研究者詳細 - 遠西　大輔

論文 - 遠西　大輔

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Markedly elevated serum level of presepsin in agranulocytosis with hematologic malignancy: A potential prognostic factor in a single-institution retrospective study after granulocyte transfusion. 国際誌

Takuya Fukumi, Keiko Fujii, Wataru Kitamura, Kazuhiro Ikeuchi, Naomi Asano, Akira Yamamoto, Hiroki Kobayashi, Takumi Kondo, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Ken-Ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda, Nobuharu Fujii

Laboratory medicine 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: No established criteria exist for assessing the effectiveness of granulocyte transfusion (GTX) or biomarkers for predicting fatal infections in neutropenia. This study aimed to assess whether a novel sepsis marker, presepsin (P-SEP), is a useful prognostic indicator during GTX. METHODS: We collected frozen serum from 8 patients who had undergone GTX between September 2022 and October 2023 and measured their P-SEP levels. We compared these results with clinical records and assessed the alterations before and after GTX and their association with prognosis. RESULTS: The post-transfusion neutrophil count increased in all cases. In 5 of 8 patients (62.5%), P-SEP levels were reduced 1 day after GTX. Pretransfusion P-SEP levels were statistically significantly lower in the group of patients who survived and overcame infection after transfusion (GTX-survived) than in the group of patients who did not survive (GTX-nonsurvived) (1493 pg/mL vs 6658 pg/mL, P =.04). Transfused cell counts and changes in P-SEP levels 1 day after GTX were better in the GTX-survived group than in the GTX-nonsurvived group, although the difference was not statistically significant. DISCUSSION: Presepsin is a biomarker that can be assessed in patients undergoing GTX for agranulocytosis. A clinically significant increase in P-SEP levels before GTX may indicate ineffective GTX and an unfavorable prognosis.

DOI： 10.1093/labmed/lmae118

A randomized controlled trial of conventional GVHD prophylaxis with or without teprenone for the prevention of severe acute GVHD. 国際誌

Wataru Kitamura, Keiko Fujii, Mitsuru Tsuge, Toshiharu Mitsuhashi, Hiroki Kobayashi, Chihiro Kamoi, Akira Yamamoto, Takumi Kondo, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Ken-Ichi Matsuoka, Nobuharu Fujii, Yoshinobu Maeda

Annals of hematology 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Therapies that effectively suppress graft-versus-host disease (GVHD) without compromising graft-versus-leukemia/lymphoma (GVL) effects is important in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematopoietic malignancies. Geranylgeranylacetone (GGA) is a main component of teprenone, a gastric mucosal protectant commonly used in clinical practice. In preclinical models, GGA suppresses proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), which are associated with GVHD as well as induces thioredoxin-1 (Trx-1), which suppresses GVHD while maintaining GVL effects. Here, we investigated whether the addition of teprenone to standard GVHD prophylaxis could reduce the cumulative incidence of severe acute GVHD (aGVHD) without attenuating GVL effects. This open-label, randomized clinical trial enrolled 40 patients (21 control and 19 teprenone group) who received allo-HSCT between May 2022 and February 2023 in our institution. Patients in the teprenone group received 50 mg of teprenone orally thrice daily for 21 days from the initiation of the conditioning regimen. The cumulative incidence of severe aGVHD by day 100 after allo-HSCT was not significantly different in the two groups (27.9 vs. 16.1%, p = 0.25). The exploratory studies revealed no obvious changes in Trx-1 levels, but the alternations from baseline in IL-1β and TNF-α levels at day 28 after allo-HSCT tended to be lower in the teprenone group. In conclusion, we could not demonstrate that teprenone significantly prevented the development of severe aGVHD. Discrepancy with preclinical model suggests that appropriate dose of teprenone may be necessary to induce the expression of antioxidant enzymes that suppress severe aGVHD. Clinical Trial Registration number:jRCTs 061210072.

DOI： 10.1007/s00277-025-06269-2

Myelodysplastic neoplasms with repeating TAFRO syndrome-like symptoms.

Kenta Hayashino, Nobuharu Fujii, Tomohiro Nagano, Daisuke Ikeda, Kanako Fujiwara, Risa Hashida, Wataru Kitamura, Hiroki Kobayashi, Takumi Kondo, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

International journal of hematology 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

TAFRO syndrome is a systemic disease characterized by thrombocytopenia, anasarca, fever, systemic inflammation, reticulin fibrosis, renal insufficiency, and organomegaly. Although the pathogenesis of TAFRO syndrome remains unknown, it may be associated with cytokine storm and abnormal immune function. Herein, we present a case of a 65-year-old man who was diagnosed with myelodysplastic neoplasms (MDS) with repeating TAFRO syndrome-like symptoms. At ages 59 and 63 years, he developed TAFRO syndrome and was treated with immunosuppressive therapy, which improved these symptoms. At age 65 years, he had TAFRO syndrome-like symptoms with pancytopenia, chromosomal abnormalities, and dysplasia. The patient was subsequently diagnosed with MDS and treated with methylprednisolone, rituximab, bortezomib, and tocilizumab. His MDS-related and TAFRO syndrome-like symptoms simultaneously improved following treatment. Although the patient was not diagnosed with MDS at the first and second events, chromosomal abnormalities were detected, revealing increased clonal cells. MDS can be complicated by immune disorders associated with increased malignant clonal cells. Additionally, patients with MDS exhibit hypercytokinemia, including interleukin-6 and vascular endothelial growth factor. This case indicates that increased clonal cells and hypercytokinemia caused by MDS may lead to abnormal immune function and induce TAFRO syndrome-like symptoms.

DOI： 10.1007/s12185-025-03937-x

A fatal case of enterovirus A71-induced meningoencephalitis following allogenic hematopoietic stem cell transplantation. 国際誌

Yayoi Ueda, Hiroki Kobayashi, Hideaki Fujiwara, Hideharu Hagiya, Risa Hashida, Saya Kubota, Mami Takemoto, Kenta Hayashino, Kanako Fujiwara, Tomohiro Nagano, Ryuichiro Hiyama, Keiko Fujii, Takumi Kondo, Keisuke Seike, Noboru Asada, Daisuke Ennishi, Nobuharu Fujii, Ken-Ichi Matsuoka, Maeda Yoshinobu

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 31 ( 4 ) 102630 - 102630 2025年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Enterovirus A71 (EV-A71) is a major pathogen responsible for hand, foot, and mouth disease (HFMD) in infants and children. EV-A71 infection represents an epidemic in the Asia-Pacific region, and can cause serious central nervous system (CNS) infections in immunocompromised patients that can result in paralysis, disability, or death. There have been few reports in the literature concerning EV-A71 CNS infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adult patients. We describe the case of a 63-year-old woman with EV-A71 meningoencephalitis who underwent a second allo-HSCT for relapsed refractory myelodysplastic syndrome. She developed disturbance of consciousness during intubation due to severe pulmonary impairment following allo-HSCT. Despite the absence of pleocytosis in the cerebrospinal fluid, enterovirus was detected in her cerebral spinal fluid using the Biofire® FilmArray® Meningitis/Encephalitis (ME) panel, which was later identified as EV-A71 at a referral center. Despite a transient improvement in her level of consciousness after intravenous immunoglobulin administration, she did not fully recover. The patient also showed muscle weakness as well as pulmonary impairment that necessitated a tracheotomy. Our case demonstrated the utility of the FilmArray® ME panel as a screening tool for detecting multiple potential pathogens until a specific pathogen could be identified using other diagnostic methods. Clinicians should be aware that EV-A71 CNS infection can occur among adults with severe immunodeficient conditions, and that it leads poor clinical outcomes. Our case suggests that continuous monitoring for this potentially fatal pathogen is warranted for immunocompromised patients.

DOI： 10.1016/j.jiac.2025.102630

Severe hypophosphatemia following idecabtagene vicleucel regardless of the severity of cytokine release syndrome

Kenta Hayashino, Wataru Kitamura, Nobuharu Fujii, Toshiki Terao, Hiroki Kobayashi, Chihiro Kamoi, Takumi Kondo, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Yoshinobu Maeda

Cytotherapy 2025年1月

[Treatment outcomes of axicabtagene ciloleucel for relapsed/refractory diffuse large B-cell lymphoma: a retrospective analysis at a single institution].

Wataru Kitamura, Nobuharu Fujii, Chihiro Kamoi, Toshiki Terao, Akira Yamamoto, Hiroki Kobayashi, Takumi Kondo, Keisuke Seike, Hideaki Fujiwara, Keiko Fujii, Noboru Asada, Daisuke Ennishi, Yoshinobu Maeda

[Rinsho ketsueki] The Japanese journal of clinical hematology 66 ( 2 ) 81 - 91 2025年

記述言語：日本語掲載種別：研究論文（学術雑誌）

The advent of anti-CD19 chimeric antigen receptor-T cell therapy has dramatically changed the treatment strategy for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Three products are recently available in Japan, but to the best of our knowledge, real-world data are only available for tisagenlecleucel. This study was a retrospective analysis of 27 patients who received axicabtagene ciloleucel (axi-cel) for R/R DLBCL at our institution. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 24 (88.9%) and 8 patients (29.6%), respectively, and corticosteroids were used in 19 patients (70.4%). The median follow-up period was 8.1 months (range, 1.0-23.2), and the 6-month progression-free survival and overall survival rates were 80.2% (95% confidence interval [CI], 58.8-91.3) and 92.0% (95%CI, 71.6-97.9), respectively. Although our study was limited by its small sample size and short follow-up period, it demonstrated that axi-cel was highly effective and safe at our institution.

DOI： 10.11406/rinketsu.66.81

P143: Original protocol for presumed germline pathogenic variants in cancer genome profiling tests

Mashu Futagawa, Hideki Yamamoto, Fumino Kato, Chika Fukano, Risa Osumi, Yusaku Urakawa, Tetsuya Okazaki, Shuta Tomida, Daisuke Ennishi, Akira Hirasawa

Genetics in Medicine Open 3 102987 - 102987 2025年

Oral Inflammation and Microbiome Dysbiosis Exacerbate Chronic Graft-versus-host Disease

Yui Kambara, Hideaki Fujiwara, Akira Yamamoto, Kazuyoshi Gotoh, Shuma Tsuji, Mari Kunihiro, Tadashi Oyama, Toshiki Terao, Ayame Sato, Takehiro Tanaka, Daniel Peltier, Keisuke Seike, Hisakazu Nishimori, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-ichi Matsuoka, Yoshihiko Soga, Pavan Reddy, Yoshinobu Maeda

Blood Journal 2024年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：American Society of Hematology

The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in GVHD pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients post-hematopoietic cell transplantation associated with increased chronic GVHD (cGVHD) even in patients receiving post-transplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes (LNs) both pre- and post-transplantation activated antigen-presenting cells (APCs), thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increased in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD.

DOI： 10.1182/blood.2024024540

Outcomes of allogeneic SCT versus tisagenlecleucel in patients with R/R LBCL and poor prognostic factors.

Kenta Hayashino, Toshiki Terao, Hisakazu Nishimori, Wataru Kitamura, Hiroki Kobayashi, Chihiro Kamoi, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

International journal of hematology 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

This study investigated the efficacy of tisagenlecleucel (tisa-cel) and allogeneic hematopoietic stem cell transplantation (allo-SCT) for patients with relapsed and/or refractory (r/r) large B-cell lymphoma (LBCL) with poor prognostic factors, defined as performance status (PS) ≥ 2, multiple extranodal lesions (EN), chemorefractory disease, or higher lactate dehydrogenase (LDH). Overall, the allo-SCT group demonstrated worse progression-free survival (PFS), higher non-relapse mortality, and a similar relapse/progression rate. Notably, the tisa-cel group showed better PFS than the allo-SCT group among patients with chemorefractory disease (3.2 vs. 2.0 months, p = 0.092) or higher LDH (4.0 vs. 2.0 months, p = 0.018), whereas PFS in the two cellular therapy groups was similar among those with PS ≥ 2 or multiple EN. Survival time after relapse post-cellular therapy in patients with poor prognostic factors was 1.6 with allo-SCT and 4.6 months with tisa-cel. These findings were confirmed in a propensity score matching cohort. In conclusion, tisa-cel resulted in better survival than allo-SCT in patients with poor prognostic factors. However, patients who relapsed post-cellular therapy had dismal outcomes regardless of therapy. Further strategies are warranted to improve outcomes in these patients.

DOI： 10.1007/s12185-024-03888-9

Axillary Reactive Lymphoid Hyperplasia, Likely Due to Unicentric Castleman Disease, and the Concurrent Presence of Orbital Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma: A Six-Year Follow-Up Study. 国際誌

Toshihiko Matsuo, Takehiro Tanaka, Tomokazu Fuji, Daisuke Ennishi

Cureus 16 ( 11 ) e73775 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Castleman disease is a lymphadenopathy of unknown cause at a single site, which is designated as unicentric Castleman disease, or at multiple sites designated as multicentric Castleman disease. We present a patient who showed axillary reactive lymphoid hyperplasia, likely due to unicentric Castleman disease, and orbital extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma in a six-year follow-up. A 76-year-old man had a painless left axillary mass for an unknown period and also left complete blepharoptosis with no other systemic symptoms. Suspected of lymphoma, iliac bone marrow biopsy showed no anomalous cells, and positron emission tomography demonstrated abnormal uptake at the left axilla and in the left superior anterior orbit. Incisional biopsy of the left axillary mass demonstrated hyperplastic lymphoid follicles with an atrophic germinal center and prominent small vessels in the follicular center, indicative of unicentric Castleman disease. One year later, annual follow-up positron emission tomography disclosed a high uptake site, next to the previously-identified cyst, in the pancreatic body. Trans-gastric fine needle pancreatic biopsy proved adenocarcinoma and he underwent subtotal stomach-preserving pancreaticoduodenectomy with jejunal anastomosis. He was well for six months after the surgery and thus, underwent resection of the left orbital lesion at 78 years old. The pathology of the orbital lesion showed ambiguous nodular structure with massive infiltration with CD20-positive medium-sized lymphoid cells which were κ monotype in immunoglobulin light chain restriction, indicative of MALT lymphoma. In the four-year period of the COVID-19 pandemic, he was healthy and followed with no treatment until the age of 82 years when he underwent radiation (46 Gy) to the left axillary lesion which did not regress. He then underwent eyelid levator muscle plication for left blepharoptosis since the left orbital lesion remained unpalpable. The six-year follow-up showed that concurrent and independent orbital MALT lymphoma and axillary reactive lymphoid hyperplasia, likely due to unicentric Castleman disease, were both stable. The present case illustrates how important it is to make pathological diagnoses in different anatomical lesions after the initial diagnosis of Castleman disease.

DOI： 10.7759/cureus.73775

中枢神経原発リンパ腫におけるplasmablastサブポピュレーションの分子学的特性について

小林宏紀, 千々松良太, 直井友亮, 大谷理浩, 水田亮, 藤井謙太郎, 石田穣治, 村上裕之, 氏家英貴, 池内一廣, 浦田知宏, 清家圭介, 藤原英晃, 淺田騰, 藤井伸治, 松岡賢市, 佐藤康晴, 前田嘉信, 遠西大輔

日本血液学会学術集会 86回 O3 - 2 2024年10月

小児・AYA世代がんのゲノム医療小児・AYA世代の肉腫におけるゲノム医療の意義

中田英二, 遠西大輔, 二宮貴一朗, 冨田秀太, 山本英喜, 岡崎哲也, 平沢晃, 豊岡伸一, 尾崎敏文

日本癌治療学会学術集会抄録集 62回 OSY16 - 2 2024年10月

Response to Imatinib in a Patient With Gastric Adenocarcinoma With KIT Q556_K558 In-Frame Deletion: A Case Report. 国際誌

Kiichiro Ninomiya, Daisuke Ennishi, Kunio Okamoto, Midori Ando, Satoko Nakamura, Shuta Tomida, Yoshiyuki Ayada, Go Makimoto, Eiki Ichihara, Natsuko Okita, Shinichi Toyooka, Yoshinobu Maeda, Masahiro Tabata

JCO precision oncology 8 e2400228 2024年9月

新たながん遺伝子パネル検査 TruSight Oncology 500(TSO500)の臨床的意義(Clinical relevance of novel comprehensive genomic profiling assay - TruSight Oncology 500(TSO500))

遠西大輔, 冨田秀太, 松井啓隆, 藤野泰輝, 檜井孝夫, 杉本健樹, 川上耕史, 松本光史, 山本弥寿子, 曳野肇, 二宮貴一朗, 山本英喜, 柳井広之, 平沢晃, 豊岡伸一, 豊岡伸一

日本癌学会総会記事 83回 P - 2114 2024年9月

肉腫におけるゲノム医療の進歩 C-CATデータを用いた肉腫のゲノム解析

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 国定俊之, 藤原智洋, 二川摩周, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 8 ) S1727 - S1727 2024年9月

Simulation-based Bone Marrow Aspiration and Trephine Biopsy Education for Medical Students: A Non-randomized Controlled Trial.

Akira Yamamoto, Hisakazu Nishimori, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Introduction Despite the critical role of bone marrow aspiration and a trephine biopsy (BMAT) in the diagnosis and management of hematological diseases, research on effective teaching methods is limited. Medical students traditionally learn to perform BMAT through observation and replication, which poses a risk to patient safety. Therefore, we developed a novel BMAT simulator for undergraduate medical students using a simulation-based education program. Methods This program, designed for fourth- and fifth-year medical students at Okayama University Medical School, included pre-study materials and one hour of simulation training. Internists practicing hematology served as the controls. Before and after the simulation training, the students completed questionnaires regarding self-confidence, self-evaluation, interest, and knowledge. The procedures were evaluated objectively using a checklist at the end of the program. Results There were significant improvements in self-evaluation, self-confidence, interest, and knowledge acquisition after the simulation program (p≤0.001). The checklist revealed that the mean overall proficiency level of the students was 76.9%, which was significantly higher than that of internists (63.5%) (p≤0.01). Conclusion Our simulation-based education program using the novel BMAT simulator improved medical students' BMAT knowledge and skills.

DOI： 10.2169/internalmedicine.3998-24

Recent updates on treatment options for primary follicular lymphoma of the gastrointestinal tract. 国際誌

Masaya Iwamuro, Takehiro Tanaka, Daisuke Ennishi, Motoyuki Otsuka

Expert review of gastroenterology & hepatology 1 - 9 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Primary gastrointestinal follicular lymphoma is a subtype of follicular lymphoma that originates directly from the gastrointestinal tract. Pathologically, it exhibits substantial similarities with the secondary gastrointestinal involvement observed in nodal follicular lymphoma. However, primary gastrointestinal follicular lymphoma presents clinically distinct features, necessitating divergent considerations in treatment selection compared with nodal follicular lymphoma. AREAS COVERED: This narrative review focused on recent articles (2018-2023) regarding the long-term prognosis and treatment options for gastrointestinal follicular lymphoma. In addition, a brief overview of gastrointestinal follicular lymphomas is provided. EXPERT OPINION: Patients with primary gastrointestinal follicular lymphoma often present with a low tumor burden. Lymphoma lesions typically remain asymptomatic for several years or may undergo spontaneous regression without immediate treatment. Therefore, a 'watch and wait' approach is justified. Conversely, when large tumor masses are identified in the gastrointestinal tract, the potential for tumor bleeding or intestinal obstruction requires timely therapeutic interventions.

DOI： 10.1080/17474124.2024.2380337

Activated CD4<sup>+</sup> T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy

Wataru Kitamura, Noboru Asada, Shuntaro Ikegawa, Hideaki Fujiwara, Chihiro Kamoi, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Ken-ichi Matsuoka, Yoshinobu Maeda

Internal Medicine 63 ( 13 ) 1863 - 1872 2024年7月

Safety and efficacy of acalabrutinib and obinutuzumab in treatment-naive chronic lymphocytic leukemia: a Japanese phase 1 study. 国際誌

Jun Takizawa, Takanori Teshima, Daisuke Ennishi, Satoshi Ichikawa, Ritsuro Suzuki, Akira Kojima, Yusuke Takahashi, Nobuya Hayashi, Hisashi Kawasumi, Kosho Murayama, Patricia Cheung, Toshio Kawata, Koji Izutsu

Leukemia & lymphoma 1 - 9 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

DOI： 10.1080/10428194.2024.2370436

Combination of reduced post‐transplant cyclophosphamide and early tacrolimus initiation increases the incidence of chronic graft‐versus‐host disease in human leukocyte antigen‐haploidentical peripheral blood stem‐cell transplantation

Toshiki Terao, Takumi Kondo, Makoto Nakamura, Hiroki Takasuka, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Yoshinobu Maeda, Ken‐ichi Matsuoka

eJHaem 2024年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

Abstract

We evaluated the clinical impacts of the concurrent modification of post‐transplant cyclophosphamide (PTCy) dose and tacrolimus (Tac)‐initiation timing in 61 patients with human leukocyte antigen‐haploidentical transplantation. Reduced‐dose PTCy (80 mg/kg) was associated with a higher incidence of moderate‐to‐severe chronic graft‐versus‐host disease (GVHD) than standard‐dose PTCy (100 mg/kg) (35.0% vs. 26.6%, p = 0.053). Notably, early‐initiation Tac (day ‐1) increased moderate‐to‐severe chronic GVHD than standard‐initiation Tac (day 5) in the reduced‐dose PTCy group (p = 0.032), whereas Tac‐initiation timing did not impact chronic GVHD in the standard‐dose PTCy group. These data indicate that the combination of reduced‐dose PTCy and early‐initiation Tac can amplify chronic GVHD.

DOI： 10.1002/jha2.962

加速する骨・軟部腫瘍に対するゲノム医療: 現状と課題肉腫におけるゲノム医療の現状と課題

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 藤原智洋, 国定俊之, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1457 - S1457 2024年6月

加速する骨・軟部腫瘍に対するゲノム医療: 現状と課題肉腫におけるゲノム医療の現状と課題

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 藤原智洋, 国定俊之, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1457 - S1457 2024年6月

Understanding the intrinsic biology of diffuse large B-cell lymphoma: recent advances and future prospects.

Yusuke Naoi, Daisuke Ennishi

International journal of hematology 2024年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoid tumor, and accounts for approximately 30-40% of non-Hodgkin lymphomas. Although the prognosis has significantly improved with the advent of rituximab combination chemotherapy in the early 2000s, recurrence still occurs in about 40% of cases. Even though chemotherapy with increased dose-intensity is used in recurrent cases, the prognosis of such patients remains poor. Thus, the development of personalized medicine, including molecular-targeted drugs, is required to improve the prognosis of DLBCL patients, and further understanding of the molecular pathogenesis of DLBCL is essential for this purpose. With recent advances in genetic analysis technology, unknown genetic abnormalities and gene expression patterns have been discovered, and based on these discoveries, progress is being made in elucidating and subdividing molecular pathologies. This article summarizes recent findings regarding molecular pathogenesis in DLBCL using transcriptome and genomics technologies, and outlines the path to personalized medicine.

DOI： 10.1007/s12185-024-03780-6

HAVCR2ホモ接合型変異を有し家族内発症した皮下脂肪織炎様T細胞リンパ腫

植田裕子, 藤井伸治, 松原千哲, 近藤歌穂, 寺尾俊紀, 松村彰文, 清家圭介, 藤原英晃, 淺田騰, 遠西大輔, 藤井敬子, 松岡賢市, 森坂広行, 綾田善行, 吉野正, 前田嘉信

臨床血液 65 ( 5 ) 465 - 466 2024年5月

ABC-DLBCLにおけるCD79B発現低下の臨床的・生物学的意義の解明と検証

直井友亮, 千々松良太, 浦田知宏, 角南一貴, 今井利, 名和由一郎, 平松靖史, 山本和彦, 藤井総一郎, 吉田功, 矢野朋文, 高田尚良, 佐藤康晴, 前田嘉信, 遠西大輔

日本リンパ網内系学会会誌 64 90 - 90 2024年5月

造血幹細胞移植後の難治性腸管合併症に対して腸管切除術を施行した2症例

田中謙太郎, 山本晃, 藤井伸治, 近藤喜太, 田中健大, 清家圭介, 藤原英晃, 淺田騰, 遠西大輔, 藤井敬子, 松岡賢市, 松川昭博, 吉野正, 前田嘉信

臨床血液 65 ( 5 ) 454 - 454 2024年5月

Endoscopic manifestation of intestinal transplant-associated microangiopathy after stem cell transplantation. 国際誌

Masaya Iwamuro, Daisuke Ennishi, Nobuharu Fujii, Ken-Ichi Matsuoka, Takehiro Tanaka, Toshihiro Inokuchi, Sakiko Hiraoka, Motoyuki Otsuka

BMC gastroenterology 24 ( 1 ) 140 - 140 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Endoscopic features of intestinal transplant-associated microangiopathy (iTAM) have not been comprehensively investigated. This study aimed to examine the endoscopic characteristics of patients diagnosed with iTAM. METHODS: This retrospective analysis included 14 patients pathologically diagnosed with iTAM after stem cell transplantation for hematolymphoid neoplasms (n = 13) or thalassemia (n = 1). The sex, age at diagnosis, endoscopic features, and prognosis of each patient were assessed. Serological markers for diagnosing transplant-associated thrombotic microangiopathy were also evaluated. RESULTS: The mean age at the time of iTAM diagnosis was 40.2 years. Patients diagnosed based on the pathognomonic pathological changes of iTAM presented with diverse symptoms at the times of endoscopic examinations, including diarrhea (n = 10), abdominal pain (n = 5), nausea (n = 4), appetite loss (n = 2), bloody stools (n = 2), abdominal discomfort (n = 1), and vomiting (n = 1). At the final follow-up, six patients survived, while eight patients succumbed, with a median time of 100.5 days (range: 52-247) post-diagnosis. Endoscopic manifestations included erythematous mucosa (n = 14), erosions (n = 13), ulcers (n = 9), mucosal edema (n = 9), granular mucosa (n = 9), and villous atrophy (n = 4). Erosions and/or ulcers were primarily observed in the colon (10/14, 71%), followed by the ileum (9/13, 69%), stomach (4/10, 40%), cecum (5/14, 36%), duodenum (3/10, 30%), rectum (4/14, 29%), and esophagus (1/10, 10%). Cytomegalovirus infection (n = 4) and graft-versus-host disease (n = 2) coexisted within the gastrointestinal tract. Patients had de novo prolonged or progressive thrombocytopenia (6/14, 43%), decreased hemoglobin concentration (4/14, 29%), reduced serum haptoglobin level (3/14, 21%), and a sudden and persistent increase in lactate dehydrogenase level (2/14, 14%). Peripheral blood samples from 12 patients were evaluated for schistocytes, with none exceeding 4%. CONCLUSIONS: This study provides a comprehensive exploration of the endoscopic characteristics of iTAM. Notably, all patients exhibited erythematous mucosa throughout the gastrointestinal tract, accompanied by prevalent manifestations, such as erosions (93%), ulcers (64%), mucosal edema (64%), granular mucosa (64%), and villous atrophy (29%). Because of the low positivity for serological markers of transplant-associated thrombotic microangiopathy in patients with iTAM, endoscopic evaluation and biopsy of these lesions are crucial, even in the absence of these serological features.

DOI： 10.1186/s12876-024-03221-y

Chimeric antigen receptor T-cell therapy after COVID-19 in refractory high-grade B-cell lymphoma.

Kenta Hayashino, Keisuke Seike, Kanako Fujiwara, Kaho Kondo, Chisato Matsubara, Toshiki Terao, Wataru Kitamura, Chihiro Kamoi, Hideaki Fujiwara, Noboru Asada, Hisakazu Nishimori, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

International journal of hematology 119 ( 4 ) 459 - 464 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although chimeric antigen receptor T-cell (CAR-T) therapies have dramatically improved the outcomes of relapsed/refractory B-cell malignancies, recipients suffer from severe humoral immunodeficiencies. Furthermore, patients with coronavirus disease 2019 (COVID-19) have a poor prognosis, as noted in several case reports of recipients who had COVID-19 before the infusion. We report the case of a 70-year-old woman who developed COVID-19 immediately before CAR-T therapy for high-grade B-cell lymphoma. She received Tixagevimab-Cilgavimab chemotherapy and radiation therapy but never achieved remission. She was transferred to our hospital for CAR-T therapy, but developed COVID-19. Her symptoms were mild and she was treated with long-term molnupiravir. On day 28 post-infection, lymphodepleting chemotherapy was restarted after a negative polymerase chain reaction (PCR) test was confirmed. The patient did not experience recurrence of COVID-19 symptoms or severe cytokine release syndrome. Based on the analysis and comparison of the previous reports with this case, we believe that CAR-T therapy should be postponed until a negative PCR test is confirmed. In addition, Tixagevimab-Cilgavimab and long term direct-acting antiviral agent treatment can be effective prophylaxis for severe COVID-19 and shortening the duration of infection.

DOI： 10.1007/s12185-024-03711-5

Collection efficiency and safety of large-volume leukapheresis for the manufacturing of tisagenlecleucel. 国際誌

Wataru Kitamura, Tomohiro Urata, Keiko Fujii, Takuya Fukumi, Kazuhiro Ikeuchi, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Ken-Ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda, Nobuharu Fujii

Transfusion 2024年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: In patients with relapsed or refractory B cell acute lymphoblastic leukemia or B cell non-Hodgkin lymphoma (r/r B-ALL/B-NHL) with low CD3+ cells in the peripheral blood (PB), sufficient CD3+ cell yield in a single day may not be obtained with normal-volume leukapheresis (NVL). Large-volume leukapheresis (LVL) refers to the processing of more than three times the total blood volume (TBV) in a single session for PB apheresis; however, the efficiency and safety of LVL for manufacturing of tisagenlecleucel (tisa-cel) remain unclear. This study aimed to investigate the tolerability of LVL. STUDY DESIGN AND METHODS: We retrospectively collected data on LVL (≥3-fold TBV) and NVL (<3-fold TBV) performed for patients with r/r B-ALL/B-NHL in our institution during November 2019 and September 2023. All procedures were performed using a continuous mononuclear cell collection (cMNC) protocol with the Spectra Optia. RESULTS: Although pre-apheresis CD3+ cells in the PB were significantly lower in LVL procedures (900 vs. 348/μL, p < .01), all patients could obtain sufficient CD3+ cell yield in a single day with a comparably successful rate of final products (including out-of-specification) between the two groups (97.2% vs. 100.0%, p = 1.00). The incidence and severity of citrate toxicity (no patients with grade ≥ 3) during procedures was not significantly different between the two groups (22.2% vs. 26.1%, p = .43) and no patient discontinued leukapheresis due to any complications. CONCLUSION: LVL procedures using Spectra Optia cMNC protocol was well tolerated and did not affect the manufacturing of tisa-cel.

DOI： 10.1111/trf.17765

A Learning Program for Treatment Recommendations by Molecular Tumor Boards and Artificial Intelligence. 国際誌

Kuniko Sunami, Yoichi Naito, Yusuke Saigusa, Toraji Amano, Daisuke Ennishi, Mitsuho Imai, Hidenori Kage, Masashi Kanai, Hirotsugu Kenmotsu, Keigo Komine, Takafumi Koyama, Takahiro Maeda, Sachi Morita, Daisuke Sakai, Makoto Hirata, Mamoru Ito, Toshiyuki Kozuki, Hiroyuki Sakashita, Hidehito Horinouchi, Yusuke Okuma, Atsuo Takashima, Toshio Kubo, Shuichi Hironaka, Yoshihiko Segawa, Yoshihiro Yakushijin, Hideaki Bando, Akitaka Makiyama, Tatsuya Suzuki, Ichiro Kinoshita, Shinji Kohsaka, Yuichiro Ohe, Chikashi Ishioka, Kouji Yamamoto, Katsuya Tsuchihara, Takayuki Yoshino

JAMA oncology 10 ( 1 ) 95 - 102 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

IMPORTANCE: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential. OBJECTIVE: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system. DESIGN, SETTING, AND PARTICIPANTS: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021. EXPOSURES: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point. RESULTS: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03). CONCLUSIONS AND RELEVANCE: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

DOI： 10.1001/jamaoncol.2023.5120

Clinical significance of gynecological examinations in long-term follow-ups

Chihiro Kamoi, Nobuharu Fujii, Hirofumi Matsuoka, Kanayo Takahashi, Akira Yamamoto, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

Japanese Journal of Transplantation and Cellular Therapy 13 ( 2 ) 74 - 80 2024年

Transcriptome analysis of the cytokine storm-related genes among the subtypes of idiopathic multicentric Castleman disease

Asami Nishikori, Midori Filiz Nishimura, Shuta Tomida, Ryota Chijimatsu, Himawari Ueta, You Cheng Lai, Yuri Kawahara, Yudai Takeda, Sayaka Ochi, Tomoka Haratake, Daisuke Ennishi, Naoya Nakamura, Shuji Momose, Yasuharu Sato

Journal of Clinical and Experimental Hematopathology 2024年

Recurrent Cerebral Hemorrhaging with Platelet Dysfunction Accompanied by Anti-glycoprotein VI Autoantibodies in a Patient with TAFRO Syndrome.

Akira Yamamoto, Hisakazu Nishimori, Toshiaki Shirai, Katsuhiro Takano, Aya Komura, Yui Kambara, Takuya Fukumi, Tomohiro Urata, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Kenji Niiya, Katsue Suzuki-Inoue, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 63 ( 13 ) 1917 - 1922 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO) syndrome is an inflammatory disorder with an unclear pathogenesis. We herein report a case of TAFRO syndrome in remission in a patient who experienced recurrent intracranial bleeding despite a normal platelet count and coagulation system. A further investigation suggested the presence of anti-glycoprotein VI (GPVI) autoantibodies in the plasma, which induced platelet dysfunction and bleeding tendency. No new bleeding or relapse of TAFRO syndrome occurred after immunosuppressive therapy was initiated. These findings may help elucidate the autoimmune pathogenesis of TAFRO syndrome.

DOI： 10.2169/internalmedicine.2799-23

[Relapsed primary central nervous system lymphoma treated with CD19 chimeric antigen receptor T-cell therapy and allogeneic hematopoietic stem cell transplantation]. 査読

Fuminari Fujii, Toshiki Terao, Hisakazu Nishimori, Kentaro Fujii, Toshihiko Matsuo, Tadashi Yoshino, Hiroko Ueda, Tadashi Oyama, Akifumi Matsumura, Kaho Kondo, Chisato Matsubara, Kanako Fujiwara, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

[Rinsho ketsueki] The Japanese journal of clinical hematology 65 ( 7 ) 622 - 627 2024年

記述言語：日本語掲載種別：研究論文（学術雑誌）

Relapsed and/or refractory (R/R) primary central nervous system lymphoma (PCNSL) has a poor prognosis. A 57-year-old man diagnosed with PCNSL achieved a complete response by high-dose methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The disease was not cured, so he was treated with the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel after the third relapse. However, the disease relapsed again 28 days after CAR T-cell therapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was attempted as curative therapy after bridging with second ASCT and tirabrutinib monotherapy. Although a temporary response was achieved, the disease relapsed 98 days after allo-HSCT. While receiving tirabrutinib for relapse after allo-HSCT, the patient developed acute respiratory failure due to transplant-related toxicity and post-transplant thrombotic microangiopathy. He died 175 days after allo-HSCT. Although various treatments for PCNSL have been investigated in recent years, the treatment strategy for R/R PCNSL has not been established. Further studies are warranted to improve the outcomes of patients with R/R PCNSL.

DOI： 10.11406/rinketsu.65.622

Evaluating the efficiency and safety of large-volume leukapheresis using the Spectra Optia continuous mononuclear cell collection protocol for peripheral blood stem cell collection from healthy donors: A retrospective study. 国際誌

Yuichi Sumii, Keiko Fujii, Takumi Kondo, Tomohiro Urata, Maiko Kimura, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-Ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda, Nobuharu Fujii

Transfusion 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Large-volume leukapheresis (LVL) refers to processing of more than three volumes of blood in a single session for peripheral blood stem cell collection. Recently, continuous mononuclear cell collection (cMNC) protocol has been developed using the Spectra Optia system, which is a widely used apheresis device. LVL using the novel protocol has been investigated in patients. However, the efficiency and safety of LVL in healthy donors using this protocol has not been characterized. Therefore, this study aimed to evaluate the efficiency and tolerability of CD34+ collection of LVL with the cMNC protocol in healthy donors. STUDY DESIGN AND METHODS: We retrospectively collected data on LVL (>3 total blood volume) and normal-volume leukapheresis (NVL) performed in healthy donors between October 2019 and December 2021. All procedures were performed using the cMNC protocol. RESULTS: Although pre-apheresis CD34+ cell count was lesser in LVL (23.5 vs. 58.0/μL, p < .001), CD34+ collection efficiency was comparable between LVL and NVL (61.2% vs. 61.4%, p = .966). Platelet loss was significantly higher in LVL compared to NVL (38.0% vs. 29.4%, p < .001), with no correlation between attrition of platelet and processing blood volume. Moreover, the incidence of citrate toxicity during procedures was comparable between the two groups (31.6% vs. 21.4%, p = .322). All LVL procedures could be completed without any adverse events. CONCLUSION: Allogeneic LVL procedure using Spectra Optia cMNC protocol was well tolerated by the donors and resulted in efficient collection of CD34+ cells, which was comparable to that of NVL.

DOI： 10.1111/trf.17563

空間トランスクリプトーム解析による間質性肺炎合併肺癌の病態解明

大亀正義, 枝園和彦, 松岡篤志, 冨田秀太, 東原朋諒, 向原史晃, 林直宏, 土生智大, 吉川真生, 諏澤憲, 山本寛斉, 遠西大輔, 豊岡伸一

肺癌 63 ( 5 ) 493 - 493 2023年10月

高用量もしくは長期間のステロイド治療はtisagenlecleucelの効果を減弱させる

寺尾俊紀, 北村亘, 藤井伸治, 鴨井千尋, 藤原加奈子, 近藤歌穂, 松原千哲, 林野健太, 清家圭介, 藤原英晃, 淺田騰, 遠西大輔, 西森久和, 藤井敬子, 松岡賢市, 前田嘉信

日本血液学会学術集会 85回 519 - 519 2023年10月

Distribution and clinical impact of molecular subtypes with Dark Zone signature of DLBCL in a Japanese real-world study. 国際誌

Tomohiro Urata, Yusuke Naoi, Aixiang Jiang, Merrill Boyle, Kazutaka Sunami, Toshi Imai, Yuichiro Nawa, Yasushi Hiramatsu, Kazuhiko Yamamoto, Soichiro Fujii, Isao Yoshida, Tomofumi Yano, Ryota Chijimatsu, Hiroyuki Murakami, Kazuhiro Ikeuchi, Hiroki Kobayashi, Katsuma Tani, Hideki Ujiie, Hirofumi Inoue, Shuta Tomida, Akira Yamamoto, Takumi Kondo, Hideaki Fujiwara, Noboru Asada, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Keisuke Sawada, Shuji Momose, Jun-Ichi Tamaru, Asami Nishikori, Yasuharu Sato, Tadashi Yoshino, Yoshinobu Maeda, David W Scott, Daisuke Ennishi

Blood advances 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone, that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, that include the dark zone signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a dataset from the cohort of BC Cancer (BCC) (n = 804). Of the 1050 patients where DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to be germinal center B-cell-like (GCB)-DLBCL, activated B-cell-like (ABC)-DLBCL, and DZsigpos-DLBCL, respectively, with the highest prevalence of ABC-DLBCL differing significantly from that of BCC (P < 0.001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with two-year overall survival rates of 88%, 75%, and 66%, respectively (P < 0.0001), with patients of the DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes following rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all P < 0.05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas.

DOI： 10.1182/bloodadvances.2023010402

Feasibility of Flow Cytometry Analysis of Gastrointestinal Tract-Residing Lymphocytes in Hematopoietic Stem Cell Transplant Recipients.

Masaya Iwamuro, Takumi Kondo, Daisuke Ennishi, Nobuharu Fujii, Ken-Ichi Matsuoka, Takahide Takahashi, Araki Hirabata, Takehiro Tanaka, Fumio Otsuka, Yoshinobu Maeda, Hiroyuki Okada

Acta medica Okayama 77 ( 4 ) 347 - 357 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

The feasibility of lymphocyte isolation and flow cytometry using a single endoscopic biopsy specimen from the gastrointestinal tract of patients who have undergone hematopoietic stem cell transplantation has not been investigated. We acquired 51 endoscopic biopsy specimens from the gastrointestinal tract of 35 patients. We divided the flow cytometry samples into two groups: group A, successful lymphocyte isolation (n=24), and group B, incomplete isolation (n=27). We compared the backgrounds of the samples between the groups to reveal crucial elements in the successful isolation of lymphocytes residing in the gastrointestinal tract. Comparison between the groups revealed lymphocyte isolation success rates differed between biopsy sites. Isolation was most successful in samples from the duodenum (8/9, 88.9%), followed by the ileum (4/8, 50.0%), large intestine (4/11, 36.4%), and stomach (8/23, 34.8%). Tacrolimus was used more frequently in group B (92.6%) than in group A (62.5%) (p=0.015). Logistic regression analysis revealed that isolation from the duodenum or ileum was a significant factor for successful isolation, while tacrolimus use was not statistically significant. In conclusion, the duodenum and ileum are more suitable sites than the stomach and colorectum for acquiring samples for flow cytometry.

DOI： 10.18926/AMO/65740

Negative Prognostic Impact of High-Dose or Long-Term Corticosteroid Use in Patients with Relapsed or Refractory B-Cell Lymphoma Who Received Tisagenlecleucel. 国際誌

Toshiki Terao, Wataru Kitamura, Nobuharu Fujii, Noboru Asada, Chihiro Kamoi, Kanako Fujiwara, Kaho Kondo, Chisato Matsubara, Kenta Hayashino, Keisuke Seike, Hideaki Fujiwara, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

Transplantation and cellular therapy 29 ( 9 ) 573.e1-573.e8 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The prognostic impact of corticosteroid therapy in patients receiving tisagenlecleucel (tisa-cel) treatment who are more likely to develop cytokine release syndrome (CRS) remains unclear. This study aimed to evaluate the clinical impact and lymphocyte kinetics of corticosteroid administration for CRS in 45 patients with relapsed and/or refractory B-cell lymphoma treated with tisa-cel. This was a retrospective evaluation of all consecutive patients diagnosed with relapsed and/or refractory diffuse large B-cell lymphoma, follicular lymphoma with histologic transformation to large B-cell lymphoma, or follicular lymphoma who received commercial-based tisa-cel treatment. The best overall response rate, complete response rate, median progression-free survival (PFS), and median overall survival (OS) were 72.7%, 45.5%, 6.6 months, and 15.3 months, respectively. CRS (predominantly grade 1/2) occurred in 40 patients (88.9%), and immune effector cell-associated neurotoxicity syndrome (ICANS) of all grades occurred in 3 patients (6.7%). No grade ≥3 ICANS occurred. Patients with high-dose (≥524 mg, methylprednisolone equivalent; n = 12) or long-term (≥8 days; n = 9) corticosteroid use had inferior PFS and OS to patients with low-dose or no corticosteroid use (both P < .05). The prognostic impact remained even in 23 patients with stable disease (SD) or progressive disease (PD) before tisa-cel infusion (P = .015). but not in patients with better disease status (P = .71). The timing of corticosteroid initiation did not have a prognostic impact. Multivariate analysis identified high-dose corticosteroid use and long-term corticosteroid use as independent prognostic factors for PFS and OS, respectively, after adjusting for elevated lactate dehydrogenase level before lymphodepletion chemotherapy and disease status (SD or PD). Lymphocyte kinetics analysis demonstrated that after methylprednisolone administration, the proportions of regulatory T cells (Tregs), CD4+ central memory T (TCM) cells, and natural killer (NK) cells were decreased, whereas the proportion of CD4+ effector memory T (TEM) cells was increased. Patients with a higher proportion of Tregs at day 7 had a lower incidence of CRS, but this did not affect prognosis, indicating that early elevation of Tregs may serve as a biomarker for CRS development. Furthermore, patients with higher numbers of CD4+ TCM cells and NK cells at various time points had significantly better PFS and OS, whereas the number of CD4+ TEM cells did not impact prognostic outcomes. This study suggests that high-dose or long-term corticosteroid use attenuates the efficacy of tisa-cel, especially in patients with SD or PD. Additionally, patients with high levels of CD4+ TCM cells and NK cells after tisa-cel infusion had longer PFS and OS.

DOI： 10.1016/j.jtct.2023.06.018

Efficient granulocyte collection method using high concentrations of medium molecular weight hydroxyethyl starch

Takumi Kondo, Keiko Fujii, Nobuharu Fujii, Yuichi Sumii, Tomohiro Urata, Maiko Kimura, Masayuki Matsuda, Shuntaro Ikegawa, Kana Washio, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken‐ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda

Transfusion 2023年6月

Utility of Comprehensive Genomic Profiling for Precise Diagnosis of Pediatric-Type Diffuse High-Grade Glioma.

Keigo Makino, Yoshihiro Otani, Kentaro Fujii, Joji Ishida, Shuichiro Hirano, Yasuki Suruga, Kana Washio, Kenji Nishida, Hiroyuki Yanai, Shuta Tomida, Daisuke Ennishi, Isao Date

Acta medica Okayama 77 ( 3 ) 323 - 330 2023年6月

記述言語：英語

In the current World Health Organization classification of central nervous system tumors, comprehensive genetic and epigenetic analyses are considered essential for precise diagnosis. A 14-year-old male patient who presented with a cerebellar tumor was initially diagnosed with glioblastoma and treated with radiation and concomitant temozolomide chemotherapy after resection. During maintenance temozolomide therapy, a new contrast-enhanced lesion developed in the bottom of the cavity formed by the resection. A second surgery was performed, but the histological findings in specimens from the second surgery were different from those of the first surgery. Although genome-wide DNA methylation profiling was conducted using frozen tissue for a precise diagnosis, the proportion of tumor cells was insufficient and only normal cerebellum was observed. We then performed comprehensive genetic analysis using formalin-fixed paraffin-embedded sections, which revealed MYCN amplification without alteration of IDH1, IDH2, or Histone H3. Finally, the patient was diagnosed with pediatric-type diffuse high-grade glioma, H3-wildtype and IDH-wildtype. In conclusion, comprehensive genetic and epigenetic analysis should be considered in pediatric brain tumor cases.

DOI： 10.18926/AMO/65502

臍帯血移植後にHTLV-1感染T細胞の多クローン性増殖を伴って発症した肺合併症に対し抗CCR4抗体が著効した1例

松原千哲, 松岡賢市, 近藤歌穂, 藤原加奈子, 寺尾俊紀, 植田裕子, 松村彰文, 守山喬史, 村上裕之, 近藤匠, 清家圭介, 藤原英晃, 淺田騰, 遠西大輔, 西森久和, 藤井敬子, 藤井伸治, 前田嘉信

臨床血液 64 ( 6 ) 563 - 563 2023年6月

臍帯血移植後にHTLV-1感染T細胞の多クローン性増殖を伴って発症した肺合併症に対し抗CCR4抗体が著効した1例

松原千哲, 松岡賢市, 近藤歌穂, 藤原加奈子, 寺尾俊紀, 植田裕子, 松村彰文, 守山喬史, 村上裕之, 近藤匠, 清家圭介, 藤原英晃, 淺田騰, 遠西大輔, 西森久和, 藤井敬子, 藤井伸治, 前田嘉信

臨床血液 64 ( 6 ) 563 - 563 2023年6月

Hematopoietic stem cell–derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide

Yuichi Sumii, Takumi Kondo, Shuntaro Ikegawa, Takuya Fukumi, Miki Iwamoto, Midori Filiz Nishimura, Hiroyuki Sugiura, Yasuhisa Sando, Makoto Nakamura, Yusuke Meguri, Takashi Matsushita, Naoki Tanimine, Maiko Kimura, Noboru Asada, Daisuke Ennishi, Yoshinobu Maeda, Ken-ichi Matsuoka

JCI Insight 8 ( 8 ) 2023年4月

Long-term outcomes of patients with primary intestinal follicular lymphoma managed with watch-and-wait strategy. 国際誌

Masaya Iwamuro, Takehiro Tanaka, Daisuke Ennishi, Kazuhiro Matsueda, Masao Yoshioka, Koji Miyahara, Chihiro Sakaguchi, Mamoru Nishimura, Teruya Nagahara, Tomohiko Mannami, Ryuta Takenaka, Shohei Oka, Masafumi Inoue, Hidetaka Takimoto, Tomoki Inaba, Sayo Kobayashi, Tatsuya Toyokawa, Hirofumi Tsugeno, Seiyuu Suzuki, Sachiko Sawada, Shouichi Tanaka, Takao Tsuzuki, Hiroyuki Okada

Scientific reports 13 ( 1 ) 5858 - 5858 2023年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Patients with primary intestinal follicular lymphoma are often followed-up without a specific treatment, and this approach is called the "watch-and-wait approach." However, the long-term outcomes of this patient group have not been sufficiently investigated. We enrolled patients with primary intestinal follicular lymphoma who were diagnosed before 2016 and managed with the watch-and-wait approach in 20 institutions. We retrospectively investigated the overall, disease-specific, and event-free survival rates as well as the rate of spontaneous regression. Among the 248 patients with follicular lymphoma with gastrointestinal involvement, 124 had localized disease (stage I or II1). We analyzed the data of 73 patients who were managed using the watch-and-wait approach. During the mean follow-up period of 8.3 years, the follicular lymphoma had spontaneously resolved in 16.4% of the patients. The 5-year and 10-year overall survival rates were 92.9% and 87.1%, respectively. With disease progression (n = 7), initiation of therapy (n = 7), and histologic transformation to aggressive lymphoma (n = 0) defined as events, the 5-year and 10-year event-free survival rates were 91.1% and 86.9%, respectively. No patient died of progressive lymphoma. Thus, both 5-year and 10-year disease-specific survival rates were 100%. In conclusion, an indolent long-term clinical course was confirmed in the patients with primary intestinal follicular lymphoma. The watch-and-wait strategy is a reasonable approach for the initial management of these patients.

DOI： 10.1038/s41598-023-32736-9

当院における再発難治性びまん性大細胞型B細胞性リンパ腫に対するtisagenlecleucelの治療成績

北村亘, 藤井伸治, 鴨井千尋, 阿部将也, 住居優一, 浦田知宏, 谷勝真, 高木尚江, 山本晃, 清家圭介, 藤原英晃, 淺田騰, 遠西大輔, 西森久和, 藤井敬子, 松岡賢市, 前田嘉信

日本輸血細胞治療学会誌 69 ( 2 ) 331 - 331 2023年4月

当院における再発難治性びまん性大細胞型B細胞性リンパ腫に対するtisagenlecleucelの治療成績

北村亘, 藤井伸治, 鴨井千尋, 阿部将也, 住居優一, 浦田知宏, 谷勝真, 高木尚江, 山本晃, 清家圭介, 藤原英晃, 淺田騰, 遠西大輔, 西森久和, 藤井敬子, 松岡賢市, 前田嘉信

日本輸血細胞治療学会誌 69 ( 2 ) 331 - 331 2023年4月

Bone marrow microenvironment disruption and sustained inflammation with prolonged haematologic toxicity after CAR T-cell therapy. 国際誌

Wataru Kitamura, Noboru Asada, Yusuke Naoi, Masaya Abe, Hideaki Fujiwara, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Tadashi Yoshino, Yoshinobu Maeda

British journal of haematology 202 ( 2 ) 294 - 307 2023年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Mechanisms of prolonged cytopenia (PC) after chimeric antigen receptor (CAR) T-cell therapy, an emerging therapy for relapsed or refractory diffuse large B-cell lymphoma, remain elusive. Haematopoiesis is tightly regulated by the bone marrow (BM) microenvironment, called the 'niche'. To investigate whether alterations in the BM niche cells are associated with PC, we analysed CD271+ stromal cells in BM biopsy specimens and the cytokine profiles of the BM and serum obtained before and on day 28 after CAR T-cell infusion. Imaging analyses of the BM biopsy specimens revealed that CD271+ niche cells were severely impaired after CAR T-cell infusion in patients with PC. Cytokine analyses after CAR T-cell infusion showed that CXC chemokine ligand 12 and stem cell factor, niche factors essential for haematopoietic recovery, were significantly decreased in the BM of patients with PC, suggesting reduced niche cell function. The levels of inflammation-related cytokines on day 28 after CAR T-cell infusion were consistently high in the BM of patients with PC. Thus, we demonstrate for the first time that BM niche disruption and sustained elevation of inflammation-related cytokines in the BM following CAR T-cell infusion are associated with subsequent PC.

DOI： 10.1111/bjh.18747

[Ⅲ. The Role of Comprehensive Genomic Profiling in Sarcoma].

Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Shinichi Toyooka, Daisuke Ennishi, Hideki Yamamoto, Kiichiro Ninomiya, Shuta Tomida, Akira Hirasawa, Mashu Futagawa, Masahiro Tabata

Gan to kagaku ryoho. Cancer & chemotherapy 50 ( 3 ) 314 - 320 2023年3月

Musculoskeletal Tumor 骨・軟部腫瘍骨・軟部腫瘍におけるがん遺伝子プロファイリング検査骨・軟部腫瘍診療におけるがん遺伝子パネルの役割

中田英二, 藤原智洋, 国定俊之, 尾崎敏文, 豊岡伸一, 遠西大輔, 山本英喜, 二宮貴一朗, 冨田秀太, 平沢晃, 二川摩周, 田端雅弘

癌と化学療法 50 ( 3 ) 314 - 320 2023年3月

Pre-infusion factors predicting early failure after tisagenlecleucel for patients with relapsed/refractory diffuse large B-cell lymphoma: A single institute retrospective analysis

Wataru Kitamura, Nobuharu Fujii, Chihiro Kamoi, Tomohiro Urata, Hiroki Kobayashi, Akira Yamamoto, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Ken-ichi Matsuoka, Yoshinobu Maeda

Japanese Journal of Transplantation and Cellular Therapy 12 ( 4 ) 259 - 267 2023年

Early initiation of low-dose gilteritinib maintenance improves posttransplant outcomes in patients with R/R FLT3mut AML. 国際誌

Toshiki Terao, Ken-Ichi Matsuoka, Hiroko Ueda, Akifumi Matsumura, Chisato Matsubara, Kaho Kondo, Takumi Kondo, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Yoshinobu Maeda

Blood advances 7 ( 5 ) 681 - 686 2022年12月

Association between early corticosteroid administration and long-term survival in non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation.

Yui Kambara, Nobuharu Fujii, Yoshiaki Usui, Akira Yamamoto, Hisao Higo, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

International journal of hematology 117 ( 4 ) 578 - 589 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Non-infectious pulmonary complications (NIPCs) after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with poor outcomes. It is important to maximize the effectiveness of primary treatment because secondary treatment has not been established. We analyzed data from 393 patients who underwent allogeneic HSCT during a 10-year period. Thirty-seven were diagnosed with NIPCs, which consisted of idiopathic pneumonia syndrome, bronchiolitis obliterans, and interstitial lung disease including cryptogenic organizing pneumonia. Among these, 18 died (Dead group) while 19 remained alive (Alive group) during the study period. The median time between NIPC diagnosis and first administration of ≥ 1 mg/kg/day corticosteroids (prednisolone dose equivalent) was significantly longer in the Dead group than the Alive group, at 9 days versus 4 days (p = 0.01). We further divided these cases into those who received prednisolone within seven days and after 8 days. We found that the ≤ 7 days group were more likely to survive after their NIPC diagnosis compared to the ≥ 8 days group (p = 0.06). Our analysis showed that early initiation of corticosteroid therapy is associated with long-term survival in NIPCs.

DOI： 10.1007/s12185-022-03517-3

Concordance Between Recommendations From Multidisciplinary Molecular Tumor Boards and Central Consensus for Cancer Treatment in Japan

Yoichi Naito, Kuniko Sunami, Hidenori Kage, Keigo Komine, Toraji Amano, Mitsuho Imai, Takafumi Koyama, Daisuke Ennishi, Masashi Kanai, Hirotsugu Kenmotsu, Takahiro Maeda, Sachi Morita, Daisuke Sakai, Kousuke Watanabe, Hidekazu Shirota, Ichiro Kinoshita, Masashiro Yoshioka, Nobuaki Mamesaya, Mamoru Ito, Shinji Kohsaka, Yusuke Saigusa, Kouji Yamamoto, Makoto Hirata, Katsuya Tsuchihara, Takayuki Yoshino

JAMA Network Open 5 ( 12 ) e2245081 - e2245081 2022年12月

掲載種別：研究論文（学術雑誌）出版者・発行元：American Medical Association (AMA)

Importance

Quality assurance of molecular tumor boards (MTBs) is crucial in cancer genome medicine.

Objective

To evaluate the concordance of recommendations by MTBs and centrally developed consensus treatment recommendations at all 12 leading institutions for cancer genomic medicine in Japan using 50 simulated cases.

Design, Setting, and Participants

This was a prospective quality improvement study of 50 simulated cancer cases. Molecular tumor boards from 12 core hospitals independently recommended treatment for 50 cases blinded to the centrally developed consensus treatment recommendations. The study’s central committee consisted of representatives from all 12 core hospitals in Japan who selected the 50 simulated cases from The Cancer Genome Atlas database, including frequently observed genomic alterations. The central committee recommended centrally developed consensus treatment. The concordance rate for genomically matched treatments between MTBs and centrally developed consensus treatment recommendations was evaluated. Data analysis was conducted from January 22 to March 3, 2021.

Exposures

Simulated cases of cancer.

Main Outcomes and Measures

The primary outcome was concordance, defined as the proportion of recommendations by MTBs concordant with centrally developed consensus treatment recommendations. A mixed-effects logistic regression model, adjusted for institutes as a random intercept, was applied. High evidence levels were defined as established biomarkers for which the treatment was ready for routine use in clinical practice, and low evidence levels were defined as biomarkers for genomically matched treatment that were under investigation.

Results

The Clinical Practice Guidance for Next-Generation Sequencing in Cancer Diagnosis and Treatment (edition 2.1) was used for evidence-level definition. The mean concordance between MTBs and centrally developed consensus treatment recommendations was 62% (95% CI, 57%-65%). Each MTB concordance varied from 48% to 86%. The concordance rate was higher in the subset of patients with colorectal cancer (100%; 95% CI, 94.0%-100%), ROS1 fusion (100%; 95% CI, 85.5%-100%), and high evidence level A/R (A: 88%; 95% CI, 81.8%-93.0%; R:100%; 95% CI, 92.6%-100%). Conversely, the concordance rate was lower in cases of cervical cancer (11%; 95% CI, 3.1%-26.1%), TP53 mutation (16%; 95% CI, 12.5%-19.9%), and low evidence level C/D/E (C: 30%; 95% CI, 24.7%-35.9%; D: 25%; 95% CI, 5.5%-57.2%; and E: 18%; 95% CI, 13.8%-23.0%). Multivariate analysis showed that evidence level (high [A/R] vs low [C/D/E]: odds ratio, 4.4; 95% CI, 1.8-10.8) and TP53 alteration (yes vs no: odds ratio, 0.06; 95% CI, 0.03-0.10) were significantly associated with concordance.

Conclusions and Relevance

The findings of this study suggest that genomically matched treatment recommendations differ among MTBs, particularly in genomic alterations with low evidence levels wherein treatment is being investigated. Sharing information on matched therapy for low evidence levels may be needed to improve the quality of MTBs.

DOI： 10.1001/jamanetworkopen.2022.45081

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12月

軟部肉腫に対する薬物療法がん遺伝子パネルに基づく肉腫診療

中田英二, 藤原智洋, 国定俊之, 平沢晃, 遠西大輔, 尾崎敏文

中部日本整形外科災害外科学会雑誌 65 ( 秋季学会 ) 77 - 77 2022年10月

がん遺伝子パネルに基づく肉腫診療

中田英二, 藤原智洋, 平沢晃, 二川摩周, 遠西大輔, 山本英喜, 冨田秀太, 久保寿夫, 田端雅弘, 国定俊之, 豊岡伸一, 尾崎敏文

日本癌治療学会学術集会抄録集 60回 O49 - 4 2022年10月

がん遺伝子パネルに基づく肉腫診療

中田英二, 藤原智洋, 平沢晃, 二川摩周, 遠西大輔, 山本英喜, 冨田秀太, 久保寿夫, 田端雅弘, 国定俊之, 豊岡伸一, 尾崎敏文

日本癌治療学会学術集会抄録集 60回 O49 - 4 2022年10月

Expert panel consensus recommendations on the use of circulating tumor <scp>DNA</scp> assays for patients with advanced solid tumors

Mitsuho Imai, Yoshiaki Nakamura, Kuniko Sunami, Hidenori Kage, Keigo Komine, Takafumi Koyama, Toraji Amano, Daisuke Ennishi, Masashi Kanai, Hirotsugu Kenmotsu, Takahiro Maeda, Sachi Morita, Daisuke Sakai, Hideaki Bando, Akitaka Makiyama, Tatsuya Suzuki, Makoto Hirata, Shinji Kohsaka, Katsuya Tsuchihara, Yoichi Naito, Takayuki Yoshino

Cancer Science 2022年9月

Chronological improvement in precision oncology implementation in Japan

Kuniko Sunami, Yoichi Naito, Keigo Komine, Toraji Amano, Daisuke Ennishi, Mitsuho Imai, Hidenori Kage, Masashi Kanai, Hirotsugu Kenmotsu, Takafumi Koyama, Takahiro Maeda, Sachi Morita, Daisuke Sakai, Shinji Kohsaka, Katsuya Tsuchihara, Yusuke Saigusa, Takayuki Yoshino

Cancer Science 2022年9月

骨・軟部腫瘍の基礎科学のトピックスクリニカルシークエンスによる肉腫のゲノム医療

中田英二, 藤原智洋, 国定俊之, 二川摩周, 遠西大輔, 久保寿夫, 平沢晃, 尾崎敏文

日本整形外科学会雑誌 96 ( 8 ) S1533 - S1533 2022年9月

Establishment of a reference single-cell RNA sequencing dataset for human pancreatic adenocarcinoma. 国際誌

Ryota Chijimatsu, Shogo Kobayashi, Yu Takeda, Masatoshi Kitakaze, Shotaro Tatekawa, Yasuko Arao, Mika Nakayama, Naohiro Tachibana, Taku Saito, Daisuke Ennishi, Shuta Tomida, Kazuki Sasaki, Daisaku Yamada, Yoshito Tomimaru, Hidenori Takahashi, Daisuke Okuzaki, Daisuke Motooka, Takahito Ohshiro, Masateru Taniguchi, Yutaka Suzuki, Kazuhiko Ogawa, Masaki Mori, Yuichiro Doki, Hidetoshi Eguchi, Hideshi Ishii

iScience 25 ( 8 ) 104659 - 104659 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Single-cell RNA sequencing (scRNAseq) has been used to assess the intra-tumor heterogeneity and microenvironment of pancreatic ductal adenocarcinoma (PDAC). However, previous knowledge is not fully universalized. Here, we built a single cell atlas of PDAC from six datasets containing over 70 samples and >130,000 cells, and demonstrated its application to the reanalysis of the previous bulk transcriptomic cohorts and inferring cell-cell communications. The cell decomposition of bulk transcriptomics using scRNAseq data showed the cellular heterogeneity of PDAC; moreover, high levels of tumor cells and fibroblasts were indicative of poor-prognosis. Refined tumor subtypes signature indicated the tumor cell dynamics in intra-tumor and their specific regulatory network. We further identified functionally distinct tumor clusters that had close interaction with fibroblast subtypes via different signaling pathways dependent on subtypes. Our analysis provided a reference dataset for PDAC and showed its utility in research on the microenvironment of intra-tumor heterogeneity.

DOI： 10.1016/j.isci.2022.104659

Red blood cell depletion in small‐volume bone marrow processing using manipulation with third‐party red blood cells: A comparison of the performance of the <scp>COBE</scp> spectra and the spectra Optia systems

Yuichi Sumii, Nobuharu Fujii, Keiko Fujii, Takumi Kondo, Tomohiro Urata, Maiko Kimura, Kana Washio, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken‐ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda

Transfusion 2022年8月

Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma. 国際誌

Katsuyoshi Takata, Lauren C Chong, Daisuke Ennishi, Tomohiro Aoki, Michael Yu Li, Avinash Thakur, Shannon Healy, Elena Viganò, Tao Dao, Daniel Kwon, Gerben Duns, Julie S Nielsen, Susana Ben-Neriah, Ethan Tse, Stacy S Hung, Merrill Boyle, Sung Soo Mun, Christopher M Bourne, Bruce Woolcock, Adèle Telenius, Makoto Kishida, Shinya Rai, Allen W Zhang, Ali Bashashati, Saeed Saberi, Gianluca D'Antonio, Brad H Nelson, Sohrab P Shah, Pamela A Hoodless, Ari M Melnick, Randy D Gascoyne, Joseph M Connors, David A Scheinberg, Wendy Béguelin, David W Scott, Christian Steidl

The Journal of clinical investigation 132 ( 10 ) 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.

DOI： 10.1172/JCI145343

Successful neutrophil engraftment supported by granulocyte transfusion in adult allogeneic transplant patients with peri-transplant active infection

Shuntaro Ikegawa, Nobuharu Fujii, Keiko Fujii, Maiko Kimura, Masayuki Matsuda, Takumi Kondo, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-ichi Matsuoka, Yoshinobu Maeda

Transfusion and Apheresis Science 103453 - 103453 2022年5月

Low hematocrit reduces the efficiency of <scp>CD34</scp> ⁺ cell collection when using the Spectra Optia continuous mononuclear cell collection procedure

Takumi Kondo, Nobuharu Fujii, Keiko Fujii, Yuichi Sumii, Tomohiro Urata, Maiko Kimura, Masayuki Matsuda, Shuntaro Ikegawa, Kana Washio, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken‐ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda

Transfusion 2022年3月

Chronic active Epstein–Barr virus infection presenting as refractory chronic sinusitis

Wataru Kitamura, Hideaki Fujiwara, Akifumi Matsumura, Takaya Higaki, Rei Shibata, Tomohiro Toji, Soichiro Fujii, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Ken-ichi Matsuoka, Tadashi Yoshino, Yoshinobu Maeda

International Journal of Hematology 2022年2月

Response to entrectinib in a malignant glioneuronal tumor with ARHGEF2-NTRK fusion

Kazuhiko Kurozumi, Kentaro Fujii, Kana Washio, Joji Ishida, Yoshihiro Otani, Tamotsu Sudo, Makoto Tahara, Koichi Ichimura, Daisuke Ennishi, Isao Date

Neuro-Oncology Advances 4 ( 1 ) 2022年1月

Sequential Combination of FLAM and Venetoclax plus Azacitidine to Bridge to Cord Blood Transplantation in a Patient with Primary Induction Failure Acute Myeloid Leukemia. 国際誌

Hiroyuki Murakami, Ken-Ichi Matsuoka, Takeru Asano, Takashi Moriyama, Akifumi Matsumura, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Tomohiro Toji, Tadashi Yoshino, Yoshinobu Maeda

Case reports in oncology 15 ( 3 ) 974 - 979 2022年

記述言語：英語

Venetoclax (VEN) is an oral B-cell lymphoma-2 (BCL-2) inhibitor that has been widely used to treat various hematological disorders. Recent studies have demonstrated that VEN in combination with fludarabine-enhanced high-dose cytarabine (FLA) is effective for treating relapsed or refractory acute myeloid leukemia (AML). In the combination therapy, salvage chemotherapy and VEN are basically concurrently administrated; however, further optimization may enable the treatment to apply to larger numbers of patients with various clinical backgrounds. Here, we describe a case of refractory AML treated with a sequential combination of the intensive chemotherapy (fludarabine, cytarabine, and mitoxantrone; FLAM) and VEN/AZA to bridge to an unrelated cord blood transplantation (uCBT). By continuously adding VEN/AZA after FLAM, the patient achieved morphologic leukemia free state with only minor toxicities. Blood cell counts did not recover until the time of transplantation because of the deep myelosuppression caused by the treatment sequence, but the infection risk was safely managed during this period. After engraftment, maintenance therapy with VEN/AZA was performed, and the patient has survived without disease recurrence for over 9 months after transplantation. Our case suggests that bridging therapy with VEN and AZA from the time of the last chemotherapy to allogeneic transplantation may provide an effective and tolerable treatment strategy for refractory AML. Further studies of larger numbers of cases are needed to validate the effectiveness of this treatment.

DOI： 10.1159/000526697

Genomic Profiling of a Case of Glioneuronal Tumor with Neuropil-like Islands

Nobushige Tsuboi, Joji Ishida, Yosuke Shimazu, Hisanori Edaki, Atsuhito Uneda, Yoshihiro Otani, Kentaro Fujii, Kazuhiko Kurozumi, Daisuke Ennishi, Hiroyuki Yanai, Isao Date

Acta Medica Okayama 76 ( 4 ) 473 - 477 2022年

Retroperitoneal leiomyosarcoma in a female patient with a germline splicing variant RAD51D c.904-2A > T: a case report. 国際誌

Mashu Futagawa, Hideki Yamamoto, Mariko Kochi, Yusaku Urakawa, Reimi Sogawa, Fumino Kato, Mika Okazawa-Sakai, Daisuke Ennishi, Katsunori Shinozaki, Hirofumi Inoue, Hiroyuki Yanai, Akira Hirasawa

Hereditary cancer in clinical practice 19 ( 1 ) 48 - 48 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development. CASE PRESENTATION: A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3'-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma. CONCLUSIONS: We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.

DOI： 10.1186/s13053-021-00205-x

Transformation to diffuse large B-cell lymphoma with germinal center B-cell like subtype and discordant light chain expression in a patient with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma.

Hiroki Kobayashi, Noboru Asada, Yuria Egusa, Tomoka Ikeda, Misa Sakamoto, Masaya Abe, Daisuke Ennishi, Masahiro Sakata, Akinobu Takaki, Soichiro Kawahara, Yusuke Meguri, Hisakazu Nishimori, Nobuharu Fujii, Ken-Ichi Matsuoka, Yasuharu Sato, Tadashi Yoshino, Yoshinobu Maeda

International journal of hematology 114 ( 3 ) 401 - 407 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare indolent B-cell neoplasm, and a gain-of-function mutation in the myeloid differentiation primary response 88 (MYD88), L265P, is a commonly recurring mutation in patients with WM/LPL. Histological transformation of WM/LPL to an aggressive lymphoma such as diffuse large B-cell lymphoma (DLBCL) is rare, and transformed DLBCL has a worse prognosis than de novo DLBCL, partly because transformed DLBCL is mostly classified as non-germinal center B-cell-like (non-GCB) subtype. We herein describe a 75-year-old man with DLBCL with a history of WM/LPL. DLBCL in this patient showed the GCB subtype, and the light chain restriction of DLBCL was different from that of the antecedent WM/LPL, indicating that the two types of lymphoma cells had distinctive origins. However, DLBCL in this patient harbored the MYD88 L265P mutation, and polymerase chain reaction and Sanger sequencing of the DLBCL and WM/LPL for immunoglobulin heavy chain gene rearrangement suggested a clonal relationship between the two lymphomas. Since the outcome of transformed DLBCL is worse than for de novo DLBCL, it is important to evaluate the clonal relationship between primary WM/LPL and the corresponding transformed DLBCL, even if the DLBCL expresses a GCB subtype or discordant light chain restriction.

DOI： 10.1007/s12185-021-03157-z

Secretory carcinoma of the skin with lymph node metastases and recurrence in both lungs: A case report. 国際誌

Kohei Taniguchi, Hiroyuki Yanai, Tatsuya Kaji, Toshio Kubo, Daisuke Ennishi, Akira Hirasawa, Tadashi Yoshino

Journal of cutaneous pathology 48 ( 8 ) 1069 - 1074 2021年8月

記述言語：英語

Secretory carcinoma of the skin is an extremely rare adnexal tumor, histopathologically identical to homologous lesions in the salivary glands and breast tissue. Although this tumor was previously reported as indolent, we report a case of secretory carcinoma of the skin with metastases and recurrence. The patient, a 31-year-old women, had a subcutaneous mass in the right axilla. The resected specimen contained a circumscribed mass, with proliferating tumor cells that exhibited prominent nucleoli. They exhibited glandular and papillary growth patterns and there were amphophilic secretions in the glands. Immunohistochemically, the tumor cells were positive for mammaglobin and S100. The tumor was surrounded by sweat glands and there was no mammary glandular tissue, suggesting that it was derived from axillary sweat glands. Accordingly, we made a diagnosis of secretory carcinoma of the skin. Four years after the operation, there were metastases in both lungs. The resected specimen revealed a tumor identical to that of the original skin tumor. Next-generation sequencing-based multiplex gene assay performed on the metastatic tissue revealed an ETV6-NTRK3 fusion gene. This is a rare case report of secretory carcinoma of the skin with lymph node metastases and recurrence in both lungs.

DOI： 10.1111/cup.14028

Characterization of DLBCL with a PMBL gene expression signature. 国際誌

Gerben Duns, Elena Viganò, Daisuke Ennishi, Clementine Sarkozy, Stacy S Hung, Elizabeth Chavez, Katsuyoshi Takata, Christopher Rushton, Aixiang Jiang, Susana Ben-Neriah, Bruce W Woolcock, Graham W Slack, Eric D Hsi, Jeffrey W Craig, Laura K Hilton, Sohrab P Shah, Pedro Farinha, Anja Mottok, Randy D Gascoyne, Ryan D Morin, Kerry J Savage, David W Scott, Christian Steidl

Blood 138 ( 2 ) 136 - 148 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Primary mediastinal large B-cell lymphoma (PMBL) is a type of aggressive B-cell lymphoma that typically affects young adults, characterized by presence of a bulky anterior mediastinal mass. Lymphomas with gene expression features of PMBL have been described in nonmediastinal sites, raising questions about how these tumors should be classified. Here, we investigated whether these nonmediastinal lymphomas are indeed PMBLs or instead represent a distinct group within diffuse large B-cell lymphoma (DLBCL). From a cohort of 325 de novo DLBCL cases, we identified tumors from patients without evidence of anterior mediastinal involvement that expressed a PMBL expression signature (nm-PMBLsig+; n = 16; 5%). A majority of these tumors expressed MAL and CD23, proteins typically observed in bona fide PMBL (bf-PMBL). Evaluation of clinical features of nm-PMBLsig+ cases revealed close associations with DLBCL, and a majority displayed a germinal center B cell-like cell of origin (GCB). In contrast to patients with bf-PMBL, patients with nm-PMBLsig+ presented at an older age and did not show pleural disease, and bone/bone marrow involvement was observed in 3 cases. However, although clinically distinct from bf-PMBL, nm-PMBLsig+ tumors resembled bf-PMBL at the molecular level, with upregulation of immune response, JAK-STAT, and NF-κB signatures. Mutational analysis revealed frequent somatic gene mutations in SOCS1, IL4R, ITPKB, and STAT6, as well as CD83 and BIRC3, with the latter genes significantly more frequently affected than in GCB DLBCL or bf-PMBL. Our data establish nm-PMBLsig+ lymphomas as a group within DLBCL with distinct phenotypic and genetic features. These findings may have implications for gene expression- and mutation-based subtyping of aggressive B-cell lymphomas and related targeted therapies.

DOI： 10.1182/blood.2020007683

Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression. 国際誌

Makoto Nakamura, Yusuke Meguri, Shuntaro Ikegawa, Takumi Kondo, Yuichi Sumii, Takuya Fukumi, Miki Iwamoto, Yasuhisa Sando, Hiroyuki Sugiura, Noboru Asada, Daisuke Ennishi, Shuta Tomida, Emi Fukuda-Kawaguchi, Yasuyuki Ishii, Yoshinobu Maeda, Ken-Ichi Matsuoka

Scientific reports 11 ( 1 ) 13125 - 13125 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

DOI： 10.1038/s41598-021-92526-z

A Case of Metastatic Fumarate Hydratase-Deficient-like Renal Cell Carcinoma Successfully Managed by Ipilimumab plus Nivolumab.

Takanori Sekito, Atsushi Takamoto, Yasuyuki Kobayashi, Masao Mitsui, Shogo Watari, Risa Kubota, Takuya Sadahira, Takehiro Iwata, Shingo Nishimura, Kohei Edamura, Tomoko Sako, Motoo Araki, Masami Watanabe, Toyohiko Watanabe, Rei Shibata, Daisuke Ennishi, Yasutomo Nasu

Acta medica Okayama 75 ( 3 ) 397 - 402 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

We report a 62-year-old male with metastatic fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) without fumarate hydratase (FH) mutation (FH-deficient-like RCC). The International Metastatic RCC Database Consortium risk score was intermediate, and immunotherapy with nivolumab and ipilimumab (Ipi/ Nivo) was initiated. Four cycles of Ipi/Nivo and 5 cycles of nivolumab resulted in a complete response of the metastases. Hypophysitis occurred as an immune-related adverse event after four cycles of Ipi/Nivo. The prognosis of patients with FH-deficient RCC is generally poor. Few reports of FH-deficient RCC successfully treated with Ipi/Nivo have been published. Ipi/Nivo can be effective for treating FH-deficient RCC.

DOI： 10.18926/AMO/62237

Effects of Gram-negative Rod Blood Stream Infection on Acute GVHD in Allogeneic Hematopoietic Stem Cell Transplantation: A Single-institute Analysis.

Masaaki Nishinohara, Hisakazu Nishimori, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Ken-Ichi Matsuoka, Keiko Fujii, Nobuharu Fujii, Yoshinobu Maeda

Acta medica Okayama 75 ( 3 ) 279 - 287 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

A bloodstream infection (BSI) is the most common serious infectious complication of hematopoietic stem cell transplantation (HSCT). BSI promotes an inflammatory state, which exacerbates acute graft-versus-host disease (GVHD). We investigated whether a Gram-negative rod bloodstream infection (GNR-BSI), which develops early after allo-HSCT, affected the onset or exacerbated acute GVHD in 465 patients who underwent allo-HSCT from 1995 through 2015 at a single institution. Eighty-eight patients (19%) developed BSI during the study period. Among the cultures, 50 (57%) were Gram-positive cocci (GPC) and 31 (35%) were GNR. Of the 465 patients, 187 (40%) developed acute GVHD of grade II or higher within the first 100 days post-allogeneic HSCT: 124 (27%) had acute GVHD grade II, 47 (10%) had grade III, and 16 (3%) had grade IV. Multivariate analysis revealed that GNR-BSI was a significant risk factor for grade II-IV acute GVHD (grade II-IV: hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.03-2.97; grade III-IV: HR 2.37, 95% CI 1.03-5.43). These results suggest that GNR-BSI may predict the onset and exacerbation of acute GVHD.

DOI： 10.18926/AMO/62219

Safety and antitumor activity of acalabrutinib for relapsed/refractory B-cell malignancies: A Japanese phase I study. 国際誌

Koji Izutsu, Kiyoshi Ando, Daisuke Ennishi, Hirohiko Shibayama, Junji Suzumiya, Kazuhito Yamamoto, Satoshi Ichikawa, Koji Kato, Kyoya Kumagai, Priti Patel, Sakura Iizumi, Nobuya Hayashi, Hisashi Kawasumi, Kosho Murayama, Hirokazu Nagai

Cancer science 112 ( 6 ) 2405 - 2415 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

This multicenter, open-label, phase I study assessed the safety and antitumor activity of acalabrutinib in Japanese patients with relapsed/refractory (r/r) B-cell malignancies. Parts 1 (dose confirmation) and 2 (dose expansion) of this three-part study are reported. Treatment was a single dose of 100 mg acalabrutinib (day 1), followed by a washout period and then twice daily 100 mg acalabrutinib in part 1, or twice daily 100 mg acalabrutinib in part 2. Patients from parts 1 and 2 with r/r chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and r/r mantle cell lymphoma (MCL) were assessed as r/r CLL/SLL and r/r MCL cohorts, respectively. Twenty-five patients received treatment (part 1, n = 6). Median age was 71.0 years. Nine (one patient from part 1) and 13 (two patients from part 1) patients were included in the r/r CLL/SLL and r/r MCL cohorts, respectively. Treatment-related adverse events (AEs) occurred in 88% of patients (grade ≥3, 36%); the most common were headache (28%) and purpura (24%), both grade 1/2. No AEs resulted in treatment discontinuation or death. Median duration of treatment was 31, 20, and 7 months for part 1, r/r CLL/SLL cohort, and r/r MCL cohort, respectively. Overall response rate (ORR) was 89% and 62% for the r/r CLL/SLL and r/r MCL cohorts, respectively. The median progression-free survival (PFS) was not reached for the r/r CLL/SLL cohort and was 7 months for the r/r MCL cohort. Acalabrutinib (100 mg twice daily) was generally safe and well-tolerated in adult Japanese patients with B-cell malignancies.

DOI： 10.1111/cas.14886

Molecular attributes underlying central nervous system and systemic relapse in diffuse large B-cell lymphoma. 国際誌

Keren Isaev, Daisuke Ennishi, Laura Hilton, Brian Skinnider, Karen L Mungall, Andrew J Mungall, Mehran Bakhtiari, Rosemarie Tremblay-LeMay, Anjali Silva, Susana Ben-Neriah, Merrill Boyle, Diego Villa, Marco A Marra, Christian Steidl, Randy D Gascoyne, Ryan Morin, Kerry J Savage, David W Scott, Robert Kridel

Haematologica 106 ( 5 ) 1466 - 1471 2021年5月

Correction to: The initial assessment of expert panel performance in core hospitals for cancer genomic medicine in Japan.

Kuniko Sunami, Yoichi Naito, Eriko Aimono, Toraji Amano, Daisuke Ennishi, Hidenori Kage, Masashi Kanai, Keigo Komine, Takafumi Koyama, Takahiro Maeda, Sachi Morita, Daisuke Sakai, Shinji Kohsaka, Katsuya Tsuchihara, Takayuki Yoshino

International journal of clinical oncology 26 ( 5 ) 1007 - 1007 2021年5月

The impact of MYC and BCL2 structural variants in tumors of DLBCL morphology and mechanisms of false-negative MYC IHC. 国際誌

Brett Collinge, Susana Ben-Neriah, Lauren Chong, Merrill Boyle, Aixiang Jiang, Tomoko Miyata-Takata, Pedro Farinha, Jeffrey W Craig, Graham W Slack, Daisuke Ennishi, Anja Mottok, Barbara Meissner, Elizabeth A Chavez, Alina S Gerrie, Diego Villa, Ciara Freeman, Kerry J Savage, Laurie H Sehn, Ryan D Morin, Andrew J Mungall, Randy D Gascoyne, Marco A Marra, Joseph M Connors, Christian Steidl, David W Scott

Blood 137 ( 16 ) 2196 - 2208 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

When the World Health Organization defined high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) as a clinical category, rearrangements were the only structural variant (SV) incorporated. An "atypical double-hit" category has been proposed, encompassing tumors with concurrent MYC and BCL2 SVs other than cooccurring translocations (ie, copy number variations [CNVs]). Although the identification of a gene expression signature (DHITsig) shared among tumors harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2) has confirmed a common underlying biology, the biological implication of MYC and BCL2 CNVs requires further elucidation. We performed a comprehensive analysis of MYC and BCL2 SVs, as determined by fluorescent in situ hybridization (FISH), in a cohort of 802 de novo tumors with diffuse large B-cell lymphoma morphology. Although BCL2 CNVs were associated with increased expression, MYC CNVs were not. Furthermore, MYC and BCL2 CNVs, in the context of atypical double-hit, did not confer a similar gene expression profile as HGBL-DH/TH-BCL2. Finally, although MYC immunohistochemistry (IHC) has been proposed as a screening tool for FISH testing, 2 mechanisms were observed that uncoupled MYC rearrangement from IHC positivity: (1) low MYC messenger RNA expression; and (2) false-negative IHC staining mediated by a single-nucleotide polymorphism resulting in an asparagine-to-serine substitution at the 11th amino acid residue of MYC (MYC-N11S). Taken together, these results support the current exclusion of MYC and BCL2 CNVs from HGBL-DH/TH and highlight the ability of a molecular-based classification system to identify tumors with shared biology that FISH and IHC fail to fully capture.

DOI： 10.1182/blood.2020007193

Nodal Peripheral T-cell Lymphoma with T Follicular Helper Phenotype Presenting as Chorea during Treatment: A Case Report and Literature Review.

Wataru Kitamura, Daisuke Ennishi, Ryoya Yukawa, Ryo Sasaki, Chikamasa Yoshida, Hiroki Takasuka, Hideaki Fujiwara, Noboru Asada, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Koji Abe, Tadashi Yoshino, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 60 ( 19 ) 3155 - 3160 2021年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

A 72-year-old man presented with chorea while undergoing treatment for recurrence of nodal peripheral T-cell lymphoma with T follicular helper (TFH) phenotype. An examination by brain N-isopropyl-p-iodoamphetamine (123I-IMP)-single photon emission computed tomography (SPECT) revealed no abnormalities other than a decreased cerebral blood flow (CBF) in the left striatum. After four courses of salvage chemotherapy, his clinical symptoms and asymmetric cerebral perfusion improved, suggesting that the decreased CBF had caused chorea. The significance of brain SPECT has not been fully clarified in patients with chorea-associated malignant lymphoma, warranting further investigations. Brain SPECT is an alternative approach to identify abnormalities in such patients.

DOI： 10.2169/internalmedicine.7180-21

Post-transplantation cyclophosphamide restores early B-cell lymphogenesis that suppresses subsequent chronic graft-versus-host disease. 国際誌

Miki Iwamoto, Shuntaro Ikegawa, Takumi Kondo, Yusuke Meguri, Makoto Nakamura, Yasuhisa Sando, Hiroyuki Sugiura, Yuichi Sumii, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Misako Shibakura, Yoshinobu Maeda, Ken-Ichi Matsuoka

Bone marrow transplantation 56 ( 4 ) 956 - 959 2021年4月

Author Correction: 5-aminolevulinic acid-mediated photodynamic therapy can target aggressive adult T cell leukemia/lymphoma resistant to conventional chemotherapy. 国際誌

Yasuhisa Sando, Ken-Ichi Matsuoka, Yuichi Sumii, Takumi Kondo, Shuntaro Ikegawa, Hiroyuki Sugiura, Makoto Nakamura, Miki Iwamoto, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Atae Utsunomiya, Takashi Oka, Yoshinobu Maeda

Scientific reports 11 ( 1 ) 6420 - 6420 2021年3月

Pretransplant nivolumab further enhanced Treg expansion after posttransplant cyclophosphamide; another aspect for immune tolerance by PTCy after nivolumab. 国際誌

Shuntaro Ikegawa, Yusuke Meguri, Kentaro Mizuhara, Takuya Fukumi, Hiroki Kobayashi, Yuichi Sumii, Takumi Kondo, Yasuhisa Sando, Miki Iwamoto, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Yuka Fujisawa, Toshi Imai, Yoshinobu Maeda, Ken-Ichi Matsuoka

Leukemia 35 ( 3 ) 929 - 931 2021年3月

The initial assessment of expert panel performance in core hospitals for cancer genomic medicine in Japan.

Kuniko Sunami, Yoichi Naito, Eriko Aimono, Toraji Amano, Daisuke Ennishi, Hidenori Kage, Masashi Kanai, Keigo Komine, Takafumi Koyama, Takahiro Maeda, Sachi Morita, Daisuke Sakai, Shinji Kohsaka, Katsuya Tsuchihara, Takayuki Yoshino

International journal of clinical oncology 26 ( 3 ) 443 - 449 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Since June 2019, cancer genomic profiling (CGP) tests have been reimbursed by the National Health Insurance system in Japan, with restrictions for government-designated hospitals with a molecular tumor board composed of multidisciplinary specialists, known as an expert panel (EP). The standardization of EPs is a critical challenge for implementing precision oncology in the clinical setting. METHODS: Data on consecutive cases who underwent the CGP tests at 11 core hospitals between June 2019 and January 2020 were collected. We evaluated the proportions of cases that received genomically matched treatments, including investigational new drugs (INDs) based on CGP results, and/or for which genetic counseling was recommended. Two simulated cases were annotated by each EP. The annotated reports were then centrally assessed. RESULTS: Each EP mainly discussed the applicability to genomically matched treatments and the necessity of performing genetic counseling. A pre-review of the report by key members in each EP reportedly made the EP conference more interactive and efficient, and thereby saved time. A total of 747 cases underwent CGP tests, 28 cases (3.7%) received genomically matched treatment, and 17 cases (2.3%) were referred for genetic counseling. Annotated reports for the simulated cases varied across the EPs, particularly the number of recommended IND trials, which seemed to be associated with the actual number of participants in IND trials. CONCLUSIONS: This investigation provides reference data for the application of precision oncology in a clinical setting. Further investigations on the standardization of clinical annotations are warranted.

DOI： 10.1007/s10147-020-01844-1

Follow-up with serum IgG4-monitoring in 8 patients with IgG4-related disease diagnosed by a lacrimal gland mass.

Toshihiko Matsuo, Takehiro Tanaka, Yasuharu Sato, Hitomi Kataoka, Mayu Uka, Daisuke Ennishi, Tomofumi Yano

Journal of clinical and experimental hematopathology : JCEH 61 ( 1 ) 10 - 21 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

The diagnostic criteria for IgG4-related disease were previously published and serum IgG4 measurement has been reimbursed by national health insurance in Japan since 2012. Eight patients diagnosed with IgG4-related disease based on lacrimal gland masses were retrospectively reviewed. The 8 patients were 3 men and 5 women ranging in age from 52 to 77 (median, 63) years at the initial visit and their follow-up period ranged from 0.25 to 11 (median, 7) years. Bilateral and unilateral involvement were noted in 4 patients each; 2 on the right side and 2 on the left side in those with unilateral involvement. Serum IgG4 was high in 5 of 8 patients at the initial visit. Five patients with no systemic signs were followed without treatment, whereas oral steroids were administered and tapered in the other 3 patients who exhibited systemic signs. One patient with a history of radiation for MALT lymphoma in bilateral lacrimal glands developed IgG4-related disease in the left lacrimal gland 10 years later and was followed without treatment. Nine years later, her serum IgG4 level increased to 1500 mg/dL and paracardiac lesions, found on positron emission tomography, were confirmed to be MALT lymphoma by needle biopsy, leading to systemic chemotherapy. The other 7 patients had neither local recurrence nor additional systemic signs. Serum IgG4 monitoring may be useful to detect systemic complications in IgG4-related ophthalmic disease and markedly high serum IgG4 levels may indicate new lymphoma at other sites.

DOI： 10.3960/jslrt.20048

Aggressive B-cell lymphoma(DLBCL, HGBCL)のゲノム異常による病型分類

遠西大輔

臨床血液 62 ( 5 ) 418 - 423 2021年

Total body irradiation-based haploidentical hematopoietic stem cell transplantation using posttransplant cyclophosphamide after administration of inotuzumab ozogamicin: A case report. 国際誌

Masaya Abe, Nobuharu Fujii, Kentaro Mizuhara, Tomohiro Urata, Yuichi Sumii, Yuki Fujiwara, Keisuke Seike, Yasuhisa Sando, Makoto Nakamura, Keiko Fujii, Kyosuke Saeki, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-Ichi Matsuoka, Yoshinobu Maeda

Leukemia research reports 15 100241 - 100241 2021年

記述言語：英語

Owing to the poor prognosis of relapsed or refractory acute lymphoblastic leukemia (ALL), hematopoietic stem cell transplantation (HSCT) followed by effective salvage therapy is required. Inotuzumab ozogamicin (INO) was developed for ALL refractory to standard chemotherapy. However, previous reports suggest that sinusoidal obstruction syndrome (SOS) risk increases in patients with HSCT receiving INO, especially with dual alkylating agents. We report a case of relapsed Philadelphia chromosome-negative B-ALL where the patient underwent haploidentical HSCT using fludarabine/total body irradiation conditioning and posttransplant cyclophosphamide. Successful engraftment was achieved without SOS development.

DOI： 10.1016/j.lrr.2021.100241

DLBCLとhigh-grade B-cell lymphomaの分子病態に関わる最近の知見

遠西大輔

臨床血液 62 ( 6 ) 624 - 630 2021年

記述言語：日本語出版者・発行元：一般社団法人日本血液学会

悪性リンパ腫の中でも最も患者数の多いびまん性大細胞型リンパ腫（diffuse large B-cell lymphoma, DLBCL）は，臨床的，生物学的に非常に不均一な疾患単位であり，様々な分子遺伝学的異常が腫瘍形成に関わっていると考えられる。これまで，特に細胞起源に関わる遺伝子発現プロファイルや免疫微小環境の特徴，遺伝子解析技術の進歩による新規遺伝子異常の発見により，分子病態の解明と細分類化が進んでいる。このような分子学的特徴は臨床予後とも関連性が示され，DLBCLの個別化医療を考える上で非常に重要な因子である。本稿ではDLBCLの分子病態の最新の知見を紹介しながら，個別化医療の可能性についても述べていく。

DOI： 10.11406/rinketsu.62.624

その他リンク： https://search.jamas.or.jp/link/ui/2021315726

Transformed diffuse large B-cell lymphoma from marginal zone lymphoma in the anterior mediastinum: A case report and review of the literature

Wataru Kitamura, Noboru Asada, Tetsuya Tabata, Rei Shibata, Tatsuya Nishi, Yuka Kato, Hiroki Takasuka, Hideaki Fujiwara, Daisuke Ennishi, Hisakazu Nishimori, Nobuharu Fujii, Ken-ichi Matsuoka, Katsuyuki Kiura, Tadashi Yoshino, Yoshinobu Maeda

Journal of Clinical and Experimental Hematopathology 2021年

Four Cases of Desquamative Esophagitis Occurring after Hematopoietic Stem Cell Transplantation.

Masaya Iwamuro, Daisuke Ennishi, Ken-Ichi Matsuoka, Takehiro Tanaka, Shotaro Okanoue, Yuka Obayashi, Hiroyuki Sakae, Yoshiro Kawahara, Hiroyuki Okada

Internal medicine (Tokyo, Japan) 59 ( 23 ) 3015 - 3022 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

We herein report four patients with desquamative esophagitis that developed one to nine days after peripheral blood stem cell transplantation (PBSCT). Three patients underwent allogeneic PBSCT for leukemia, and the other underwent autologous PBSCT for pineoblastoma. Esophagogastroduodenoscopy revealed mucosal sloughing and fresh blood in the esophagus. Fasting and intravenous proton pump inhibitor therapy in addition to blood transfusion improved the esophageal lesions within five to seven days in three patients. These cases indicate that desquamative esophagitis can occur in patients who receive hematopoietic stem cell transplantation. Although blood transfusions may be required, it can be resolved within seven days.

DOI： 10.2169/internalmedicine.4977-20

Allogeneic hematopoietic stem cell transplantation in a prior lung transplant recipient.

Yuki Fujiwara, Ken-Ichi Matsuoka, Miki Iwamoto, Yuichi Sumii, Masaya Abe, Kentaro Mizuhara, Tomohiro Urata, Kyosuke Saeki, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Junichi Sugita, Hajime Kobayashi, Takahiro Oto, Yoshinobu Maeda

International journal of hematology 112 ( 6 ) 871 - 877 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Hematological diseases after solid organ transplant (SOT) are an emerging issue as the number of long-term SOT survivors increases. Expertise in managing patients requiring allogeneic hematopoietic stem cell transplantation (HSCT) after SOT from independent donors is needed; however, clinical reports of HSCT after SOT are limited, and the feasibility and risk are not well understood. In particular, HSCT in prior lung transplant recipients is thought to be complicated as the lung is immunologically distinct and is constantly exposed to the surrounding environment. Herein, we describe a case of successful HSCT in a patient with myelodysplastic syndromes who had previously received a lung transplant from a deceased donor for bronchiolitis obliterans syndrome. Reports about cases of HSCT after lung transplant are quite rare; thus, we discuss the mechanisms of immune tolerance through the clinical course of our case. This case suggests that HSCT after SOT can be considered a therapeutic option in cases where the transplanted organ is functionally retained and the hematological disease is in remission.

DOI： 10.1007/s12185-020-02967-x

Treatment outcomes of IgG4-producing marginal zone B-cell lymphoma: a retrospective case series.

Yuichi Sumii, Noboru Asada, Yasuharu Sato, Koh-Ichi Ohshima, Masanori Makita, Yusuke Yoshimoto, Yuka Sogabe, Kenji Imajo, Yusuke Meguri, Daisuke Ennishi, Hisakazu Nishimori, Nobuharu Fujii, Ken-Ichi Matsuoka, Tadashi Yoshino, Yoshinobu Maeda

International journal of hematology 112 ( 6 ) 780 - 786 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

IgG4-producing marginal zone B-cell lymphomas (MZLs) have been recently proposed as a subtype of MZLs. Despite the abundant literature on pathophysiological features of this type of lymphoma, only a few retrospective studies pertaining to the treatment outcomes have been reported, and its prognosis remains unclear. We retrospectively analyzed seven patients with IgG4-producing MZLs diagnosed at our institute, with specific reference to treatment and outcomes. The median age was 69.0 years (55-79), and all were males. The median follow-up period was 66.6 months (8-121). All patients had localized disease; four patients had tumors of the ocular adnexa, whereas two had retroperitoneal tumors. Five patients were treated with irradiation (30 Gy/15 fr) (n = 4) or surgery (n = 1), resulting in tumor reduction. Two patients were treated by chemotherapy or irradiation. Among them, one commenced rituximab monotherapy, which led to an inadequate reduction of the tumor. Subsequent irradiation induced complete response (CR). The other patient experienced repeated relapses during follow-up and finally achieved CR by combination chemotherapy. Treatment was well tolerated in all cases, and none of the patients showed disease progression at the last follow-up visit. Our results indicate that the standard treatments for MZLs are generally appropriate for IgG4-producing MZL.

DOI： 10.1007/s12185-020-02968-w

Adult T-cell Leukemia-lymphoma with Primary Breast Involvement: A Case Report and Literature Review.

Hiroki Kobayashi, Noboru Asada, Takuro Igawa, Masaya Abe, Yusuke Meguri, Daisuke Ennishi, Hisakazu Nishimori, Nobuharu Fujii, Ken-Ichi Matsuoka, Tadashi Yoshino, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 59 ( 21 ) 2757 - 2761 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Breast involvement of Adult T-cell leukemia-lymphoma (ATLL) is extremely rare, and the data on the characteristics are limited. We herein describe a 49-year-old woman who presented with skin involvement of ATLL. Positron emission tomography/computed tomography showed bilateral breast lesions. Although the patient once achieved a complete metabolic response, a relapse of her ATLL occurred. The patient received subsequent allogeneic hematopoietic stem cell transplantation (HSCT). To our knowledge, only four cases of ATLL with breast involvement have previously been reported, and the prognoses have generally been poor. Breast lesions of ATLL have aggressive features, and intensive systemic chemotherapy and HSCT are required to improve survival.

DOI： 10.2169/internalmedicine.5077-20

Efficacy of HLA virtual cross-matched platelet transfusions for platelet transfusion refractoriness in hematopoietic stem cell transplantation (vol 60, pg 473, 2020)

Keisuke Seike, Nobuharu Fujii, Naomi Asano, Shigenori Ohkuma, Yasushi Hirata, Keiko Fujii, Yasuhisa Sando, Makoto Nakamura, Kazunori Naito, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-ichi Matsuoka, Kazuo Tsubaki, Fumio Otsuka, Yoshinobu Maeda

TRANSFUSION 60 ( 11 ) 2765 - 2765 2020年11月

5-aminolevulinic acid-mediated photodynamic therapy can target aggressive adult T cell leukemia/lymphoma resistant to conventional chemotherapy. 国際誌

Yasuhisa Sando, Ken-Ichi Matsuoka, Yuichi Sumii, Takumi Kondo, Shuntaro Ikegawa, Hiroyuki Sugiura, Makoto Nakamura, Miki Iwamoto, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Atae Utsunomiya, Takashi Oka, Yoshinobu Maeda

Scientific reports 10 ( 1 ) 17237 - 17237 2020年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Photodynamic therapy (PDT) is an emerging treatment for various solid cancers. We recently reported that tumor cell lines and patient specimens from adult T cell leukemia/lymphoma (ATL) are susceptible to specific cell death by visible light exposure after a short-term culture with 5-aminolevulinic acid, indicating that extracorporeal photopheresis could eradicate hematological tumor cells circulating in peripheral blood. As a bridge from basic research to clinical trial of PDT for hematological malignancies, we here examined the efficacy of ALA-PDT on various lymphoid malignancies with circulating tumor cells in peripheral blood. We also examined the effects of ALA-PDT on tumor cells before and after conventional chemotherapy. With 16 primary blood samples from 13 patients, we demonstrated that PDT efficiently killed tumor cells without influencing normal lymphocytes in aggressive diseases such as acute ATL. Importantly, PDT could eradicate acute ATL cells remaining after standard chemotherapy or anti-CCR4 antibody, suggesting that PDT could work together with other conventional therapies in a complementary manner. The responses of PDT on indolent tumor cells were various but were clearly depending on accumulation of protoporphyrin IX, which indicates the possibility of biomarker-guided application of PDT. These findings provide important information for developing novel therapeutic strategy for hematological malignancies.

DOI： 10.1038/s41598-020-74174-x

Toward a New Molecular Taxonomy of Diffuse Large B-cell Lymphoma. 国際誌

Daisuke Ennishi, Eric D Hsi, Christian Steidl, David W Scott

Cancer discovery 10 ( 9 ) 1267 - 1281 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Diffuse large B-cell lymphoma (DLBCL) represents a grouping of clinically and biologically heterogeneous tumors. Application of advanced molecular technology has significantly expanded our knowledge of DLBCL pathobiology, allowing identification of subgroups with common, potentially targetable, biological themes. Here, we review the recent molecular analyses that could provide a paradigm shift to a new taxonomy, foundational to the rational transition to precision medicine. We discuss how classification systems may be synthesized into a common taxonomy, drawing strength from the relationships between genetic alterations, gene expression, and tumor microenvironment. Finally, challenges to translating such a taxonomy to the clinic will be outlined.

DOI： 10.1158/2159-8290.CD-20-0174

Persistent hypogammaglobulinemia due to immunoglobulin class switch impairment by peri-transplant rituximab therapy.

Kentaro Mizuhara, Nobuharu Fujii, Yusuke Meguri, Takahide Takahashi, Michinori Aoe, Makoto Nakamura, Keisuke Seike, Yasuhisa Sando, Keiko Fujii, Masaya Abe, Yuichi Sumii, Tomohiro Urata, Yuki Fujiwara, Kyosuke Saeki, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-Ichi Matsuoka, Yoshinobu Maeda

International journal of hematology 112 ( 3 ) 422 - 426 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Post-transplant lymphoproliferative disorder (PTLD) is one of the most serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab is effective for PTLD; however, rituximab can produce adverse effects, including hypogammaglobulinemia. Here, we present the case of an 18-year-old female with refractory cytopenia of childhood who developed persistent selective hypogammaglobulinemia with low immunoglobulin G (IgG) 2 and IgG4 levels and monoclonal protein after rituximab therapy against probable PTLD. Despite B-cell recovery, the serum IgG levels gradually declined, reaching < 300 mg/dL at 33 months after rituximab treatment. In addition, class-switched memory (CD27 + IgD -) B cells were limited in phenotypic analysis. These findings suggest that peri-HSCT rituximab may contribute to an abnormal B-cell repertoire induced by impaired immunoglobulin class switch.

DOI： 10.1007/s12185-020-02886-x

Single Cell Phenotypic Profiling of 27 DLBCL Cases Reveals Marked Intertumoral and Intratumoral Heterogeneity. 国際誌

Michael D Nissen, Manabu Kusakabe, Xuehai Wang, Guillermo Simkin, Deanne Gracias, Kateryna Tyshchenko, Ainsleigh Hill, Justin Meskas, Stacy Hung, Elizabeth A Chavez, Daisuke Ennishi, Tomohiro Aoki, Clementine Sarkozy, Joseph M Connors, Pedro Farinha, Graham W Slack, Randy D Gascoyne, Ryan R Brinkman, David W Scott, Christian Steidl, Andrew P Weng

Cytometry. Part A : the journal of the International Society for Analytical Cytology 97 ( 6 ) 620 - 629 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell-of-origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B-cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naïve patients. We found that malignant B-cells from each patient occupied unique regions in 37-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case, we were able to demonstrate direct correspondence between protein-level phenotypic subsets and DNA mutation-defined subclones. In summary, CyTOF analysis can resolve both intertumoral and intratumoral heterogeneity among primary samples and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones. © 2019 International Society for Advancement of Cytometry.

DOI： 10.1002/cyto.a.23919

An Endoscopic Biopsy Specimen Contains Adequate Lymphocytes for Flow Cytometric Analysis of Light Chain Expression in the Gastrointestinal Mucosa. 国際誌

Masaya Iwamuro, Katsunori Matsueda, Takahide Takahashi, Sizuma Omote, Takehiro Tanaka, Daisuke Ennishi, Fumio Otsuka, Tadashi Yoshino, Hiroyuki Okada

Annals of clinical and laboratory science 50 ( 3 ) 348 - 353 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Flow cytometry has not been widely used in routine clinical practice for the diagnosis of gastrointestinal lymphoma; this is mainly because of the absence of an appropriate protocol. Here, we established a protocol for flow cytometric analysis of a single biopsy specimen from the gastrointestinal mucosa and investigated its sensitivity and specificity. DESIGN: In this prospective study, we enrolled patients with previously diagnosed gastrointestinal lymphoma and patients with gastrointestinal lesions that were suspected to be lymphoma. RESULTS: Overall, 15 patients with gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (N=8), duodenal follicular lymphoma (grade 1; N=5), and benign lymphoid hyperplasia (ileum, N=1, and rectum, N=1) were included in this study. Of these, lymphocytes were isolated from 14 patients (93.3%). There were 200,000-1,500,000 viable cells per patient. Biopsy specimens from 10 out of the 12 patients with lymphoma were positive for light chain restriction; the two patients with benign lymphoid hyperplasia showed negative results. CONCLUSIONS: An adequate number of lymphocytes for flow cytometry could be isolated from a single specimen of endoscopic mucosal biopsy from 93.3% of the patients. Overall, the sensitivity of flow cytometric analysis of light chain expression for the diagnosis of B-cell lymphoma was 83.3%, and the specificity was 100%. Although further investigation is required as the sample size of the present study was small, our study suggests a potential option for diagnosing B-cell lymphoma in the gastrointestinal mucosa.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial. 国際誌

Kazuyuki Shimada, Motoko Yamaguchi, Yoshiko Atsuta, Kosei Matsue, Keijiro Sato, Shigeru Kusumoto, Hirokazu Nagai, Jun Takizawa, Noriko Fukuhara, Koji Nagafuji, Kana Miyazaki, Eiichi Ohtsuka, Masataka Okamoto, Yasumasa Sugita, Toshiki Uchida, Satoshi Kayukawa, Atsushi Wake, Daisuke Ennishi, Yukio Kondo, Tohru Izumi, Yoshihiro Kin, Kunihiro Tsukasaki, Daigo Hashimoto, Masaaki Yuge, Atsumi Yanagisawa, Yachiyo Kuwatsuka, Satoko Shimada, Yasufumi Masaki, Nozomi Niitsu, Hitoshi Kiyoi, Ritsuro Suzuki, Takashi Tokunaga, Shigeo Nakamura, Tomohiro Kinoshita

The Lancet. Oncology 21 ( 4 ) 593 - 602 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

DOI： 10.1016/S1470-2045(20)30059-0

TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma. 国際誌

Daisuke Ennishi, Shannon Healy, Ali Bashashati, Saeed Saberi, Christoffer Hother, Anja Mottok, Fong Chun Chan, Lauren Chong, Libin Abraham, Robert Kridel, Merrill Boyle, Barbara Meissner, Tomohiro Aoki, Katsuyoshi Takata, Bruce W Woolcock, Elena Viganò, Michael Gold, Laurie L Molday, Robert S Molday, Adele Telenius, Michael Y Li, Nicole Wretham, Nancy Dos Santos, Mark Wong, Natasja N Viller, Robert A Uger, Gerben Duns, Abigail Baticados, Angel Madero, Brianna N Bristow, Pedro Farinha, Graham W Slack, Susana Ben-Neriah, Daniel Lai, Allen W Zhang, Sohrab Salehi, Hennady P Shulha, Derek S Chiu, Sara Mostafavi, Alina S Gerrie, Da Wei Huang, Christopher Rushton, Diego Villa, Laurie H Sehn, Kerry J Savage, Andrew J Mungall, Andrew P Weng, Marcel B Bally, Ryan D Morin, Gabriela V Cohen Freue, Louis M Staudt, Joseph M Connors, Marco A Marra, Sohrab P Shah, Randy D Gascoyne, David W Scott, Christian Steidl

Nature medicine 26 ( 4 ) 577 - 588 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and 'eat-me' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation-a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.

DOI： 10.1038/s41591-020-0757-z

Efficacy of HLA virtual cross-matched platelet transfusions for platelet transfusion refractoriness in hematopoietic stem cell transplantation. 国際誌

Keisuke Seike, Nobuharu Fujii, Naomi Asano, Shigenori Ohkuma, Yasushi Hirata, Keiko Fujii, Yasuhisa Sando, Makoto Nakamura, Kazunori Naito, Kyosuke Saeki, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-Ichi Matsuoka, Kazuo Tsubaki, Fumio Otsuka, Yoshinobu Maeda

Transfusion 60 ( 3 ) 473 - 478 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Cross-matched platelet (cross-matched PLT) transfusion is effective for immune-mediated platelet transfusion refractoriness (PTR), but is more costly and time-consuming for physical cross-match than using standard PLT units. Recent studies have reported the utility of human leucocyte antigens (HLA) virtual cross-matched PLT (HLA-matched PLT) that is defined as HLA-A/B matched or no antibody against donor-specific antigen. Here, we evaluated the effect of HLA-matched PLTs for PTR in post hematopoietic stem cell transplant (HSCT) recipients. STUDY DESIGN AND METHODS: Our study included a total of 241 PLTs in 16 patients who underwent HSCT at Okayama University Hospital between 2010 and 2017, receiving either HLA-matched or cross-matched PLTs. We calculated the 24-hour corrected count increments (CCI-24) to evaluate the effect of PLTs. A CCI-24 ≥ 4500 was considered to be a successful transfusion. RESULTS: We analyzed 139 cross-matched PLTs and 102 HLA-matched PLTs. In the immune-mediated PTR, the rate of successful transfusion was 60.5% for cross-matched PLT and 63.4% for HLA-matched PLT (p = 0.825). On the other hand, the median CCI-24 for cross-matched PLT transfusions and HLA-matched PLT transfusions were 1856 and 5824 (p < 0.001), with a success rate of 28.1 and 54.1% in cases with non-immune-mediated PTR, respectively (p = 0.001). CONCLUSION: The effectiveness of HLA-matched PLT is not inferior to cross-matched PLT. This result indicates that physical cross-match can be omitted in post HSCT PTR.

DOI： 10.1111/trf.15664

Technique for single-step lymphocyte isolation from an endoscopic biopsy specimen for the diagnosis of gastrointestinal lymphoma. 国際誌

Masaya Iwamuro, Takahide Takahashi, Natsuki Watanabe, Sizuma Omote, Katsunori Matsueda, Takehiro Tanaka, Daisuke Ennishi, Fumio Otsuka, Tadashi Yoshino, Hiroyuki Okada

MethodsX 7 101095 - 101095 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）

In this paper, we introduce a simplified, one-step procedure for lymphocyte isolation from an endoscopically biopsied fragment. For lymphocyte isolation, an endoscopically harvested specimen and 5 mL of normal saline solution were placed in a wire mesh strainer set in a porcelain bowl. To obtain the lymphocyte suspension, the solid specimen was crushed using the rubber portion of a plunger of a 10 mL injection syringe. Flow cytometry was performed using the lymphocyte suspension. For validating our methods, the one-step lymphocyte isolation technique was used to perform flow cytometry on samples from 23 patients with (n = 12) or without (n = 11) gastrointestinal lymphoma. Flow cytometry of light chain expression was performed in all patient samples (feasibility: 100%). Sensitivity was 83.3% (10/12) and specificity was 100% (11/11). In conclusion, lymphocytes isolated from a single endoscopic biopsy specimen using our simplified and quick procedure are suitable for flow cytometry. Considering that flow cytometry has an important advantage of providing the results on the examination day itself, the results of this study suggest that flow cytometric analysis using our single-step lymphocyte isolation technique can be potentially used to diagnose lymphoma in the gastrointestinal mucosa. •We introduce a simplified, one-step procedure for lymphocyte isolation from an endoscopically biopsied fragment.•Our technique is feasible for flow cytometric analysis in patients with gastrointestinal lymphoma as well as those with gastrointestinal lesions that are suspected to be lymphoma.

DOI： 10.1016/j.mex.2020.101095

Diffuse Large B-Cell Lymphomas with a Molecular PMBCL Expression Signature Represent a Distinct Molecular Subtype Associated with Poor Clinical Outcome

Gerben Duns, Elena Vigano, Daisuke Ennishi, Clementine Sarkozy, Stacy Hung, Elizabeth Chavez, Katsuyoshi Takata, Anja Mottok, Randy D. Gascoyne, Ryan D. Morin, Kerry J. Savage, David W. Scott, Christian Steidl

BLOOD 134 2019年11月

Feasibility of flow cytometric analysis of restricted light chain in endoscopic biopsy specimens from patients with gastrointestinal tract B cell lymphoma: a pilot study. 国際誌

Katsunori Matsueda, Masaya Iwamuro, Takahide Takahashi, Sizuma Omote, Kenji Nishida, Takehiro Tanaka, Daisuke Ennishi, Fumio Otsuka, Tadashi Yoshino, Hiroyuki Okada

BMC research notes 12 ( 1 ) 571 - 571 2019年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Gastrointestinal tract lymphomas are currently detected more frequently due to advances in endoscopic technology. The aim of this study was to assess the feasibility of flow cytometric analysis of restricted light chain in endoscopic biopsy specimens for the diagnosis of gastrointestinal tract B-cell lymphoma. We prepared viable cell suspensions from unfixed specimens obtained from 10 consecutive patients who had a previous histological diagnosis of gastrointestinal tract B-cell lymphoma. We performed immunophenotypic studies with multi-color flow cytometry and assessed clonality through examination of immunoglobulin light chain expression exclusively in a population identified by anti-CD45 or CD20 antibodies. RESULTS: We could perform light chain expression analysis with 2 endoscopic biopsy specimens from all 10 patients with gastrointestinal tract B-cell lymphoma. We conclude that flow cytometric analysis of endoscopic biopsy specimens is feasible and thus likely useful for the diagnosis of gastrointestinal tract B-cell lymphoma in clinical settings. Trial registration UMIN Clinical Trials Registry, UMIN000027730. Registered 12 June 2017.

DOI： 10.1186/s13104-019-4578-4

Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition. 国際誌

Daisuke Ennishi, Katsuyoshi Takata, Wendy Béguelin, Gerben Duns, Anja Mottok, Pedro Farinha, Ali Bashashati, Saeed Saberi, Merrill Boyle, Barbara Meissner, Susana Ben-Neriah, Bruce W Woolcock, Adèle Telenius, Daniel Lai, Matt Teater, Robert Kridel, Kerry J Savage, Laurie H Sehn, Ryan D Morin, Marco A Marra, Sohrab P Shah, Joseph M Connors, Randy D Gascoyne, David W Scott, Ari M Melnick, Christian Steidl

Cancer discovery 9 ( 4 ) 546 - 563 2019年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II-deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I- and MHC-II-negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant Ezh2 Y641. Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming. SIGNIFICANCE: We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin-specific context. Specifically, EZH2 mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination.See related commentary by Velcheti et al., p. 472.This article is highlighted in the In This Issue feature, p. 453.

DOI： 10.1158/2159-8290.CD-18-1090

Salvage Haploidentical Transplantation Using Low-dose ATG for Early Disease Relapse after First Allogeneic Transplantation: A Retrospective Single-center Review.

Sachiyo Okamoto, Ken-Ichi Matsuoka, Maiko Sakamoto, Yoshiaki Usui, Yuki Fujiwara, Takumi Kondo, Katsuma Tani, Kyosuke Saeki, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Yoshinobu Maeda

Acta medica Okayama 73 ( 2 ) 161 - 171 2019年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Second allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for patients who relapse after first allo-SCT. Human leukocyte antigen (HLA)-haploidentical related donors provide the broad opportunity to conduct second SCT at the appropriate time, but the efficacy of second SCT from haploidentical donors after relapse has not been established. We retrospectively analyzed the records of 33 patients who underwent second SCT. Twenty patients underwent haplo-SCT with low-dose antithymocyte globulin (ATG), and the other 13 patients underwent conventional- SCTs, including HLA-matched related peripheral blood, unrelated bone marrow or cord blood. Three years after the second SCT, the overall survival (OS) and progression-free survival (PFS) of all patients were 32.5% and 23.9%. Multivariate analyses indicated that non-complete response at second SCT, less than 1-year interval to relapse after first- SCT, and total score ≥ 3 on the hematopoietic cell transplantation-specific comorbidity index were significantly associated with a lower PFS rate. The haplo- and conventional- SCT groups showed equivalent results regarding OS, PFS, cumulative incidences of relapse, non-relapse mortality and graft-versus-host disease. The neutropenic period after transplantation was significantly shorter in haplo- SCT than conventional- SCT (10.5 days vs. 16 days, p=0.001). Our analysis revealed that haplo-SCT could be an alternative therapeutic option for relapsed patients after first SCT.

DOI： 10.18926/AMO/56652

Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma. 国際誌

Daisuke Ennishi, Aixiang Jiang, Merrill Boyle, Brett Collinge, Bruno M Grande, Susana Ben-Neriah, Christopher Rushton, Jeffrey Tang, Nicole Thomas, Graham W Slack, Pedro Farinha, Katsuyoshi Takata, Tomoko Miyata-Takata, Jeffrey Craig, Anja Mottok, Barbara Meissner, Saeed Saberi, Ali Bashashati, Diego Villa, Kerry J Savage, Laurie H Sehn, Robert Kridel, Andrew J Mungall, Marco A Marra, Sohrab P Shah, Christian Steidl, Joseph M Connors, Randy D Gascoyne, Ryan D Morin, David W Scott

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 37 ( 3 ) 190 - 201 2019年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression. PATIENTS AND METHODS: We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data. RESULTS: We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH- BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non-light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH- BCL2, 11 of 25 DHITsig-positive-transformed follicular lymphomas were classified as HGBL-DH/TH- BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested. CONCLUSION: We have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH- BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.

DOI： 10.1200/JCO.18.01583

B細胞性リンパ腫

遠西大輔

臨床血液 60 ( 5 ) 434 - 440 2019年

DLBCLの遺伝子異常に基づく分類と層別化治療の可能性

遠西大輔

臨床血液 60 ( 9 ) 1186 - 1192 2019年

記述言語：日本語出版者・発行元：一般社団法人日本血液学会

びまん性大細胞型リンパ腫（diffuse large B-cell lymphoma, DLBCL）は臨床的，生物学的に非常に不均一な疾患単位であり，様々な分子遺伝学的異常が腫瘍形成に関わっていると考えられる。最近の遺伝子解析技術の進歩により，新規遺伝子異常が次々と発見され，またそれらに基づく分子病態の解明と細分類化が進んでいる。さらに遺伝子異常や分子学的特徴と臨床予後の関連性が明らかにされつつあり，これらは今後の新規治療薬や臨床試験の適応を考える上で重要な因子として，DLBCLの今後の個別化医療（プレシジョンメディシン）を考える上で非常に重要な因子である。本稿ではDLBCLの分子病態の最新の知見を紹介しながら，遺伝子異常による層別化治療の可能性について解説し，それらの臨床的意義についても述べる。

DOI： 10.11406/rinketsu.60.1186

その他リンク： https://search.jamas.or.jp/link/ui/2020081718

High-resolution architecture and partner genes of MYC rearrangements in lymphoma with DLBCL morphology. 国際誌

Lauren C Chong, Susana Ben-Neriah, Graham W Slack, Ciara Freeman, Daisuke Ennishi, Anja Mottok, Brett Collinge, Pau Abrisqueta, Pedro Farinha, Merrill Boyle, Barbara Meissner, Robert Kridel, Alina S Gerrie, Diego Villa, Kerry J Savage, Laurie H Sehn, Reiner Siebert, Ryan D Morin, Randy D Gascoyne, Marco A Marra, Joseph M Connors, Andrew J Mungall, Christian Steidl, David W Scott

Blood advances 2 ( 20 ) 2755 - 2765 2018年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Genomic rearrangements in the MYC locus occur in ∼12% of lymphomas with diffuse large B-cell lymphoma (DLBCL) morphology and are associated with inferior outcome. Previous studies exploring MYC rearrangements have primarily used fluorescence in situ hybridization (FISH) assays to characterize break-apart status but have rarely examined breakpoint location, and in some cases have not examined partner identity. We performed targeted sequencing of MYC, BCL2, BCL6, and the immunoglobulin (IG) loci in 112 tumors with DLBCL morphology harboring MYC rearrangement. We characterized the location of the MYC rearrangement at base pair resolution and identified the partner in 88 cases. We observed a cluster of breakpoints upstream of the MYC coding region and in intron 1 (the "genic cluster"). Genic cluster rearrangements were enriched for translocations involving IGH (80%), whereas nongenic rearrangements occurred mostly downstream of the MYC gene with a variety of partners, including IGL and IGK Other recurrent partners included BCL6, ZCCHC7, and RFTN1, which has not previously been described as a MYC partner. We compared 2 commercially available FISH break-apart assays for the MYC locus and observed discordant results in 32% of cases examined, including some with MYC-IGL and MYC-IGK rearrangements. In cases of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH), so-called "double-hit" lymphomas, the majority of MYC rearrangements had non-IG partners (65%), with breakpoints outside the genic cluster (72%). In patients with de novo HGBL-DH of DLBCL morphology, MYC-IG rearrangements showed a trend toward inferior time to progression and overall survival compared with MYC-non-IG rearrangements. Our data reveal clinically relevant architecture of MYC rearrangements in lymphomas with DLBCL morphology.

DOI： 10.1182/bloodadvances.2018023572

Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma. 国際誌

Sarah E Arthur, Aixiang Jiang, Bruno M Grande, Miguel Alcaide, Razvan Cojocaru, Christopher K Rushton, Anja Mottok, Laura K Hilton, Prince Kumar Lat, Eric Y Zhao, Luka Culibrk, Daisuke Ennishi, Selin Jessa, Lauren Chong, Nicole Thomas, Prasath Pararajalingam, Barbara Meissner, Merrill Boyle, Jordan Davidson, Kevin R Bushell, Daniel Lai, Pedro Farinha, Graham W Slack, Gregg B Morin, Sohrab Shah, Dipankar Sen, Steven J M Jones, Andrew J Mungall, Randy D Gascoyne, Timothy E Audas, Peter Unrau, Marco A Marra, Joseph M Connors, Christian Steidl, David W Scott, Ryan D Morin

Nature communications 9 ( 1 ) 4001 - 4001 2018年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3' UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

DOI： 10.1038/s41467-018-06354-3

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. 国際誌

David W Scott, Rebecca L King, Annette M Staiger, Susana Ben-Neriah, Aixiang Jiang, Heike Horn, Anja Mottok, Pedro Farinha, Graham W Slack, Daisuke Ennishi, Norbert Schmitz, Michael Pfreundschuh, Grzegorz S Nowakowski, Brad S Kahl, Joseph M Connors, Randy D Gascoyne, German Ott, William R Macon, Andreas Rosenwald

Blood 131 ( 18 ) 2060 - 2064 2018年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) is a newly defined entity in the latest World Health Organization Classification. Accurate diagnosis would appear to mandate fluorescence in situ hybridization (FISH) for all tumors with diffuse large B-cell lymphoma (DLBCL) morphology. We present the results of FISH, cell-of-origin, and immunohistochemistry (IHC) testing from 1228 DLBCL biopsies from 3 clinical trials and a population-based registry. HGBL-DH/TH made up 7.9% of the DLBCL, confined primarily to the germinal center B-cell-like (GCB; 13.3%) compared with activated B-cell-like (ABC; 1.7%) subtype (P < .001). HGBL-DH/TH with BCL2 rearrangement is a GCB phenomenon with no cases observed in 415 ABC DLBCL. A screening strategy restricting FISH testing to tumors of GCB subtype (by Lymph2Cx or Hans IHC) plus dual protein expression of MYC and BCL2 by IHC could limit testing to 11% to 14% of tumors, with a positive predictive value of 30% to 37%; however, this strategy would miss approximately one-quarter of tumors with HBGL-DH/TH with BCL2 rearrangement and one-third of all HGBL-DH/TH. These results provide accurate estimation of the proportion of HGBL-DH/TH among tumors with DLBCL morphology and allow determination of the impact of various methods available to screen DLBCL tumors for FISH testing.

DOI： 10.1182/blood-2017-12-820605

Assessment of Capture and Amplicon-Based Approaches for the Development of a Targeted Next-Generation Sequencing Pipeline to Personalize Lymphoma Management. 国際誌

Stacy S Hung, Barbara Meissner, Elizabeth A Chavez, Susana Ben-Neriah, Daisuke Ennishi, Martin R Jones, Hennady P Shulha, Fong Chun Chan, Merrill Boyle, Robert Kridel, Randy D Gascoyne, Andrew J Mungall, Marco A Marra, David W Scott, Joseph M Connors, Christian Steidl

The Journal of molecular diagnostics : JMD 20 ( 2 ) 203 - 214 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Targeted next-generation sequencing panels are increasingly used to assess the value of gene mutations for clinical diagnostic purposes. For assay development, amplicon-based methods have been preferentially used on the basis of short preparation time and small DNA input amounts. However, capture sequencing has emerged as an alternative approach because of high testing accuracy. We compared capture hybridization and amplicon sequencing approaches using fresh-frozen and formalin-fixed, paraffin-embedded tumor samples from eight lymphoma patients. Next, we developed a targeted sequencing pipeline using a 32-gene panel for accurate detection of actionable mutations in formalin-fixed, paraffin-embedded tumor samples of the most common lymphocytic malignancies: chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and follicular lymphoma. We show that hybrid capture is superior to amplicon sequencing by providing deep more uniform coverage and yielding higher sensitivity for variant calling. Sanger sequencing of 588 variants identified specificity limits of thresholds for mutation calling, and orthogonal validation on 66 cases indicated 93% concordance with whole-genome sequencing. The developed pipeline and assay identified at least one actionable mutation in 91% of tumors from 219 lymphoma patients and revealed subtype-specific mutation patterns and frequencies consistent with the literature. This pipeline is an accurate and sensitive method for identifying actionable gene mutations in routinely acquired biopsy materials, suggesting further assessment of capture-based assays in the context of personalized lymphoma management.

DOI： 10.1016/j.jmoldx.2017.11.010

AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis. 国際誌

Matt Teater, Pilar M Dominguez, David Redmond, Zhengming Chen, Daisuke Ennishi, David W Scott, Luisa Cimmino, Paola Ghione, Jayanta Chaudhuri, Randy D Gascoyne, Iannis Aifantis, Giorgio Inghirami, Olivier Elemento, Ari Melnick, Rita Shaknovich

Nature communications 9 ( 1 ) 222 - 222 2018年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas. This phenotype is associated with increased cytosine methylation heterogeneity, but not with increased AICDA-mediated somatic mutation burden. Reciprocally, the cytosine methylation heterogeneity characteristic of normal GC B cells is lost upon AICDA depletion. These observations are relevant to human patients, since DLBCLs with high AICDA expression manifest increased methylation heterogeneity vs. AICDA-low DLBCLs. Our results identify AICDA as a driver of epigenetic heterogeneity in B-cell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases.

DOI： 10.1038/s41467-017-02595-w

Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact. 国際誌

Daisuke Ennishi, Anja Mottok, Susana Ben-Neriah, Hennady P Shulha, Pedro Farinha, Fong Chun Chan, Barbara Meissner, Merrill Boyle, Christoffer Hother, Robert Kridel, Daniel Lai, Saeed Saberi, Ali Bashashati, Sohrab P Shah, Ryan D Morin, Marco A Marra, Kerry J Savage, Laurie H Sehn, Christian Steidl, Joseph M Connors, Randy D Gascoyne, David W Scott

Blood 129 ( 20 ) 2760 - 2770 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

The clinical significance of MYC and BCL2 genetic alterations in diffuse large B-cell lymphoma (DLBCL), apart from translocations, has not been comprehensively investigated using high-resolution genetic assays. In this study, we profiled MYC and BCL2 genetic alterations using next-generation sequencing and high-resolution SNP array in 347 de novo DLBCL cases treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) at the British Columbia Cancer Agency. Cell-of-origin (COO) subtype was determined by Lymph2Cx digital gene expression profiling. We showed that the incidence of MYC/BCL2 genetic alterations and their clinical significance were largely dependent on COO subtypes. It is noteworthy that the presence of BCL2 gain/amplification is significantly associated with poor outcome in activated B-cell-like and BCL2 translocation with poor outcome in germinal center B-cell subtypes, respectively. Both have prognostic significance independent of MYC/BCL2 dual expression and the International Prognostic Index (IPI). Furthermore, the combination of BCL2 genetic alterations with IPI identifies markedly worse prognostic groups within individual COO subtypes. Thus, high-resolution genomic assays identify extremely poor prognostic groups within each COO subtype on the basis of BCL2 genetic status in this large, uniformly R-CHOP-treated population-based cohort of DLBCL. These results suggest COO subtype-specific biomarkers based on BCL2 genetic alterations can be used to risk-stratify patients with DLBCL treated with immunochemotherapy.

DOI： 10.1182/blood-2016-11-747022

Clinical and prognostic significance of aberrant T-cell marker expression in 225 cases of de novo diffuse large B-cell lymphoma and 276 cases of other B-cell lymphomas. 国際誌

Naoko Tsuyama, Daisuke Ennishi, Masahiro Yokoyama, Satoko Baba, Reimi Asaka, Yuko Mishima, Yasuhito Terui, Kiyohiko Hatake, Kengo Takeuchi

Oncotarget 8 ( 20 ) 33487 - 33500 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Expression of T-cell markers, generally investigated for immunophenotyping of T-cell lymphomas, is also observed in several types of B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We previously reported that CD5 expression in DLBCL is an inferior prognostic factor in the era of rituximab. However, data regarding the frequencies, histological relevance, and prognostic importance of T-cell markers other than CD5 are currently unavailable. In the present study, we comprehensively evaluated the expression of T-cell markers (CD2, CD3, CD4, CD5, CD7, and CD8) in 501 B-cell lymphomas, including 225 DLBCLs, by flow cytometry and subsequent immunohistochemistry. T-cell markers other than CD5, such as CD2, CD4, CD7, and CD8, were expressed in 27 (5%) patients, and notably, all of these cases were classified as large B-cell lymphoma subtypes: 25 DLBCLs and 2 intravascular large B-cell lymphomas. CD5 and other T-cell markers were expressed in 15% (31/225) and 10% (25/225) of DLBCL cases, respectively. Five of them co-expressed CD5 and other T-cell markers. Retrospectively analyzing the prognostic relevance of T-cell markers in 169 patients with primary DLBCL treated with rituximab-based chemotherapy, we showed that only CD5 was a strong predictor of poor survival. This study provides information about the occurrence of T-cell markers other than CD5 in B-cell lymphomas, their frequent histological subtypes, and their prognostic significance in DLBCL. CD5 was reconfirmed as a negative prognostic marker in DLBCL patients receiving rituximab-inclusive chemotherapy, whereas T-cell markers other than CD5 were found to have no impact on clinicopathological and survival analyses.

DOI： 10.18632/oncotarget.16532

CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas. 国際誌

Yanwen Jiang, Ana Ortega-Molina, Huimin Geng, Hsia-Yuan Ying, Katerina Hatzi, Sara Parsa, Dylan McNally, Ling Wang, Ashley S Doane, Xabier Agirre, Matt Teater, Cem Meydan, Zhuoning Li, David Poloway, Shenqiu Wang, Daisuke Ennishi, David W Scott, Kristy R Stengel, Janice E Kranz, Edward Holson, Sneh Sharma, James W Young, Chi-Shuen Chu, Robert G Roeder, Rita Shaknovich, Scott W Hiebert, Randy D Gascoyne, Wayne Tam, Olivier Elemento, Hans-Guido Wendel, Ari M Melnick

Cancer discovery 7 ( 1 ) 38 - 53 2017年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)-derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas. SIGNIFICANCE: Our findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38-53. ©2016 AACR.See related commentary by Höpken, p. 14This article is highlighted in the In This Issue feature, p. 1.

DOI： 10.1158/2159-8290.CD-16-0975

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study. 国際誌

Robert Kridel, Fong Chun Chan, Anja Mottok, Merrill Boyle, Pedro Farinha, King Tan, Barbara Meissner, Ali Bashashati, Andrew McPherson, Andrew Roth, Karey Shumansky, Damian Yap, Susana Ben-Neriah, Jamie Rosner, Maia A Smith, Cydney Nielsen, Eva Giné, Adele Telenius, Daisuke Ennishi, Andrew Mungall, Richard Moore, Ryan D Morin, Nathalie A Johnson, Laurie H Sehn, Thomas Tousseyn, Ahmet Dogan, Joseph M Connors, David W Scott, Christian Steidl, Marco A Marra, Randy D Gascoyne, Sohrab P Shah

PLoS medicine 13 ( 12 ) e1002197 2016年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. METHODS AND FINDINGS: Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. CONCLUSIONS: Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

DOI： 10.1371/journal.pmed.1002197

Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. 国際誌

Michael Boice, Darin Salloum, Frederic Mourcin, Viraj Sanghvi, Rada Amin, Elisa Oricchio, Man Jiang, Anja Mottok, Nicolas Denis-Lagache, Giovanni Ciriello, Wayne Tam, Julie Teruya-Feldstein, Elisa de Stanchina, Wing C Chan, Sami N Malek, Daisuke Ennishi, Renier J Brentjens, Randy D Gascoyne, Michel Cogné, Karin Tarte, Hans-Guido Wendel

Cell 167 ( 2 ) 405 - 418 2016年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM(P37-V202)) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein.

DOI： 10.1016/j.cell.2016.08.032

Impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL. 国際誌

Kerry J Savage, Graham W Slack, Anja Mottok, Laurie H Sehn, Diego Villa, Roopesh Kansara, Robert Kridel, Christian Steidl, Daisuke Ennishi, King L Tan, Susana Ben-Neriah, Nathalie A Johnson, Joseph M Connors, Pedro Farinha, David W Scott, Randy D Gascoyne

Blood 127 ( 18 ) 2182 - 8 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Dual expression of MYC and BCL2 by immunohistochemistry (IHC) is associated with poor outcome in diffuse large B-cell lymphoma (DLBCL). Dual translocation of MYC and BCL2, so-called "double-hit lymphoma," has been associated with a high risk of central nervous system (CNS) relapse; however, the impact of dual expression of MYC and BCL2 (dual expressers) on the risk of CNS relapse remains unknown. Pretreatment formalin-fixed paraffin-embedded DLBCL biopsies derived from patients subsequently treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were assembled on tissue microarrays from 2 studies and were evaluated for expression of MYC and BCL2 by IHC. In addition, cell of origin was determined by IHC and the Lymph2Cx gene expression assay in a subset of patients. We identified 428 patients who met the inclusion criteria. By the recently described CNS risk score (CNS-International Prognostic Index [CNS-IPI]), 34% were low risk (0 to 1), 45% were intermediate risk (2 to 3), and 21% were high risk (4 or greater). With a median follow-up of 6.8 years, the risk of CNS relapse was higher in dual expressers compared with non-dual expressers (2-year risk, 9.7% vs 2.2%; P = .001). Patients with activated B-cell or non-germinal center B-cell type DLBCL also had an increased risk of CNS relapse. However, in multivariate analysis, only dual expresser status and CNS-IPI were associated with CNS relapse. Dual expresser MYC(+) BCL2(+) DLBCL defines a group at high risk of CNS relapse, independent of CNS-IPI score and cell of origin. Dual expresser status may help to identify a high-risk group who should undergo CNS-directed evaluation and consideration of prophylactic strategies.

DOI： 10.1182/blood-2015-10-676700

Cell of origin of transformed follicular lymphoma. 国際誌

Robert Kridel, Anja Mottok, Pedro Farinha, Susana Ben-Neriah, Daisuke Ennishi, Yvonne Zheng, Elizabeth A Chavez, Hennady P Shulha, King Tan, Fong Chun Chan, Merrill Boyle, Barbara Meissner, Adele Telenius, Laurie H Sehn, Marco A Marra, Sohrab P Shah, Christian Steidl, Joseph M Connors, David W Scott, Randy D Gascoyne

Blood 126 ( 18 ) 2118 - 27 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Follicular lymphoma (FL) is an indolent disease but transforms in 2% to 3% of patients per year into aggressive, large cell lymphoma, a critical event in the course of the disease associated with increased lymphoma-related mortality. Early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed FL (TFL) is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (<5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 TFL patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation, as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (Hazard ratio, 13.3; P < .001). We also show that composite histology at the time of transformation predicts favorable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-center B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like (ABC) subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates the existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL.

DOI： 10.1182/blood-2015-06-649905

The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. 国際誌

Ana Ortega-Molina, Isaac W Boss, Andres Canela, Heng Pan, Yanwen Jiang, Chunying Zhao, Man Jiang, Deqing Hu, Xabier Agirre, Itamar Niesvizky, Ji-Eun Lee, Hua-Tang Chen, Daisuke Ennishi, David W Scott, Anja Mottok, Christoffer Hother, Shichong Liu, Xing-Jun Cao, Wayne Tam, Rita Shaknovich, Benjamin A Garcia, Randy D Gascoyne, Kai Ge, Ali Shilatifard, Olivier Elemento, Andre Nussenzweig, Ari M Melnick, Hans-Guido Wendel

Nature medicine 21 ( 10 ) 1199 - 208 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.

DOI： 10.1038/nm.3943

Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies. 国際誌

David W Scott, Anja Mottok, Daisuke Ennishi, George W Wright, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J Savage, Laurie H Sehn, Graham W Slack, Christian Steidl, Louis M Staudt, Joseph M Connors, Lisa M Rimsza, Randy D Gascoyne

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33 ( 26 ) 2848 - 56 2015年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). PATIENTS AND METHODS: Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays. RESULTS: The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression). CONCLUSION: Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.

DOI： 10.1200/JCO.2014.60.2383

Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. 国際誌

Alessandro Pastore, Vindi Jurinovic, Robert Kridel, Eva Hoster, Annette M Staiger, Monika Szczepanowski, Christiane Pott, Nadja Kopp, Mark Murakami, Heike Horn, Ellen Leich, Alden A Moccia, Anja Mottok, Ashwini Sunkavalli, Paul Van Hummelen, Matthew Ducar, Daisuke Ennishi, Hennady P Shulha, Christoffer Hother, Joseph M Connors, Laurie H Sehn, Martin Dreyling, Donna Neuberg, Peter Möller, Alfred C Feller, Martin L Hansmann, Harald Stein, Andreas Rosenwald, German Ott, Wolfram Klapper, Michael Unterhalt, Wolfgang Hiddemann, Randy D Gascoyne, David M Weinstock, Oliver Weigert

The Lancet. Oncology 16 ( 9 ) 1111 - 1122 2015年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. METHODS: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). FINDINGS: We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). INTERPRETATION: Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. FUNDING: Deutsche Krebshilfe, Terry Fox Research Institute.

DOI： 10.1016/S1470-2045(15)00169-2

Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma. 国際誌

Sylvia Hartmann, Claudia Döring, Emily Vucic, Fong Chun Chan, Daisuke Ennishi, Thomas Tousseyn, Christiane de Wolf-Peeters, Sven Perner, Iwona Wlodarska, Christian Steidl, Randy D Gascoyne, Martin-Leo Hansmann

British journal of haematology 169 ( 3 ) 415 - 22 2015年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte rich large B cell lymphoma (THRLBCL) usually affect middle-aged men, show tumour cells with a B cell phenotype and a low tumour cell content. Whereas the clinical behaviour of NLPHL is indolent, THRLBCL presents with advanced stage disease and an aggressive behaviour. In the present study, array comparative genomic hybridization was performed in seven typical NLPHL, four THRLBCL-like NLPHL variants, six THRLBCL and four diffuse large B cell lymphomas (DLBCL) derived from NLPHL. The number of genomic aberrations was higher in THRLBCL compared with typical and THRLBCL-like variant of NLPHL. Gains of 2p16.1 and losses of 2p11.2 and 9p11.2 were commonly observed in typical and THRLBCL-like variants of NLPHL as well as THRLBCL. Gains of 2p16.1, affecting the REL locus were confirmed in an independent cohort. Expression of the REL protein was observed at similar frequencies in typical and THRLBCL-like variant of NLPHL as well as THRLBCL (33-38%). In conclusion, the present study reveals further similarities between NLPHL and THRLBCL on the genomic level, confirming that these entities are part of a pathobiological spectrum with common molecular features, but varying clinical presentations.

DOI： 10.1111/bjh.13310

Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients. 国際誌

Emilia L Lim, Diane L Trinh, David W Scott, Andy Chu, Martin Krzywinski, Yongjun Zhao, A Gordon Robertson, Andrew J Mungall, Jacqueline Schein, Merrill Boyle, Anja Mottok, Daisuke Ennishi, Nathalie A Johnson, Christian Steidl, Joseph M Connors, Ryan D Morin, Randy D Gascoyne, Marco A Marra

Genome biology 16 18 - 18 2015年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, with 30% to 40% of patients failing to be cured with available primary therapy. microRNAs (miRNAs) are RNA molecules that attenuate expression of their mRNA targets. To characterize the DLBCL miRNome, we sequenced miRNAs from 92 DLBCL and 15 benign centroblast fresh frozen samples and from 140 DLBCL formalin-fixed, paraffin-embedded tissue samples for validation. RESULTS: We identify known and candidate novel miRNAs, 25 of which are associated with survival independently of cell-of-origin and International Prognostic Index scores, which are established indicators of outcome. Of these 25 miRNAs, six miRNAs are significantly associated with survival in our validation cohort. Abundant expression of miR-28-5p, miR-214-5p, miR-339-3p, and miR-5586-5p is associated with superior outcome, while abundant expression of miR-324-5p and NOVELM00203M is associated with inferior outcome. Comparison of DLBCL miRNA-seq expression profiles with those from other cancer types identifies miRNAs that were more abundant in B-cell contexts. Unsupervised clustering of miRNAs identifies two clusters of patients that have distinct differences in their outcomes. Our integrative miRNA and mRNA expression analyses reveal that miRNAs increased in abundance in DLBCL appear to regulate the expression of genes involved in metabolism, cell cycle, and protein modification. Additionally, these miRNAs, including one candidate novel miRNA, miR-10393-3p, appear to target chromatin modification genes that are frequent targets of somatic mutation in non-Hodgkin lymphomas. CONCLUSIONS: Our comprehensive sequence analysis of the DLBCL miRNome identifies candidate novel miRNAs and miRNAs associated with survival, reinforces results from previous mutational analyses, and reveals regulatory networks of significance for lymphomagenesis.

DOI： 10.1186/s13059-014-0568-y

Duodenal follicular lymphoma: comprehensive gene expression analysis with insights into pathogenesis. 国際誌

Katsuyoshi Takata, Motohiko Tanino, Daisuke Ennishi, Akira Tari, Yasuharu Sato, Hiroyuki Okada, Yoshinobu Maeda, Naoe Goto, Hiroshi Araki, Mai Harada, Midori Ando, Masaya Iwamuro, Mitsune Tanimoto, Kazuhide Yamamoto, Randy D Gascoyne, Tadashi Yoshino

Cancer science 105 ( 5 ) 608 - 15 2014年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Follicular lymphoma (FL) of the gastrointestinal tract, particularly duodenal follicular lymphoma (DFL), is a rare variant of FL with indolent clinical behavior, and this disease is included in the 2008 World Health Organization classification system. In contrast to nodal follicular lymphoma (NFL), DFL occurs most frequently in the second part of the duodenum, lacks follicular dendritic cell meshworks and has memory B-cell characteristics. However, its molecular pathogenesis is still unclear. In the present study, we examined 10 DFL, 18 NFL and 10 gastric MALT lymphoma samples using gene expression analysis. Quantitative RT-PCR experiments and immunohistochemical analysis for 72 formalin-fixed, paraffin-embedded tissues from an independent series, including 32 DFL, 19 gastric MALT lymphoma and 27 NFL samples, were performed for validation of microarray data. Gene expression profiles of the three lymphoma types were compared using 2918 differentially expressed genes (DEG) and results suggested that DFL shares characteristics of MALT lymphoma. Among these DEG, CCL20 and MAdCAM-1 were upregulated in DFL and MALT but downregulated in NFL. In contrast, protocadherin gamma subfamily genes were upregulated in DFL and NFL. Quantitative RT-PCR and immunohistochemical studies demonstrated concordant results. Double immunofluorescence studies revealed that CCL20 and CCR6 were co-expressed in both DFL and MALT. We hypothesize that increased expression of CCL20 and MAdCAM-1 and co-expression of CCL20 and CCR6 may play an important role in tumorigenesis.

DOI： 10.1111/cas.12392

Germinal center B-cell-like versus non-germinal center B-cell-like as important prognostic factor for localized nodal DLBCL.

Toshiyuki Habara, Yasuharu Sato, Katsuyoshi Takata, Noriko Iwaki, Hirokazu Okumura, Hiroshi Sonobe, Takehiro Tanaka, Yorihisa Orita, Lamia Abd Al-Kader, Naoko Asano, Daisuke Ennishi, Tadashi Yoshino

Journal of clinical and experimental hematopathology : JCEH 52 ( 2 ) 91 - 9 2012年

記述言語：英語掲載種別：研究論文（学術雑誌）

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. Although many investigations have been performed on the prognostic factors of DLBCL, no reports have focused on localized nodal DLBCL. We examined the prognostic significance of 39 Japanese patients with localized nodal DLBCL with special reference to the germinal center B-cell-like (GCB) versus non-germinal center B-cell-like (NGCB) types. The median age was 65 years with 23 males and 16 females. Using Hans algorithm of immunohistochemistry, 18 patients (46%) exhibited GCB type and 21 (54%) exhibited NGCB type. Twenty-nine patients (74%) presented with disease in the neck (neck group) and 10 (26%) had disease in non-neck regions (non-neck group). Comparing Hans, Choi, and Muris algorithms, patients with GCB type showed statistically significant progression-free survival (PFS) only with Hans algorithm (P = 0.022, P = 0.100, and P = 0.130, respectively). Patient survival analyses revealed that GCB-type patients by Hans algorithm had a better PFS (P = 0.012), and neck-group patients had better PFS and overall survival (OS) (P = 0.018 and P = 0.012, respectively). Univariate analysis revealed that only neck vs. non-neck exhibited a significant difference in terms of OS (P = 0.026). Multivariate analysis revealed that GCB type by Hans algorithm and neck vs. non-neck were significantly different in terms of PFS (P = 0.025 and P = 0.033, respectively). Therefore, the subclassifications of GCB type vs. NGCB type and neck vs. non-neck are important predictive prognostic factors in localized nodal DLBCL.

Association between insulin-like growth factor-1 polymorphisms and stomach cancer risk in a Japanese population. 国際誌

Daisuke Ennishi, Kohei Shitara, Hidemi Ito, Satoyo Hosono, Miki Watanabe, Seiji Ito, Akira Sawaki, Yasushi Yatabe, Kenji Yamao, Kazuo Tajima, Mitsune Tanimoto, Hideo Tanaka, Nobuyuki Hamajima, Keitaro Matsuo

Cancer science 102 ( 12 ) 2231 - 5 2011年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

The insulin-like growth factor (IGF) signaling system plays a central role in cellular growth, differentiation and proliferation. Although the association between IGF1 gene polymorphisms and cancer risk has been evaluated for several carcinomas, this association has not yet been examined for stomach cancer. We investigated the association between IGF1 polymorphisms and the risk of stomach cancer in a Japanese population. A total of 703 patients with stomach cancer and 1462 non-cancer control subjects were enrolled in this case-control study. Associations between polymorphisms of 10 IGF1 loci and the risk of stomach cancer were evaluated using odds ratios (OR) and 95% confidence intervals (CI) in multiple logistic regression models. We observed that the C allele in rs1520220 and the G allele in rs4764887 were significantly associated with stomach cancer risk in the per-allele model after adjusting for other risk factors (OR: 1.14 [95% CI: 1.00-1.30] and OR: 1.18 [95% CI: 1.02-1.36], respectively). We also observed a positive and dose-dependent association between the number of risk alleles and stomach cancer risk (P-trend: 0.019) when examining the two loci in the same model. These associations were still seen after adjusting for potential confounders, including sex, age, smoking status, history of diabetes and family history of stomach cancer. We did not find any significant interaction between these factors and the number of risk alleles. In conclusion, we observed a significant association between IGF1 polymorphisms and stomach cancer risk among a Japanese population. Examination of the biological significance of IGF1 is warranted.

DOI： 10.1111/j.1349-7006.2011.02062.x

The utility of positron emission tomography/computed tomography in the staging of extranodal natural killer/T-cell lymphoma. 国際誌

Hideaki Fujiwara, Yoshinobu Maeda, Yuichiro Nawa, Masayuki Yamakura, Daisuke Ennishi, Yukihiro Miyazaki, Katsuji Shinagawa, Masamichi Hara, Kosei Matsue, Mitsune Tanimoto

European journal of haematology 87 ( 2 ) 123 - 9 2011年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Natural killer (NK)/T-cell lymphoma cases are rarely discovered using positron emission tomography/computed tomography (PET/CT). We compared the utility of PET/CT and that of conventional methods (CMs; CT with IV contrast, biopsies from primary sites, and bone marrow examinations) in the staging of extranodal NK/T-cell lymphoma. Nineteen untreated patients with extranodal NK/T-cell lymphoma at three institutions were analyzed. PET/CT and CMs were applied for initial workups following diagnosis. PET/CT and CMs were compared and evaluated for their ability to detect tumor lesions and their influence on the staging and treatment strategies. In total, 116 lesions were detected by CM and PET/CT. Using PET/CT, 108 lesions (93%) were discovered. The number of nodal lesions was 28: all were positive by PET/CT and 26 (93%) by CMs. The number of extranodal lesions was 89: 84 (94%) and 54 (61%) lesions were positive by PET/CT and CMs, respectively. PET/CT was superior to CMs in detecting cutaneous lesions [31/31 lesions (100%) vs. 20/31 lesions (65%), respectively; P=0.042]. Bone marrow involvement was confirmed pathologically in only seven patients; four cases (57%) were positive by PET/CT. Using CMs, ten patients (53%) were stages I-II and nine (47%) were stages III-IV. Using PET/CT, eight patients (42%) were in stages I-II and 11 (58%) were in stages III-IV. PET/CT findings altered the stage and treatment strategy in two cases (11%). Our study demonstrated that PET/CT is a useful tool for detecting extranodal lesions in NK/T-cell lymphoma, particularly cutaneous lesions. PET/CT may therefore influence future staging and treatment strategies.

DOI： 10.1111/j.1600-0609.2011.01645.x

Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: a multicenter, retrospective analysis in Japan. 国際誌

Katsuyoshi Takata, Hiroyuki Okada, Naoki Ohmiya, Shotaro Nakamura, Yasuhiko Kitadai, Akira Tari, Taiji Akamatsu, Hiroki Kawai, Shu Tanaka, Hiroshi Araki, Takashi Yoshida, Hirokazu Okumura, Hogara Nishisaki, Tamotsu Sagawa, Norihiko Watanabe, Nobuyoshi Arima, Noritaka Takatsu, Masanao Nakamura, Shunichi Yanai, Hiroyasu Kaya, Toshiaki Morito, Yasuharu Sato, Hisataka Moriwaki, Choitsu Sakamoto, Yasumasa Niwa, Hidemi Goto, Tsutomu Chiba, Takayuki Matsumoto, Daisuke Ennishi, Tomohiro Kinoshita, Tadashi Yoshino

Cancer science 102 ( 8 ) 1532 - 6 2011年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II(1) GI-FL. Of the 125 patients, the small intestine was examined in 70 patients, with double-balloon endoscopy and/or capsule endoscopy. The most frequently involved GI-FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP-positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression-free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI-FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course.

DOI： 10.1111/j.1349-7006.2011.01980.x

Allogeneic hematopoietic stem cell transplantation for advanced extranodal natural killer/T-cell lymphoma, nasal type. 国際誌

Daisuke Ennishi, Yoshinobu Maeda, Nobuharu Fujii, Eisei Kondo, Katsuji Shinagawa, Kazuma Ikeda, Koichi Ichimura, Tadashi Yoshino, Mitsune Tanimoto

Leukemia & lymphoma 52 ( 7 ) 1255 - 61 2011年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The prognosis for patients with advanced or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is extremely poor. Thus, allogeneic stem cell transplantation (allo-HSCT) should be considered for this disease. However, reports of allo-HSCT for ENKL are limited because of the rarity of the disease. Here, we describe the clinical course of 12 cases of advanced and refractory ENKL treated with allo-HSCT, including five cases with cord blood transplant. With a median follow-up of 13 months (range, 1-168 months), seven patients are alive in remission, five have died, and one treatment-related death occurred. All patients with disease progression at transplant died of disease progression, whereas seven of eight patients with a complete or partial response are long-term survivors. Allo-HSCT is a feasible and promising consolidation therapy for advanced and relapsed ENKL. The disease status before allo-HSCT is well associated with general outcome, and thus induction treatment is very important for this disease.

DOI： 10.3109/10428194.2011.572322

CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab. 国際誌

K Miyazaki, M Yamaguchi, R Suzuki, Y Kobayashi, A M Maeshima, N Niitsu, D Ennishi, J-I Tamaru, K Ishizawa, M Kashimura, Y Kagami, K Sunami, H Yamane, M Nishikori, H Kosugi, T Yujiri, R Hyo, N Katayama, T Kinoshita, S Nakamura

Annals of oncology : official journal of the European Society for Medical Oncology 22 ( 7 ) 1601 - 1607 2011年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era. PATIENTS AND METHODS: We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab. RESULTS: No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P < 0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease. CONCLUSIONS: Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.

DOI： 10.1093/annonc/mdq627

Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. 国際誌

Daisuke Ennishi, Yoshinobu Maeda, Nozomi Niitsu, Minoru Kojima, Koji Izutsu, Jun Takizawa, Shigeru Kusumoto, Masataka Okamoto, Masahiro Yokoyama, Yasushi Takamatsu, Kazutaka Sunami, Akira Miyata, Kayoko Murayama, Akira Sakai, Morio Matsumoto, Katsuji Shinagawa, Akinobu Takaki, Keitaro Matsuo, Tomohiro Kinoshita, Mitsune Tanimoto

Blood 116 ( 24 ) 5119 - 25 2010年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.

DOI： 10.1182/blood-2010-06-289231

Cancer of unknown primary site: a review of 28 cases and the efficacy of cisplatin/docetaxel therapy at a single institute in Japan.

Hisakazu Nishimori, Shunji Takahashi, Katsuyuki Kiura, Daisuke Ennishi, Takayuki Kobayashi, Koji Sano, Eiji Shinozaki, Masahiro Yokoyama, Yuko Mishima, Yasuhito Terui, Keisho Chin, Nobuyuki Mizunuma, Yoshinori Ito, Seiichiro Nishimura, Kengo Takeuchi, Yuichi Ishikawa, Masahiko Oguchi, Mitsune Tanimoto, Kiyohiko Hatake

Acta medica Okayama 64 ( 5 ) 285 - 91 2010年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

We evaluated the efficacy and toxicity of cisplatin/docetaxel (CDDP/TXT) chemotherapy and identified prognostic factors in Japanese patients with cancer of unknown primary site (CUP). Twenty-eight consecutive patients seen at a single institute were reviewed retrospectively. Sixteen patients were treated with TXT 80 mg/m2, followed by CDDP 75 mg/m2. The overall response rate to CDDP/TXT treatment was 62.5%, with a median survival time (MST) of 22.7 months. Common adverse reactions were myelosuppression and hyponatremia. The MST of all 28 patients with CUP was 8.3 months, and the 1-year overall survival rate was 45.6%. Univariate analysis identified 5 prognostic factors:performance status, liver involvement, bone involvement, pleural involvement, and lymph node involvement. In conclusion, CDDP/TXT chemotherapy is effective with tolerable toxicity in patients with CUP. Japanese patients with CUP might be chemosensitive and may survive longer.

Is statin use really associated with efficacy of rituximab? 国際誌

Hiroaki Asai, Masahiro Yokoyama, Yasuhito Terui, Daisuke Ennishi, Kengo Takeuchi, Kiyohiko Hatake

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 28 ( 24 ) e424-5; author reply e427-8 2010年8月

Statin-independent prognosis of patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy. 国際誌

D Ennishi, H Asai, Y Maeda, K Shinagawa, K Ikeda, M Yokoyama, Y Terui, K Takeuchi, T Yoshino, K Matsuo, K Hatake, M Tanimoto

Annals of oncology : official journal of the European Society for Medical Oncology 21 ( 6 ) 1217 - 1221 2010年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: A recent laboratory study indicated that statins impaired the antitumor effects of rituximab by inducing conformational changes in CD20. Although these findings raised significant concerns about statin use during rituximab treatment, their clinical significance is unclear. PATIENTS AND METHODS: We conducted a retrospective study investigating the effects of statins on the prognosis of diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). Newly diagnosed DLBCL patients were analyzed (n = 256), including 35 patients taking statins. RESULTS: The 3-year progression-free survival rates were 84% and 73% (P = 0.38), while the overall survival rates were 89% and 78% (P = 0.28) for those patients treated with and without statins, respectively. After adjusting for the International Prognostic Index and serum cholesterol level, statin use was not associated with prognosis. CONCLUSIONS: These results indicate that statins do not influence the clinical prognosis of DLBCL treated with RCHOP. Further studies with larger numbers of patients are warranted to confirm the prognostic significance of statins for patients with DLBCL receiving rituximab-containing chemotherapy.

DOI： 10.1093/annonc/mdp490

Incidental detection of acute lymphoblastic leukemia on [18F]fluorodeoxyglucose positron emission tomography. 国際誌

Daisuke Ennishi, Yoshinobu Maeda, Masami Niiya, Katsuji Shinagawa, Mitsune Tanimoto

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27 ( 36 ) e269-70 2009年12月

An imaging-based rapid evaluation method for complement-dependent cytotoxicity discriminated clinical response to rituximab-containing chemotherapy. 国際誌

Yuji Mishima, Natsuhiko Sugimura, Yuko Matsumoto-Mishima, Yasuhito Terui, Kengo Takeuchi, Suzuka Asai, Daisuke Ennishi, Hiroaki Asai, Masahiro Yokoyama, Kiyotsugu Kojima, Kiyohiko Hatake

Clinical cancer research : an official journal of the American Association for Cancer Research 15 ( 10 ) 3624 - 32 2009年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Rituximab has greatly improved the efficacy of chemotherapy regimens for CD20-positive non-Hodgkin's lymphoma. However, although several mechanisms of action of rituximab have been identified, the exact therapeutic functions of these mechanisms remains to be clarified. In addition, there is no established prognostic marker to predict an individual response. This study verified the validity of ex vivo complement-dependent cytotoxicity (CDC) susceptibility as a predictor of pathologic tumor regression in patients undergoing rituximab-containing chemotherapy and examined whether CDC contributes to the mechanism of action of rituximab. EXPERIMENTAL DESIGN: A rapid assay system was established to evaluate the tumoricidal activity of rituximab using a living cell-imaging technique. We analyzed lymph node biopsies obtained from 234 patients with suspected lymphomas and estimated the association between CDC susceptibility and the response to rituximab-containing chemotherapy in diffuse large B-cell lymphoma and follicular lymphoma. RESULTS: This study revealed that CDC susceptibility of lymphoma cells freshly obtained from patients was strongly associated with response to rituximab-containing chemotherapy in both diffuse large B-cell lymphoma and follicular lymphoma. This correlation was not apparent in cases that received chemotherapy without rituximab. CONCLUSIONS: The system that we have established allows a successful assessment of rituximab-induced CDC and can distinguish cases refractory to rituximab-containing chemotherapy. The association between CDC susceptibility and therapy response suggests that CDC is pivotal in the ability of chemotherapy including rituximab to induce remission.

DOI： 10.1158/1078-0432.CCR-08-1536

Soluble interleukin-2 receptor retains prognostic value in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP (RCHOP) therapy. 国際誌

D Ennishi, M Yokoyama, Y Terui, H Asai, S Sakajiri, Y Mishima, S Takahashi, H Komatsu, K Ikeda, K Takeuchi, M Tanimoto, K Hatake

Annals of oncology : official journal of the European Society for Medical Oncology 20 ( 3 ) 526 - 33 2009年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Soluble interleukin-2 receptor (SIL-2R) is known to be a prognostic parameter in patients with diffuse large B-cell lymphoma (DLBCL) receiving cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy. However, its prognostic value has not been well known since the introduction of rituximab. PATIENTS AND METHODS: We retrospectively evaluated the prognostic impact of SIL-2R in 228 DLBCL patients, comparing 141 rituximab-combined CHOP (RCHOP)-treated patients with 87 CHOP-treated patients as a historical control. RESULTS: Patients with high serum SIL-2R showed significantly poorer event-free survival (EFS) and overall survival (OS) than patients with low SIL-2R in both the RCHOP group (2-year EFS, 66% versus 92%, P<0.001; OS, 82% versus 95%, P=0.005) and the CHOP group (2-year EFS, 40% versus 82%; OS, 61% versus 90%, both P<0.001). Multivariate analysis including the five parameters of International Prognostic Index (IPI) and two-categorized IPI revealed that SIL-2R was an independent prognostic factor for EFS and OS in the RCHOP group as well as in the CHOP group. CONCLUSIONS: Our results demonstrate that SIL-2R retains its prognostic value in the rituximab era. The prognostic value of SIL-2R in DLBCL patients receiving rituximab-combined chemotherapy should be reassessed on a larger scale and by long-term follow-up.

DOI： 10.1093/annonc/mdn677

CD5 expression is potentially predictive of poor outcome among biomarkers in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy. 国際誌

D Ennishi, K Takeuchi, M Yokoyama, H Asai, Y Mishima, Y Terui, S Takahashi, H Komatsu, K Ikeda, M Yamaguchi, R Suzuki, M Tanimoto, K Hatake

Annals of oncology : official journal of the European Society for Medical Oncology 19 ( 11 ) 1921 - 6 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Several biomarkers indicating poor prognosis have been reassessed in patients receiving rituximab combination chemotherapy for diffuse large B-cell lymphoma (DLBCL). However, few studies have investigated outcome in relation to a combination of these biomarkers. In addition, no large-scale studies have reassessed the outcome of patients with CD5-positive DLBCL treated with rituximab. PATIENTS AND METHODS: We conducted a retrospective study and investigated the predictive value of three biomarkers -- BCL2, germinal center (GC) phenotype and CD5 -- in 121 DLBCL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone. RESULTS: CD5-positive patients showed significantly poorer event-free survival (EFS) and overall survival (OS) than CD5-negative patients (2-year EFS, 18% versus 73%, P < 0.001; 2-year OS, 45% versus 91%, P = 0.001). However, no significant difference in outcome according to BCL2 or GC phenotype was observed. Multivariate analysis revealed that CD5 expression was a significant prognostic factor for EFS [hazard ratio 14.2, 95% confidence interval (CI) 4.7-43.2] and OS (hazard ratio 20.3, 95% CI 3.6-114.4). CONCLUSIONS: CD5 expression was the only significant prognostic factor among the biomarkers examined in this study. Further studies with larger numbers are warranted to confirm the prognostic significance of CD5 expression for patients with DLBCL receiving rituximab-containing chemotherapy.

DOI： 10.1093/annonc/mdn392

Does rituximab really induce hepatitis C virus reactivation? 国際誌

Daisuke Ennishi, Masahiro Yokoyama, Yasuhito Terui, Kengo Takeuchi, Kazuma Ikeda, Mitsune Tanimoto, Kiyohiko Hatake

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26 ( 28 ) 4695 - 6 2008年10月

Increased incidence of interstitial pneumonia by CHOP combined with rituximab.

Daisuke Ennishi, Yasuhito Terui, Masahiro Yokoyama, Yuko Mishima, Shunji Takahashi, Kengo Takeuchi, Kazuma Ikeda, Mitsune Tanimoto, Kiyohiko Hatake

International journal of hematology 87 ( 4 ) 393 - 397 2008年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Several authors have reported interstitial pneumonia (IP) during rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, while others have encountered Pneumocystis jirovecii pneumonia during rituximab-combined bi-weekly CHOP. Herein, we report that 13 of 90 (14%) patients developed IP during R-CHOP therapy, compared with none of 105 patients treated with CHOP alone as a historical control. There were no differences in baseline data between patients undergoing the two therapies. Among R-CHOP-treated patients, serum beta-D-glucan was increased in 8 of 12 (75%) IP patients compared with none of 30 non-IP patients examined. In five IP patients who underwent sputum evaluation, two were positive for P. jirovecii by the polymerase chain reaction and another two were positive for Candida albicans. No other organisms were detected as causative pathogens. Treatment with steroids, sulfamethoxazole-trimethoprim (ST), and antifungals was effective. Our results suggest that R-CHOP raises the incidence of IP, possibly through increasing the susceptibility to P. jirovecii and fungal infection. The need for prophylactic antifungals and ST during R-CHOP should be evaluated by randomized controlled trials.

DOI： 10.1007/s12185-008-0066-7

Monitoring serum hepatitis C virus (HCV) RNA in patients with HCV-infected CD20-positive B-cell lymphoma undergoing rituximab combination chemotherapy. 国際誌

Daisuke Ennishi, Yasuhito Terui, Masahiro Yokoyama, Yuko Mishima, Shunji Takahashi, Kengo Takeuchi, Hiroaki Okamoto, Mitsune Tanimoto, Kiyohiko Hatake

American journal of hematology 83 ( 1 ) 59 - 62 2008年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Several studies have shown that the frequency of hepatitis C virus (HCV) infection is high in patients with B-cell non-Hodgkin's lymphoma (NHL). In these studies, liver dysfunction during chemotherapy has been demonstrated, but changes in HCV ribonucleic acid (RNA) levels during chemotherapy have not been well documented. In this study, we monitored serum HCV RNA levels and liver function in five HCV-infected patients with B-cell NHL undergoing treatment with rituximab-combination chemotherapy. Increased HCV RNA levels during or after the chemotherapy were observed in all five patients, and a significant increase in transaminases was seen in one case. In this case, serum HCV RNA level dramatically decreased at the time of the increase of transaminases, and this suggested that the cause of liver damage was an immune reaction against hepatocytes with HCV and not any anticancer drug induced liver toxicity. Monitoring of serum HCV RNA levels and transaminases may be helpful to understand the cause of liver dysfunction in patients receiving chemotherapy. However, increases of HCV viral load were not associated with the occurrence of liver dysfunction in this study. Further studies will be necessary to investigate more fully the relationship between changes in HCV viral load and liver function during chemotherapy for HCV-infected patients.

Rituximab plus CHOP as an initial chemotherapy for patients with disseminated MALT lymphoma. 国際誌

Daisuke Ennishi, Masahiro Yokoyama, Yuko Mishima, Chie Watanabe, Yasuhito Terui, Shunji Takahashi, Kengo Takeuchi, Kazuma Ikeda, Mitsune Tanimoto, Kiyohiko Hatake

Leukemia & lymphoma 48 ( 11 ) 2241 - 3 2007年11月

A case of acute promyelocytic leukemia during gefitinib treatment.

Daisuke Ennishi, Nobuo Sezaki, Tadasi Senoo, Yasuhito Terui, Kiyohiko Hatake, Norihiko Hino

International journal of hematology 84 ( 3 ) 284 - 5 2006年10月

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