本 大吾, 佐古田 幸美, 竹田 潔, 赤司 浩一, 原田 実根, 谷本 光音, 豊嶋 崇徳
臨床血液, 49, 9, 891, 891, (一社)日本血液学会-東京事務局, 2008年09月
日本語

再発・治療抵抗性多発性骨髄腫に対するbortezomib治療　　　　　　　　　　　　　　　
角南 一貴, 賀川 久美子, 尾崎 修治, 吾郷 浩厚, 平松 靖史, 豊嶋 崇徳, 赤司 浩一, 矢野 朋文, 朝倉 昇司, 下野 玄英, 名和 由一郎, 前田 嘉信, 多林 孝之, 牧田 雅典, 竹内 誠, 原 雅道, 宮田 明, 安倍 正博, 谷本 光音
臨床血液, 49, 9, 905, 905, (一社)日本血液学会-東京事務局, 2008年09月
日本語

Infectious complications in chronic graft-versus-host disease: a retrospective study of 145 recipients of allogeneic hematopoietic stem cell transplantation with reduced- and conventional-intensity conditioning regimens
S. Yamasaki, Y. Heike, S. Mori, T. Fukuda, D. Maruyama, R. Kato, E. Usui, K. Koido, S. Kim, R. Tanosaki, K. Tobinai, T. Teshima, Y. Takaue
TRANSPLANT INFECTIOUS DISEASE, 10, 4, 252, 259, WILEY-BLACKWELL, 2008年08月, ［査読有り］
英語, 研究論文（学術雑誌）, To assess infectious complications associated with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced- and conventional-intensity conditioning regimens (RIC, n = 91,; CIC, n = 54, respectively), we retrospectively analyzed data from 145 consecutive patients with cGVHD after allogeneic HSCT from a human leukocyte antigen-matched related or unrelated donor. In the present retrospective analysis, 57% (83/145) of patients with cGVHD developed infections, with a mortality rate of 27% (22/83). The incidences of bacteremia (n = 28), central venous catheter-related infections (n. = 1.1), bacterial pneumonia (n = 4), invasive aspergillosis (n = 7), and adenoviral hemorrhagic cystitis (n = 8) were significantly higher in patients with prednisolone dose >= 1mg/kg at the time of diagnosis of cGVHD. The present results suggest that infections associated with cGVHD, especially after high-dose prednisolone, are predictive of poor outcome regardless of whether the patient received RIC or CIC.

An unexpected cause of a febrile patient with huge splenomegaly
Atsushi Nonami, Hidetaka Yamamoto, Masafumi Nakamura, Koji Nagafuji, Takanori Teshima
CLINICAL RHEUMATOLOGY, 27, 7, 941, 943, SPRINGER LONDON LTD, 2008年07月, ［査読有り］
英語, 研究論文（学術雑誌）, We report an unexpected cause of a febrile patient with huge splenomegaly. A 32-year-old patient with fever and huge splenomegaly was admitted to our hospital. Diagnostic splenectomy revealed that the enlarged spleen adhered strongly to the abdominal organs. Pathologically, the splenic parenchyma showed no malignant cells, and the soft tissue adjacent to the splenic hilum showed a proliferation of fibroblastic or myofibroblastic spindle cells with fibrosis and lymphoplasmacytic infiltration. These findings lead to a diagnosis of peritoneal fibrosis, and an administration of 50 mg/day of prednisolone alleviated all the symptoms. The differential diagnosis of huge splenomegaly with fever usually includes hematolymphoid malignancies and infectious diseases; however, our case was diagnosed as idiopathic retroperitoneal fibrosis. Our case suggests that when we see patients with fever and huge splenomegaly, differential diagnosis should include retroperitoneal fibrosis.

Posttransplant administration of cyclophosphamide and donor lymphocyte infusion induces potent antitumor immunity to solid tumor
Masatoshi Eto, Yoriyuki Kamiryo, Ario Takeuchi, Masahiko Harano, Katsunori Tatsugami, Mamoru Harada, Keijiro Kiyoshima, Masumitsu Hamaguchi, Takanori Teshima, Masazumi Tsuneyoshi, Yasunobu Yoshikai, Seiji Naito
CLINICAL CANCER RESEARCH, 14, 9, 2833, 2840, AMER ASSOC CANCER RESEARCH, 2008年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose: Nonmyeloablative allogeneic stem cell transplantation (SCT) has been increasingly used for the treatment of hematologic and solid malignancies, and mature donor T cells are considered to be the main effectors of the graft-versus-tumor (GVT) activity. However, the association between degree of donor chimerism and intensity of GVT effects has not been fully elucidated. We recently proposed a unique nonmyeloablative cell therapy using posttransplant cyclophosphamide and donor lymphocyte infusion, by which a significant antitumor effect against murine renal cell carcinoma, RENCA, was induced, although the level of mixed chimerism was relatively low. In this study, we attempted to clarify a role of chimerism for in vivo antitumor effects on GVT effects in radiation-associated nonmyeloablative SCT.
Experimental Design: We assessed antitumor effects on RENCA tumors and the degree of donor chimerism after several doses of irradiation followed by allogeneic SCT and compared the results with those of cyclophosphamide-based cell therapy.
Results: Allogeneic SCT following sublethal irradiation (6 Gy) induced almost complete donor chimerism, whereas cyclophosphamide-based cell therapy produced low levels of donor chimerism. Nonetheless, GVT activity was much more potent in cyclophosphamide-based cell therapy than irradiation-conditioned SCT Furthermore, cyclophosphamide-conditioned SCT induced more potent immune reconstitution with less severe graft-versus-host disease than irradiation-conditioned SCT
Conclusions: Our results indicate that a high level of chimerism is not essential for the in vivo antitumor effect of nonmyeloablative allogeneic cell therapy against solid tumor and that the recovery of peripheral lymphocytes after the initial immunosuppression might be a critical event for the elicitation of in vivo antitumor effects of that treatment modality.

造血細胞移植ガイドライン GVHD
豊嶋崇徳, 伊藤雅文, 井上雅美, 加藤剛二, 谷口修一, 宮村耕一, 森下剛久, 矢部普正, 日本造血細胞移植学会ガイドライン委員会
造血細胞移植モノグラフ，日本造血細胞移植学会．名古屋, 2008年, ［査読有り］

Preparation of functionally preserved CD4+CD25high regulatory T cells from leukapheresis products from ulcerative colitis patients, applicable to regulatory T-cell transfer therapy
Y. Sumida, K. Nakamura, K. Kanayama, H. Akiho, T. Teshima, R. Takayanagi
CYTOTHERAPY, 10, 7, 698, 710, INFORMA HEALTHCARE, 2008年, ［査読有り］
英語, 研究論文（学術雑誌）, Background Ulcerative colitis (UC) is an intractable disease; therefore new therapies need to be developed. CD4+ CD25high regulatory T cells (Treg) significantly ameliorate colitis in animal models. In active UC patients, although Treg are functionally preserved, their proportion in peripheral blood decreases. Thus Treg transfer therapy is expected to be efficacious for UC. During leukapheresis for UC, Treg are depleted, as well as colitogenic effector leukocytes. We therefore designed a leukapheresis/Treg transfer therapy in which Treg are isolated from leukapheresis products and transfused to patients, and studied large-scale germ-free methods of Treg preparation. Methods Using the CliniMACS cell selection system, we conducted Treg isolation experiments from leukapheresis products in which B and CD8+ T cells were depleted, followed by positive selection of CD25+ cells. In some experiments, isolated Treg or non-Treg were expanded with interleukin-2 (IL-2) transforming growth factor (TGF)-1. Expression of a Treg-specific marker, FOXP3, and gut-homing receptors, and suppressor activity of isolated or cultured cells, were analyzed. Results CD4+ CD25high T cells were collected and efficiently enriched with a good recovery rate. Isolated cells preferentially expressed FOXP3 and significantly suppressed T-cell proliferation in vitro. In addition, isolated Treg could be efficiently expanded, and Treg could be induced from non-Treg with TGF-1 in vitro. TGF-1 significantly up-regulated E7 and 47 integrins. Discussion We have established a method of Treg isolation from leukapheresis products that can be used clinically; therefore, Treg transfer therapy is feasible in combination with leukapheresis for UC. Expansion or induction of Treg in vitro may be another approach to Treg-based immunotherapy.

GVHD制御と移植免疫寛容誘導の展望　　　　　　　　　　　　　　　
豊嶋 崇徳
日本組織適合性学会誌, 15, 1, 9, 26, 2008年
日本語, 研究論文（学術雑誌）

Chronic graft-versus-host disease: How can we release Prometheus?
Takanori Teshima, Thomas A. Wynn, Robert J. Soiffer, Ken-Ichi Matsuoka, Paul J. Martin
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 14, 1, 142, +, ELSEVIER SCIENCE INC, 2008年01月
英語, 研究論文（学術雑誌）

GVHDとGVLのメカニズムの再考察
豊嶋 崇徳
臨床血液, 49, 8, 592, 597, 「臨床血液」編集部, 2008年
日本語, 研究論文（学術雑誌）

母子間免疫寛容理論に基づく同種造血幹細胞移植
松岡 賢市, 青山 一利, 小山 幹子, 橋本 大吾, 朝倉 昇司, 一戸 辰夫, 谷本 光音, 豊嶋崇徳
岡山医学会雑誌, 120, 1, 23, 28, 岡山医学会, 2008年
日本語, 研究論文（学術雑誌）

A novel strategy for the treatment of acute graft-versus-host disease: removal of excessive inflammatory cytokines using the adsorbent
Takami A, Teshima T, Ushizaki K, Taniguchi T, Endo T, Sakurai H, Nakao S
BONE MARROW TRANSPLANTATION, 41, 1, S229, 2008年, ［査読有り］
34th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation/24nd Meeting of the EBMT-Nurses-Group/7th Meeting of the EBMT-Data-Management-Group, Florence, ITALY, MAR 30-APR 02, 2008

Successful treatment of primary plasma cell leukaemia by allogeneic stem cell transplantation from haploidentical sibling
Atsushi Nonami, Toshihiro Miyamoto, Mika Kuroiwa, Yuya Kunisaki, Kenjiro Kamezaki, Katsuto Takenaka, Naoki Harada, Takanori Teshima, Mine Harada, Koji Nagafuji
JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 37, 12, 969, 972, OXFORD UNIV PRESS, 2007年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Primary plasma cell leukaemia (PCL) is a rare, aggressive neoplasm of plasma cell dyscrasia. Conventional chemotherapy is usually ineffective, with an overall survival of only 8 months. Here, we describe a 42-year-old man with primary PCL, who was successfully treated with haploidentical (2-HLA loci mismatched) haematopoietic stem-cell transplantation (HSCT). To overcome the human leukocyte antigen (HLA) disparity, in vivo T-cell purging by the pre-transplant administration of antithymocyte globulin followed by a conventional prophylactic treatment against graft-versus-host disease (GVHD) resulted in an avoidance of severe GVHD as well as infectious complications. The patient has maintained complete remission for 13 months after haploidentical HSCT, indicating that a graft-versus-PCL effect might be preserved. Haploidentical HSCT can be a potentially curative treatment for patients with primary PCL who do not have an HLA-identical donor.

A Novel Strategy for the Treatment of Acute Graft-Versus-Host Disease Using the Adsorbent To Remove Excessive Inflammatory Cytokines.
Akiyoshi Takami, Takanori Teshima, Koshin Ushizaki, Takumi Taniguchi, Tohru Endo, Hiroshi Sakurai, Yukio Kondo, Hirohito Yamazaki, Shigeru Shimadoi, Hirokazu Okumura, Shinji Nakao
Blood, 110, 11, 5001, 5001, American Society of Hematology, 2007年11月16日
英語, 研究論文（学術雑誌）,
Acute graft-versus-host disease (aGVHD) remains the major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). Previous studies show that inflammatory cytokines such as tumor necrosis factor alfa (TNFα), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-18 (IL-18) are involved in the pathogenesis of aGVHD, and that the excess of these cytokines is associated with severity and mortality of aGVHD. We hypothesized that removal of these excessive cytokines from patients’ blood at the onset of aGVHD might improve the treatment outcome. A novel absorbent CTR can effectively adsorb small- to middle-sized proteins like cytokines and enterotoxins in vitro. In view of future exploitation of extracorporeal treatment using CTR column, we tested whether CTR could remove these inflammatory cytokines from blood. When the serum containing a mix of recombinant cytokines was incubated with a CTR adsorbent for 2 hrs, 55% of TNFα, 81% of IL-6, 83% of IL-8, and 22% of IL-18 were successfully removed. Next, we measured TNFα, soluble TNFα receptor 1 (TNFR1), IL-6, IL-8, and IL-18 levels in serum samples obtained from 5 patients (median age 38y, range 26–63y) who underwent myeloablative SCT in 4 and non-myeloablative SCT in 1. AGVHD developed in 2 with grade 3 and in 3 with grade 2. When cytokine levels in patients were expressed as a ratio to the mean cytokine level in control serum samples obtained from three healthy individuals, the mean ratios of TNFα, TNFR1, IL-6, IL-8, and IL-18 at the onset of aGVHD were 6.0 (range, 1.2–12.0), 6.5 (2.5–9.0), 274 (3.5–651), 48.3 (11.3–75.2), and 6.7 (3.2–10.8). The CTR adsorption considerably reduced the concentrations of these cytokines except for IL-18 (Figure 1). The adsorption rates of these cytokines were 64% for TNFα, 48% for TNFR1, 59% for IL-6, more than 94% for IL-8, and 0% for IL-18. The efficient removal of inflammatory cytokines suggests that extracorporeal blood purification with CTR column may be effective in the treatment of aGVHD. This treatment strategy may be promising because it essentially has no deleterious effects on immune functions of SCT recipients unlike other GVHD treatments.


Figure Figure

Breast-Feeding Mediates Feto-Maternal Tolerance and Improves Outcome of Allogeneic Bone Marrow Transplantation.
Kazutoshi Aoyama, Ken-ichi Matsuoka, Daigo Hashimoto, Tatsuo Ichinohe, Mine Harada, Mitsune Tanimoto, Takanori Teshima
Blood, 110, 11, 2165, 2165, American Society of Hematology, 2007年11月16日
研究論文（学術雑誌）,
The widespread application of hematopoietic stem cell transplantation (HSCT) is limited by lack of a histocompatible donor in a proportion of patients who have a rare HLA haplotype. For these patients, allogeneic HSCT from an HLA-mismatched relative donor is complicated with a high incidence of severe graft-versus-host disease (GVHD). Exposure to noninherited maternal antigens (NIMAs) during pregnancy may have an impact on transplantation later in life. We recently demonstrated in a mouse model that a “child-to-mother” BMT from a NIMA-exposed donor reduced the mortality and morbidity of GVHD, but a “mother-to-child” BMT did not reduce GVHD (Matsuoka, 2006). We therefore hypothesized that breast-feeding could play a role on the induction of the tolerogenic NIMA effect. To test this hypothesis, we generated NIMA-exposed mice by mating a B6 (H–2b) male and a B6D2F1 (H–2b/d) female to generate H–2b/b offspring. These H–2b/b offspring were then nursed by either a B6D2F1 mother (in utero and oral exposure to NIMAs) or a B6 foster mother (in utero exposure to NIMAs). Transplantation from donors exposed to NIMA in utero alone produced more severe GVHD than BMT from in utero and orally exposed donors, demonstrating that breast-feeding is required for the induction of maximum NIMA effects. Next, to examine whether breast-feeding alone could mediate NIMA effects, we generated mice exposed to NIMA orally by nursing a new born B6 mouse with a B6D2F1 foster mother. CD4+ T cells isolated from these mice were cultured with B6D2F1 stimulators. Proliferation of these cells in response to NIMAs was significantly reduced in comparison to that from the controls. Lethally irradiated B6D2F1 recipients were transplanted with 2 × 106 T cells from these mice or controls together with 5 × 106 T cell-depleted bone marrow from control donors. Five days after transplant, donor T cell expansion and production of IFN-γ were significantly reduced in recipients of orally NIMA exposed donors than controls, resulting in a significant reduction of GVHD mortality (48% vs 80%, p&lt;0.05). The tolerogenic milk effects were completely abolished when lethally irradiated B6D2F1 mice were transplanted with 1 × 106 CD25-depleted CD4+ T cells from the milk-mediated NIMA-exposed mice, thus suggesting that donor CD4+ CD25+ T cells play a role in the tolerogenic milk effects. Next, we hypothesized that generation of regulatory T cells in neonates during lactation period is essential for the induction of the tolerogenic milk effects. The anti-CD25 mAbs, PC61, is capable of depleting CD25+ cells in vivo. New born B6 mice nursed by a B6D2F1 foster mother were subcutaneously injected with anti-CD25 mAbs on days 1 and 8 of life, resulting in a decrease in numbers of Foxp3+ CD4+ CD25+ cells in spleens at 3-week-old. These mice were used as BMT donors at 8-week-old when the numbers of the regulatory T cells had recovered. After BMT from these donors, reduction of GVHD was not observed. These results suggest that development of Foxp3+ CD4+ CD25+ regulatory T cells during lactation is critical for the induction of the tolerogenic milk effects. Our findings may have immediate implications for clinical BMT to use a NIMA-mismatched donor in the absence of a HLA-identical donor in HLA mismatched HSCT.

Toxoplasmosis encephalitis following severe graft-vs.-host disease after allogeneic hematopoietic stem cell transplantation: 17 yr experience in Fukuoka BMT group
Yayoi Matsuo, Shoichiro Takeishi, Toshihiro Miyamoto, Atsushi Nonami, Yoshikane Kikushige, Yuya Kunisaki, Kenjiro Kamezaki, Liping Tu, Hajime Hisaeda, Katsuto Takenaka, Naoki Harada, Tomohiko Kamimura, Yuju Ohno, Tetsuya Eto, Takanori Teshima, Hisashi Gondo, Mine Harada, Koji Nagafuji
EUROPEAN JOURNAL OF HAEMATOLOGY, 79, 4, 317, 321, BLACKWELL PUBLISHING, 2007年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Toxoplasmosis is a rare but rapidly fatal complication that can occur following hematopoietic stem cell transplantation (HSCT). Over a 17-yr period at our institutions, a definite diagnosis of toxoplasmosis was made in only two of 925 allogeneic HSCT recipients (0.22%) and none of 641 autologous HSCT recipients. These two patients received a conventional conditioning regimen followed by transplantation from an HLA-matched donor; however, they developed severe graft-vs.-host disease, which required intensive immunosuppressive therapy. Despite prophylactic treatment with trimethoprim/sulfamethoxazole, their immunosuppressive state, as indicated by a low CD4(+) cell count, might have resulted in toxoplasmosis encephalitis. Rapid and non-invasive methods such as a polymerase chain reaction (PCR) test of their cerebrospinal fluid for Toxoplasma gondii and magnetic resonance imaging of the brain were useful for providing a definitive diagnosis and prompt therapy in these patients: one patient stabilized and survived after responding to treatment with pyrimethamine/sulfodiazine whereas the other died of bacterial infection. In addition, retrospective PCR analyses of the frozen stored peripheral blood samples disclosed that detection of T. gondii preceded the onset of disease, indicating routine PCR testing of peripheral blood specimens may be an early diagnostic tool. It should be noted that when patients receiving HSCT have an unexplained fever and/or neurological complications, PCR tests should be considered to avoid cerebral lesions and improve the outcome of the patients.

Distinctive expression of myelomonocytic markers and down-regulation of CD34 in acute myelogenous leukaemia with FLT3 tandem duplication and nucleophosmin mutation
Yasuo Mori, Goichi Yoshimoto, Takashi Kumano, Toshihiro Miyamoto, Tadafumi Lino, Katsuto Takenaka, Hiromi Iwasaki, Naoki Harada, Naoko Kinukawa, Koji Nagafuji, Takanori Teshima, Kazuya Shimoda, Koichi Akashi, Mine Harada
EUROPEAN JOURNAL OF HAEMATOLOGY, 79, 1, 17, 24, WILEY-BLACKWELL, 2007年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: Patients with acute myelogenous leukaemia (AML) show co-existing frequently internal tandem duplications of FLT3 (FLT3-ITD) and mutations of nucleophosmin (NPM1-Mt). We investigated the biological and clinical significance of FLT3-ITD and/or NPM1-Mt in this context. Methods: We analysed 89 AML patients according to whether NPM1 and FLT3-ITD were single mutants, double mutants, or wild type for both. Results: FLT3-ITD was detected in 19 of 89 patients (21.3%), while NPM1-Mt was detected in 19 of 89 patients (21.3%); eight of 89 patients (9.0%) carried both FLT3-ITD and NPM1-Mt. By multivariate analysis, white blood cell count and peripheral blood blast cell count at diagnosis were significantly higher in patients with FLT3-ITD but not in those with only NPM1-Mt. NPM1-Mt was significantly related to female gender, normal karyotype, and M4 or M5 disease according to French-American-British criteria. In addition, leukaemic blast cells with NPM1-Mt, FLT3-ITD, or both expressed CD34 less frequently than wild-type blasts (P < 0.0001 and P = 0.005 respectively), while myelomonocytic markers such as CD11 b and CD14 were expressed more frequently in patients with NPM1-Mt. Conclusion: FLT3-ITD may increase potential for cell proliferation to produce a leukaemic population; NPM1-Mt may cause cells to develop along the myelomonocytic lineage. Extensive analyses and detailed experiments will be required to clarify how NPM1 and FLT3 mutations interact in leukaemogenesis.

Successful treatment of primary cardiac lymphoma by rituximab-CHOP and high-dose chemotherapy with autologous peripheral blood stem cell transplantation
Atsushi Nonami, Katsuto Takenaka, Kenjiro Kamezaki, Toshihiro Miyamoto, Naoki Harada, Koji Nagafuji, Takanori Teshima, Mine Harada
INTERNATIONAL JOURNAL OF HEMATOLOGY, 85, 3, 264, 266, CARDEN JENNINGS PUBL CO LTD, 2007年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Primary cardiac lymphoma (PCL) is defined as lymphoma involving only the heart and/or pericardium, or with an intrapericardial location of the main tumor mass. It is an extremely rare type of lymphoma and has a poor prognosis because of diagnostic delay and the disease site. PCL is histologically characterized by a mostly diffuse large B-cell lymphoma. The median survival time has been reported to be 7 months. We present the case of a 55-year-old woman who presented with chest oppression and dyspnea on effort. Following a close examination, PCL with a high International Prognostic Index was diagnosed. She received 6 courses of R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) and achieved complete remission. The patient then underwent a consolidation therapy consisting of high-dose chemotherapy including rituximab, followed by autologous peripheral blood stem cell transplantation. There were no complications, such as pulmonary embolism, fatal arrhythmia, or acute heart failure, throughout chemotherapy. Our experience indicates that this therapy is safe and effective and can improve the outcome of high-risk PCL.

Lymphopenia-induced proliferation of donor T cells reduces their capacity for causing acute graft-versus-host disease
Yoshinobu Maeda, Isao Tawara, Takanori Teshima, Chen Liu, Daigo Hashimoto, Ken-ichi Matsuoka, Mitsune Tanimoto, Pavan Reddy
EXPERIMENTAL HEMATOLOGY, 35, 2, 274, 286, ELSEVIER SCIENCE INC, 2007年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective. T cells that undergo lymphopenia-induced proliferation (LIP) are characterized by greater effector and anti-tumor function than naive T cells. But the ability of these T cells in causing graft-versus-host disease (GVHD) is not known.
Methods. We tested the hypothesis that donor T cells that had undergone LIP would cause more severe GVHD than naive T cells by utilizing well-characterized murine experimental models of allogeneic bone marrow transplantation (BMT).
Results. Contrary to our hypothesis, LIP of donor T cells under either noninflammatory or irradiated conditions caused significantly reduced GVHD as determined by survival, clinical, pathologic, and biochemical parameters than naive T cells. Compared to naive donor T cells, LIP T cells demonstrated reduced expansion in vivo and in vitro after allogeneic BMT. The reduction in GVHD mortality and severity was observed across multiple strains after allogeneic BMT. In vivo mechanistic studies by cell depletion demonstrated an increase in the CD44(hi) "memory" phenotype T cells and not the CD4(+)CD25(+) T cell subset to be critical for the reduction in GVHD.
Conclusions. These data demonstrate that LIP of T cells regulates acute GVHD severity in contrast to their ability to cause increased allograft rejection, autoimmunity, or anti-tumor immunity. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.

Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease
Yukimi Sakoda, Daigo Hashimoto, Shoji Asakura, Kengo Takeuchi, Mine Harada, Mitsune Tanimoto, Takanori Teshima
BLOOD, 109, 4, 1756, 1764, AMER SOC HEMATOLOGY, 2007年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2(k)) recipients were reconstituted with T-cell-depleted bone marrow cells from major histocompatibility complex [MHC] class II-deficient (H2-Ab1(-/-)) B6 (H-2(b)) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4(+) T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4(+) T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD. (Blood. 2007;109:1756-1764) (c) 2007 by The American Society of Hematology.

ドナー造血幹細胞由来細胞が慢性graft-versus-host disease(GVHD)を起こす　　　　　　　　　　　　　　　
佐古田 幸美, 橋本 大吾, 朝倉 昇司, 竹内 賢吾, 原田 実根, 谷本 光音, 豊嶋 崇徳
日本内科学会雑誌, 96, Suppl., 156, 156, (一社)日本内科学会, 2007年02月
日本語

Successful treatment of myelodysplastic syndrome (MDS)-related intestinal Behçet's disease by up-front cord blood transplantation
Nonami A, Takenaka K, Sumida C, Aizawa K, Kamezaki K, Miyamoto T, Harada N, Nagafuji K, Teshima T, Harada M
Intern Med, 46, 20, 1753, 1756, JAPAN SOC INTERNAL MEDICINE, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, [症例報告]

Collection of mobilized peripheral blood stem cells from a donor with severe iron deficient anemia
Kenjirou Kamezaki, Toshihiro Miyamoto, Tomoko Henzan, Akihiko Numata, Hiromi Iwasaki, Koji Nagafuji, Mine Harada, Takanori Teshima, Koichi Akashi
JOURNAL OF CLINICAL APHERESIS, 22, 5, 292, 294, WILEY-LISS, 2007年, ［査読有り］
英語, 研究論文（学術雑誌）, We report a 45-year-old woman with iron deficient anemia (IDA) who underwent a collection of allogeneic peripheral blood stem cells (PBSCs) induced by granulocyte-colony stimulating factor (G-CSF) after a rapid improvement of IDA by iron replacement. Her peripheral red blood cells (RBCs) after iron therapy were composed of two different-sized subpopulations; one consisted of microcytes, which were iron deficient RBCs, and another of normocytes, which were produced after iron replacement. On the first day of PBSC collection, the interface setting was maintained aiming at 2% hematocrit as usual; however, PBSCs could not be collected adequately. Sedimentation of iron deficient, lighter RBCs under centrifugation within a blood cell separator could be similar to that of mononuclear cells, and the lighter RBCs could contaminate the mononuclear cell layer, resulting in the collection of the lighter layers of mononuclear cells than desired. On the second day, we succeeded in obtaining enough PBSCs by collecting heavier layers than those collected on the first day by using a 4% hematocrit and monitoring white blood cell counts of the collection line serially. It should be noted that the lighter RBCs from a donor with a history of IDA could complicate collection of PBSCs.

輸血前後の感染症マーカー検査についての日本輸血・細胞治療学会運用マニュアル
熊川みどり, 長井一浩, 豊嶋崇徳, 水落利明, 佐川公矯, 高橋孝喜, 山口一成
日本輸血細胞治療学会誌, 53, 6, 602, 606, 2007年, ［査読有り］
日本語

FTY720 enhances the activation-induced apoptosis of donor T cells and modulates graft-versus-host disease
Daigo Hashimoto, Shoji Asakura, Ken-ichi Matsuoka, Yukimi Sakoda, Motoko Koyama, Kazutoshi Aoyama, Mitsune Tanimoto, Takanori Teshima
EUROPEAN JOURNAL OF IMMUNOLOGY, 37, 1, 271, 281, WILEY-V C H VERLAG GMBH, 2007年01月, ［査読有り］
英語, 研究論文（学術雑誌）, FTY720 is a novel immunosuppressant that improves the outcomes after solid organ and bone marrow transplantation (BMT) due to the sequestration of T cells into LN. We tested the hypothesis that the sequestration of donor T cells in LN by FTY720 would enhance their interaction with host APC, thus causing a greater degree of activation-induced apoptosis of alloreactive T cells, and thereby resulting in a reduction of graft-vs.-host disease (GVHD). The short-term administration of FTY720 improved the recipient survival after allogeneic BMT. FTY720 treatment facilitated a rapid contraction of the donor T cell pool in association with an increased degree of apoptosis of donor T cells. The donor T cell reactivity to host alloantigens was diminished in host's LN and adoptive transfer of donor T cells isolated from LN of FTY720-treated recipients of allogeneic BMT induced less severe GVHD in secondary recipients than the transfer from controls. Caspase-dependent apoptosis was involved in this mechanism because FTY720-induced protection was abrogated when a pan-caspase inhibitor was administered. These findings thus demonstrate the presence of a novel mechanism by which FTY720 modulates the allogeneic T cell responses: namely, by the induction of activation-induced apoptosis of alloreactive T cells in LN.

GVHDとGVLの基礎と臨床応用　　　　　　　　　　　　　　　
豊嶋 崇徳
血液フロンティア, 17, 3, 357, 366, 2007年
日本語, 研究論文（学術雑誌）

GVHDとGVL　　　　　　　　　　　　　　　
豊嶋 崇徳
分子細胞治療, 6, 2, 118, 123, 2007年
日本語, 研究論文（学術雑誌）

はじめに．造血幹細胞移植後のGVHD　　　　　　　　　　　　　　　
豊嶋 崇徳
医学のあゆみ, 222, 3, 157, 2007年
日本語, 研究論文（学術雑誌）

急性GVHDの病態と治療　　　　　　　　　　　　　　　
豊嶋 崇徳
医学のあゆみ, 222, 3, 165, 169, 2007年
日本語, 研究論文（学術雑誌）

ドナー由来胸腺依存性Ｔ細胞によるGVHD
佐古田幸美, 豊嶋崇徳
血液・腫瘍科, 55, 4, 458, 463, 科学評論社, 2007年
日本語, 研究論文（学術雑誌）

FTY720によるマウス同種骨髄移植後のドナーリンパ球のアポトーシス誘導とGVHD予防　　　　　　　　　　　　　　　
橋本 大吾, 朝倉 昇司, 松岡 賢市, 佐古田 幸美, 小山 幹子, 青山 一利, 谷本 光音, 赤司 浩一, 豊嶋 崇徳
臨床血液, 47, 9, 1017, 1017, (一社)日本血液学会-東京事務局, 2006年09月
日本語

Bone marrow transplantation improves outcome in a mouse model of congenital muscular dystrophy
Hiroki Hagiwara, Yutaka Ohsawa, Shoji Asakura, Tatsufumi Murakami, Takanori Teshima, Yoshihide Sunada
FEBS LETTERS, 580, 18, 4463, 4468, ELSEVIER SCIENCE BV, 2006年08月, ［査読有り］
英語, 研究論文（学術雑誌）, We examined whether pathogenesis in dystrophin-deficient (mdx) mice and laminin-alpha 2-deficient (dy) mice is ameliorated by bone marrow transplantation (BMT). Green fluorescent protein (GFP) mice were used as donors. In mdx mice, BMT failed to produce any significant differences in muscle pathology, although some GFP-positive fibers with restored dystrophin expression were observed. In contrast, in the dy mice, BMT led to a significant increase in lifespan and an increase in growth rate, muscle strength, and respiratory function. We conclude that BMT improved outcome in dy mice but not mdx mice. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Calcineurin inhibitor-induced irreversible neuropathic pain after allogeneic hematopoietic stem cell transplantation
N Fujii, K Ikeda, M Koyama, K Aoyama, T Masunari, E Kondo, T Matsuzaki, S Mizobuchi, A Hiraki, T Teshima, K Shinagawa, F Ishimaru, M Tanimoto
INTERNATIONAL JOURNAL OF HEMATOLOGY, 83, 5, 459, 461, CARDEN JENNINGS PUBL CO LTD, 2006年06月, ［査読有り］
英語, 研究論文（学術雑誌）, The calcineurin inhibitors (Cls) cyclosporine A and tacrolimus are essential for graft-versus-host disease prophylaxis but are associated with adverse effects, including neurotoxicity We report a case of irreversible Cl-induced neuropathic pain following allogeneic hematopoietic stem cell transplantation. The patient developed dysesthesia, electric shock-like pain. and severe itching followed by intractable analgesic-resistant pain in the lower extremities. There were no abnormal radiographic findings, and there was no improvement with a reduction of Cl dosage or with administration of a calcium channel blocker. These clinical findings are similar to but inconsistent with Cl-induced musculoskeletal pain syndromes previously reported in organ transplantation.

Impact of fetal-maternal tolerance in hematopoietic stem cell transplantation
Takanori Teshima, Ken-ichi Matsuoka, Tatsuo Ichinohe
ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS, 54, 3, 165, 172, INST IMMUNOLOGY & EXPERIMENTAL THERAPY, 2006年05月
英語, 研究論文（学術雑誌）, Allogeneic hematopoietic stem cell transplantation (HSCT) is known to cure various hematological disorders; however, its widespread use is limited due to a lack of histocompatible donors. Reciprocal cell traffic between the mother and fetus during pregnancy gives rise to postpartum fetal-maternal lymphohematopoietic microchimerism, which is frequently detected in the blood or tissue of healthy individuals. Studies in clinical and experimental transplantation provide evidence that exposure to non-inherited maternal antigens (NIMAs) during pregnancy may result in long-lasting fetomaternal microchimerism and tolerance induction. Studies of HLA-mismatched HSCT have suggested a relatively lower incidence of severe graft-versus-host disease (GVHD) after transplantation from a NIMA-mismatched donor. Studies using a mouse model have also demonstrated a "child-to-mother" bone marrow transplantation from an NIMA-exposed donor to reduce the morbidity and mortality of GVHD in an antigen-specific manner while preserving the graft-versus-leukemia effects and favoring the immune reconstitution, thus resulting in a marked improvement in outcome after HSCT. Prospective clinical studies are therefore warranted to confirm these beneficial effects of fetal-maternal tolerance in allogeneic HSCT.

Complete donor chimaerism of Langerhans cells in lymph node early after allogeneic bone marrow transplantation
K Ikeda, T Shichishima, T Teshima, K Ogawa, A Nakamura-Shichishima, H Tajima, H Noji, Y Hashimoto, K Takeyama, T Ishibashi, H Ohto, M Abe, Y Maruyama
EUROPEAN JOURNAL OF HAEMATOLOGY, 76, 3, 261, 264, BLACKWELL PUBLISHING, 2006年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Host-derived Langerhans cells (LCs) are crucial antigen-presenting cells that cause graft-vs.-host disease after allogeneic haematopoietic stem cell transplantation (HSCT). However, chimaerism of LCs after allogeneic HSCT is largely unknown in humans. We here report a case that developed dermatopathic lymphadenitis accompanied by an accumulation of donor-derived LCs in the second month after allogeneic HSCT with reduced-intensity conditioning. This is the first case to show that donor LCs have the ability to migrate into draining lymph nodes and replace host LCs early after HSCT in humans.

Transient respiratory disturbance by granulocyte-colony-stimulating factor administration in healthy donors of allogeneic peripheral blood progenitor cell transplantation
Yoshida, I, K Matsuo, T Teshima, D Hashimoto, Y Tanimoto, M Harada, M Tanimoto
TRANSFUSION, 46, 2, 186, 192, BLACKWELL PUBLISHING, 2006年02月, ［査読有り］
英語, 研究論文（学術雑誌）, BACKGROUND: Allogeneic peripheral blood progenitor cell (PBPC) transplantation requires granulocyte-colony-stimulating factor (G-CSF) administration to mobilize PBPCs in healthy donors. The effects of G-CSF on pulmonary functions, however, have not been clearly elucidated in PBPC donors.
STUDY DESIGN AND METHODS: Respiratory status by measurements of arterial blood gas was prospectively evaluated serially in 25 healthy donors (9 men, 16 women; age, 18-61 years) administered a dose of 10 mu g per kg for 5 days.
RESULTS: White blood cell (WBC) counts increased in all the subjects after G-CSF administration; means on Days 0, 3, and 5 were 6 x 10(9), 33.4 x 10(9), and 33.6 x 10(9) per L, respectively. The mean PaO2 values on the respective days were 93.1, 85.8, and 81.8 mmHg, and these changes were significant (p < 0.0001), remaining significant after adjustment for the WBC count. Levels of both PaCO2 and AaDO(2) were significantly higher after G-CSF administration than those before G-CSF administration (p < 0.0001 and p = 0.0004, respectively). SaO(2) was significantly decreased after G-CSF administration (p = 0.0002). Age was identified as a significant predictive factor for the increase of AaDO(2) and PaO2 decline. These observations clearly indicate that the gas exchange was significantly affected during G-CSF administration in healthy PBPC donors.
CONCLUSION: Considering an increasing use of PBPC mobilization by G-CSF, careful monitoring of the respiratory status is important to ensure safety of PBPC donors, especially elderly donors.

血液型不適合移植でのCOBE Spectraを用いた骨髄濃縮法の検討
平安山知子, 宮本敏浩, 和泉賢一, 沼田晃彦, 亀崎健次郎, 山崎聡, 清島久美, 宮本京子, 橋本大吾, 岩崎潤子, 岩崎浩巳, 長藤宏司, 原田実根, 稲葉頌一, 豊嶋崇徳, 赤司浩一
日本輸血細胞治療学会誌, 52, 6, 693, 697, The Japan Society of Transfusion Medicine and Cell Therapy, 2006年, ［査読有り］
日本語, 血液型不適合骨髄移植を行う際は, 輸注に伴う有害事象を避けるため, 骨髄液中の赤血球・血漿除去が必要である. 今回われわれは, 血液成分分離装置COBE Spectra により, 骨髄液から単核球を分離することで, 骨髄細胞濃縮を行った血液型不適合骨髄移植20例において, その有用性について検討した. COBE Spectra を用いた骨髄濃縮により, 赤血球量は98.4%除去され, 最終赤血球量は4.2±2.4mlであった. 有核細胞回収率は34.0±8.38%, CD34陽性細胞回収率は112.3±36.3%であった. 20症例全例で, 移植後の溶血反応および生着不全は認めず, 移植後造血回復は速やかであった. COBE Spectra を用いることで, 清潔な無菌閉鎖回路内において骨髄濃縮が可能となり, 処理時間も短縮された. 種々の細胞免疫療法の用途で広く普及しているCOBE Spectra を用いた骨髄濃縮法は, 血液型不適合骨髄移植における骨髄濃縮の標準的方法として有用であると考えられた.

Fetal tolerance to maternal antigens improves the outcome of allogeneic bone marrow transplantation by a CD4(+)CD25(+) T-cell-dependent mechanism
K Matsuoka, T Ichinohe, D Hashimoto, S Asakura, M Tanimoto, T Teshima
BLOOD, 107, 1, 404, 409, AMER SOC HEMATOLOGY, 2006年01月, ［査読有り］
英語, 研究論文（学術雑誌）, The lack of donor availability is a major limitation to the widespread use of allogeneic hematopoietic stem cell transplantation, and therefore it would be beneficial to identify less immunogenic HLA mismatches. The maternal and fetal antigens that are transmitted through the bidirectional transplacental passage during pregnancy may induce tolerance to noninherited maternal antigens (NIMAs) in offspring and to inherited paternal antigens (IPAs) in the mother. Using mouse models of bone marrow transplantation (BMT), we found that a "child-to-mother" BMT from a NIMA-exposed donor reduced the morbidity and mortality of graft-versus-host disease in an antigen-specific manner; however, a "mother-to-child" BMT from an IPA-exposed donor did not. The NIMA-complementary BMT preserved the graft-versus-leukemia effects and favored the immune reconstitution, thus resulting in a marked improvement of the outcome after BMT. These tolerogenic NIMA effects were completely abolished by the depletion of CD4(+)CD25(+) cells from the donor inocula, thus suggesting the involvement of CD4(+)CD25(+) regulatory T cells in the tolerogenic NIMA effects. Our findings may therefore have profound implications on the performance of clinical BMT while also potentially helping to develop new strategies for using a NIMA-mismatched donor in the absence of an HLA-identical donor.

GVHDとGVLの病態生理　　　　　　　　　　　　　　　
豊嶋 崇徳
血液・腫瘍科, 52, 3, 344, 359, 2006年
日本語, 研究論文（学術雑誌）

サイトカインとGVHD　　　　　　　　　　　　　　　
豊嶋 崇徳
内科, 98, 2, 313, 318, 2006年
日本語, 研究論文（学術雑誌）

Maternal antigensへの免疫学的寛容とCD4+CD25+制御性T細胞　　　　　　　　　　　　　　　
松岡賢市, 一戸辰夫, 豊嶋崇徳
血液・腫瘍科, 53, 4, 362, 367, 2006年
日本語, 研究論文（学術雑誌）

造血幹細胞移植における免疫反応―移植片対宿主病―　　　　　　　　　　　　　　　
豊嶋 崇徳
Sysmex Journal, 29, 39, 48, 2006年
日本語, 研究論文（学術雑誌）

同種免疫反応の制御 Graft-versus-host disease (GVHD)　　　　　　　　　　　　　　　
豊嶋 崇徳
今日の移植, 19, 1, 65, 72, 2006年
日本語, 研究論文（学術雑誌）

Fetal-maternal microchimerism: impact on hematopoietic stem cell transplantation
T Ichinohe, T Teshima, K Matsuoka, E Maruya, H Saji
CURRENT OPINION IN IMMUNOLOGY, 17, 5, 546, 552, CURRENT BIOLOGY LTD, 2005年10月
英語, 研究論文（学術雑誌）, Reciprocal cell traffic between mother and fetus during pregnancy gives rise to postpartum fetal-maternal lymphohematopoietic microchimerism, which is frequently detected in blood or tissue from healthy individuals. Although such microchimerism has been implicated in the pathogenesis of autoimmune diseases and tissue repair, recent clinical experiences have suggested the association of microchimerism with acquired immunologic hyporesponsiveness to non-inherited maternal HLA antigens (NIMAs) or inherited paternal HLAantigens (IPAs); T cell-replete HLA- haploidentical hematopoietic stem cell transplantation from a microchimeric IPA/NIMA-mismatched donor confers relatively lower incidence of severe graft-versus-host disease. The underlying mechanisms by which fetal-maternal microchimerism contributes to IPA/NIMA-specific tolerance are still elusive, although emerging experimental evidence suggests an involvement of the central deletion of IPA/NIMA-reactive T cells, the induction of peripheral regulatory T cells, and affinity-dependent modulation of NIMA-reactive B cells.

Impact of human leucocyte antigen mismatch on graft-versus-host disease and graft failure after reduced intensity conditioning allogeneic haematopoietic stem cell transplantation from related donors
T Teshima, K Matsuo, K Matsue, F Kawano, S Taniguchi, M Hara, K Hatanaka, M Tanimoto, M Harada, S Nakao, Y Abe, A Wake, T Eto, Y Takemoto, M Imamura, S Takahashi, Y Ishida, Y Kanda, M Kasai, Y Takaue
BRITISH JOURNAL OF HAEMATOLOGY, 130, 4, 575, 587, BLACKWELL PUBLISHING, 2005年08月, ［査読有り］
英語, 研究論文（学術雑誌）, The impact of human leucocyte antigen (HLA) incompatibility between donor and recipient on graft-versus-host disease (GVHD) and graft failure after reduced-intensity conditioning stem cell transplantation (RICT) remains to be elucidated. We retrospectively analysed outcome in 341 patients who underwent RICT from related donors for haematological malignancies. The overall cumulative incidence of grade II-IV acute GVHD (aGVHD) was 40% for all subjects; 39% in recipients with HLA-matched donors, 44% in those with one-locus-mismatched donors, and 50% in those with two- to three-loci-mismatched donors. In a Cox regression model adjusted for potential confounders, the tendency for grade II-IV aGVHD (P = 0.01), chronic GVHD (cGVHD) (P = 0.05) and graft failure (P = 0.033) increased with HLA disparity. Use of peripheral blood grafts instead of marrow was a risk factor for cGVHD. Use of antithymocyte globulin was associated with reduced aGVHD and cGVHD. Overall survival (OS) in recipients of two- to three-loci-mismatched RICT at 2 years (18%) was significantly worse than that in patients who received one-locus-mismatched RICT (51%) and HLA-matched RICT (48%) (P < 0.0001). A two- to three-loci mismatch was identified as an independent risk factor for OS (P < 0.001), but there was no significant difference in OS between HLA-matched and one-locus-mismatched RICT. HLA incompatibility between the donor and recipient is an important risk factor for graft failure, aGVHD, cGVHD and OS after RICT. RICT from a one-locus-mismatched donor may represent an effective alternative approach in patients with high-risk malignancies who lack HLA-matched related donors.

The engraftment of transplanted bone marrow-derived cells into the olfactory epithelium
H Tsujigiwa, K Nishizaki, T Teshima, Y Takeda, J Yoshinobu, A Takeuchi, Y Orita, Y Sugata, H Nagatsuka, N Nagai
BRAIN RESEARCH, 1052, 1, 10, 15, ELSEVIER SCIENCE BV, 2005年08月, ［査読有り］
英語, 研究論文（学術雑誌）, To investigate whether bone marrow cells migrate and are engrafted into the olfactory epithelium and differentiate into olfactory neurons, bone marrow cells of green fluorescence protein (GFP) mice were transplanted into lethally irradiated recipient mice. Immunohistochemical staining was performed to evaluate the engraftment of donor bone marrow cells into the olfactory epithelium. Immunostaining for GFP was found initially in the olfactory epithelium 2 weeks after bone marrow reconstruction. The percentage of GFP positive cells increased up to 12 months after bone marrow reconstruction. Double staining for GFP and olfactory marker protein showed that a population of the GFP-positive cells had characteristics of olfactory neurons. These results demonstrate that bone marrow cells can be engrafted in the olfactory epithelium and then differentiate into olfactory neuron cells. (c) 2005 Elsevier B.V. All rights reserved.

Early immune reaction after reduced-intensity cord-blood transplantation for adult patients
Y Kishi, M Kami, S Miyakoshi, Y Kanda, N Murashige, T Teshima, E Kusumi, S Hara, T Matsumura, K Yuji, K Masuoka, A Wake, S Morinaga, M Kanemaru, T Hayashi, Y Tanaka, S Taniguchi
TRANSPLANTATION, 80, 1, 34, 40, LIPPINCOTT WILLIAMS & WILKINS, 2005年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Background. To investigate immune reactions after reduced-intensity cord-blood transplantation (RI-CBT).
Materials and Methods. We reviewed medical records of 57 adult RI-CBT recipients. Preparative regimen comprised fludarabine, total-body irradiation, and either melphalan (n=51) or busulfan (n=6). Graft-versus-host disease (GvHD) prophylaxis was cyclosporine. PostRI-CBT immune reactions were classified according to time course: pre-engraftment immune reactions (PIR), engraftment syndrome (ES), and GvHD.
Results. Forty-five patients achieved engraftment at a median of day 19. PIR was characterized by high-grade fever and weight gain and developed on a median of day 9 in 35 of the 45 evaluable patients, including 3 who did not achieve engraftment. PIR subsided spontaneously in 12 patients, whereas corticosteroids were required in the other 23. ES and grade I to IV acute GvHD developed in 36 and 29 patients, respectively. GvHD could not be distinguished from preceding PIR or ES in 10 patients. Causes of the 32 nonrelapse mortalities included GvHD (n=5) and FIR (n=1). There were no significant differences in relapse and nonrelapse deaths between patients with PIR and those without it (18% vs. 5%, and 60% vs. 65%, respectively).
Conclusions. Immune reactions after RI-CBT can be categorized into three distinct subtypes.

Both perforin and Fas ligand are required for the regulation of alloreactive CD8(+) T cells during acute graft-versus-host disease
Y Maeda, RB Levy, P Reddy, C Liu, SG Clouthier, T Teshima, JLM Ferrara
BLOOD, 105, 5, 2023, 2027, AMER SOC HEMATOLOGY, 2005年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Fas ligand (FasL) and perforin pathways not only are the major mechanisms of T cell-mediated cytotoxicity but also are involved in homeostatic regulation of these T cells. In the present study, we tested whether CD8(+) donor T cells that are deficient in both perforin and FasL (cytotoxic double deficient [cdd]) could induce graft-versus-host disease (GVHD) in a major histocompatibility complex class I-mismatched lethally irradiated murine model. Interestingly, recipients of cdd CD8(+) T cells demonstrated significantly greater serum levels of interferon gamma and tumor necrosis factor alpha and histopathologic damage from GVHD than wild-type (wt) T cells on day 30 after allogeneic bone marrow transplantation (P < .05). Wt and either perforin-deficient or FasL-deficient CD8(+) T cells expanded early after transplantation followed by a contraction phase in which the majority of expanded CD8(+) T cells were eliminated. In contrast, cdd CD8(+) T cells exhibited prolonged expansion and reduced apoptosis to alloantigen stimulation in vivo and in vitro. Together these results suggest that donor cdd CD8(+) T cells expand continuously and cause lethal GVHD, and that both perforin and Fast-are required for the contraction of alloreactive CD8(+) T cells. (C) 2005 by The American Society of Hematology.

Stimulation of host NKT cells by synthetic glycolipid regulates acute graft-versus-host disease by inducing Th2 polarization of donor T cells
D Hashimoto, S Asakura, S Miyake, T Yamamura, L Van Kaer, C Liu, M Tanimoto, T Teshima
JOURNAL OF IMMUNOLOGY, 174, 1, 551, 556, AMER ASSOC IMMUNOLOGISTS, 2005年01月, ［査読有り］
英語, 研究論文（学術雑誌）, NKT cells are a unique immunoregulatory T cell population that produces large amounts of cytokines. We have investigated whether stimulation of host NKT cells could modulate acute graft-vs-host disease (GVHD) in mice. Injection of the synthetic NKT cell ligand alpha-galactosylceramide (alpha-GalCer) to recipient mice on day 0 following allogeneic bone marrow transplantation promoted Th2 polarization of donor T cells and a dramatic reduction of serum TNF-alpha, a critical mediator of GVHD. A single injection of alpha-GalCer to recipient mice significantly reduced morbidity and mortality of GVHD. However, the same treatment was unable to confer protection against GVHD in NKT cell-deficient CD1d knockout (CDld(-/-)) or IL-4(-/-) recipient mice or when STAT6(-/-)mice were used as donors, indicating the critical role of host NKT cells, host production of IL-4, and Th2 cytokine responses mediated by donor T cells on the protective effects of alpha-GalCer against GVHD. Thus, stimulation of host NKT cells through administration of NKT ligand can regulate acute GVHD by inducing Th2 polarization of donor T cells via STAT6-dependent mechanisms and might represent a novel strategy for prevention of acute GVHD.

Graft-versus-host disease (GVHD)の制御
豊嶋 崇徳
日本内科学会誌, 94, 7, 1356, 1361, The Japanese Society of Internal Medicine, 2005年
日本語, 研究論文（学術雑誌）, Cyclosprineの導入によって急性GVHDの制御がある程度達成され,同種造血幹細胞移植は急速に普及した.しかし一旦発症した急性GVHDの治療成績はいまだ不十分で,さらに慢性GVHDの減少は依然達成されておらず,移植後のQOL (quality of life)と生命予後の大きな危険因子となっている.近年,新規薬剤や各種抗体療法の開発,研究が進み,新たな細胞療法の展開とあわせて注目される.

GVHDの発症メカニズム
豊嶋 崇徳
日本小児血液学会雑誌, 19, 84, 86, 2005年
日本語, 研究論文（学術雑誌）

GVHDとGVTの病態　　　　　　　　　　　　　　　
豊嶋 崇徳
綜合臨床, 54, 6, 1737, 1743, 2005年
日本語, 研究論文（学術雑誌）

移植免疫と腫瘍免疫　　　　　　　　　　　　　　　
豊嶋 崇徳
Urology View, 3, 3, 48, 52, 2005年
日本語, 研究論文（学術雑誌）

NKT細胞刺激による急性GVHD予防　　　　　　　　　　　　　　　
橋本 大吾, 朝倉 昇司, 三宅 幸子, 山村 隆, Van Kaer Luc, Liu Chen, 谷本 光音, 豊嶋 崇徳
日本血液学会・日本臨床血液学会総会プログラム・抄録集, 66回・46回, 747, 747, 日本臨床血液学会, 2004年09月
日本語

Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease
UA Duffner, Y Maeda, KR Cooke, P Reddy, R Ordemann, C Liu, JLM Ferrara, T Teshima
JOURNAL OF IMMUNOLOGY, 172, 12, 7393, 7398, AMER ASSOC IMMUNOLOGISTS, 2004年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Alloantigen expression on host APCs is essential to initiate graft-vs-host disease (GVHD); however, critical APC subset remains to be elucidated. We compared the ability of dendritic cells (DCs) and B cells to initiate acute GVHD by an add-back study of MHC class II-expressing APCs (II+/+) into MHC class II-deficient (II-/-) mice that were resistant to CD4-dependent GVHD. Injection of host-derived, but not donor-derived, II+/+ DCs or host-derived II+/+ B cells, was sufficient to break GVHD resistance of II-/- mice and induced lethal acute GVHD. By contrast, host-derived II+/+ B cells, both naive and LPS stimulated, failed to induce activation or tolerance of donor CD4(+) T cells. Similarly, in a model of CD8-dependent GVHD across MHC class I mismatch injection of allogeneic DCs, but not B cells, induced robust proliferation of donor CD8(+) T cells and broke GVHD resistance of chimeric recipients in which APCs were syngeneic to donors. These results demonstrate that host-derived DCs are critical in printing donor CD4(+) and CD8(+) T cells to cause GVHD, and selective targeting of host DCs may be a promising strategy to prevent GVHD.

Peripheral blood circulating immature cell counts predict CD34+ cell yields in G-CSF-induced PBPC mobilization in healthy donors
T Kozuka, K Ikeda, T Teshima, C Yoshida, K Shinagawa, K Kojima, K Matsuo, A Bessho, K Sunami, Y Hiramatsu, Y Maeda, T Noguchi, K Yamamoto, N Fujii, T Imai, KK Kusumoto, K Masuda, K Takenaka, F Ishimaru, K Niiya, N Koide, M Tanimoto, M Harada
TRANSFUSION, 44, 4, 526, 532, BLACKWELL PUBLISHING INC, 2004年04月, ［査読有り］
英語, 研究論文（学術雑誌）, BACKGROUND: It has been previously reported that the number of circulating immature cells (CIC) in peripheral blood (PB) estimates the number of CD34+ cells collected in G-CSIF plus chemotherapy-induced PBPC mobilization. The correlation of CIC counts in PB with CD34+ cell yield and its usefulness was evaluated in G-CSF-induced PBPC mobilization for healthy donors.
STUDY DESIGN AND METHODS: CIC counts in PB and CD34+ cell counts in the apheresis product from 122 collections were assessed, and the relationship between these two variables was evaluated with the Pearson rank correlation analysis, the chi-squared test, and the U-test.
RESULTS: CIC counts were correlated weakly with the number of CD34+ cells per L of blood processed in the apheresis product (Pearson rank correlation analysis; r = 0.357, p < 0.0001). When a level of 1.7 x 10(9) CICs per L was selected as a cutoff value, the sensitivity and specificity for collecting more than 20 x 10(6) CD34+ cells per L of blood processed were 63.6 and 77.5 percent, respectively.
CONCLUSION: The present study suggests that the number of CICs in PB may estimate the number of CD34+ cells collected. The data indicate that CIC counts above 1.7 x 10(9) per L can be used as a good predictor for PBPC collections containing more than 20 x 10(6) CD34+ cells per L of blood processed in a single apheresis procedure.

Involvement of ERK1/2 and p38 MAP kinase in doxorubicin-induced uPA expression in human RC-K8 lymphoma and NCI-H69 small cell lung carcinoma cells
M Niiya, K Niiya, M Shibakura, N Asaumi, C Yoshida, K Shinagawa, T Teshima, F Ishimaru, K Ikeda, M Tanimoto
ONCOLOGY, 67, 3-4, 310, 319, KARGER, 2004年, ［査読有り］
英語, 研究論文（学術雑誌）, We previously demonstrated the doxorubicin-induced urokinase-type plasminogen activator (uPA) expression in human RC-K8 lymphoma cells and NCI-H69 small cell lung carcinoma cells in which reactive oxygen species might be involved. Western blotting analysis revealed phosphorylation/ activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) 1/2, p38 MAP kinase and stress-activated protein kinase/c-jun N-terminal protein kinase (SAPK/JNK) in doxorubicin-treated RC-K8 and H69 cells, and, therefore, we attempted to identify the MAP kinases implicated in doxorubicin-induced uPA expression by the use of their specific inhibitors. U0126, SB202190 and JNKI-1, inhibitors for MAPK kinase, (MEK) 1/2, p38 MAP kinase and SAPK/JNK, respectively, specifically and clearly inhibited their corresponding kinases. U0126 and SB202190, but not JNKI-1, almost completely inhibited the doxorubicin-induced uPA expression in both RC-K8 and H69 cells. However, U0126 rather enhanced the doxorubicin-induced activation of caspase-3 and poly ADP-ribose polymerase (PARP), and U0126 itself activated caspase-3 and PARP. Interestingly, JNKI-1 inhibited the doxorubicin-induced activation of caspase-3 and PARP. Therefore, doxorubicin treatment activates the above three kinases, but different MAP kinase signaling is responsible in the doxorubicin-induced caspase activation and expression of uPA. Thus, we could possibly manipulate the direction of doxorubicin-induced MAP kinase activation and the effects of doxorubicin on the tumor cell biology by the use of MAP kinase inhibitors. Copyright (C) 2004 S. Karger AG, Basel.

[Clinical evaluation of cefozopran as treatment for febrile neutropenia].
Takashi Saito, Masamichi Hara, Katsuji Shinagawa, Yuichiro Nawa, Koichi Nakase, Makoto Takeuchi, Akira Miyata, Shunnichi Fukuda, Kazutaka Sunami, Kenji Imajoh, Tomofumi Yano, Kensuke Kojima, Takanori Teshima, Nobuharu Fujii, Fumihiko Ishimaru, Kazuma Ikeda, Mine Harada, Mitsune Tanimoto
Gan to kagaku ryoho. Cancer & chemotherapy, 31, 1, 61, 5, 2004年01月, ［国内誌］
日本語, 研究論文（学術雑誌）, Clinical effects and safety of cefozopran (CZOP) were evaluated by the Okayama Bone Marrow Transplantation Group. Twenty-five patients expected to experience febrile neutropenia during induction chemotherapy or consolidation chemotherapy of acute leukemia were enrolled between July 2000 and November 2002. CZOP was administrated by drip infusion at 4g/day bid for a minimum of 3 days. The clinical effects and safety were evaluated in 20 patients with fever of 37.5 degrees C or more from a clinically suspected infection. The underlying disease was acute myeloid leukemia in 17 patients, acute lymphoid leukemia in 1 and acute promyelogeneous leukemia in 1. The complicating infections were sepsis and suspected sepsis. Clinical efficacy was excellent in 11 patients, good in 1, fair in 2 and poor in 6, with an efficacy rate of 60.0%. The efficacy rate in patients whose albumin levels before therapy were less than 3.8 g/dl was 37.5%, whereas the rate in patients whose albumin levels before therapy were between 3.8 g/dl and 5.3 g/dl was 80.0%. The efficacy rate in patients whose neutrophil counts before therapy were less than 100/microliter was 50.0%, whereas the rate in patients whose neutrophil counts after therapy were less than 100/microliter was 53.8%. The efficacy rate in patients whose neutrophil counts both before and after therapy were less than 100/microliter was 37.5%. Side effect of exanthema was observed in 1 patient. These results indicate that CZOP is an effective and safe antibiotic for the treatment of febrile neutropenia in patients with hematological malignancies.

GVHDとGVL　　　　　　　　　　　　　　　
豊嶋 崇徳
分子細胞治療, 3, 5, 512, 517, 2004年
日本語, 研究論文（学術雑誌）

GVHDの新しい理解
豊嶋 崇徳
最新医学, 59, 1, 128, 134, 最新医学社, 2004年
日本語, 研究論文（学術雑誌）

Role of CXCR3-induced donor T-cell migration in acute GVHD
U Duffner, B Lu, GC Hildebrandt, T Teshima, DL Williams, P Reddy, R Ordemann, SG Clouthier, K Lowler, C Liu, C Gerard, KR Cooke, JLM Ferrara
EXPERIMENTAL HEMATOLOGY, 31, 10, 897, 902, ELSEVIER SCIENCE INC, 2003年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective. The chemokine receptor CXCR3 has an important role in the migration of effector T cells. To investigate the role of CXCR3 on donor cells in acute graft vs host disease (GVHD) we used a well-defined experimental bone marrow transplantation (BMT) model where acute GVHD is mediated by donor CD8(+) T cells against minor histocompatibility antigens. Methods. Lethally irradiated C3H.SW recipients were transplanted from either wild-type B6 or CXCR3(-/-) B6 donors. Donor T-cell expansion was analyzed in the spleen and small intestine of recipients by FACS. Donor T-cell function was analyzed by cytokine secretion. The severity of acute GVHD was assessed by histopathological analysis of intestine and liver, GVHD clinical scores, and survival after BMT.
Results. Significantly higher numbers of donor CD8(+) CXCR3(-/-) T cells were found in the spleen on days +7 and +14 compared to donor wild-type T cells. By contrast, the number of CD8+ T cells in the small bowel of BMT recipients from CXCR3(-/-) donors was sevenfold lower than from wild-type donors. Systemic concentrations of INF-gamma and TNF-alpha were equivalent between groups. Animals that received CXCR3(-/-) donor T cells demonstrated diminished GI tract and liver damage and showed improved survival after BMT compared to recipients of wild-type donor cells (43% vs 0%, p < 0.001).
Conclusion. The migration of donor CD8(+) T cells to GVHD target organs such as the intestine depends on the expression of CXCR3 and contributes significantly to GVHD damage and overall mortality. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc.

Repifermin (keratinocyte growth factor-2) reduces the severity of graft-versus-host disease while preserving a graft-versus-leukemia effect
SG Clouthier, KR Cooke, T Teshima, KP Lowler, C Liu, K Connolly, JLM Ferrara
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 9, 9, 592, 603, CARDEN JENNINGS PUBL CO LTD, 2003年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Graft-versus-host disease (GVHD) is the principal complication after allogeneic bone marrow transplantation (BAIT). Reductions in systemic GVHD are frequently associated with a corresponding diminishment of the graft-versus-leukemia (GVL) response. In this study, we tested the effects of a novel recombinant human keratinocyte growth factor, repifermin (keratinocyte growth factor-2), on the induction of GVHD in a well-defined murine BMT model (B6 --> B6D2F1). Administration of repifermin (5 mg/kg/d) to allogeneic BAIT recipients resulted in a significant decrease in both systemic GVHD and target organ histopathology. Repifermin treatment also reduced serum levels of tumor necrosis factor alpha and lipopolysaccharide compared with control mice. In contrast, repifermin did not affect T-cell proliferation, cytokine production, or cytotoxic responses to host antigens. When 2000 host-derived P815 (H-2(d)) leukemia cells were added to the bone marrow inoculum, repifermin preserved GVL effects and resulted in significantly delayed mortality compared with control-treated allogeneic BMT recipients. Collectively, these data suggest that repifermin administration may represent a novel strategy to separate the toxicity of GVHD from the beneficial GVL effects after allogeneic BAIT. (C) 2003 American Society for Blood and Marrow Transplantation.

Impaired thymic negative selection causes autoimmune graft-versus-host disease
T Teshima, P Reddy, C Liu, D Williams, KR Cooke, JLM Ferrara
BLOOD, 102, 2, 429, 435, AMER SOC HEMATOLOGY, 2003年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Animal models with impaired thymic negative selection do not always cause autoimmune diseases despite the development of an autoreactive T-cell repertoire. We investigated the requirements for the development of systemic autoimmune disease by using bone marrow chimeras that lacked expression of major histocompatibility complex (MHC) class II on thymic antigen-presenting cells (APCs), leading to impaired negative selection. We found that impaired negative selection mediated by absence of MHC class II, but not MHC class I, permitted the development of systemic autoimmune disease that is indistinguishable from acute graft-versus-host disease (GVHD). Thymectomy prevented disease, confirming the causal association of the thymus with its development. Adoptive transfer of CD4(+) T cells caused GVHD in secondary hosts only when they were irradiated, and cotransfer of peripheral CD4(+) and CD8(+) T cells from naive mice prevented the disease. These results demonstrate that impaired thymic negative selection can cause lethal autoimmune disease indistinguishable from acute GVHD in the context of a proinflammatory milieu when peripheral regulatory mechanisms are absent. (C) 2003 by The American Society of Hematology.

Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays
T Ichiba, T Teshima, R Kuick, DE Misek, C Liu, Y Takada, Y Maeda, P Reddy, DL Williams, SM Hanash, JLM Ferrara
BLOOD, 102, 2, 763, 771, AMER SOC HEMATOLOGY, 2003年07月, ［査読有り］
英語, 研究論文（学術雑誌）, The liver, skin, and gastrointestinal tract are major target organs of acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT). In order to gain a better understanding of acute GVHD in the liver, we compared the gene expression profiles of livers after experimental allogeneic and syngeneic BMT using oilgonucleotide microarray. At 35 days after allogeneic BMT when hepatic GVHD was histologically evident, genes related to cellular effectors and acute-phase proteins were up-regulated, whereas genes largely related to metabolism and endocrine function were down-regulated. At day 7 after BMT before the development of histologic changes in the liver, interferon gamma (IFN-gamma)-inducible genes, major histocompatibility (MHC) class II molecules, and genes related to leukocyte trafficking had been up-regulated. Immunohistochemistry demonstrated that expression of IFN-gamma protein itself was increased in the spleen but not in hepatic tissue. These results suggest that the increased expression of genes associated with the attraction and activation of donor T cells induced by IFN-gamma early after BMT is important in the initiation of hepatic GVHD in this model and provide new potential molecular targets for early detection and intervention of acute GVHD. (C) 2003 by The American Society of Hematology.

Over-expression of the dominant-negative isoform of Ikaros confers resistance to dexamethasone-induced and anti-IgM-induced apoptosis
N Sezaki, F Ishimaru, M Takata, T Tabayashi, K Nakase, T Kozuka, K Fujii, H Nakayama, T Teshima, M Harada, M Tanimoto
BRITISH JOURNAL OF HAEMATOLOGY, 121, 1, 165, 169, BLACKWELL PUBLISHING LTD, 2003年04月, ［査読有り］
英語, 研究論文（学術雑誌）, In previous studies, we demonstrated an over-expression of the dominant-negative isoform of the transcription factor Ikaros, Ik-6, in patients with B-cell malignancies, including blast crisis of chronic myelogenous leukaemia and acute lymphoblastic leukaemia. To investigate the consequence of over-expression of Ik-6 in B cells, we constructed Ik-6 transfectants of the FDH-1 and Ramos cell lines. FDH-1, which was established from a patient with early pre-B acute lymphoblastic leukaemia, undergoes apoptosis with dexamethasone treatment, whereas Ramos undergoes apoptosis following anti-IgM antibody treatment. Compared with the wild type, the over-expression of Ik-6 rendered the FDH-1 and Ramos transfectants resistant to dexamethasone-induced and anti-IgM-induced apoptosis respectively. An immunoblotting study demonstrated bcl-2 upregulation in anti-IgM-induced Ramos Ik-6 transfectants, but not in FDH-1 Ik-6 transfectants. Further investigations of the mechanism of leukaemogenesis associated with the over-expression of Ik-6 are warranted.

Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects
P Reddy, T Teshima, G Hildebrandt, DL Williams, C Liu, KR Cooke, JLM Ferrara
BLOOD, 101, 7, 2877, 2885, AMER SOC HEMATOLOGY, 2003年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Interleukin-18 (IL-18) is a unique cytokine that modulates both T(H)1/IT(H)2 responses, but its ability to modulate diseases through induction of T(H)2 cytokines is unclear. It has been shown to play an important role in allogeneic bone marrow transplantation (BMT). Because immune responses of allogeneic BM donors may affect acute graft-versus-host disease (GVHD), we investigated the effect of pretreating BM transplant donors with IL-18 on the severity of acute GVHD using a well-characterized experimental BMT model (BALB/c-->B6). Pretreatment of allogeneic BM transplant donors with IL-18 significantly improved survival (80% vs 0%; P <.001), and reduced clinical, biochemical, and pathologic indices of acute GVHD in BM transplant recipients. IL-18 pretreatment was associated with reduced interferon γ (IFN-γ) and greater IL-4 secretion by donor T cells after BMT. Acute GVHD mortality was reduced when IL-18 was administered to donors deficient in IFN-γ and signal transducer and activator of transcription 4 (STAT4) but not STAT6 signaling molecules, suggesting a critical role for STAT6 signaling in IL-18's protective effect. IL-18 treatment did not alter donor CD8(+) cytotoxic T-lymphocyte (CTL) activity and preserved graft-versus-leukemia (GVL) effects after allogeneic BMT (70% vs 10%; P <.01). Together these data illustrate that pretreatment of donors with IL-18 prior to allogeneic BMT attenuates acute GVHD in a STAT6-dependent mechanism while preserving GVL effects.

Pulmonary infiltration with eosinophilia syndrome complicated with non-Hodgkin’s lymphoma of B cell lineage
Fujii M, Tanimoto Y, Kiguchi T, Takehara H, Fujimori Y, Teshima T, Kanehiro A, Shinagawa K, Tada S, Kataoka M, Tanimoto M
Allergology International, 52, 3, 161, 164, Blackwell Publishing, 2003年, ［査読有り］
英語, 研究論文（学術雑誌）, [症例報告]

成人Ｂ細胞性急性リンパ性白血病(ALL L3)における長期予後の改善　　　　　　　　　　　　　　　
石丸文彦, 近藤英生, 藤井伸治, 豊嶋崇徳, 品川克至, 池田和眞, 谷本光音
内科専門医会誌, 15, 4, 618, 621, 2003年, ［査読有り］
[症例報告]

The pathophysiology of acute graft-versus-host disease　　　　　　　　　　　　　　　
International Journal of Hematology, 78, 181, 187, 2003年
英語, 研究論文（学術雑誌）

Predictive value of circulating immature cell counts in peripheral blood for timing of peripheral blood progenitor cell collection after G-CSF plus chemotherapy-induced mobilization
T Kozuka, K Ikeda, T Teshima, K Kojima, K Matsuo, A Bessho, K Sunami, Y Hiramatsu, Y Maeda, T Noguchi, K Yamamoto, N Fujii, T Imai, K Takenaka, K Shinagawa, F Ishimaru, K Niiya, N Koide, M Tanimoto, M Harada
TRANSFUSION, 42, 11, 1514, 1522, AMER ASSOC BLOOD BANKS, 2002年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: Enumeration of CD34+ cells in peripheral blood (PB) before apheresis predicts the number of CD34+ cells collected, although flow cytometric techniques used are complex and expensive. In an attempt to determine the optimal timing for peripheral blood progenitor cell (PBPC) collection, the usefulness of circulating immature cell (CIC) counts in PB was evaluated.
Study design and methods: CIC counts in PB and CD34+ cell counts in the apheresis product from 249 collections were assessed, and the relationship between these two parameters was evaluated by with the Pearson rank correlation analysis, the Fisher exact test, and the U-test.
Results: CIC counts were correlated significantly with the number of CD34+ cells per kg of patient's body weight in the apheresis product (Pearson rank correlation analysis: r=0.635, p<0.0001). When a level of 1x10(9) CICs per L was selected as a cutoff value, the sensitivity and specificity for collecting more than 1x10(6) CD34+ cells per kg of body weight were 75.7 and 85.5 percent, respectively.
Conclusion: The present study strongly suggests that the number of CICs in PB may estimate the number of CD34+ cells collected. The data indicate that CIC counts above 1x10(9) per L can be used as a good predictor for PBPC collections containing more than 1x10(6) CD34+ cells per kg of body weight in a single apheresis procedure.

Interleukin 18 preserves a perforin-dependent graft-versus-leukemia effect after allogeneic bone marrow transplantation
P Reddy, T Teshima, G Hildebrandt, U Duffner, Y Maeda, KR Cooke, JLM Ferrara
BLOOD, 100, 9, 3429, 3431, AMER SOC HEMATOLOGY, 2002年11月, ［査読有り］
英語, 研究論文（学術雑誌）, We have recently shown that early administration of interleukin 18 (IL-18) after bone marrow transplantation (BMT) attenuates acute graft-versus-host disease (GVHD) in a lethally irradiated parent into F1 (B6-->B6D2F1) BMT model. In this study, we investigated whether IL-18 can maintain graft-versus-leukemia (GVL) effect in this context. B6D2F1 mice received transplants of T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either syngeneic (H2(b/d)) or allogeneic B6 (H2(b)) donors. Recipient mice were treated with recombinant murine IL-18 or the control diluent. Initial studies demonstrated that IL-18 treatment did not affect the proliferative responses or the cytolytic effector functions of T cells after BMT. In subsequent experiments, animals also received host-type P815 mastocytoma cells at the time of BMT. All syngeneic BM transplant recipients died from leukemia by day 18. The allogeneic BM transplant recipients effectively rejected their leukemia regardless of treatment and IL-18 significantly reduced GVHD-related mortality. Examination of the cytotoxic mechanisms with perforin-deficient donor T cells demonstrated that perforin is critical for the GVL effect. Taken together these data demonstrate that IL-18 can attenuate acute GVHD without impairing the in vitro cytolytic function or the in vivo GVL activity after allogeneic BMT.

Acute graft-versus-host disease does not require alloantigen expression on host epithelium
T Teshima, R Ordemann, P Reddy, S Gagin, C Liu, KR Cooke, JLM Ferrara
NATURE MEDICINE, 8, 6, 575, 581, NATURE AMERICA INC, 2002年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Alloantigen expression on host antigen-presenting cells (APCs) is essential to initiate graft-versus-host disease (GvHD); therefore, alloantigen expression on host target epithelium is also thought to be essential for tissue damage. We tested this hypothesis in mouse models of GvHD using bone-marrow chimeras in which either major histocompatibility complex class I or class II alloantigen was expressed only on APCs. We found that acute GvHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents acute GvHD. These results pertain particularly to CD4-mediated GvHD but also apply, at least in part, to CD8-mediated GvHD. These results challenge current paradigms about the antigen specificity of GvHD effector mechanisms and confirm the central roles of both host APCs and inflammatory cytokines in acute GvHD.

Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease
R Ordemann, R Hutchinson, J Friedman, SJ Burakoff, P Reddy, U Duffner, TM Braun, C Liu, T Teshima, JLM Ferrara
JOURNAL OF CLINICAL INVESTIGATION, 109, 9, 1249, 1256, AMER SOC CLINICAL INVESTIGATION INC, 2002年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Older bone marrow transplantation (BMT) recipients are at heightened risk for acute graft-versus-host disease (GVHD) after allogeneic BMT, but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality, morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice, which also secreted more TNF-alpha and IL-12 after LPS stimulation. In a B6 --> B6D2F1 model, CD4(+) donor T cells but not CD8(+) T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2F1 BM chimeras created with either old or young BM. Four months after chimera creation, allogeneic BMT from B6 donors caused significantly worse GVHD in old BM chimeras. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. These data demonstrate a hitherto unsuspected mechanism of amplified donor T cell responses by aged allogeneic host APCs that increases acute GVHD in aged recipients in this BMT model.

Graft-versus-host disease in the absence of the spleen after allogeneic bone marrow transplantation
SG Clouthier, JLM Ferrara, T Teshima
TRANSPLANTATION, 73, 10, 1679, 1681, LIPPINCOTT WILLIAMS & WILKINS, 2002年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Background. The spleen is considered to be an important secondary lymphoid organ where acute graft-versus-host disease (GVHD) is initiated by donor T cells that recognize host alloantigens after allogeneic bone-marrow transplantation (BMT). The influence of splenectomy on the development of GVHD prior to BMT has yet to be determined.
Methods. The mortality and severity of murine GVHD of unsplenectomized, splenectomized, and sham-operated recipients of allogeneic BMT were compared in a blinded fashion. Serum levels of interferon (IFN)-gamma were measured 7 days after BMT, as an index of systemic donor T-cell responses.
Results. Mortality and morbidity of acute GVHD were not significantly affected by splenectomy in a major histocompatibility complex (MHC)-mismatched, CD4-driven murine GVHD model and a minor histocompatibility antigen (MiHA)-mismatched, CD8-driven GVHD model. Serum levels of IFN-gamma also were not different between the groups.
Conclusion. GVHD can readily develop after allogeneic BMT, even in the absence of the spleen, in these mouse models.

Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8+ dendritic cells and reduces experimental acute graft-versus-host disease.
Teshima T, Reddy P, Lowler KP, KuKuruga MA, Liu C, Cooke KR, Ferrara JLM
Blood, 99, 5, 1825, 1832, AMER SOC HEMATOLOGY, 2002年03月, ［査読有り］
英語, 研究論文（学術雑誌）, Recent evidence suggests that dendritic cells (DCs) can regulate and amplify immune responses. FIt3 ligand (FL)-derived DC function was tested as a stimulator of allogeneic lymphocytes In vitro and in vivo. Treatment of mice with FL dramatically expanded DC number, but DCs isolated from FL-treated mice (FL DCs) were poor stimulators of allogeneic T-cell responses In vitro. Further activation of FL DCs did not restore their stimulatory ability, and FL DCs did not suppress the stimulation of the allogeneic T cells by normal DCs. FL treatment significantly increased the CD8alpha(+) DC subset, which appeared to be the reason for their poor stimulatory capacity. These observations were confirmed in vivo using a mouse model of acute graft-versus-host disease (GVHD) wherein host DCs play a critical role. FL, treatment of recipients before allogeneic bone marrow transplantation dramatically suppressed donor T-cell responses to host antigens, thereby reducing GVHD mortality (P <.01). These data represent a novel strategy that alters host DCs and reduces acute GVHD.

Donor leukocyte infusion from immunized donors increases tumor vaccine efficacy after allogeneic bone marrow transplantation
T Teshima, C Liu, KP Lowler, G Dranoff, JLM Ferrara
CANCER RESEARCH, 62, 3, 796, 800, AMER ASSOC CANCER RESEARCH, 2002年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Donor T cells play a critical role in mediating both harmful graft-versus-host disease (GVHD) and beneficial graft-versus-tumor effect after allogeneic bone marrow transplantation (BMT). We have recently demonstrated a novel treatment strategy to stimulate specific antitumor activity with preservation of tolerance to host antigens after T cell-depleted allogeneic BMT by vaccination of recipients with irradiated B16 melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor. In this marine system, donor leukocyte infusion from a donor immunized with the recipient-derived B16 vaccines enhanced clinical activity of tumor vaccines without exacerbating GVHD. CD4(+) T cells are essential for this enhancement. lit vitro analysis of splenocytes from donor leukocyte infusion donor mice demonstrated that immunization of donors with the recipient-derived B16 vaccines elicited potent T-cell proliferation and cytokine responses specific to B16 antigens. These results demonstrate that immunization of donors with recipient-derived tumor vaccines preferentially induces tumor-specific T-cell responses and that vaccination of both donors and recipients can generate potent antitumor immunity without exacerbating GVHD. This strategy has important implications to prevent recurrence of malignancies after BMT.

New understanding of the alloresponse-new approarches to GVHD prevention　　　　　　　　　　　　　　　
Seminars in Hematology, 39, 15, 22, 2002年
英語, 研究論文（学術雑誌）

Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis
P Reddy, T Teshima, M Kukuruga, R Ordemann, C Liu, K Lowler, JLM Ferrara
JOURNAL OF EXPERIMENTAL MEDICINE, 194, 10, 1433, 1440, ROCKEFELLER UNIV PRESS, 2001年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Interleukin (IL)-18 is a recently discovered cytokine that modulates both T helper type 1 (Th1) and Th2 responses. IL-18 is elevated during acute graft-versus-host disease (GVHD). We investigated the role of IL-18 in this disorder using a well characterized murine bone marrow transplantation (BMT) model (B6 --> B6D2F1). Surprisingly, blockade of IL-18 accelerated acute GVHD-related mortality. In contrast, administration of IL-18 reduced serum tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS) levels, decreased intestinal histopathology, and resulted in significantly improved survival (75 vs. 15%, P < 0.001). Administration of IL-18 attenuated early donor T cell expansion and was associated with increased Fas expression and greater apoptosis of donor T cells. The administration of IL-18 no longer protected BMT recipients from GVHD when Fas deficient (lpr) mice were used as donors. IL-18 also lost its ability to protect against acute GVHD when interferon (IFN)-gamma knockout mice were used as donors. Together, these results demonstrate that IL-18 regulates acute GVHD by inducing enhanced Fas-mediated apoptosis of donor T cells early after BMT, and donor IFN-gamma is critical for this protective effect.

Administration of granulocyte colony-stimulating factor induces hyporesponsiveness to lipopolysaccharide and impairs antigen-presenting function of peripheral blood monocytes
K Sunami, T Teshima, Y Nawa, Y Hiramatsu, Y Maeda, K Takenaka, K Shinagawa, F Ishimaru, K Ikeda, K Niiya, M Harada
EXPERIMENTAL HEMATOLOGY, 29, 9, 1117, 1124, ELSEVIER SCIENCE INC, 2001年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective. The incidence and severity of acute graft-vs-host disease after allogeneic transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) are not greater than those after conventional bone marrow transplantation despite infusion of more than one log greater number of donor T cells in PBSC. It has been postulated that monocytes from G-CSF-mobilized donors suppress alloreactivity of donor T cells.
Materials and Methods. We investigated the phenotype and function of monocytes in normal individuals receiving 10 mug/kg of G-CSF for 4 days.
Results. Monocytes were phenotypically and functionally different after G-CSF administration from steady-state monocytes. They were characterized by an increased CD14(+)CD16(+) subpopulation, reduced expression of HLA-DR, and diminished ability to produce tumor necrosis factor-alpha and interleukin-10 to lipopolysaccharide, compared with steady-state monocytes. These alterations were not replicated by culturing monocytes with G-CSF in vitro, suggesting an indirect effect of G-CSF. In addition, the antigen-presenting function of G-CSF-mobilized monocytes was impaired.
Conclusion. Hyporesponsiveness of G-CSF-treated monocytes to lipopolysaccharide with regard to tumor necrosis factor-alpha production, together with impaired antigen-presenting function, may be responsible for the unexpectedly low incidence of graft-vs-host disease after G-CSF-mobilized PBSC transplantation. (C) 2001 International Society for Experimental Hematology. Published by Elsevier Science Inc.

LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation
KR Cooke, A Gerbitz, JM Crawford, T Teshima, GR Hill, A Tesolin, DP Rossignol, JLM Ferrara
JOURNAL OF CLINICAL INVESTIGATION, 107, 12, 1581, 1589, AMER SOC CLINICAL INVESTIGATION INC, 2001年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Acute graft-versus-host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT). Recent studies have demonstrated that the loss of gastrointestinal tract integrity, and specifically the translocation of LPS into the systemic circulation, is critical to the induction of cytokine dysregulation that contributes to GVHD. Using a mouse BMT model, we studied the effects of direct LPS antagonism on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of B975, a synthetic lipid-A analogue from day 0 to day +6, reduced serum TNF-alpha levels, decreased intestinal histopathology, and resulted in significantly improved survival and a reduction in clinical. GVHD, compared with control-treated animals. Importantly, B975 had no effect on donor T cell responses to host antigens in vivo or in vitro. When mice received lethal doses of P815 tumor cells at the time of BMT, administration of B975 did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a critical role for LPS in the early inflammatory events contributing to GVHD and suggest that a new class of pharmacologic agents, LPS antagonists, may help to prevent GVHD while preserving T cell responses to host antigens and GVL activity.

Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect
C Schmaltz, O Alpdogan, KJ Horndasch, SJ Muriglan, BJ Kappel, T Teshima, JLM Ferrara, SJ Burakoff, MRM van den Brink
BLOOD, 97, 9, 2886, 2895, AMER SOC HEMATOLOGY, 2001年05月, ［査読有り］
英語, 研究論文（学術雑誌）, In allogeneic bone marrow transplantation (BMT) donor T cells are primarily responsible for antihost activity, resulting in graft-versus-host disease (GVHD), and for antileukemia activity, resulting in the graft-versus-leukemia (GVL) effect. The relative contributions of the Fas ligand (Fast) and perforin cytotoxic pathways in GVHD and GVL activity were studied by using FasL-defective or perforin-deficient donor T cells in murine parent --> F1 models for allogeneic bone marrow transplantation. It was found that FasL-defective B6.gld donor T cells display diminished GVHD activity but have intact GVL activity. In contrast, perforin-deficient B6.pfp(-/-) donor T cells have intact GVHD activity but display diminished GVL activity. Splenic T cells from recipients of B6,gld or B6.pfp(-/-) T cells had identical proliferative and cytokine responses to host antigens; however, splenic T cells from recipients of B6.pfp-/- T cells had no cytolytic activity against leukemia cells in a cytotoxicity assay, In experiments with selected CD4(+) or CD8(+) donor T cells, the FasL pathway was important for GVHD activity by both CD4(+) and CD8+ T cells, whereas the perforin pathway was required for CD8-mediated GVL activity. These data demonstrate in a murine model for allogeneic bone marrow transplantation that donor T cells mediate GVHD activity primarily through the FasL effector pathway and GVL activity through the perforin pathway. This suggests that donor T cells make differential use of cytolytic pathways and that the specific blockade of one cytotoxic pathway may be used to prevent GVHD without interfering with GVL activity. (Blood. 2001;97: 2886-2895) (C) 2001 by The American Society of Hematology.

Tumor cell vaccine elicits potent antitumor immunity after allogeneic T-cell-depleted bone marrow transplantation
T Teshima, N Mach, GR Hill, LY Pan, S Gillessen, G Dranoff, JLM Ferrara
CANCER RESEARCH, 61, 1, 162, 171, AMER ASSOC CANCER RESEARCH, 2001年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Allogeneic bone marrow transplantation (BMT) is currently restricted to hematological malignancies because of a lack of antitumor activity against solid cancers. We have tested a novel treatment strategy to stimulate specific antitumor activity against a solid tumor after BMT by vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). Using the B16 melanoma model, we found that vaccination elicited potent antitumor activity in recipients of syngeneic BMT in a time-dependent fashion, and that immune reconstitution was critical for the development of antitumor activity. Vaccination did not stimulate antitumor immunity after allogeneic BMT because of the post-BMT immunodeficiency associated with graft-versus-host disease (GVHD). Remarkably, vaccination was effective in stimulating potent and long-tasting antitumor activity in recipients of T-cell-depleted (TCD) allogeneic bone marrow. Recipients of TCD bone marrow who showed significant immune reconstitution by 6 weeks after BMT developed B16-specific T-cell-cytotoxic, proliferative, and cytokine responses as a function of vaccination. T cells derived from donor stem cells were, therefore, able to recognize tumor antigens, although they remained tolerant to host histocompatibility antigens. These results demonstrate that GM-CSF-based tumor cell vaccines after allogeneic TCD BMT can stimulate potent antitumor effects without the induction of GVHD, and this strategy has important implications for the treatment of patients with solid malignancies.

Pathogenesis and prevention of graft-versus-host disease
Current opinion in Organ Transplantation, 6, 265, 271, 2001年
英語, 研究論文（学術雑誌）

移植片対宿主病(GVHD)最近の理解　　　　　　　　　　　　　　　
豊嶋 崇徳
最新医学, 56, 192, 197, 2001年
日本語, 研究論文（学術雑誌）

Allogeneic peripheral blood stem cell transplantation in 23 adult patients with hematologic malignancies: A single-center experience
K Takenaka, K Shinagawa, K Sunami, N Fujii, Y Hiramatsu, Y Maeda, Y Nawa, Y Katayama, T Teshima, F Ishimaru, K Kiura, K Ikeda, M Harada
INTERNATIONAL JOURNAL OF HEMATOLOGY, 72, 3, 362, 370, CARDEN JENNINGS PUBL CO LTD, 2000年10月, ［査読有り］
英語, 研究論文（学術雑誌）, We describe a single-center experience of 23 consecutive patients (median age, 35 years) with hematologic malignancies who received allogeneic peripheral blood stem cell transplants (alloPBSCTs) from HLA-identical siblings. Ten patients had standard-risk disease and 13 had high-risk disease. Twenty-one patients received alloPBSCT as a primary transplant, and the remaining 2, with high-risk disease, as a second transplant after posttransplantation relapse. All donors received daily subcutaneous injections of granulocyte colony-stimulating factor at a dose of 10 mug/kg, and peripheral blood stem cells were collected by 1 to 3 aphereses. Median numbers of CD34(+) and CD3(+) cells infused were 5.8 x 10(6)/kg (range, 1.3-19.7 x 10(6)/kg) and 4.9 x 10(8)/kg (range, 1.9-8.6 x 10(8)/kg), respectively. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A (CyA) and methotrexate (18 patients) or CyA and methylprednisolone (5 patients). Rapid hematologic engraftment was observed in 20 of the 23 patients. Median days to absolute neutrophil counts >0.5 x 10(9)/L and platelet counts >20 x 10(9)/L were 12 (range, 9-18 days) and 14 (range, 10-128 days), respectively. Acute GVHD of grade 2-4 was observed in 6 of 20 evaluable patients (30%) and extensive chronic GVHD in 8 of 15 evaluable patients (53%). Ten of the 23 patients (44%) were surviving in continuous complete remission 191 to 1492 days (median, 643 days) posttransplantation. Treatment-related death within 100 days posttransplantation was observed in 6 of the 23 patients (26%). Six of the 23 patients (26%) developed relapse at a median 81 days (range, 38-160 days) posttransplantation. Further study is needed to assess the precise benefits of alloPBSCT compared with allogeneic bone marrow transplantation. Int J Hematol. 2000;72:362-370. (C) 2000 The Japanese Society of Hematology.

Reactivation of human herpesviruses after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation
Y Maeda, T Teshima, M Yamada, M Harada
LEUKEMIA & LYMPHOMA, 39, 3-4, 229, 239, HARWOOD ACAD PUBL GMBH, 2000年10月
英語, 研究論文（学術雑誌）, Reactivation of latent herpesviruses results in outcomes ranging from asymptomatic shedding of viruses to severe diseases, depending on the immunological competence of the host. Severe and prolonged suppression of cellular and humoral immunity after hematopoietic stem cell transplantation is accompanied by a high incidence of symptomatic recurrent herpesvirus infections, Subclinical reactivation also occurs more frequently than previously expected in transplant recipients. An increasing viral load in the blood detected by an antigenemia assay or PCR and viral shedding in regional fluids have a predictive value for subsequent diseases, Monitoring of viral DNA in the peripheral blood after allogeneic bone marrow transplantation (allo-BMT) reveals unique temporal profiles of detection fur each herpesvirus. Recent studies demonstrate that recovery of CD4+ T cells is enhanced within one month after allogeneic peripheral blood stem cell transplantation (allo-PBSCT) compared to allo-BMT, To clarify whether this immunological advantage could affect the reactivation of human herpesvirus (HHV), we monitored the emergence of viral DNA by a nested-double polymerase chain reaction in peripheral blood leukocytes, Detection rates of HHV-6 DNAs which peak at 3-4 weeks post-transplant, were significantly reduced after allo-PBSCT compared to allo-BMT, while those of other herpesviruses which tend to be reactivated later than this period (Epstein-Barr virus and cytomegalovirus) were similar between the two types of transplants. Detection of HHV-6 DNA within the first month after the transplant was associated with delayed platelet engraftment. These results underscore the important role of CD3+ T reconstitution in inhibiting virus reactivation post-transplant.

G-CSF reduces IFN- and IL-4 production by T cells after allogeneic stimulation by indirectly modulating monocyte function
Nawa Y, Teshima T, Sunami K, Hiramatsu Y, Maeda Y, Yano T, Shinagawa K, Ishimaru F, Omoto E, Harada M
Bone Marrow Transplant, 25, 10, 1035, 1040, NATURE PUBLISHING GROUP, 2000年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Despite a 10-fold increase of T cell dose, the incidence and severity of acute GVHD following allogeneic transplantation of G-CSF-mobilized PBSC is not increased compared to BMT. Experimental murine studies demonstrate that G-CSF polarizes donor T cells toward a type 2 cytokine response. To determine whether G-CSF alters T cell cytokine responses, we investigated the effects of G-CSF administration on T cell proliferative and cytokine responses to alloantigen and Con A in nonadherent PBMC (NAC) and CD3(+) T cells obtained from normal individuals before and after G-CSF administration (10 mu g/kg x 4 days). Although T cell proliferative and cytokine (IFN-gamma and IL-4) responses to alloantigen stimulation and Con A were significantly reduced in post-G-CSF NAG, they were restored by the removal of non-T cells from post-G-CSF NAG. Furthermore, there was less T cell alloreactivity in MLR in the presence of autologous post-G-CSF monocytes than in the presence of pre-G-CSF monocytes. This alteration was not replicated in vitro by culturing PBMC with G-CSF. These results suggest that G-CSF administration suppresses T cell proliferative and cytokine (IFN-gamma and IL-4) responses to allogeneic stimulation by indirectly modulating monocyte function.

G-CSF modulates cytokine profile of dendritic cells and decreases acute graft-versus-host disease through effects on the donor rather than the recipient
Reddy, V, GR Hill, LY Pan, A Gerbitz, T Teshima, Y Brinson, JLM Ferrara
TRANSPLANTATION, 69, 4, 691, 693, LIPPINCOTT WILLIAMS & WILKINS, 2000年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Allogeneic peripheral blood stem cell transplantation (PBSCT) is increasingly used instead of bone marrow transplantation, particularly in HLA identical sibling pairs. Despite the presence of significantly increased numbers of T cells in the PBSC graft, acute graft-versus-host disease (GVHD) is not increased. We have investigated whether granulocyte-colony stimulating factor (G-CSF) administration to PBSCT recipients, both with and without donor G-CSF pretreatment, further modulates acute GVHD in a murine model of PBSCT. Recipients of G-CSF mobilized splenocytes showed a significantly improved survival (P<0.001) and a reduction in GVHD score and serum LPS levels compared with control recipients. G-CSF treatment of donors, rather than recipients, had the most significant effect on reducing levels of tumor necrosis factor (TNF alpha) 7 days after transplantation. As a potential mechanism of the reduction in TNF alpha; we demonstrate G-CSF decreased dendritic cells TNF alpha, and interleukin-12 production to lipopolysaccharide, In conclusion, G-CSF modulates GVHD predominantly by its effects on donor cells, reducing the production of TNF alpha. G-CSF treatment of bone marrow transplantation recipients, without pretreatment of the donor, does not have an impact on acute GVHD.

The p55 TNF-alpha receptor plays a critical role in T cell alloreactivity
GR Hill, T Teshima, Rebel, VI, OI Krijanovski, KR Cooke, YS Brinson, JLM Ferrara
JOURNAL OF IMMUNOLOGY, 164, 2, 656, 663, AMER ASSOC IMMUNOLOGISTS, 2000年01月, ［査読有り］
英語, 研究論文（学術雑誌）, TNF-alpha is known to be an important mediator of tissue damage during allograft rejection and graft-vs-host disease (GVHD), but its role in supporting T cell responses to allogeneic Ags is unclear. We have studied this question by comparing normal mice with those lacking the P55 (p55 TNFR-/-) or p75 (p75 TNFR-/-) TNF-alpha receptors as donors in well-defined bone marrow transplant (BMT) models. Recipients of p55 TNFR-/- cells had significantly reduced mortality and morbidity from GVHD compared with the other two sources of T cells, In vitro, T cells lacking the p55 (but not the p75) TNF-alpha receptor exhibited decreased proliferation and production of Th1 cytokines in MLC, This defect was only partially restored by exogenous IL-2 and affected both CD4(+) and CD8(+) populations. CD8(+) p55 TNFR-/- proliferation was impaired independently of IL-2 whereas CTL effector function was impaired in an IL-2-dependent fashion. Inhibition of TNF-alpha with TNFR:Fc in primary MLC also impaired the proliferation and Th1 differentiation of wild-type T cells. BMT mixing experiments demonstrated that the reduced ability of p55 TNFR-/- donor cells to induce GVHD was due to the absence of the p55 TNFR on T cells rather than bone marrow cells. These data highlight the importance of TNF-alpha in alloreactive T cell responses and suggest that inhibition of the T cell p55 TNF-alpha receptor may provide an additional useful therapeutic maneuver to inhibit alloreactive T cell responses following bone marrow and solid organ transplantation.

Multiple autoimmune haemopoietic disorders and insidious clonal proliferation of large granular lymphocytes
K Akashi, T Shibuya, S Taniguchi, S Hayashi, H Iwasaki, T Teshima, Y Takamatsu, H Gondo, T Okamura, M Harada, Y Niho
BRITISH JOURNAL OF HAEMATOLOGY, 107, 3, 670, 673, BLACKWELL SCIENCE LTD, 1999年12月, ［査読有り］
英語, 研究論文（学術雑誌）, We report a patient with clonal proliferation of CD3(+)8(+)TCR alpha beta(+) large granular lymphocytes (LGL) presenting multiple episodes of autoimmune cytopenia, including autoimmune neutropenia, idiopathic thrombocytopenic purpura, autoimmune haemolytic anaemia, and pure red cell aplasia. Each disorder appeared separately or as a combination during an 11-year clinical course. The increase of blood CD3(+)8(+)TCR alpha beta(+) LGL was detected 6 years after the initial diagnosis of cptopenia, but the absolute number of LGL cells was always <1.0x10(9)/l. LGL cells were of monoclonal origin and had a chromosomal abnormality. LGL cells transiently responded to cyclosporine A therapy, which was also effective on all of these autoimmune cytopenias. Accordingly, an undetectable level of proliferation of a clonal LGL population could cause various autoimmune haemopoietic disorders.

IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation
T Teshima, GR Hill, LY Pan, YS Brinson, MRM van den Brink, KR Cooke, JLM Ferrara
JOURNAL OF CLINICAL INVESTIGATION, 104, 3, 317, 325, AMER SOC CLINICAL INVESTIGATION INC, 1999年08月, ［査読有り］
英語, 研究論文（学術雑誌）, We recently showed that IL-11 prevents lethal graft-versus-host disease (GVHD) in a murine bone marrow transplantation (BMT) model of GVHD directed against MHC and minor antigens. In this study, we have investigated whether IL-11. can maintain a graft-versus-leukemia (GVL) effect. Lethally irradiated B6D2F1 mice were transplanted with either T cell-depleted (TCD) bone marrow (BM) alone or with BM and splenic T cells from allogeneic BG donors. Animals also received host-type P815 mastocytoma cells at the time of BMT. Recipients were injected subcutaneously with recombinant human IL-11 or control diluent twice daily, from 2 days before BMT to 7 days after BMT TCD recipients all died from leukemia by day 23. All control- and IL-11 treated allogeneic animals effectively rejected their leukemia, but IL-11 also reduced GVHD-related mortality. Examination of the cellular mechanisms of GVL and GVHD in this system showed that IL-11 selectively inhibited CD4-mediated GVHD, while retaining both CD4- and CD8-mediated GVL. In addition, IL-11 treatment did not affect cyolytic effector functions of T cells after BMT either in vivo or in vitro. Studies with perforin-deficient donor T cells demonstrated that the GVL effect was perforin dependent. These data demonstrated that IL-11 can significantly reduce CD4-dependent GVHD without impairing cytolytic function or subsequent GVL activity of CD8(+) T cells. Brief treatment with IL-11 shortly after BMT may therefore represent a novel strategy for separating GVHD and GVL.

Differential roles of IL-1 and TNF- on graft-versus-host disease and graft-versus-leukemia
Hill GR, Teshima T, Gerbitz A, Pan L, Cooke KR, Brinson YS, Crawford JM, Ferrara JLM
J Clin Invest, 104, 4, 459, 467, AMER SOC CLINICAL INVESTIGATION INC, 1999年08月, ［査読有り］
英語, 研究論文（学術雑誌）, We demonstrate an increase in graft-versus-host disease (GVHD) after experimental bone marrow transplant (BMT) when cyclophosphamide (Cy) is added to an otherwise well-tolerated dose (900 cGy) of total body irradiation (TBI). Donor T cell expansion on day +13 was increased after conditioning with Cy/TBI compared with Cy or TBI alone, although cytotoxic T lymphocyte (CTL) function was not altered. Histological analysis of the gastrointestinal tract demonstrated synergistic damage by Cy/TBI and allogeneic donor cells, which permitted increased translocation of LPS into the systemic circulation. TNF-alpha and IL-1 production in response to LIPS was increased in BMT recipients after Cy/TBI conditioning. Neutralization of IL-1 significantly reduced serum LPS levels and GVHD mortality, but it did not affect donor CTL activity. By contrast, neutralization of TNF-alpha did not prevent GVHD mortality but did impair CTL activity after BMT. When P815 leukemia cells were added to the bone marrow inoculum, allogeneic BMT recipients given the TNF-alpha inhibitor relapsed at a significantly faster rate than those given the IL-1 inhibitor. To confirm that the role of TNF-alpha in graft versus leukemia (GVL) was due to effects on donor T cells, cohorts of animals were transplanted with T cells from either wild-type mice or p55 TNF-alpha receptor-deficient mice. Recipients of TNF-alpha p55 receptor-deficient T cells demonstrated a significant impairment in donor CTL activity after BMT and an increased rate of leukemic relapse compared with recipients of wild-type T cells. These data highlight the importance of conditioning in GVHD pathophysiology, and demonstrate that TNF-alpha is critical to GVL mediated by donor T cells, whereas IL-1 is not.

Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease
OI Krijanovski, GR Hill, KR Cooke, T Teshima, JM Crawford, YS Brinson, JLM Ferrara
BLOOD, 94, 2, 825, 831, AMER SOC HEMATOLOGY, 1999年07月, ［査読有り］
英語, 研究論文（学術雑誌）, The major obstacles to successful outcome after allogeneic bone marrow transplantation (BMT) for leukemia remain graft-versus-host disease (GVHD) and leukemic relapse. Improved survival after BMT therefore requires more effective GVHD prophylaxis that does not impair graft-versus-leukemia (GVL) effects, We studied the administration of human recombinant keratinocyte growth factor (KGF) in a well-characterized murine BMT model for its effects on GVHD. KGF administration from day -3 to +7 significantly reduced GVHD mortality and the severity of GVHD in the gastrointestinal(GI) tract, reducing serum lipopolysaccharide (LPS) and tumor necrosis factor (TNF)alpha levels, but preserving donor T-cell responses (cytotoxic T lymphocyte [CTL] activity, proliferation, and interleukin [IL]-2 production) to host antigens. When mice received lethal doses of P815 leukemia cells at the time of BMT, KGF treatment significantly decreased acute GVHD compared with control-treated allogeneic mice and resulted in a significantly improved leukemia-free survival (42% v 4%, P < .001). KGF administration thus offers a novel approach to the separation of GVL effects from GVHD. (C) 1999 by The American Society of Hematology.

Granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation maintains graft-versus-leukemia effects through a perforin-dependent pathway while preventing graft-versus-host disease
LP Pan, T Teshima, GR Hill, D Bungard, YS Brinson, VS Reddy, KR Cooke, LM Ferrara
BLOOD, 93, 12, 4071, 4078, AMER SOC HEMATOLOGY, 1999年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Minimization of graft-versus-host disease (GVHD) with preservation of the graft-versus-leukemia (GVL) effect is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (BMT) for patients with hematological malignancies. We and other investigators have shown that granulocyte colony-stimulating factor (G-CSF)-mobilized allogeneic peripheral stem cell transplantation (PBSCT) reduces the severity of acute GVHD in murine models. In this study, we investigated whether G-CSF-mobilized PBSC maintain their GVL effect in a murine allogeneic transplant model (B6 --> B6D2F1). be mice (H-2(b)) were injected subcutaneously with human G-CSF (100 mu g/kg/d) for 6 days and their splenocytes were harvested on day 7 as a source of PBSC. G-CSF mobilization dramatically improved transplant survival compared with nonmobilized controls (95% v 0%, P < .001). Systemic levels of lipopolysaccharide and tumor necrosis factor-cu were markedly reduced in recipients of allogeneic G-CSF-mobilized donors, but cytolytic T lymphocyte (CTL) activity against host tumor target cells p815 was retained in those recipients. When leukemia was induced in recipients by coinjection of p815 tumor cells (H-2(d)) at the time of transplantation, all surviving recipients of G-CSF-mobilized B6 donors were leukemia-free at day 70 after transplant, whereas all mice who received T-cell-depleted (TCD) splenocytes from G-CSF-mobilized B6 donors died of leukemia. When splenocytes from G-CSF-mobilized perforin-deficient (pfp(-/-)) mice were used for transplantation, 90% of recipients died of leukemia, demonstrating that perforin is a crucial pathway mediating GVL effects after G-CSF-mobilized PBSCT. These data illustrate that G-CSF-mobilized allogeneic PBSCT separate GVL from GVHD by preserving perforin-dependent donor CTL activity while reducing systemic inflammation. (C) 1999 by The American Society of Hematology.

Hematopoietic progenitor cells from allogeneic bone marrow transplant donors circulate in the very early post-transplant period
Y Katayama, N Mahmut, H Takimoto, Y Maeda, T Yano, K Kojima, T Azuma, M Hara, K Imajyo, S Takahashi, T Kai, Y Ohno, T Miyamoto, K Nagafuji, K Matsue, K Takenaka, T Teshima, K Shinagawa, F Ishimaru, E Omoto, M Harada
BONE MARROW TRANSPLANTATION, 23, 7, 659, 665, STOCKTON PRESS, 1999年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Despite the therapeutic efficacy of allogeneic bone marrow transplantation (allo-BMT), circulating hematopoietic progenitor cells after bone marrow transplantation have not been well characterized. In the present study, we focused on these 'post-transplant circulating progenitor cells (PTCPC)' which may be on their way to bone marrow. We analyzed the number of myeloid progenitor cells (CFU-GM) per 10 mi of peripheral blood (PB) on days 0 (just before transplantation), 1 (8-15 h after the completion of transplantation), 2, 3, 5, 7, 10, 14, 17, 21, 28 and 35 after allo-BMT in five transplant patients using a standard methylcellulose assay, In addition, high proliferative potential colony-forming cells (HPP-CFC) of the harvested donor bone marrow (BM) and day 1 PB of recipients were assayed in five patients. The origin of HPP-CFC from day 1 PB was analyzed by polymerase chain reaction of a DNA region containing a variable number of tandem repeats. The replating potential of these HPP-CFC was evaluated by a secondary colony assay. The proportion of CD38(negative) cells among CD34(+) cells in the harvested BM and day 1 PB was evaluated by two-color flow cytometric analysis. The number of CFU-GM on day 1 ranged from 6 to 73/10 mi PB, and became undetectable on day 5, The reappearance of PTCPC was observed on day 14, along with hematopoietic recovery. The proportion of HPP-CFC among myeloid colonies from day 1 PB was significantly higher than that from harvested BM (44.3 +/- 10.4% vs 11.3 +/- 2.1%, respectively, n = 5, P = 0.0030), These HPP-CFC from day 1 PB were confirmed to be of donor origin, More than 90% of these HPP-CFC had replating potential. Two-color flow cytometric analysis revealed that the proportion of CD34(+)CD38(negative) cells was significantly higher in day 1 PB than in the harvested Bill (61.0 +/- 16.5% vs 9.3 +/- 3.5%, respectively, n = 7, P = 0.0002), These observations suggest that both primitive and committed transplanted myeloid progenitor cells may circulate in the very early period following allo-BMT.

Monitoring of human herpesviruses after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation
Y Maeda, T Teshima, M Yamada, K Shinagawa, S Nakao, Y Ohno, K Kojima, M Hara, K Nagafuji, S Hayashi, S Fukuda, H Sawada, K Matsue, K Takenaka, F Ishimaru, K Ikeda, K Niiya, M Harada
BRITISH JOURNAL OF HAEMATOLOGY, 105, 1, 295, 302, BLACKWELL SCIENCE LTD, 1999年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Herpesviruses frequently cause serious complications after allogeneic bone marrow transplantation (allo-BMT). Recent studies have shown more rapid immune reconstitution after allogeneic peripheral blood stem cell transplantation (allo-PBSCT) compared with allo-BMT. However, it has not been clarified whether the improved immune reconstitution after allo-PBSCT is associated with a lower incidence of herpesvirus infections. We monitored the emergence of Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6) and HHV-7 DNA by a nested-double polymerase chain reaction in peripheral blood leucocytes from 22 allo-BMT and 16 allo-PBSCT patients, Each virus had an unique temporal profile of detection. HHV-6 DNA was detected most frequently at 3 weeks after transplantation, whereas CMV and EBV DNA were detected later (2-3 months). Detection rates of HHV-6 DNA at 3 and 4 weeks after allo-BMT were significantly higher than those after allo-PBSCT (9/16 v 2/13 at 3 weeks, P< 0.01; 10/21 v 1/15 at 4 weeks, P<0.01). Detection rates of the other three herpesviruses after the two types of allogeneic transplantation were not significantly different throughout observation period. Furthermore, detection of HHV-6 DNA within the first 4 weeks was associated with delayed platelet engraftment after both allo-BMT and allo-PBSCT (P<0.01). These results suggest an advantage for allo-PBSCT over allo-BMT in terms of suppression of HHV-6 reactivation and prevention of subsequent complications.

Nasal and nasal-type natural killer T-cell lymphoma
S Hirakawa, H Kuyama, S Takahashi, O Yamasaki, H Kanzaki, T Teshima, M Harada, YX Ma, T Kawabata, T Yoshino, J Arata
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 40, 2, 268, 272, MOSBY-YEAR BOOK INC, 1999年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Nasal and nasal-type natural killer (NK)/T-cell lymphomas follow an aggressive course and have a poor prognosis. Recent pathologic studies suggest that the disease is a malignant proliferation of NK cells, which often express CD56. An association with the Epstein-Barr virus has also been reported. Skin involvement occurred in each of the 3 patients studied. Radiation therapy provided some benefit to the patients in the early stages. Conventional chemotherapies were not effective. To overcome this multiple-drug resistance of the tumor cells, cyclosporine and high-dose chemotherapy was combined with peripheral-blood stem-cell transplantation, The average life span from the onset of the disease for our patients was 9.6 months. Further improvement in the management of nasal and nasal-type NK/T-cell lymphomas is necessary.

Molecular characterization of total kininogen deficiency in Japanese patients
F Ishimaru, H Dansako, K Nakase, N Fujii, N Sezaki, H Nakayama, N Fujii, Y Komiyama, K Iijima, K Takenaka, T Teshima, K Shinagawa, K Ikeda, K Niiya, M Harada
INTERNATIONAL JOURNAL OF HEMATOLOGY, 69, 2, 126, 128, CARDEN JENNINGS PUBL CO LTD, 1999年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Kininogens are multifunctional plasma glycoproteins. There are two forms of human kininogen: low molecular weight kininogen (LK) and high molecular weight kininogen (HK). Both are derived from the same gene by alternative splicing. Same patients with kininogen deficiency have been repo