Faculty Profiles - FUJII Nobuharu

Papers - FUJII Nobuharu

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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. International journal

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 2025.3

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

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. International journal

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 2025.2

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

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 2025.2

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

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. International journal

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 2025.1

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

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 2025.1

[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

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

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

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

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 2024.12

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

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

Oral calcium supplementation versus placebo in mitigating citrate reactions during apheresis: an open-label randomized control trial

Masaya Abe, Keiko Fujii, Nobuharu Fujii, Toshiharu Mitsuhashi, Takuya Fukumi, Yuichi Sumii, Maiko Kimura, Tomohiro Urata, Takumi Kondo, Fumio Otsuka, Yoshinobu Maeda

Hematology, Transfusion and Cell Therapy 2024.12

重症急性移植片対宿主病の発症抑制を目的としたテプレノン併用免疫抑制療法の開発

藤井敬子, 北村亘, 津下充, 三橋利晴, 鴨井千尋, 松原岳大, 寺尾俊紀, 林野健太, 近藤歌穂, 藤原加奈子, 植田裕子, 松原千哲, 松村彰文, 山本晃, 小林宏紀, 近藤匠, 清家圭介, 藤原英晃, 淺田騰, 遠西大輔, 西森久和, 松岡賢市, 藤井伸治, 前田嘉信

日本血液学会学術集会 86回 O2 - 6 2024.10

Out-of-pocket fertility preservation expenses: data from a Japanese nationwide multicenter survey. Reviewed

Masanori Ono, Yasushi Takai, Miyuki Harada, Akihito Horie, Yidan Dai, Eiji Kikuchi, Mitsuru Miyachi, Tetsuya Yamamoto, Nobuharu Fujii, Hiroaki Kajiyama, Atsushi Manabe, Toshiaki Yasuoka, Shinji Katsuragi, Keiko Mekaru, Tadashi Maezawa, Yuki Horage, Shinsuke Kataoka, Robert Nakayama, Takako Eguchi Nakajima, Fuminori Kimura, Chikako Shimizu, Kohei Sugimoto, Seido Takae, Yasushi Yumura, Hirotaka Nishi, Tatsuro Furui, Ken-Ichirou Morishige, Chie Watanabe, Yutaka Osuga, Nao Suzuki

International journal of clinical oncology 2024.9

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

BACKGROUND: The expenses related to fertility preservation or subsequent assisted reproductive treatments are significant for adolescents and young adult patients in Japan's current healthcare system. With fertility preservation becoming more widespread in developed countries, it is expected that these costs will be covered by insurance or subsidies. It is critical for patients, healthcare providers, and the government to know the costs that patients will be responsible for. In Japan, the costs of fertility preservation and subsequent assisted reproductive technology are not covered by insurance, but patients can apply for subsidies from the local and central governments if certain conditions are met. Presently, the above-mentioned costs, as well as the amount paid by the patient, vary by facility. Therefore, it is essential to ensure patients' continued access to necessary medical care despite the associated costs. METHODS: In this study, questionnaires were mailed to 186 certified fertility preservation facilities in Japan to assess patients who had undergone fertility preservation or assisted reproduction. The questionnaires were sent between October 27, 2023 and March 31, 2024, with 140 of the 186 facilities responding (response rate: 75.3%). RESULTS: Our findings show that approximately one-third of the costs was borne by the patients. CONCLUSION: Given these circumstances, sustainable pricing and insurance coverage are necessary for both patients and facilities.

DOI： 10.1007/s10147-024-02614-z

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

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) 2024.7

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

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

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 Reviewed

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 2024.7

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 Reviewed

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 2024.6

Publishing type：Research paper (scientific journal) Publisher：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

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 2024.5

Endoscopic manifestation of intestinal transplant-associated microangiopathy after stem cell transplantation. Reviewed International journal

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

BMC gastroenterology 24 ( 1 ) 140 - 140 2024.4

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

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. Reviewed

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 2024.4

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

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

Sigle Agent of Posttransplant Cyclophosphamide Without Calcineurin Inhibitor Controls Severity of Experimental Chronic GVHD. Reviewed

Kyosuke Saeki, Hideaki Fujiwara, Keisuke Seike, Taiga Kuroi, Hisakazu Nishimori, Takehiro Tanaka, Ken-Ichi Matsuoka, Nobuharu Fujii, Yoshinobu Maeda

Acta medica Okayama 78 ( 2 ) 123 - 134 2024.4

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

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HCT), but its pathogenesis remains unclear. Recently, haplo-identical HCT with post-transplant cyclophosphamide (Haplo-HCT with PTCY) was found to achieve a low incidence rate of acute GVHD and chronic GVHD. However, while the pathogenesis of acute GVHD following Haplo-HCT with PTCY has been well investigated, that of chronic GVHD remains to be elucidated, especially in HLA-matched HCT with PTCY. Based on its safety profile, PTCY is currently applied for the human leucocyte antigen (HLA)-matched HCT setting. Here, we investigated the mechanisms of chronic GVHD following HLA-matched HCT with PTCY using a well-defined mouse chronic GVHD model. PTCY attenuated clinical and pathological chronic GVHD by suppressing effector T-cells and preserving regulatory T-cells compared with a control group. Additionally, we demonstrated that cyclosporine A (CsA) did not show any additional positive effects on attenuation of GVHD in PTCY-treated recipients. These results suggest that monotherapy with PTCY without CsA could be a promising strategy for the prevention of chronic GVHD following HLA-matched HCT.

DOI： 10.18926/AMO/66915

Therapeutic efficacy of allogenic haematopoietic stem cell transplantation from an appropriate sibling donor to a patient with subcutaneous panniculitis-like T-cell lymphoma with a germline homozygous HAVCR2 mutation. Reviewed International journal

Hiroyuki Morisaka, Hozumi Sano, Mayuko Yamamoto, Mikiro Takaishi, Hideki Nakajima, Fumiya Ogasawara, Kazuto Togitani, Mari Tashiro, Toru Kubo, Hiroko Ueda, Nobuharu Fujii, Shigetoshi Sano

Journal of the European Academy of Dermatology and Venereology : JEADV 2024.2

Collection efficiency and safety of large-volume leukapheresis for the manufacturing of tisagenlecleucel. Reviewed International journal

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 2024.2

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

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

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

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

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

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

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

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

Protracted coronavirus disease 2019 after chimeric antigen receptor-T cell therapy successfully treated with sequential multidrug therapy. Reviewed International journal

Masahiro Yamashita, Hisao Higo, Nobuharu Fujii, Chiaki Matsumoto, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Nobuaki Miyahara

Respiratory medicine case reports 51 102104 - 102104 2024

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

A 56-year-old woman who received CD19 chimeric antigen receptor-T cell therapy for refractory diffuse large B-cell lymphoma developed severe coronavirus disease 2019 (COVID-19) and was treated with nirmatrelvir/ritonavir in April 2022. However, she experienced persistent fatigue and cough and fever in June. Computed tomography revealed bilateral ground-glass opacities (GGO), and the patient was treated with corticosteroids for organizing pneumonia after COVID-19. Partial improvement was observed, but new GGO appeared despite corticosteroid therapy. Genome analysis of severe acute respiratory syndrome coronavirus 2 detected Omicron variant BA.1.1.2, which was prevalent at the time of initial infection. The patient was diagnosed with protracted COVID-19 and was treated with remdesivir, molnupiravir, nirmatrelvir/ritonavir, and tixagevimab/cilgavimab. These treatments appeared to contribute to the improvement of protracted COVID-19.

DOI： 10.1016/j.rmcr.2024.102104

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

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

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

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. Reviewed International journal

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 2023.10

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

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

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

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 2023.8

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

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. Reviewed

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 2023.8

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

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. Reviewed International journal

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 2023.7

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

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 Reviewed

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 2023.6

Clinical characteristics of late-onset interstitial pneumonia after allogeneic hematopoietic stem cell transplantation. Reviewed

Nobuharu Fujii, Makoto Onizuka, Takahiro Fukuda, Kazuhiro Ikegame, Toshiro Kawakita, Hirohisa Nakamae, Takeshi Kobayashi, Keisuke Kataoka, Masatsugu Tanaka, Tadakazu Kondo, Koji Kato, Atsushi Sato, Tatsuo Ichinohe, Yoshiko Atsuta, Masao Ogata, Ritsuro Suzuki, Hideki Nakasone

International journal of hematology 2023.6

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation (HSCT) remain fatal. In particular, information regarding late-onset interstitial lung disease predominantly including organizing pneumonia and interstitial pneumonia (IP) is limited. A retrospective nationwide survey was conducted using data collected from the Japanese transplant outcome registry database from 2005 to 2010. This study focused on patients (n = 73) with IP diagnosed after day 90 post-HSCT. A total of 69 (94.5%) patients were treated with systemic steroids, and 34 (46.6%) experienced improvement. The presence of chronic graft-versus-host disease at the onset of IP was significantly associated with non-improvement of symptoms (odds ratio [OR] 0.35). At the time of last follow-up (median, 1471 days), 26 patients were alive. Of the 47 deaths, 32 (68%) were due to IP. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates were 38.8% and 51.8%, respectively. In the multivariate analysis, the predictive factors for OS were comorbidities at IP onset (hazard ratio [HR]: 2.19) and performance status (PS) score of 2-4 (HR 2.77). Furthermore, cytomegalovirus reactivation requiring early intervention (HR 2.04), PS score of 2-4 (HR 2.63), and comorbidities at IP onset (HR 2.90) were also significantly associated with increased risk of NRM.

DOI： 10.1007/s12185-023-03624-9

Safety and efficacy of tisagenlecleucel in patients with relapsed or refractory B-cell lymphoma: the first real-world evidence in Japan. Reviewed

Hideki Goto, Toshio Kitawaki, Nobuharu Fujii, Koji Kato, Yasushi Onishi, Noriko Fukuhara, Takuji Yamauchi, Kazunori Toratani, Hiroki Kobayashi, Shota Yoshida, Masatoshi Shimo, Koichi Onodera, Hajime Senjo, Masahiro Onozawa, Kenji Hirata, Isao Yokota, Takanori Teshima

International journal of clinical oncology 2023.4

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

BACKGROUND: Tisagenlecleucel, an autologous CD19-directed T-cell immunotherapy, can induce a durable response in adult patients with relapsed/refractory (r/r) B-cell lymphoma. METHODS: To elucidate the outcome of chimeric antigen receptor (CAR) T-cell therapy in Japanese, we retrospectively analyzed the outcomes of 89 patients who received tisagenlecleucel for r/r diffuse large B-cell lymphoma (n = 71) or transformed follicular lymphoma (n = 18). RESULTS: With a median follow-up of 6.6-months, 65 (73.0%) patients achieved a clinical response. The overall survival (OS) and event-free survival (EFS) rates at 12 months were 67.0% and 46.3%, respectively. Overall, 80 patients (89.9%) had cytokine release syndrome (CRS), and 6 patients (6.7%) had a grade ≥ 3 event. ICANS occurred in 5 patients (5.6%); only 1 patient had grade 4 ICANS. Representative infectious events of any grade were cytomegalovirus viremia, bacteremia and sepsis. The most common other adverse events were ALT elevation, AST elevation, diarrhea, edema, and creatinine elevation. No treatment-related mortality was observed. A Sub-analysis showed that a high metabolic tumor volume (MTV; ≥ 80 ml) and stable disease /progressive disease before tisagenlecleucel infusion were both significantly associated with a poor EFS and OS in a multivariate analysis (P < 0.05). Notably, the combination of these 2 factors efficiently stratified the prognosis of these patients (HR 6.87 [95% CI 2.4-19.65; P < 0.05] into a high-risk group). CONCLUSION: We report the first real-world data on tisagenlecleucel for r/r B-cell lymphoma in Japan. Tisagenlecleucel is feasible and effective, even in late line treatment. In addition, our results support a new algorithm for predicting the outcomes of tisagenlecleucel.

DOI： 10.1007/s10147-023-02334-w

Bone marrow microenvironment disruption and sustained inflammation with prolonged haematologic toxicity after CAR T-cell therapy. Reviewed International journal

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 2023.3

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

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

Bilateral Lacrimal Gland Mantle Cell Lymphoma in 11-Year Follow-Up: Case Report and Review of 48 Cases With Ocular Adnexal Presentation in the Literature. Reviewed International journal

Toshihiko Matsuo, Takehiro Tanaka, Kazuya Okada, Kenji Notohara, Keiko Fujii, Nobuharu Fujii

Journal of investigative medicine high impact case reports 11 23247096231185483 - 23247096231185483 2023

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

A 63-year-old woman, with 11-year history of breast cancer, showed bilateral lacrimal gland enlargement on magnetic resonance imaging. Gallium-67 scintigraphy, as the standard at that time in 2004, demonstrated abnormally high uptake only in bilateral lacrimal glands. The lacrimal glands were extirpated and the pathological diagnosis was mantle cell lymphoma (MCL). She underwent bilateral orbital radiation, based on no uptake of gallium-67 in other sites of the body. In a month, bone marrow biopsy revealed the infiltration with MCL, positive for cyclin D1. She showed hepatic lymphadenopathy and splenomegaly, and so received 2 cycles of alternating Hyper-CVAD therapy and high-dose methotrexate with cytarabine, combined with rituximab, in 2 months, leading to complete remission. She underwent autologous peripheral blood stem cell transplantation and was well until the age of 68 years when she showed a recurrent intratracheal submucosal lesion of lymphoma and underwent one course of reduced-dose CHOP combined with rituximab. Next year, the left rib resection revealed the metastasis of breast adenocarcinoma, leading to daily oral letrozole. Further 2 years later, computed tomographic scan demonstrated multiple submucosal nodular lesions in the trachea and bronchi, together with cervical and supraclavicular lymphadenopathy, and intratracheal lesion biopsy and bone marrow biopsy proved the involvement with MCL. She underwent 2 courses of bendamustine and rituximab, resulting in complete remission but died of metastatic breast cancer at the age of 74 years. Clinical features in 48 previous cases with ocular adnexal MCL in the literature were summarized in this study.

DOI： 10.1177/23247096231185483

Early initiation of low-dose gilteritinib maintenance improves posttransplant outcomes in patients with R/R FLT3mut AML. Reviewed International journal

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 2022.12

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

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 2022.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

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

A phase 2 study of axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma in Japan: 1-year follow-up and biomarker analysis. Reviewed

Koji Kato, Nobuharu Fujii, Shinichi Makita, Hideki Goto, Junya Kanda, Kazuyuki Shimada, Koichi Akashi, Koji Izutsu, Takanori Teshima, Natsuko Fukuda, Tokuhito Sumitani, Shota Nakamura, Hiroyuki Sumi, Shinji Shimizu, Yasuyuki Kakurai, Kenji Yoshikawa, Kensei Tobinai, Noriko Usui, Kiyohiko Hatake

International journal of hematology 2022.11

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

Axicabtagene ciloleucel (axi-cel) is an autologous, CD19-targeting chimeric antigen receptor T‑cell therapy. We recently reported the 3-month follow-up results of a phase 2, multicenter, open‑label, single-arm study of axi-cel in Japanese patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) (JapicCTI-183914). Here, we present 1-year efficacy and safety data and biomarker analysis data regarding mechanisms of resistance to axi-cel. Primary and secondary endpoints included investigator-assessed objective response rate (ORR), serious adverse events, and treatment-emergent adverse events. Axi-cel pharmacokinetics were also examined. Biomarker analysis was performed by cytokine measurement, immunohistochemistry, RNA sequencing, and whole-exome sequencing. At a median follow-up of 13.4 months, ORR was 86.7% (13/15 patients), and the complete response (CR) rate improved to 53.3% (8/15 patients) due to response conversion. Seven patients experienced disease progression, and one achieved CR after re-treatment with axi-cel. No new safety concerns were detected. Plausible resistance mechanisms to axi-cel varied among patients but included CD19 downregulation, programmed death-ligand 1 upregulation, and increased macrophage and angiogenesis signatures. The 1-year efficacy and safety of axi-cel were confirmed in Japanese patients with R/R LBCL. Resistance to treatment may involve multiple factors, including target antigen loss and an unfavorable tumor environment.Clinical trial registration: Japan Clinical Trials Information; JapicCTI-183914.

DOI： 10.1007/s12185-022-03494-7

Prevention of non-infectious pulmonary complications after intro-bone marrow stem cell transplantation in mice Reviewed International journal

Yoshiko Yamasuji-Maeda, Hisakazu Nishimori, Keisuke Seike, Akira Yamamoto, Hideaki Fujiwara, Taiga Kuroi, Kyosuke Saeki, Haruko Fujinaga, Sachiyo Okamoto, Ken-Ichi Matsuoka, Nobuharu Fujii, Takehiro Tanaka, Masahiro Fujii, Katsumi Mominoki, Takuro Kanekura, Yoshinobu Maeda

PloS one 17 ( 9 ) e0273749 2022.11

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

Non-infectious pulmonary complications including idiopathic pneumonia syndrome (IPS) and bronchiolitis obliterans syndrome (BOS), which are clinical and diagnostic manifestations of lung chronic graft-versus-host disease (GVHD), cause significant mortality after allogeneic stem cell transplantation (SCT). Increasing evidence suggests that alloantigen reactions in lung tissue play a central role in the pathogenesis of IPS and BOS; however, the mechanism is not fully understood. Several clinical and experimental studies have reported that intra-bone marrow (IBM)-SCT provides high rates of engraftment and is associated with a low incidence of acute GVHD. In the present study, allogeneic SCT was conducted in mouse models of IPS and BOS, to compare intravenous (IV)-SCT with IBM-SCT. Allogeneic IBM-SCT improved the clinical and pathological outcomes of pulmonary complications compared to those of IV-SCT. The mechanisms underlying the reductions in pulmonary complications in IBM-SCT mice were explored. The infiltrating lung cells were mainly CD11b+ myeloid and CD3+ T cells, in the same proportions as in transplanted donor cells. In an in vivo bioluminescence imaging, a higher proportion of injected donor cells was detected in the lung during the early phase (1 h after IV-SCT) than after IBM-SCT (16.7 ± 1.1 vs. 3.1 ± 0.7 × 105 photons/s/animal, IV-SCT vs. IBM-SCT, P = 1.90 × 10-10). In the late phase (5 days) after SCT, there were also significantly more donor cells in the lung after IV-SCT than after IBM-SCT or allogeneic-SCT (508.5 ± 66.1 vs. 160.1 ± 61.9 × 106 photons/s/animal, IV-SCT vs. IBM-SCT, P = 0.001), suggesting that the allogeneic reaction induces sustained donor cell infiltration in the lung during the late phase. These results demonstrated that IBM-SCT is capable of reducing injected donor cells in the lung; IBM-SCT decreases donor cell infiltration. IBM-SCT therefore represents a promising transplantation strategy for reducing pulmonary complications, by suppressing the first step in the pathophysiology of chronic GVHD.

DOI： 10.1371/journal.pone.0273749

造血幹細胞移植後患者に対する就労支援と就学支援体制(実態調査) Reviewed

鴨井千尋, 西森久和, 鷲尾佳奈, 藤井伸治, 前田嘉信

日本造血・免疫細胞療法学会雑誌 11 ( 4 ) 199 - 205 2022.10

Language：Japanese Publisher：(一社)日本造血・免疫細胞療法学会

造血幹細胞移植患者に対する就労支援と就学支援の2021年現在の実践状況を明らかにするため,中国地方の血液内科と小児血液腫瘍科の25施設31名の医師にアンケートを送付し,18施設,23名(74%)から回答を得た。就労支援の窓口は12施設(67%)が開設していたが,相談件数は半数以上が年間0件であった。自施設の就労支援体制について十分であると評価したのはわずか3名(14%)であった。就学支援の経験がある血液内科医は17名中3名(18%)と少なかった。7名(41%)がオンライン授業の経験があると回答した。自施設の高校生・大学生の就学支援体制について全ての施設が十分でないと回答した。これらの結果により,就労・就学支援体制は施設により差があり,改善の余地があることが明らかになった。多職種,他機関との協力関係を構築し,AYA世代を含む全ての患者を支援する体制の必要性が示唆された。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J07578&link_issn=&doc_id=20221028330002&doc_link_id=1390293788341809920&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390293788341809920&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_2.gif

CD19 immunostaining of a stored paraffin-embedded vitrectomy cell block of intraocular lymphoma contributing to chimera antigen receptor T-cell therapy. Reviewed

Toshihiko Matsuo, Takehiro Tanaka, Nobuharu Fujii, Kentaro Fujii, Eisei Kondo

Journal of clinical and experimental hematopathology : JCEH 62 ( 3 ) 187 - 189 2022.9

Successful haematopoietic progenitor cell collection by plerixafor in combination with reduced dose granulocyte colony-stimulating factor for severe hypoxemia provoked by high-dose granulocyte colony-stimulating factor administration. Reviewed International journal

Yui Kambara, Noboru Asada, Kaori Kondo, Yuichi Sumii, Yuki Fujiwara, Keisuke Seike, Yasuhisa Sando, Kyosuke Saeki, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

Transfusion medicine (Oxford, England) 2022.9

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 Reviewed

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 2022.8

Effect of Cryopreservation in Unrelated Bone Marrow and Peripheral Blood Stem Cell Transplantation in the Era of the COVID-19 Pandemic: An Update from the Japan Marrow Donor Program. Reviewed International journal

Yoshinobu Kanda, Noriko Doki, Minoru Kojima, Shinichi Kako, Masami Inoue, Naoyuki Uchida, Yasushi Onishi, Reiko Kamata, Mika Kotaki, Ryoji Kobayashi, Junji Tanaka, Takahiro Fukuda, Nobuharu Fujii, Koichi Miyamura, Shin-Ichiro Mori, Yasuo Mori, Yasuo Morishima, Hiromasa Yabe, Yoshiko Atsuta, Yoshihisa Kodera

Transplantation and cellular therapy 28 ( 10 ) 677.e1-677.e6 2022.7

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

During the COVID-19 pandemic, donor grafts are frequently cryopreserved to ensure that a graft is available before starting a conditioning regimen. However, there have been conflicting reports on the effect of cryopreservation on transplantation outcomes. Also, the impact of cryopreservation may differ in bone marrow (BM) transplantation (BMT) and peripheral blood stem cell (PBSC) transplantation (PBSCT). In this retrospective study, we analyzed the clinical data of both cryopreserved unrelated BMTs (n = 235) and PBSCTs (n = 118) and compared these with data from a large control cohort without cryopreservation including 4133 BMTs and 720 PBSCTs. Among the patients with cryopreserved grafts, 10 BMT recipients (4.3%) and 3 PBSCT recipients (2.5%) did not achieve neutrophil engraftment after transplantation, including 4 of the former and all 3 of the latter who died early before engraftment. In a multivariate analysis, cryopreservation was not associated with neutrophil engraftment in BMT but significantly delayed neutrophil engraftment in PBSCT (hazard ratio [HR], .82; 95% confidence interval [CI], .69 to .97; P = .023). There was an interaction with borderline significance between cryopreservation and the stem cell source (P = .067). Platelet engraftment was delayed by cryopreservation after both BMT and PBSCT. Only 2 cryopreserved grafts (<1%) were unused during the study period. The cryopreservation of unrelated donor BM and PBSC grafts is associated with a slight delay in neutrophil and platelet engraftment but an acceptable rate of graft failure. PBSC grafts may be more sensitive to cryopreservation than BM grafts. Cryopreservation is a reasonable option during COVID-19 pandemic, provided that the apheresis and transplantation centers are adept at cryopreservation. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

DOI： 10.1016/j.jtct.2022.06.022

Analysis of Immunity against Measles, Mumps, Rubella, and Varicella Zoster in Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Experience. Reviewed

Shohei Yoshida, Nobuharu Fujii, Chihiro Kamoi, Wataru Kitamura, Hideaki Fujiwara, Noboru Asada, Hisakazu Nishimori, Keiko Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

Acta medica Okayama 76 ( 3 ) 247 - 253 2022.6

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Vaccine-preventable disease (VPD) infections are more severe in immunocompromised hosts. Vaccination against measles, mumps, rubella, and varicella zoster (VZV) (MMRV) is therefore recommended for hematopoietic stem cell transplantation (HCT) recipients. However, studies on adult HCT recipients with VPD infections are limited. At our institution, we have systematically conducted serological MMRV tests as a part of check-up examinations during long-term follow-up (LTFU) after HCT since 2015. This retrospective study aimed to evaluate changes in the serostatus between before and 2 years after allogeneic HCT. Among 161 patients, the pre-transplant seropositivity was 82.7% for measles, 86.8% for mumps, 84.2% for rubella, and 94.3% for VZV. Among 56 patients who underwent LTFU including serological MMRV tests at 2 years after HCT, the percentages maintaining seroprotective antibody levels for measles, mumps, rubella and VZV were 71.5% (40/56), 51.8% (29/56), 48.2% (27/56), and 60.7% (34/56), respectively. Vaccination was recommended for 22 patients, and 12 were vaccinated. Among the 12 vaccinated patients, rates of seroconversion were examined in 2-6 patients for each of the four viruses. They were 100% (3/3) for measles, 33.3% (1/3) for mumps, 50% (3/6) for rubella, and 0% (0/2) for VZV. Further studies are warranted to clarify the effect of vaccination in adult HCT recipients.

DOI： 10.18926/AMO/63718

Comparison of cryoprotectants in hematopoietic cell infusion-related adverse events. Reviewed International journal

Kazuhiko Ikeda, Keiji Minakawa, Kenichi Yamahara, Minami Yamada-Fujiwara, Yoshiki Okuyama, Shin-Ichiro Fujiwara, Rie Yamazaki, Heiwa Kanamori, Tohru Iseki, Tokiko Nagamura-Inoue, Kazuaki Kameda, Kazuhiro Nagai, Nobuharu Fujii, Takashi Ashida, Asao Hirose, Tsutomu Takahashi, Hitoshi Ohto, Koki Ueda, Ryuji Tanosaki

Transfusion 62 ( 6 ) 1280 - 1288 2022.6

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

BACKGROUND: The standard cryoprotectant for human cellular products is dimethyl sulfoxide (DMSO), which is associated with hematopoietic cell infusion-related adverse events (HCI-AEs) in hematopoietic stem cell transplantation including peripheral blood stem cell (PBSC) transplantation (PBSCT). DMSO is often used with hydroxyethyl starch (HES), which reduces DMSO concentration while maintaining the postthaw cell recovery. The cryoprotectant medium CP-1 (Kyokuto Pharmaceutical Industrial) is widely used in Japan. After mixture of a product with CP-1, DMSO and HES concentrations are 5% and 6%, respectively. However, the safety profile of CP-1 in association with HCI-AEs has not been investigated. STUDY DESIGN AND METHODS: To compare CP-1 with other cryoprotectants, we conducted a subgroup analysis of PBSCT recipients in a prospective surveillance study for HCI-AEs. Moreover, we validated the toxicity of CP-1 in 90 rats following various dose administration. RESULTS: The PBSC products cryopreserved with CP-1 (CP-1 group) and those with other cryoprotectants, mainly 10% DMSO (non-CP-1 group), were infused into 418 and 58 recipients, respectively. The rate of ≥grade 2 HCI-AEs was higher in the CP-1 group, but that of overall or ≥grade 3 HCI-AEs was not significantly different, compared to the non-CP-1 group. Similarly, after propensity score matching, ≥grade 2 HCI-AEs were more frequent in the CP-1 group, but the ≥grade 3 HCI-AE rate did not differ significantly between the groups. No significant toxicity was detected regardless of the CP-1 dose in the 90 rats. CONCLUSIONS: Infusion of a CP-1-containing PBSC product is feasible with the respect of HCI-AEs.

DOI： 10.1111/trf.16877

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

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 2022.5

Correction to: Indications for fertility preservation not included in the 2017 Japan Society of Clinical Oncology Guideline for Fertility Preservation in Pediatric, Adolescent, and Young Adult Patients treated with gonadal toxicity, including benign diseases (International Journal of Clinical Oncology, (2022), 27, 2, (301-309), 10.1007/s10147-021-02082-9)

Masanori Ono, Kimikazu Matsumoto, Narikazu Boku, Nobuharu Fujii, Yumi Tsuchida, Tatsuro Furui, Miyuki Harada, Yoshinobu Kanda, Akira Kawai, Mitsuru Miyachi, Atsuko Murashima, Robert Nakayama, Hiroyuki Nishiyama, Chikako Shimizu, Kazuhiko Sugiyama, Yasushi Takai, Keishi Fujio, Ken Ichirou Morishige, Yutaka Osuga, Nao Suzuki

International Journal of Clinical Oncology 27 ( 4 ) 825 - 826 2022.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

The article, Indications for fertility preservation not included in the 2017 Japan Society of Clinical Oncology Guideline for Fertility Preservation in Pediatric, Adolescent, and Young Adult Patients treated with gonadal toxicity, including benign diseases written by Masanori Ono, Kimikazu Matsumoto, Narikazu Boku, Nobuharu Fujii, Yumi Tsuchida, Tatsuro Furui, Miyuki Harada, Yoshinobu Kanda, Akira Kawai, Mitsuru Miyachi, Atsuko Murashima, Robert Nakayama, Hiroyuki Nishiyama, Chikako Shimizu, Kazuhiko Sugiyama, Yasushi Takai, Keishi Fujio, Ken‑Ichirou Morishige, Yutaka Osuga, and Nao Suzuki was originally published Online First without Open Access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on February 16, 2022 to © Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0. The original article has been corrected.

DOI： 10.1007/s10147-022-02138-4

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

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 2022.3

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

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 : JCEH 62 ( 1 ) 35 - 40 2022.3

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

Marginal zone lymphoma (MZL) arising from the anterior mediastinum is rare. In the majority of reported cases, the tumor was incidentally discovered, reflecting its indolent clinical features. We present a 38-year-old woman who had no medical history, and presented with a bulky anterior mediastinal tumor complicated by life-threatening compression of the vasculature and bronchi. Biopsy specimens of the neoplasm suggested transformed diffuse large B-cell lymphoma (DLBCL) from MZL. To our best knowledge, this is the first case report of anterior mediastinum MZL associated with an aggressive clinical course and life-threatening complications likely due to transformation to DLBCL.

DOI： 10.3960/jslrt.21010

Chronic active Epstein-Barr virus infection presenting as refractory chronic sinusitis. Reviewed

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 2022.2

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

A 44-year-old Japanese man presented with fever and sore throat. He had a history of refractory chronic sinusitis that did not respond to several years of pharmacotherapy, and underwent endoscopic sinus surgery (ESS) 5 months prior to his presentation, but his symptoms persisted. A biopsy specimen was taken from the right nasal cavity, and extranodal natural killer/T-cell lymphoma, nasal type (ENKTL) was diagnosed. Two years after complete remission was achieved by chemoradiation therapy, he developed hemophagocytic lymphohistiocytosis (HLH) without recurrence of ENKTL. Epstein-Barr virus (EBV)-DNA copy number was relatively high and EBV-infected lymphocytes (CD8 + T cells) were detected in the peripheral blood. Pathological review of the biopsy specimens taken during ESS showed that CD8 + T cells with slightly atypia infiltrating the stroma were EBV positive. These findings suggested that the patient had underlying chronic active EBV infection (CAEBV) that caused the refractory chronic sinusitis, eventually developed into ENKTL, and also caused HLH. Clinicians should consider adult-onset CAEBV in the differential diagnosis of patients with refractory chronic sinusitis.

DOI： 10.1007/s12185-022-03306-y

Possible prognostic impact of WT1 mRNA expression at day + 30 after haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide for patients with myeloid neoplasm: a multicenter study from the Okayama Hematological Study Group Reviewed

Wataru Kitamura, Nobuharu Fujii, Yuichiro Nawa, Keigo Fujishita, Hiroyuki Sugiura, Takanori Yoshioka, Yuki Fujiwara, Yoshiaki Usui, Keiko Fujii, Hideaki Fujiwara, Noboru Asada, Hisakazu Nishimori, Ken-ichi Matsuoka, Yoshinobu Maeda

International Journal of Hematology 115 ( 4 ) 515 - 524 2022.2

Characterization of myeloid neoplasms following allogeneic hematopoietic cell transplantation Reviewed

Masatomo Kuno, Satoshi Yamasaki, Nobuharu Fujii, Yasushi Ishida, Takahiro Fukuda, Keisuke Kataoka, Naoyuki Uchida, Yuta Katayama, Maho Sato, Daishi Onai, Toshihiro Miyamoto, Shuichi Ota, Satoshi Yoshioka, Takahide Ara, Akira Hangaishi, Yoshiko Hashii, Makoto Onizuka, Tatsuo Ichinohe, Yoshiko Atsuta, Yoshihiro Inamoto

American Journal of Hematology 97 ( 2 ) 185 - 193 2022.2

Indications for fertility preservation not included in the 2017 Japan Society of Clinical Oncology Guideline for Fertility Preservation in Pediatric, Adolescent, and Young Adult Patients treated with gonadal toxicity, including benign diseases.

Masanori Ono, Kimikazu Matsumoto, Narikazu Boku, Nobuharu Fujii, Yumi Tsuchida, Tatsuro Furui, Miyuki Harada, Yoshinobu Kanda, Akira Kawai, Mitsuru Miyachi, Atsuko Murashima, Robert Nakayama, Hiroyuki Nishiyama, Chikako Shimizu, Kazuhiko Sugiyama, Yasushi Takai, Keishi Fujio, Ken-Ichirou Morishige, Yutaka Osuga, Nao Suzuki

International journal of clinical oncology 27 ( 2 ) 301 - 309 2022.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

In recent years, local governments in Japan have established a public financial support system for fertility preservation in pediatric, adolescent, and young adult cancer patients. Fertility preservation has become popular for patients with cancers included in the gonadal toxicity risk classification of the 2017 edition of the Guideline for Fertility Preservation in Children, Adolescents and Young Adult Cancer Patients from the Japan Society of Clinical Oncology. However, patients with cancer and non-cancer diseases that are not included in the Guideline's gonadal toxicity risk classification also often receive treatment that may affect fertility, but they are often denied the opportunity of fertility preservation because no public financial support is available for diseases not listed in the Guideline. The national research project proposes including these diseases in the indications and treatment for fertility preservation. Therefore, we cooperated with the Japan Society for Fertility Preservation and the Ministry of Health, Labour and Welfare research group to solicit opinions from experts in each therapeutic area and reviewed the literature and overseas guidelines. This paper summarizes the findings of the project. We believe that it will be an important source of information for clinicians treating patients who need fertility preservation but note that the appropriateness of fertility preservation for the disorders listed in this report needs to be continuously reviewed as medical care advances.

DOI： 10.1007/s10147-021-02082-9

Risk factors and prognosis of non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation. Reviewed

Makoto Onizuka, Nobuharu Fujii, Hideki Nakasone, Masao Ogata, Yoshiko Atsuta, Ritsuro Suzuki, Naoyuki Uchida, Kazuteru Ohashi, Yukiyasu Ozawa, Tetsuya Eto, Kazuhiro Ikegame, Hirohisa Nakamae, Masami Inoue, Takahiro Fukuda

International journal of hematology 115 ( 4 ) 534 - 544 2022.1

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

Non-infectious pulmonary complications (NIPCs) following allogeneic hematopoietic stem cell transplantation (HSCT) are relatively rare, but frequently fatal. This study investigated the pre-transplant risk factors for developing NIPCs using Japanese transplant registry database entries from 2001 to 2009. Among 13,573 eligible patients, 535 experienced NIPCs (3.9%). Multivariate analysis identified high recipient age (60 + years: HR 1.85, P = 0.003), HLA mismatch (HR 1.61, P < 0.001), female to male HSCT (HR 1.54, P < 0.001), and unrelated bone marrow transplantation (UR-BMT) (HR 3.88, P < 0.001) as significantly associated with an increased risk of NIPCs. In contrast, a non-total body irradiation (TBI) regimen with reduced intensity conditioning (RIC) were associated with a decreased risk of NIPCs compared with a cyclophosphamide (CY) + TBI regimen (busulfan + CY: HR 0.67, P = 0.009, other non-TBI: HR 0.46, P < 0.001), fludarabine-based RIC (HR 0.52, P < 0.001), and other RIC (HR 0.42, P = 0.003). The mortality rate was significantly worse for patients with NIPCs than those without (HR 1.54, 71 P < 0.001). This large-scale retrospective study suggests that both allo-reactions to donor cells and conditioning regimen toxicity contributed to NIPCs following HSCT.

DOI： 10.1007/s12185-021-03282-9

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

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

Language：English

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

A Case of Relapsed Primary Central Nervous System Lymphoma Treated with CD19-directed Chimeric Antigen Receptor T Cell Therapy. Reviewed

Ryo Mizuta, Yoshihiro Otani, Kentaro Fujii, Atsuhito Uneda, Joji Ishida, Takehiro Tanaka, Shuntaro Ikegawa, Nobuharu Fujii, Yoshinobu Maeda, Isao Date

NMC case report journal 9 275 - 280 2022

Language：English

Although high-dose methotrexate (HD-MTX) is the standard therapy for primary central nervous system lymphoma (PCNSL), the prognosis remains poor. Because 90% of PCNSL is diffuse large B-cell lymphoma (DLBCL), chimeric antigen receptor (CAR)-T cell therapy is expected to be beneficial. However, there are limited reports on CAR-T cell therapy for PCNSL because of the concern of neurotoxicity. Here, we report a case of relapsed PCNSL treated with anti-CD19 CAR-T cell therapy. A 40-year-old woman presenting with visual disturbance in her left eye was initially diagnosed with bilateral uveitis. Her histological diagnosis was DLBCL, and she was positive for CD19. Although she received chemotherapy including HD-MTX, the tumor relapsed in her right occipital lobe. She underwent remission induction therapy and then anti-CD19 CAR-T cell therapy. Cytokine release syndrome (CRS) grade 2 occurred, but there were no complications of CAR-T cell-related encephalopathy syndrome (CRES). She has achieved complete response for more than 1 year. Anti-CD19 CAR-T cell therapy is a revolutionary immunotherapy for treating relapsed or refractory (R/R) B lineage malignancies. Although there are concerns regarding CRS and CRES in central nervous system lymphoma, the use of anti-CD19 CAR-T cells to treat R/R PCNSL is safe and feasible.

DOI： 10.2176/jns-nmc.2022-0134

A survey of the support with education and jobs provided by hospitals for hematopoietic cell transplant survivors

Chihiro Kamoi, Hisakazu Nishimori, Kana Washio, Nobuharu Fujii, Yoshinobu Maeda

Japanese Journal of Transplantation and Cellular Therapy 11 ( 4 ) 199 - 205 2022

Characterization of localized macrophages in bronchiolitis obliterans after allogeneic hematopoietic cell transplantation. Reviewed

Taiga Kuroi, Nobuharu Fujii, Koichi Ichimura, Keisuke Seike, Akira Yamamoto, Yui Kambara, Seiichiro Sugimoto, Shinji Otani, Kyosuke Saeki, Hideaki Fujiwara, Hisakazu Nishiomori, Takahiro Oto, Yoshinobu Maeda

International journal of hematology 114 ( 6 ) 701 - 708 2021.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) remains one of the most devastating manifestations of chronic graft-versus-host disease in hematopoietic cell transplantation (HCT). Recent findings of BOS after lung transplantation indicate that donor (lung)-derived lung-resident macrophages contribute to BOS, suggesting that differences in the origin of immune cells and localized antigen-presenting cells cause the onset of BOS. METHODS: We identified the phenotype and origin of infiltrating macrophages using immunohistochemistry and fluorescence in situ hybridization in eight sex-mismatched HCT recipients who underwent lung transplantation for BOS after HCT. RESULTS: Most of the infiltrating macrophages appeared to be derived from donor (hematopoietic) cells in patients who developed BOS following HCT. Macrophages observed in the early-stage region of BOS were positive for cluster of differentiation (CD)68 and inducible nitric oxide synthase (iNOS) and negative for CD163 and CD206, suggesting an M1 phenotype. In the late-stage region, macrophages were negative for CD68 and iNOS in all patients, but also positive for CD163 and CD206 in some patients. CONCLUSIONS: Donor-derived M1-macrophages may be involved in the pathogenesis of the early-stage region of BOS. In addition, some macrophages in the late-stage region showed M2 polarization that might be involved in fibrosis.

DOI： 10.1007/s12185-021-03214-7

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

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 2021.10

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

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

Phase 2 study of axicabtagene ciloleucel in Japanese patients with relapsed or refractory large B-cell lymphoma Reviewed

Koji Kato, Shinichi Makita, Hideki Goto, Junya Kanda, Nobuharu Fujii, Kazuyuki Shimada, Koichi Akashi, Koji Izutsu, Takanori Teshima, Natsuko Fukuda, Tokuhito Sumitani, Hiroyuki Sumi, Shinji Shimizu, Yasuyuki Kakurai, Kenji Yoshikawa, Kensei Tobinai, Noriko Usui, Kiyohiko Hatake

International Journal of Clinical Oncology 27 ( 1 ) 213 - 223 2021.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

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

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

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

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

</sec><sec>
<title>Trial registration</title>
JapicCTI-183914.

</sec>

DOI： 10.1007/s10147-021-02033-4

Other Link： https://link.springer.com/article/10.1007/s10147-021-02033-4/fulltext.html

Desquamative esophagitis followed by esophageal cancer in a stem cell transplant recipient. Reviewed International journal

Masaya Iwamuro, Nobuharu Fujii, Shunsuke Tanabe, Hiroyuki Okada

Gastrointestinal endoscopy 2021.9

Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease Reviewed

Sachi Okawa, Kammei Rai, Nobuharu Fujii, Yuka Gion, Kiichiro Ninomiya, Yuka Kato, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Kadoaki Ohashi, Nobuaki Miyahara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Internal Medicine 60 ( 17 ) 2831 - 2837 2021.9

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

A 68-year-old man presented with a solid mass at the left renal pelvis and ureter with multiple systemic lymphadenopathies and a mass with a cavity in the right lower lobe of the lung. While a transbronchial lung biopsy revealed no malignancy, a biopsy of the renal pelvis showed marginal zone lymphoma with polyclonal IgG4-positive cells. The serum IgG4 level and presence of a bilateral orbital mass suggested Mikulicz disease. The lesions shrank following the administration of steroids. A rebiopsy confirmed lung adenocarcinoma, and its background showed IgG4-positive cells a year later. IgG4-related diseases require careful follow-up because they can be complicated by malignancy.

DOI： 10.2169/internalmedicine.6470-20

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. Reviewed

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 2021.9

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

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

中国地方・四国地方における造血器悪性腫瘍患者に対する妊孕性温存体制の実態調査 Reviewed

鴨井千尋, 藤井伸治, 嶋田明, 名和由一郎, 前田嘉信

臨床血液 62 ( 9 ) 1388 - 1392 2021.9

Authorship：Corresponding author Language：Japanese Publisher：(一社)日本血液学会-東京事務局

妊孕性温存治療に関する認識と2020年現在の実践状況を明らかにするため,中国地方と四国地方の造血器悪性腫瘍患者を治療する医師を対象に調査を行った。アンケートを血液内科と小児血液腫瘍科の46施設59診療科に送付し,52名(88.1%)から回答を得た。患者への説明について,40名(76.9%)が統一された手順はないと回答し,37名(71.2%)が主治医単独で行うと回答した。対象年齢は決まっていないという回答が多数を占めた。自施設内で妊孕性温存治療を完遂できる施設は限られている。多くは他施設との協力が可能であった。一方,自施設で妊孕性温存治療は不可能かつ連携施設も存在しないという診療科が5ヶ所存在することが明らかになった。がん治療の影響で不妊になり得る全ての患者に妊孕性温存治療に関する情報を提供すべきである。地域のネットワークを活用し,施設間連携を強化することの必要性が示唆された。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J01540&link_issn=&doc_id=20211006220005&doc_link_id=1390289631643198720&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390289631643198720&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

Effectiveness of supplemental oral calcium drink in preventing citrate-related adverse effects in peripheral blood progenitor cell collection. Reviewed International journal

Keiko Fujii, Nobuharu Fujii, Takumi Kondo, Toshiharu Mitsuhashi, Makoto Nakamura, Keisuke Seike, Yasuhisa Sando, Maiko Kimura, Masayuki Matsuda, Shuntaro Ikegawa, Hiroyuki Sugiura, Fumio Otsuka, Yoshinobu Maeda

Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 60 ( 4 ) 103147 - 103147 2021.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Peripheral blood progenitor cells (PBPCs) are a predominant graft source in allogeneic hematopoietic cell transplantation. Citrate-induced hypocalcemia remains the most frequent side effect of PBPC apheresis. Although the method for preventing severe adverse events is established, more efficient prophylaxis is required so that volunteer donors can donate PBPCs without pain and anxiety. We studied 80 healthy donors who underwent PBPC harvest between February 2014 and June 2020. Of these, 23 donors who underwent apheresis between February 2014 and December 2015 received only the standard prophylaxis of intravenous calcium gluconate. Oral calcium drinks were provided to 57 donors who underwent apheresis from January 2016 to June 2020 to supplement intravenous calcium gluconate prophylaxis. The ionized calcium (ICa) levels at multiple time intervals and the hypocalcemic symptoms were evaluated. Oral supplementation with a calcium drink maintained significantly higher ICa levels. Analysis using the inverse probability weighted regression adjustment method suggested that calcium drinks reduced the frequency of citrate-related reactions by 39.2 %. Administering a prophylactic oral calcium drink before apheresis with intravenous administration of calcium gluconate is promising to further reduce citrate-induced hypocalcemia in volunteer donors.

DOI： 10.1016/j.transci.2021.103147

Squamous Metaplasia of the Stomach Associated with Lymphoma Infiltration. Reviewed

Masaya Iwamuro, Nobuharu Fujii, Takehiro Tanaka, Hiromitsu Kanzaki, Seiji Kawano, Yoshiro Kawahara, Hiroyuki Okada

Internal medicine (Tokyo, Japan) 60 ( 14 ) 2229 - 2234 2021.7

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

We herein report a patient who presented with follicular lymphoma. Although the stomach was initially intact, mucosal redness and multiple erosions appeared in the gastric body owing to infiltration of the follicular lymphoma cells. Subsequently, a slightly depressed, white area lacking gastric mucosal structure was detected in the lesser curvature of the gastric cardia and body, where lymphoma cell infiltration was also pathologically observed beneath the stratified squamous epithelium. This case indicated that, although infrequent, prolonged mucosal injury owing to lymphoma infiltration can cause squamous metaplasia in the stomach.

DOI： 10.2169/internalmedicine.6271-20

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

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 2021.6

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

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

Cryopreservation of Unrelated Hematopoietic Stem Cells from a Blood and Marrow Donor Bank During the COVID-19 Pandemic: A Nationwide Survey by the Japan Marrow Donor Program. Reviewed International journal

Yoshinobu Kanda, Masami Inoue, Naoyuki Uchida, Yasushi Onishi, Reiko Kamata, Mika Kotaki, Ryoji Kobayashi, Junji Tanaka, Takahiro Fukuda, Nobuharu Fujii, Koichi Miyamura, Shin-Ichiro Mori, Yasuo Mori, Yasuo Morishima, Hiromasa Yabe, Yoshihisa Kodera

Transplantation and cellular therapy 27 ( 8 ) 664.e1-664.e6 2021.5

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

During the COVID-19 pandemic, donor hematopoietic stem cell grafts are frequently cryopreserved to ensure the availability of graft before starting a conditioning regimen. However, the safety of cryopreservation has been controversial in unrelated hematopoietic stem cell transplantation (HSCT), especially for bone marrow (BM) grafts. In addition, in unrelated HSCT, the effect of the time from harvest to cryopreservation of donor grafts required for the transportation of donor graft has not been fully clarified. In this study, we retrospectively analyzed the first 112 patients with available data who underwent cryopreserved unrelated blood and marrow transplantation through the Japan Marrow Donor Program during the COVID-19 pandemic. There were 112 patients, including 83 who received BM grafts and 29 who received peripheral blood stem cell (PBSC) grafts. The median time from stem cell harvest to cryopreservation was 9.9 hours (range, 2.6 to 44.0 hours), and the median time from cryopreservation to infusion was 231.2 hours. The incidence of neutrophil engraftment at day 28 after HSCT was 91.1%, and among 109 patients (excluding 3 patients with early death), all but 1 patient achieved neutrophil engraftment within 60 days after HSCT. The time to neutrophil engraftment and time to platelet engraftment were shorter in PBSC transplantation compared with BM transplantation (BMT), but the differences were not statistically significant (P = .064 and .18). Multivariate analysis among BM recipients revealed that a higher number of frozen nucleated cells and the absence of HLA mismatch were associated with faster neutrophil engraftment. The time to neutrophil engraftment after unrelated cryopreserved BMT was not different from that after unrelated BMT without cryopreservation. Our findings suggest that unrelated donor BM and PBSC grafts can be safely cryopreserved even after transit from the harvest center to the transplantation center. In the current COVID-19 pandemic, cryopreservation can be considered as an option while balancing the risks and benefits of the procedure.

DOI： 10.1016/j.jtct.2021.04.022

Successful Treatment of Acute Promyelocytic Leukemia Complicated with Endometrial Cancer by Arsenic Trioxide. Reviewed

Hiroyuki Sugiura, Hisakazu Nishimori, Hirofumi Matsuoka, Keiichiro Nakamura, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshinobu Maeda

Acta medica Okayama 75 ( 2 ) 219 - 224 2021.4

Language：English

Acute promyelocytic leukemia (APL) is a hematological emergency that requires urgent intervention because of the high incidence of early hemorrhagic death. When patients with APL experience a synchronous solid organ tumor, the tumor's treatment must also be done properly. Differentiation-inducing therapy using arsenic trioxide (ATO) has less hematological toxicity compared to cytotoxic chemotherapy and might be preferable for untreated APL patients with a synchronous solid organ tumor. Here we describe the first successful case of untreated APL and synchronous endometrial cancer (in an adult Japanese woman) treated with ATO consolidation therapy and the subsequent surgery and chemotherapy for endometrial cancer.

DOI： 10.18926/AMO/61904

Pretransplant nivolumab further enhanced Treg expansion after posttransplant cyclophosphamide; another aspect for immune tolerance by PTCy after nivolumab. Reviewed International journal

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 2021.3

A multicenter phase II study of intrabone single-unit cord blood transplantation without antithymocyte globulin. Reviewed International journal

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

Annals of hematology 100 ( 3 ) 743 - 752 2021.3

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

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

DOI： 10.1007/s00277-020-04365-z

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

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

Language：English

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

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

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 ) 2020.12

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

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

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

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 2020.12

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

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

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

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 2020.12

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

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

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

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 2020.11

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

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

Post-transplantation cyclophosphamide restores early B-cell lymphogenesis that suppresses subsequent chronic graft-versus-host disease. Reviewed International journal

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 2020.10

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

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 2020.9

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

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

Secondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case. Reviewed

Hiroyuki Sugiura, Hisakazu Nishimori, Kazuya Nishii, Tomohiro Toji, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Koh Nakata, Katsuyuki Kiura, Yoshinobu Maeda

Internal medicine (Tokyo, Japan) 59 ( 16 ) 2023 - 2028 2020.8

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

Pulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole. Secondary PAP associated with primary myelofibrosis (PMF) is extremely rare, and to our knowledge, no autopsy case has been reported. We herein report an autopsy case of secondary PAP occurring in a patient with PMF who was treated with the Janus kinase 1/2 inhibitor ruxolitinib. We confirmed a diagnosis of PAP with complications based on the pathological findings at the autopsy. Notably, this case might suggest an association between ruxolitinib treatment and PAP occurrence.

DOI： 10.2169/internalmedicine.4082-19

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

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

Bone Marrow Transplantation 55 ( 7 ) 1399 - 1409 2020.7

Publishing type：Research paper (scientific journal)

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.

DOI： 10.1038/s41409-020-0859-8

Efficacy of HLA virtual cross-matched platelet transfusions for platelet transfusion refractoriness in hematopoietic stem cell transplantation. Reviewed International journal

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 2020.3

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

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

Comparison of the clinical characteristics of TAFRO syndrome and idiopathic multicentric Castleman disease in general internal medicine: a 6‐year retrospective study Reviewed

Yoshito Nishimura, Yoshihisa Hanayama, Nobuharu Fujii, Eisei Kondo, Fumio Otsuka

Internal Medicine Journal 50 ( 2 ) 184 - 191 2020.2

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

Seike K, Fujii N, Asano N, Ohkuma S, Hirata Y , Fujii K, Sando Y, Nakamura M, Naito K , Saeki K, Meguri Y, Asada N, Ennishi D, Nishimori H, Matsuoka K, Tsubaki K, Otsuka F , Maeda Y.

Transfusion 60 ( 3 ) 473 - 478 2020.1

Chemotherapy Improved Pulmonary Arterial Hypertension in a Patient with Chronic-Active Epstein-Barr Virus Infection. Reviewed

Satoshi Akagi, Takashi Miki, Yasuhisa Sando, Nobuharu Fujii, Toshihiro Sarashina, Kazufumi Nakamura, Hiroshi Ito

International heart journal 61 ( 1 ) 191 - 194 2020.1

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

Chronic-active Epstein-Barr virus infection (CAEBV) is a rare disease that can lead to pulmonary arterial hypertension (PAH). However, the treatment for CAEBV-associated PAH has not been established. We discuss a case of improved pulmonary hypertension after chemotherapy in a patient with CAEBV-associated PAH. A 44-year old man was admitted to our hospital because of an abnormal electrocardiogram and liver dysfunction detected by annual medical examination. Echocardiography showed a dilated right ventricle and an estimated right ventricular systolic pressure of 92 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 45 mmHg and pulmonary vascular resistance of 9.8 Wood units. Laboratory examination showed granular lymphocytes and 91% natural killer cells in lymphocyte subsets in peripheral blood. We diagnosed the patient as having CAEBV-associated PAH. After two cycles of chemotherapy without PAH-specific drugs, echocardiography showed improvement in the dilated right ventricle and an estimated right ventricular systolic pressure of 59 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 27 mmHg and pulmonary vascular resistance of 2.4 Wood units. Chemotherapy may improve pulmonary hypertension in patients with CAEBV-associated PAH.

DOI： 10.1536/ihj.19-419

Prospective Phase 2 Study of Umbilical Cord Blood Transplantation in Adult Acute Leukemia and Myelodysplastic Syndrome Reviewed

Seitaro Terakura, Tetsuya Nishida, Masashi Sawa, Tomonori Kato, Kotaro Miyao, Yukiyasu Ozawa, Akio Kohno, Yasushi Onishi, Noriko Fukuhara, Masanobu Kasai, Nobuharu Fujii, Hisayuki Yokoyama, Hiroatsu Iida, Nobuhiro Kanemura, Atsushi Fujieda, Hiroatsu Ago, Yutaka Tsutsumi, Fumihiko Nakamura, Kazuhiro Yago, Yukiyoshi Moriuchi, Shuichi Ota, Haruhiko Ohashi, Atsumi Yanagisawa, Ritsuro Suzuki, Yachiyo Kuwatsuka, Yoshiko Atsuta, Koichi Miyamura, Makoto Murata

Biology of Blood and Marrow Transplantation 26 ( 1 ) 139 - 144 2020.1

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

Almost comparable transplantation outcomes have been reported with HLA-matched unrelated donor transplantation (UDT) and cord blood transplantation (CBT). We conducted a prospective phase 2 study to assess the efficacy and safety of single-unit myeloablative CBT in adult leukemia and myelodysplastic syndrome. Because the day 180 survival of UDT was approximately 80%, we determined the alternative hypothesis of expected day 180 survival with a successful engraftment rate of 80% and set the null hypothesis of threshold rate at 65%. Sixty-two patients (median age, 37 years) were registered, including 28 with acute myelogenous leukemia, 25 with acute lymphoblastic leukemia, and 9 with myelodysplastic syndrome. Of 61 eligible patients, 52 were successfully engrafted and survived at day 180 (85%; 95% confidence interval, 74% to 93%). Single-unit CBT was judged to be effective because the null hypothesis was rejected (P <. 001). Furthermore, neutrophil engraftment was observed in 57 patients (92%); the incidences of grade II-IV acute and chronic graft-versus-host disease were 30% and 32%, respectively; and the cumulative incidences of nonrelapse mortality and relapse at 2 years were 18% and 13%, respectively. The present study showed favorable survival outcomes with single-unit CBT. Therefore, this method may be considered if a well-HLA-matched UDT cannot be obtained.

DOI： 10.1016/j.bbmt.2019.09.021

Macrophage elimination in bone marrow by dexamethasone palmitate is associated with successful engraftment in patients with hemophagocytic syndrome. Reviewed

Hiroyuki Sugiura, Ken-Ichi Matsuoka, Masayuki Matsuda, Shuntaro Ikegawa, Tomoko Inomata, Taiga Kuroi, Takeru Asano, Shohei Yoshida, Hisakazu Nishimori, Keiko Fujii, Nobuharu Fujii, Yoshinobu Maeda

International journal of hematology 110 ( 2 ) 260 - 262 2019.8

Plasma exchange eliminates residual mogamulizumab but does not warrant prompt recovery of peripheral Treg levels. Reviewed International journal

Hiroyuki Sugiura, Ken-Ichi Matsuoka, Yasuhisa Sando, Yusuke Meguri, Shuntaro Ikegawa, Makoto Nakamura, Miki Iwamoto, Takanori Yoshioka, Takeru Asano, Eisei Kondo, Keiko Fujii, Nobuharu Fujii, Yoshinobu Maeda

Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 58 ( 4 ) 472 - 474 2019.8

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

Mogamulizumab (Mog), a humanized anti-CCR4 antibody, provides an important treatment option for relapsed/refractory adult T cell leukemia/lymphoma. However, administration of Mog before allogenic hematopoietic stem cell transplantation has been reported to be a risk factor for severe acute graft-versus-host disease (GVHD). The etiological hypothesis is Mogamulizumab may eradicate CCR4-positive regulatory T cells (Tregs). Theoretically, Treg homeostasis and course of GVHD can be affected by plasma exchange (PE) with decreasing plasma Mog concentration. Here, we present a case of severe acute GVHD after pretransplantation Mog, in which PE was performed for liver failure. As a result, plasma Mog concentration was decreased but it did not lead to the prompt elevation of Treg levels in peripheral blood and clinical responses of GVHD were limited to partial remission. Our case suggests that recovery of donor-derived Treg in the acute phase after HSCT is multifactorial and the single procedure of PE-based Mog depletion does not necessarily warrant the quick restoration of Treg homeostasis.

DOI： 10.1016/j.transci.2019.05.011

Plasma exchange eliminates residual mogamulizumab but does not warrant prompt recovery of peripheral Treg levels. Reviewed

Sugiura H, Matsuoka K, Sando Y, Meguri Y, Ikegawa S, Nakamura M, Iwamoto M, Yoshioka T, Asano T, Kondo E, Fujii K, Fujii N, Maeda Y.

Transfusion and Apheresis Science. S1473-0502 ( 19 ) 30123 - 30125 2019.7

High dose chemotherapy with autologous stem cell transplantation in primary central nervous system lymphoma: Data from the japan society for hematopoietic cell transplantation (JSHCT) registry Reviewed

Kondo Eisei, Ikeda Takashi, Izutsu Koji, Chihara Dai, Shimizu-Koresawa Risa, Fujii Nobuharu, Sakai Tomoyuki, Kondo Tadakazu, Kubo Kohmei, Kato Yuichi, Akasaka Takashi, Fukuda Takahiro, Ichinohe Tatsuo, Atsuta Yoshiko, Suzumiya Junji, Suzuki Ritsuro

BONE MARROW TRANSPLANTATION 54 453 - 455 2019.7

High-Dose Chemotherapy with Autologous Stem Cell Transplantation in Primary Central Nervous System Lymphoma: Data From the Japan Society for Hematopoietic Cell Transplantation Registry Reviewed

Kondo E, Ikeda T, Izutsu K, Chihara D, Shimizu-Koresawa R, Fujii N, Sakai T, Kondo T, Kubo K, Kato Y, Akasaka T, Fukuda T, Ichinohe T, Atsuta Y, Suzumiya J, Suzuki R; Adult Lymphoma Working Group of the Japan Society for Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant. 25 ( 5 ) 899 - 905 2019.5

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

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 2019.4

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

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

Long-term outcomes in patients treated in the intensive care unit after hematopoietic stem cell transplantation. Reviewed

Makoto Nakamura, Nobuharu Fujii, Kazuyoshi Shimizu, Shuntaro Ikegawa, Keisuke Seike, Tomoko Inomata, Yasuhisa Sando, Keiko Fujii, Hisakazu Nishimori, Ken-Ichi Matsuoka, Hiroshi Morimatsu, Yoshinobu Maeda

International journal of hematology 108 ( 6 ) 622 - 629 2018.12

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

The number of patients who are successfully discharged from the intensive care unit (ICU) after hematopoietic stem cell transplantation (HSCT) remains limited. Most previous studies have evaluated short-term outcomes using ICU mortality; there have been comparatively fewer reports of long-term outcomes. We retrospectively analyzed 39 HSCT patients admitted to the ICU for the first time between April 2008 and July 2014. Performance status was evaluated in four long-term survivors in July 2016. Median age at ICU admission was 54 years (range 30-68). In total, 33 patients (70.2%) required mechanical ventilation and 31 patients (66%) required dialysis. The median OS from first ICU admission was 41 days (95% confidence interval [CI]: 22-64) and the 1-year survival rate was 12.8% (95% CI 4.7-25.2). No statistically significant factors were associated with short-term outcomes. Among long-term outcomes, a second or subsequent HSCT and neutropenia at ICU admission were significant risk factors. Four of 10 ICU survivors have survived with good performance status for a median of 1994 (1203-2633) days. Our results suggest that the number of prior transplants and neutropenia at ICU admission may influence OS.

DOI： 10.1007/s12185-018-2536-x

Neurolymphomatosis in the cauda Equina Diagnosed by an Open Biopsy. Reviewed

Sasaki R, Ohta Y, Yamada Y, Tadokoro K, Takahashi Y, Sato K, Shang J, Takemoto M, Hishikawa N, Yamashita T, Yasuhara T, Date I, Ikegawa S, Fujii N, Abe K.

Intern Med 57 ( 23 ) 3463 - 3465 2018.12

抗Fybに加え新たに抗KANNOを産生した1症例 Reviewed

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

日本輸血細胞治療学会誌 64 ( 6 ) 829 - 830 2018.12

Villous atrophy in the terminal ileum is a specific endoscopic finding correlated with histological evidence and poor prognosis in acute graft-versus-host disease after allo-hematopoietic stem cell transplantation. Reviewed International journal

Yuusaku Sugihara, Sakiko Hiraoka, Nobuharu Fujii, Shiho Takashima, Yasushi Yamasaki, Toshihiro Inokuchi, Masahiro Takahara, Kenji Kuwaki, Keita Harada, Takehiro Tanaka, Hiroyuki Okada

BMC gastroenterology 18 ( 1 ) 111 - 111 2018.7

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

BACKGROUND: Graft-versus-host disease (GVHD) is a common complication of allo-hematopoietic stem cell transplantation (allo-HSCT). Endoscopic biopsy can provide a definitive diagnosis, but the optimal endoscopic approach for diagnosis remains uncertain. This study evaluated whether ileocolonoscopic imaging can predict acute GVHD severity after allo-HSCT. METHODS: Consecutive patients who underwent allo-HSCT were referred to our institution, and those diagnosed with acute GVHD by pathology were included in this retrospective study. RESULTS: Fifty-one of 261 patients who underwent ileocolonoscopy were suspected to have acute intestinal GVHD. We performed univariate and multivariate conditional logistic regression with stepwise variable selection; villous atrophy in the terminal ileum remained a statistically significant predictor of GVHD severity (odds ratio, 4.69; 95% confidence interval, 1.07-20.60, P = 0.04). Patients were classified into three groups based on ileal endoscopic findings in the terminal ileum: group S, GVHD with severe villous atrophy; group M, mild atrophy; and group N, no atrophy. Compared with patients in groups M and N, those in group S had significant clinical GVHD at diagnosis (P = 0.03). In group S, three of four, compared with five of 13 patients in groups M and N, required the addition of second-line agents (P = 0.02). CONCLUSIONS: This study showed that severe atrophy of the terminal ileum predicts severe clinical GVHD that is likely to be refractory to steroid treatment. Thus, the severity of terminal ileum atrophy may serve as a tool in predicting clinically severe GVHD. TRIAL REGISTRATION: Trial Registration Number UMIN 000022805 , Registration date July 1, 2016.

DOI： 10.1186/s12876-018-0829-4

Adverse Events Associated With Infusion of Hematopoietic Stem Cell Products: A Prospective and Multicenter Surveillance Study. Reviewed International journal

Kazuhiko Ikeda, Hitoshi Ohto, Yoshiki Okuyama, Minami Yamada-Fujiwara, Heiwa Kanamori, Shin-Ichiro Fujiwara, Kazuo Muroi, Takehiko Mori, Kinuyo Kasama, Tohru Iseki, Tokiko Nagamura-Inoue, Nobuharu Fujii, Takashi Ashida, Kazuaki Kameda, Junya Kanda, Asao Hirose, Tsutomu Takahashi, Kazuhiro Nagai, Keiji Minakawa, Ryuji Tanosaki

Transfusion medicine reviews 2018.6

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

Adverse events (AEs) associated with blood transfusions, including component-specific red cell, platelet, and plasma products, have been extensively surveyed. In contrast, surveillance of AEs associated with hematopoietic stem cell (HSC) products in HSC transplantation (HSCT) has been less rigorous, even though HSC products include a diversity of immature and mature hematopoietic cells, substantial plasma, and dimethyl sulfoxide (DMSO) in the case of cryopreserved HSC products. HSC infusion-related AEs have been attributed to DMSO toxicity, but AEs associated with the infusion of noncryopreserved HSC products are not uncommon. To quantify the frequencies, types, and risk factors of HSC infusion-related AEs, we implemented national surveillance for AEs observed within 24 hours after infusion. Herein we report on 1125 HSCTs, including 570 peripheral blood stem cell transplantations (PBSCTs) (290 autologous [auto-] and 280 allogeneic [allo-]), 332 allo-bone marrow transplantations (allo-BMTs) and 223 allo-cord blood transplantations (allo-CBTs). Unexpectedly, incidences of grade ≥ 2 AEs were most frequent in allo-BMTs (37.7%) with no DMSO in any product compared with auto-/allo-PBSCTs (20.9%, P < .001) and allo-CBTs (19.3%, P < .001) typically cryopreserved with DMSO. Hypertension was most often noted in BMTs, whereas nausea/vomiting, fever, and allergic reactions were most frequent in allo-PBSCTs. In a multivariate analysis, a history of transfusion reactions was a risk factor for overall AEs in all HSCTs (odds ratio [OR] = 1.459, P = .045). For grade ≥ 2 AEs in allo-HSCTs, a history of transfusion reactions (OR = 1.551, P = .044) for overall AEs, and high infusion volume (OR = 7.544, P = .005) and allo-PBSCTs (versus BMTs, OR = 9.948, P = .002) for allergic reactions were identified as risk factors. These findings suggest that some factors unrelated to DMSO, such as allo-antigens, contribute to HSC infusion-related AEs. As severe AEs, a total of 117 grade ≥ 3 AEs were reported in 1125 HSCTs, including life-threatening complications in 3 (0.3%) HSCTs: 1 allo-CBT (anaphylaxis) and 2 allo-PBSCTs (hypoxia, kidney injury) with cryopreserved product. Our data show that HSC infusion risks vary by product, can be severe, and should be monitored with the same rigor as modern transfusion hemovigilance programs.

DOI： 10.1016/j.tmrv.2018.05.005

自己血輸血の変遷貯血式・希釈式・回収式症例数と時代背景を顧みて

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

日本輸血細胞治療学会誌 64 ( 2 ) 442 - 442 2018.4

同種造血幹細胞移植後の好中球減少患者に対する顆粒球輸注療法

藤井伸治, 池川俊太郎, 藤井敬子, 佐伯恭昌, 廻勇輔, 浅田騰, 西森久和, 松岡賢市, 大塚文男, 前田嘉信

日本輸血細胞治療学会誌 64 ( 2 ) 453 - 453 2018.4

Progressive multifocal leukoencephalopathy after T-cell replete HLA-haploidentical transplantation with post-transplantation cyclophosphamide graft-versus-host disease prophylaxis. International journal

Shuntaro Ikegawa, Nobuharu Fujii, Koh Tadokoro, Kota Sato, Miki Iwamoto, Masayuki Matsuda, Tomoko Inomata, Hiroyuki Sugiura, Takeru Asano, Shohei Yoshida, Hisakazu Nishimori, Ken-Ichi Matsuoka, Yoshinobu Maeda

Transplant infectious disease : an official journal of the Transplantation Society 20 ( 2 ) e12850 2018.4

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

A 52-year-old man suffered from progressive multifocal leukoencephalopathy (PML) after human leukocyte antigen (HLA)-haploidentical transplantation with post-transplantation cyclophosphamide (PTCY). Mirtazapine, mefloquine, and cytarabine failed to improve his symptoms, and he finally died 4.5 months after PML onset. This is the first case report of a patient with PML after HLA-haploidentical transplantation with PTCY. Although T-cell replete HLA-haploidentical transplantation with PTCY has enabled early immune reconstitution, PML should be considered if a patient's mental condition deteriorates.

DOI： 10.1111/tid.12850

Progressive multifocal leukoencephalopathy after T-cell replete HLA-haploidentical transplantation with post-transplantation cyclophosphamide graft-versus-host disease prophylaxis. Reviewed

Ikegawa S, Fujii N, Tadokoro K, Sato K, Iwamoto M, Matsuda M, Inomata T, Sugiura H, Asano T, Yoshida S, Nishimori H, Matsuoka KI, Maeda Y.

Transpl Infect Dis 20 ( 2 ) e12850 - e12850 2018.1

Mild renal dysfunction defined by creatinine clearance rate has limited impact on clinical outcomes after allogeneic hematopoietic stem cell transplantation. Reviewed

Ikegawa S, Matsuoka KI, Inomata T, Ikeda N, Sugiura H, Kuroi T, Asano T, Yoshida S, Nishimori H, Fujii N, Kondo E, Maeda Y, Tanimoto M.

International Journal of Hematology 107 ( 5 ) 568 - 577 2018.1

Neurolymphomatosis in the Cauda Equina Diagnosed by an Open Biopsy

Ryo Sasaki, Yasuyuki Ohta, Yuto Yamada, Koh Tadokoro, Yoshiaki Takahashi, Kota Sato, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Takao Yasuhara, Isao Date, Shuntaro Ikegawa, Nobuharu Fujii, Koji Abe

INTERNAL MEDICINE 57 ( 23 ) 3463 - 3465 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

Neurolymphomatosis is a rare form of extranodal malignant lymphoma defined as the infiltration of malignant lymphocytes into the central or peripheral nerve. We herein report a case of neurolymphomatosis in the cauda equina diagnosed by an open surgical biopsy. He presented with muscle weakness, atrophy, numbness and hypoesthesia in the bilateral lower extremities with the accumulation of (18)fluoro-2-deoxyglucose (FDG) in the bilateral cauda equina. Cerebrospinal fluid cytology (three times) and flow cytometry (two times) and biopsies of the left rural nerve, bone marrow, paranasal sinus and left testis were all negative for malignancy, so finally we performed a surgical open biopsy of the cauda equina by laminectomy and diagnosed him with diffuse large B-cell lymphoma in the cauda equina. He was successfully treated with the disappearance of the FDG accumulation for a long time. The present case suggested that an early open biopsy of the cauda equina may be considered for cases of suspected neurolymphomatosis in the cauda equina for a good outcome.

DOI： 10.2169/internalmedicine.1049-18

健常人ドナーにおけるクエン酸中毒 CMNCモードとMNCモードで違いがあるのか

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

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

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

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

Am J Hematol. 2017.9

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

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

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

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

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

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

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

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

DOI： 10.1007/s12185-017-2204-6

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

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

Cytotherapy 19 ( 4 ) 514 - 520 2017.4

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

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

DOI： 10.1016/j.jcyt.2016.12.007

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

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

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

Ruxolitinib treatment for GvHD in patients with myelofibrosis Reviewed

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

Bone Marrow Transplantation 51 ( 12 ) 1584 - 1587 2016.12

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

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

Transfusion 56 ( 4 ) 886 - 92 2016.4

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

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

DOI： 10.1111/trf.13437

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

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

Transfusion 56 ( 1 ) 231 - 236 2016.1

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

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

DOI： 10.1111/trf.13283

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

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

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

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

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

DOI： 10.2169/internalmedicine.54.4390

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

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

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

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

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

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

DOI： 10.4049/jimmunol.1400973

多発転移に伴い血小板減少を合併した頭部血管肉腫の1例 Reviewed

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

Skin Cancer 29 ( 3 ) 323 - 327 2015.2

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

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

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

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

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

Acta Med Okayama 69 ( 5 ) 2015.1

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

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

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

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

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

J Immunol 193 ( 5 ) 2565 - 2573 2014.9

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

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

Journal of Immunology 193 ( 5 ) 2565 - 2573 2014.9

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

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

DOI： 10.4049/jimmunol.1400954

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

池田亮、小郷博昭、浅野尚美、浅田騰、藤井敬子、藤井伸治

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

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

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

Human Pathology 45 ( 7 ) 1379 - 1387 2014.7

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

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

臨床血液 55 ( 5 ) 587 - 587 2014.5

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

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

日本老年医学会雑誌 51 ( 3 ) 293 - 293 2014.5

Bronchiolitis obliterans with allogeneic hematopoietic cell transplantation: a 10-year experience of the Okayama BMT Group. Reviewed

Nobuharu Fujii, Koichi Nakase, Shoji Asakura, Keitaro Matsuo, Yuichiro Nawa, Kazutaka Sunami, Hisakazu Nishimori, Ken-Ichi Matsuoka, Eisei Kondo, Yoshinobu Maeda, Katsuji Shinagawa, Masamichi Hara, Mitsune Tanimoto

International journal of hematology 99 ( 5 ) 644 - 651 2014.5

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Bronchiolitis obliterans (BO) is a devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively studied 465 patients who underwent HSCT in the Okayama BMT Group between 2000 and 2009, and describe the detailed clinical features of 13 patients with BO. The 5-year cumulative incidence of BO was 3.43 %. The median time from transplantation to onset of BO was 15 months. In seven of the 13 patients, the primary symptom was only cough, indicating that cough was an important initial symptom for early diagnosis. The median duration from the onset of BO to the requirement of O2 supplementation was 13 months and the main cause of death was respiratory failure. History of chronic graft-versus-host disease was a significant risk factor. Furthermore, female recipients were at greater risk of BO than male recipients; however, no other previously reported risk factors were detected. It is currently difficult to prevent BO on the basis of the reported risk factors. A novel strategy for the early diagnosis and treatment of BO is required.

DOI： 10.1007/s12185-014-1556-4

Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease Reviewed

Sugiyama Haruko, Maeda Yoshinobu, Nishimori Hisakazu, Yamasuji Yoshiko, Matsuoka Ken-ichi, Fujii Nobuharu, Kondo Eisei, Shinagawa Katsuji, Tanaka Takehiro, Takeuchi Kengo, Teshima Takanori, Tanimoto Mitsune

Biology of Blood and Marrow Transplantation 20 ( 2 ) 183 - 191 2014.2

新しい全自動型血液成分分離装置Spectra Optiaを用いた末梢血幹細胞採取-COBE Spectraと比較して- Reviewed

藤井敬子,藤井伸治,淺田騰,西森久和,狩山由貴,池田亮,浅野尚美,小郷博昭,岩月啓氏

日本輸血細胞治療学会誌 59 ( 6 ) 799 - 804 2014.1

Complete resolution of steroid-resistant organizing pneumonia associated with myelodysplastic syndrome following allogeneic hematopoietic cell transplantation. Reviewed International journal

Takeru Asano, Nobuharu Fujii, Daigo Niiya, Hisakazu Nishimori, Keiko Fujii, Ken-Ichi Matsuoka, Koichi Ichimura, Toshihisa Hamada, Eisei Kondo, Yoshinobu Maeda, Yasushi Tanimoto, Katsuji Shinagawa, Mitsune Tanimoto

SpringerPlus 3 3 - 3 2014.1

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

Pulmonary complications in patients with hematological malignancies are often caused by infection but are sometimes associated with an underlying disease such as organizing pneumonia (OP). Here, we report a case of life-threatening steroid-resistant OP associated with myelodysplastic syndrome (MDS) and successfully performed allogeneic hematopoietic cell transplantation (HSCT). A 33-year-old female with refractory anemia with excess blasts-1 that had progressed from refractory anemia with ringed sideroblasts and concomitant Sweet's syndrome was admitted. Multiple pulmonary infiltrates were revealed on a chest computed tomography scan, which progressively worsened even after chemotherapy and corticosteroid therapy. No evidence of infection was observed in bronchoalveolar lavage fluid. A histological examination of a transbronchial lung biopsy specimen showed lymphocyte invasion with fibrosis, indicating that the pulmonary infiltrates were OP associated with MDS. Before transplantation, she suffered from respiratory failure and required oxygen supplementation. She developed idiopathic pneumonitis syndrome on day 61 that responded well to corticosteroid therapy, and the OP pulmonary infiltrates improved gradually after HSCT, She was discharged on day 104 and is well without recurrence of OP or MDS 2 years after HSCT.

DOI： 10.1186/2193-1801-3-3

Pre-transplant risk factors for cryptpgenic organizing pneumonia/brnchiolitis obliterans organizing pneumonia after hematopoietic cell transplantation. Reviewed

Nakasone H, Onizuka M, Suzuki N, Fujii N, Taniguchi S, Kakihana K, Ogawa H, Miyamura K, Eto T, Sakamaki H, Yabe H, Morishima Y, Kato K, Suzuki R, Fukuda T.

Bone Marrow Transplantation 1 - 7 2013.10

Erdheim-Chester病が強く疑われた下垂体機能低下症の一例 Reviewed

三好智子,大塚文男,稲垣謙一,田中康司,越智可奈子,藤井一恭,藤井伸治,当真貴志雄,中村絵里,塚本尚子,武田昌也,三村由香里,小倉俊郎,景山甚郷,槇野博史

日本内分泌学会誌 89 ( Suppl. ) 21 - 23 2013.6

Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens Reviewed

WARREN EH

Blood 115 3869 - 3878 2010.5

Total bacterial counts on oral mucosa after using a commercial saliva substitute in patients undergoing hematopoietic cell transplantation. Reviewed

SIgiura Y, Soga Y, Yamabe K, Tsutani S, Tanimoto I, Maeda H, Kokeguchi S, Fujii N, Ishimaru F, Tanimoto M, Nishimura F, Takashiba S.

Support Care Cancer 2010.5

Total bacterial counts on oral mucosa after using a commercial saliva substitute in patients undergoing hematopoietic cell transplantation Reviewed

Yuko Sugiura, Yoshihiko Soga, Kokoro Yamabe, Soichiro Tsutani, Ichiro Tanimoto, Hiroshi Maeda, Susumu Kokeguchi, Nobuharu Fujii, Fumihiko Ishimaru, Mitsune Tanimoto, Fusanori Nishimura, Shogo Takashiba

SUPPORTIVE CARE IN CANCER 18 ( 3 ) 395 - 398 2010.3

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

The commercial saliva substitute OralbalanceA (R) has been reported to alleviate symptoms of postradiotherapy xerostomia in head and neck cancer patients. OralbalanceA (R) may also be effective for xerostomia in patients undergoing hematopoietic cell transplantation (HCT) with high-dose chemotherapy and total-body irradiation. However, HCT patients are in a severely compromised condition, and saliva substitute must not promote infection. We reported previously that OralbalanceA (R) has antimicrobial effects against microbial species detected during HCT in vitro. This study was performed to determine the in vivo effects of OralbalanceA (R) on oral mucosal total bacterial counts in patients undergoing HCT.
A total of 18 neutropenic patients undergoing HCT were enrolled in this study. Before and after 1 week of OralbalanceA (R) use, bacterial samples were obtained from patients by wiping an area of I center dot 1 cm on the buccal mucosa with sterilized cotton swabs. Total bacterial counts of the obtained samples were examined by quantitative polymerase chain reaction amplification of the bacterial 16S ribosomal RNA gene. As controls, bacterial samples were also obtained from ten healthy subjects, and total bacterial counts were examined.
No significant increase in bacterial count was observed with use of OralbalanceA (R). None of the patients showed bacterial counts above the range found in healthy controls after using OralbalanceA (R).
In neutropenic patients undergoing HCT, OralbalanceA (R) did not increase the total counts of oral mucosal bacteria beyond the range found in healthy controls. Oral care using OralbalanceA (R) may alleviate the symptoms induced by hyposalivation without promoting infection.

DOI： 10.1007/s00520-009-0789-x

A distinct subset of self-renewing human memory CD8+T cells survives cytotoxic chemotherapy Reviewed

TURTLE CJ

Immunity 31 834 - 834 2009.11

Efficacy and feasibility of IDEA therapy for refractory or relapsed non-Hodgkin's lymphoma. Reviewed International journal

Hisakazu Nishimori, Nobuharu Fujii, Yoshinobu Maeda, Ken-Ichi Matsuoka, Katsuto Takenaka, Katsuji Shinagawa, Kazuma Ikeda, Keitaro Matsuo, Mine Harada, Mitsune Tanimoto

Anticancer research 29 ( 5 ) 1749 - 54 2009.5

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

BACKGROUND: The effects of a novel salvage regimen, IDEA (ifosfamide, cytosine arabinoside, etoposide and dexamethasone), which does not include anthracycline or platinum, in patients with non-Hodgkin's lymphoma (NHL) were examined. PATIENTS AND METHODS: Thirty-four patients with refractory or relapsed NHL were treated with IDEA. RESULTS: The overall remission and complete remission rates were 67.6% and 35.3%, respectively. The toxicity of IDEA was tolerable. With a median follow-up of 14 months, one-year overall survival (OS) and progression-free survival rates were 75.1% and 43.7%, respectively. Adequate numbers of CD34(+) cells were obtained in 77.8% of the patients assigned to receive autologous peripheral blood stem cell (PBSC) transplantation. High-dose chemotherapy with autologous PBSC transplantation was carried out in 14 patients; their 3-year OS was 75.0%, with a median follow-up of 38 months. CONCLUSION: IDEA is an effective second-line chemotherapy regimen for NHL patients and has an excellent PBSC-mobilizing effect.

The effect of adding rituximab to CHOP-based therapy on clinical outcomes for Japanese patients with diffuse large B-cell lymphoma : a propensity score matching analysis Reviewed

NISHIMORI Hisakazu, MATSUO Keitaro, MAEDA Yoshinobu, NAWA Yuichiro, SUNAMI Kazutaka, TOGITANI Kazuto, TAKIMOTO Hidetaka, HIRAMATSU Yasushi, KIGUCHI Toru, YANO Tomofumi, YAMANE Hiromichi, TABAYASHI Takayuki, TAKEUCHI Makoto, MAKITA Masanori, SEZAKI Nobuo, YAMASUJI Yoshiko, SUGIYAMA Haruko, TABUCHI Takahiro, KATAOKA Itaru, FUJII Nobuharu, ISHIMARU Fumihiko, SHINAGAWA Katsuji, IKEDA Kazuma, HARA Masamichi, YOSHINO Tadashi, TANIMOTO Mitsune, the West-Japan Hematology and Oncology Group West-JHOG

Int J Hematol. 89 ( 3 ) 326 - 331 2009.4

Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation Reviewed

HIRAMATSU Yasushi, MAEDA Yoshinobu, FUJII Nobuharu, SAITO Takashi, NAWA Yuichiro, HARA Masamichi, YANO Tomofumi, ASAKURA Shoji, SUNAMI Kazutaka, TABAYASHI Takayuki, MIYATA Akira, MATSUOKA Ken-ichi, SHINAGAWA Katsuji, IKEDA Kazuma, MATSUO Keitaro, TANIMOTO Mitsune, for the West-Japan Hematology and Oncology Group West-JHOG

88 ( 5 ) 588 - 595 2008.12

Evaluation of xerostomia in hematopoietic cell transplantation by a simple capacitance method device. Reviewed International journal

Yuko Sugiura, Yoshihiko Soga, Sachiko Nishide, Kotoe Kono, Kanayo Takahashi, Nobuharu Fujii, Fumihiko Ishimaru, Mitsune Tanimoto, Fusanori Nishimura, Shogo Takashiba

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 16 ( 10 ) 1197 - 200 2008.10

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

GOALS: Hematopoietic cell transplantation (HCT) may lead to the development of xerostomia. However, there have been few reports of xerostomia in HCT patients based on objective data. We investigated moisture in the oral mucosa in patients undergoing HCT by the capacitance method using a convenient device, Moisture Checker for Mucus (MCM; Life Co., Ltd., Saitama, Japan). SUBJECTS AND METHODS: Thirty-six patients undergoing HCT at Okayama University Hospital of Medicine and Dentistry (Male = 22, Female = 14; age = 41.6 +/- 16.2 years old) were enrolled in this study. Moisture in the oral mucosa was measured by MCM in accordance with the manufacturer's instructions. The results were obtained as MCM values (%), which are the weight percentage of water content in the oral mucosal epithelium. As controls, moisture of the oral mucosa was also examined in healthy volunteers (Male = 27, Female = 35; age = 43.0 +/- 14.6 years old). MAIN RESULTS: Throughout the examination period, MCM values were significantly lower in patients who underwent HCT than in controls. The degree of mucosal moisture in HCT patients showed wide interindividual differences. CONCLUSION: The degree of mucosal moisture in HCT patients was low and showed wide interindividual differences. Evaluation of xerostomia using such a device may contribute to appropriate oral care with saliva substitute.

DOI： 10.1007/s00520-008-0470-9

C19orf48 encodes a minor histocompatibility antigen recognized by CD8+ cytotoxic T cells from renal cell carcinoma patients. Reviewed

Tykodi SS, Fujii N, Vigneron N, Lu SM, Mito JK, Miranda MX, Chou J, Voong LN, Thompson JA, Sandmaier BM, Cresswell P, Van den Eynde BJ, Riddell SR, Warren EH.

Clinical Cancer Research 2008.8

DDX3Y encodes a class I MHC-restricted H-Y antigen that is expressed in leukemic stem cells Reviewed

Rosinski KV, Fujii N, Mito JK, Koo KK, Xuereb SM, Sala-Torra O, Gibbs JS, Radich JP, Akatsuka Y, Van den Eynde BJ, Riddell SR, Warren EH.

Blood 2008.5

Antimicrobial effects of the saliva substitute, Oralbalance, against microorganisms from oral mucosa in the hematopoietic cell transplantation period. Reviewed International journal

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

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 16 ( 4 ) 421 - 4 2008.4

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

GOALS: The commercially available saliva substitute Oralbalance has been reported to alleviate symptoms of post-radiotherapy xerostomia in head and neck cancer patients. Oralbalance may also be effective for xerostomia in patients undergoing hematopoietic cell transplantation (HCT) with high-dose chemotherapy and total-body irradiation. However, HCT patients are severely compromised, and saliva substitute must therefore not promote infection. This study was performed to determine the effects of Oralbalance on microbial species identified during HCT. PATIENTS AND METHODS: Microbial identification of oral mucosa was performed in 28 patients undergoing HCT. The antimicrobial effects of Oralbalance against bacteria and fungi detected in the HCT period were examined in vitro. Briefly, bacteria and fungi were spread on agar plates, and 0.1g of Oralbalance gel was applied (about phi1cm). After incubation at 37 degrees C for 24h, the presence of a transparent zone of inhibition around Oralbalance was observed. MAIN RESULTS: Not only bacterial species constituting normal flora of the oral mucosa but also those not usually constituting normal flora, e.g., coagulase-negative Staphylococcus, were detected. A transparent zone was observed around Oralbalance in all bacterial species examined. No transparent zone was observed for Candida albicans, but growth was inhibited in the area where Oralbalance was applied. CONCLUSIONS: Oralbalance does not facilitate increases in microorganisms in the HCT period. Oral care with Oralbalance does not promote infection in patients undergoing HCT.

DOI： 10.1007/s00520-007-0391-z

Appearance of multidrug-resistant opportunistic bacteria on the gingiva during leukemia treatment. Reviewed International journal

Yoshihiko Soga, Takashi Saito, Fusanori Nishimura, Fumihiko Ishimaru, Junji Mineshiba, Fumi Mineshiba, Hirokazu Takaya, Hideaki Sato, Chieko Kudo, Susumu Kokeguchi, Nobuharu Fujii, Mitsune Tanimoto, Shogo Takashiba

Journal of periodontology 79 ( 1 ) 181 - 6 2008.1

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

BACKGROUND: Dentists generally recognize the importance of periodontal treatment in patients with leukemia, with the most attention paid to preventing the development of odontogenic infection. For physicians, the worst type of infection is one caused by multidrug-resistant bacteria. Here, we report a patient with an abnormal increase in multidrug-resistant opportunistic bacteria in the gingiva during hematopoietic cell transplantation (HCT). METHODS: A 53-year-old woman receiving HCT for leukemia had an insufficient blood cell count for invasive periodontal treatment before HCT. Even brushing caused difficulties with hemostasis. Therefore, frequent pocket irrigation and local minocycline administration were performed. RESULTS: The multidrug-resistant opportunistic bacterium Stenotrophomonas maltophilia was detected first in phlegm 2 days before HCT, and it was detected in a gingival smear and a blood sample 7 and 11 days after HCT, respectively. The patient developed sepsis on day 11 and died 14 days after HCT. Frequent irrigation and local antibiotic application were ineffective against S. maltophilia on the gingiva. Inflammatory gingiva without scaling and root planing showed bleeding tendency, and this interfered with the eradication of this bacterium. CONCLUSIONS: The gingiva in patients undergoing leukemia treatment acts as sites of proliferation and reservoirs for multidrug-resistant opportunistic bacteria. Severe systemic infection by multidrug-resistant bacteria in such patients with leukemia also may involve the gingiva. To prevent abnormal increases in such bacteria on the gingiva, scaling and/or root planing before chemotherapy, which reduces bleeding on brushing during the neutropenic period caused by chemotherapy, may contribute to infection control in such patients, although it was impossible in this case.

DOI： 10.1902/jop.2008.070205

Predominant Infiltration of Monocytes in Chronic Graft-Versus-Host Disease Reviewed

Namba Noriko, Shinagawa Katsuji, Fujii Nobuharu, Maeda Yoshinobu, Ishimaru Fumihiko, Ikeda Kazuma, Matsui Toshimitsu, Tanimoto Mitsune, Katayama Yoshio

Transplantation 83 ( 2 ) 220 - 224 2007.1

Loss or down-regulation of HLA class I expression at the allelic level in freshly isolated leukemic blasts Reviewed International journal

Kozo Masuda, Akio Hiraki, Nobuharu Fujii, Toshiyuki Watanabe, Motoyuki Tanaka, Kosei Matsue, Yoichiro Ogama, Mamoru Ouchida, Kenji Shimizu, Kazuma Ikeda, Mitsune Tanimoto

CANCER SCIENCE 98 ( 1 ) 102 - 108 2007.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

Loss or down-regulation of human leukocyte antigen (HLA) class I expression has been demonstrated in a variety of solid tumors. To date, such altered HLA expression has not been studied extensively in freshly isolated leukemic blasts. If it occurs, leukemic cells could escape T-cell surveillance as a consequence. Genotypes of nine leukemic cell lines were determined using a polymerase chain reaction for HLA classes I and II. Cells were also examined for HLA beta 2-microglobulin, and allele-specific HLA protein expression using flow cytometry. Next, 44 samples of freshly isolated leukemic blasts from 43 patients with malignant hematological diseases were examined for allele-specific HLA expression using flow cytometry. Microsatellite analysis was performed to determine heterozygosity in the HLA region on chromosome 6. Genotype analysis for HLA class I together with microsatellite analysis demonstrated loss of HLA haplotype in HL-60 cells. No loss of HLA haplotype was observed in 44 samples of freshly isolated leukemic blasts. As reported previously, flow cytometric analysis rarely demonstrated loss or down-regulation of HLA expression at initial diagnosis (3/39; 7.7%); however, this was evident in two of five cases in relapse (40.0%), which contrasts with previous reports. In one patient with acute leukemia, HLA-A2 cell surface expression was present at initial diagnosis, lost at relapse, and completely restored after 48 h of culture in the presence of interferon-gamma. These results suggest loss of allele-specific HLA expression may be involved in the pathogenesis of relapse in patients with leukemia. The findings should be valuable in designing new strategies for clinical immunotherapy.

DOI： 10.1111/j.1349-7006.2006.00356.x

Early kinetics of engraftment following reduced-intensity stem cell transplantation: Fludarabine and cyclophosphamide versus fludarabine and busulfan. Reviewed

Teruhiko Kozuka, Fumihiko Ishimaru, Keitaro Matsuo, Hiromi Nakashima, Nobuharu Fujii, Kenichi Matsuoka, Eisei Kondo, Yoshio Katayama, Yoshinobu Maeda, Katsuji Shinagawa, Kazuma Ikeda, Mitsune Tanimoto

BLOOD 108 ( 11 ) 838A - 838A 2006.11

Calcineurin inhibitor-induced irreversible neuropathic pain after allogeneic hematopoietic stem cell transplantation Reviewed

N Fujii, K Ikeda, M Koyama, K Aoyama, T Masunari, E Kondo, T Matsuzaki, S Mizobuchi, A Hiraki, T Teshima, K Shinagawa, F Ishimaru, M Tanimoto

INTERNATIONAL JOURNAL OF HEMATOLOGY 83 ( 5 ) 459 - 461 2006.6

Language：English Publishing type：Research paper (scientific journal) Publisher：CARDEN JENNINGS PUBL CO LTD

The calcineurin inhibitors (Cls) cyclosporine A and tacrolimus are essential for graft-versus-host disease prophylaxis but are associated with adverse effects, including neurotoxicity We report a case of irreversible Cl-induced neuropathic pain following allogeneic hematopoietic stem cell transplantation. The patient developed dysesthesia, electric shock-like pain. and severe itching followed by intractable analgesic-resistant pain in the lower extremities. There were no abnormal radiographic findings, and there was no improvement with a reduction of Cl dosage or with administration of a calcium channel blocker. These clinical findings are similar to but inconsistent with Cl-induced musculoskeletal pain syndromes previously reported in organ transplantation.

DOI： 10.1532/IJH97.05154

Other Link： http://orcid.org/0000-0003-0995-9405

Serum cytokine concentrations and acute graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: Concurrent measurement of ten cytokines and their respective ratios using cytometric bead array Reviewed

N Fujii, A Hiraki, K Aoe, T Murakami, K Ikeda, K Masuda, K Matsuo, K Shinagawa, F Ishimaru, K Sugi, Z Darzynkiewicz, M Tanimoto

INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 17 ( 5 ) 881 - 885 2006.5

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Both inflammatory and anti-inflammatory cytokines have been reported to be associated with acute graft-versus-host disease (aGVHD). However, their role and possible mutual interactions during aGVHD are not well understood. Eight patients with aGVHD and eight without who had undergone allogeneic HLA-identical peripheral blood stem cell transplantation were studied. The patients had no other complications known to affect serum concentration of cytokines, including infection. Serum concentrations of IL-1B, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha and IFN-gamma were concurrently measured by a new technique, the cytometric bead array (CBA). We found that serum concentrations of IL-5, IL-6 and IL-10 were significantly higher in patients with aGVHD than in patients without it. By ratiometric analysis, the ratios of IL-5/IL-2, IL-5/IL-4, IL-6/IL-4 in patients with aGVHD were increased compared to the patients with no evidence of aGVHD. ROC analysis demonstrated that the ratio of IL-5/IL-4 was the most sensitive parameter associated with aGVHD. The second best marker of aGVHD was increased IL-5 concentration. Thus, our results indicate that the ratio of a particular cytokine/cytokine could be a potential diagnostic marker for aGVHD, more sensitive that the serum level of a given cytokine. This observation is consistent with a cross-talk among some cytokines and their possible interactions via respective receptors on cytokine-producing cells; these interactions may play an important role in pathogenesis of aGVHD. Further studies including a large number of patients and concurrent measurement of a variety of cytokines are needed to fully assess the diagnostic value of the cytokine ratiometric analysis. The CBA methodology provides a convenient and useful tool in such studies.

Other Link： http://orcid.org/0000-0003-1761-6314

Activated human umbilical cord blood dendritic cells kill tumor cells without damaging normal hematological progenitor cells Reviewed

J Shi, K Ikeda, N Fujii, E Kondo, K Shinagawa, F Ishimaru, K Kaneda, M Tanimoto, Li, X, Q Pu

CANCER SCIENCE 96 ( 2 ) 127 - 133 2005.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Apart from their role as antigen presenting cells, human peripheral blood monocyte and CD34+ cell-derived dendritic cells (DC), have been demonstrated to exert cytotoxicity against some tumor cells, and their tumoricidal activity can be enhanced by some stimili. However, there have been no reports concerning the tumoricidal activity of human cord blood dendritic cells (CBDC). In this article, we report that human cord blood monocyte-derived DC acquire the ability to kill hematological tumor cells, after activation with lipopolysaccharicle (LIPS) or gamma-interferon (IFN-gamma), associated with the enhanced TNF-alpha-related apoptosis-inducing ligand (TRAIL) expression in CBDC cytoplasm. The CD14-positive cells collected from cord blood were induced to CBDC in vitro. After activation with IFN-gamma for 12 h, CBDC exhibited cytotoxicity against HL60 and Jurkat cells, while activation with LPS induced cytotoxicity against Daudi and Jurkat cells. However, both LPS- and IFN-gamma-stimulatecl CBDC showed no cytotoxic activity against normal CD14-negative cord blood mononuclear cells. The formation of umbilical cord hematopoietic progenitor colonies, identified as burst-forming unit-erythroid and colony-forming unit granulocyte-macrophage, was not inhibited by stimulated or unstimulated CBDC. IFN-gamma or LPS stimulation enhanced intracellular but not cellular surface TRAIL, and neither intracellular nor cellular surface tumor necrosing factor-alpha and Fas Ligand as analyzed by flow cytometry. Our results show that activated CBDC can serve as cytotoxic cells against hematological tumor cells without damaging the normal hematopoietic progenitor cells.

DOI： 10.1111/j.1349-7006.2005.00017.x

Other Link： http://orcid.org/0000-0003-0995-9405

Expression of SOCS3 mRNA in bone marrow cells from CML patients associated with cytogenetic response to IFN-alpha. Reviewed International journal

Kazuto Takeuchi, Ikuya Sakai, Hirosi Narumi, Masaki Yasukawa, Kensuke Kojima, Yoko Minamoto, Tomoaki Fujisaki, Kazushi Tanimoto, Masamichi Hara, Akihiko Numata, Hisashi Gondo, Masuhiro Takahashi, Nobuharu Fujii, Kozo Masuda, Shigeru Fujita

Leukemia research 29 ( 2 ) 173 - 8 2005.2

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

Previously, we have demonstrated that constitutive expression of suppressor of cytokine signaling-3 (SOCS3) affects the sensitivity of chronic myelogenous leukemia (CML) cell lines to interferon-alpha (IFN-alpha). In the present study, we analyzed the expression of SOCS3 mRNA in bone marrow cells from patients with CML at diagnosis, with the aid of real-time polymerase chain reaction. SOCS3 mRNA expression in bone marrow cells from CML patients who responded well to IFN-alpha therapy was significantly lower than that in cells from healthy volunteers and patients who were resistant to IFN-alpha therapy. Methylation of SOCS3 promoter was absent in bone marrow cells from all CML patients examined. These results indicate that the expression of SOCS3 mRNA is inversely associated with the sensitivity to IFN-alpha both in vitro and in vivo and that differences in SOCS3 mRNA expression are not due to the methylation status of SOCS3 promoters.

High frequency of allele-specific rown-regulation of HLA class I expression in lung cancer cell lines Reviewed

Akio Hiraki, Nobuharu Fujii, Tomoyuki Murakami, Katsuyuki Kiura, Keisuke Aoe, Hiromichi Yamane, Kozo Masuda, Tadashi Maeda, Kazuro Sugi, Zbigniew Darzynkiewicz, Mitsune Tanimoto, Mine Harada

Anticancer Research 24 ( 3 A ) 1525 - 1528 2004.5

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

Loss or down-regulation of HLA expression has been demonstrated in various types of solid tumors and is considered to be one of the mechanisms of tumor immunoescape. The effectiveness of immunotherapy using tumor-specific antigens (TSA) largely depends on the expression of the appropriate HLA class I alleles on the tumor cells. We analyzed the allele-specific HLA class I surface expression of six lung cancer cell lines using a broad panel of allele-specific monoclonal antibodies, as well as the effect of IFN-γ on HLA expression. Flow cytometric analysis displayed a wide range, from minimal to a high degree of expression of monomorphic HLA class I among the studied cell lines. Allele-specific loss or down-regulation of HLA also was observed in 5 out of 6 cell lines. Our results suggest that lung cancer patients considered for specific immunotherapy should be examined with respect to the expression of specific HLA class I allele binding the TSA.

好中球減少時の発熱に対するCefozopranの有効性に関する検討.

齋藤崇、原雅道、品川克至、名和由一郎、中瀬浩一、竹内誠、宮田明、福田俊一、角南一貴、今城健二、矢野朋文、小島研介、豊嶋崇徳、藤井伸治、石丸文彦、池田和真、原田実根、谷本光音

癌と化学療法 2004.4

Peripheral blood circulating immature cell counts predict CD34+ cell yields in G-CSF-induced PBPC mobilization in healthy donors

Kozuka T, Ikeda K, Teshima T, Yoshida C, Shinagawa K, Kojima K, Matsuo K, Bessho A, Sunami K, Hiramatsu Y, Maeda Y, Noguchi T, Yamamoto K, Fujii N, Imai T, et.al

Transfusion 2004.4

FLJ10849, a septin family gene, fuses MLL in a novel leukemia cell line CNLBC1 derived from chronic neutrophilic leukemia in transformation with t(4;11)(q21;q23) Reviewed

KOJIMA K

Leukemia 18 998 - 1005 2004.4

Peripheral blood circulating immature cell counts predict CD34+ cell yields in G-CSF-induced PBPC mobilization in healthy donors. Reviewed International journal

Teruhiko Kozuka, Kazuma Ikeda, Takanori Teshima, Chikamasa Yoshida, Katsuji Shinagawa, Kensuke Kojima, Keitaro Matsuo, Akihiro Bessho, Kazutaka Sunami, Yasushi Hiramatsu, Yoshinobu Maeda, Toshio Noguchi, Kazuhiko Yamamoto, Nobuharu Fujii, Toshi Imai, Kinuyo Kaneda Kusumoto, Kozo Masuda, Katsuto Takenaka, Fumihiko Ishimaru, Kenji Niiya, Norio Koide, Mitsune Tanimoto, Mine Harada

Transfusion 44 ( 4 ) 526 - 32 2004.4

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

BACKGROUND: It has been previously reported that the number of circulating immature cells (CIC) in peripheral blood (PB) estimates the number of CD34+ cells collected in G-CSF plus chemotherapy-induced PBPC mobilization. The correlation of CIC counts in PB with CD34+ cell yield and its usefulness was evaluated in G-CSF-induced PBPC mobilization for healthy donors. STUDY DESIGN AND METHODS: CIC counts in PB and CD34+ cell counts in the apheresis product from 122 collections were assessed, and the relationship between these two variables was evaluated with the Pearson rank correlation analysis, the chi-squared test, and the U-test. RESULTS: CIC counts were correlated weakly with the number of CD34+ cells per L of blood processed in the apheresis product (Pearson rank correlation analysis; r=0.357, p<0.0001). When a level of 1.7 x 10(9) CICs per L was selected as a cutoff value, the sensitivity and specificity for collecting more than 20 x 10(6) CD34+ cells per L of blood processed were 63.6 and 77.5 percent, respectively. CONCLUSION: The present study suggests that the number of CICs in PB may estimate the number of CD34+ cells collected. The data indicate that CIC counts above 1.7 x 10(9) per L can be used as a good predictor for PBPC collections containing more than 20 x 10(6) CD34+ cells per L of blood processed in a single apheresis procedure.

[Clinical evaluation of cefozopran as treatment for febrile neutropenia].

Takashi Saito, Masamichi Hara, Katsuji Shinagawa, Yuichiro Nawa, Koichi Nakase, Makoto Takeuchi, Akira Miyata, Shunnichi Fukuda, Kazutaka Sunami, Kenji Imajoh, Tomofumi Yano, Kensuke Kojima, Takanori Teshima, Nobuharu Fujii, Fumihiko Ishimaru, Kazuma Ikeda, Mine Harada, Mitsune Tanimoto

Gan to kagaku ryoho. Cancer & chemotherapy 31 ( 1 ) 61 - 5 2004.1

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

Clinical effects and safety of cefozopran (CZOP) were evaluated by the Okayama Bone Marrow Transplantation Group. Twenty-five patients expected to experience febrile neutropenia during induction chemotherapy or consolidation chemotherapy of acute leukemia were enrolled between July 2000 and November 2002. CZOP was administrated by drip infusion at 4g/day bid for a minimum of 3 days. The clinical effects and safety were evaluated in 20 patients with fever of 37.5 degrees C or more from a clinically suspected infection. The underlying disease was acute myeloid leukemia in 17 patients, acute lymphoid leukemia in 1 and acute promyelogeneous leukemia in 1. The complicating infections were sepsis and suspected sepsis. Clinical efficacy was excellent in 11 patients, good in 1, fair in 2 and poor in 6, with an efficacy rate of 60.0%. The efficacy rate in patients whose albumin levels before therapy were less than 3.8 g/dl was 37.5%, whereas the rate in patients whose albumin levels before therapy were between 3.8 g/dl and 5.3 g/dl was 80.0%. The efficacy rate in patients whose neutrophil counts before therapy were less than 100/microliter was 50.0%, whereas the rate in patients whose neutrophil counts after therapy were less than 100/microliter was 53.8%. The efficacy rate in patients whose neutrophil counts both before and after therapy were less than 100/microliter was 37.5%. Side effect of exanthema was observed in 1 patient. These results indicate that CZOP is an effective and safe antibiotic for the treatment of febrile neutropenia in patients with hematological malignancies.

Cyclic thrombocytopenia and polycythemia vera

KOJIMA K

Ann Hematol. 82 61 - 63 2003.4

Plasma stromal cell-derived factor-1 during granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilization.

Kozuka T, Ishimaru F, Fujii K, Masuda K, Kaneda K, Imai T, Fujii N, Ishikura H, Hongo S, Watanabe T, Shinagawa K, Ikeda K, Niiya K, Harada M, Tanimoto M

Bone Marrow Transplant 2003.4

Human herpes virus-8-negative primary effusion lymphoma in a patient with common variable immunodeficiency.

Hisamoto A, Yamane H, Hiraki A, Maeda Y, Fujii N, Sasaki K, Miyake T, Sasaki T, Nakamura T, Kiura K, Tanimoto M, Kamei H

Leuk Lymphoma 2003.4

成人B細胞性急性リンパ性白血病(ALL L3)における長期予後の改善.

石丸文彦, 近藤英生, 藤井伸治, 豊嶋崇徳, 品川克至, 池田和眞, 谷本光音

内科専門医会誌 2003.4

Potential limitations in using minor histocompatibility antigen-specific cytotoxic T cells for targeting solid tumor cells

MIYAZAKI M

Clin Immunol. 107 198 - 201 2003.4

Successful treatment with cyclosporin A of myelodysplastic syndrome with erythroid hypoplasia associated with t(6;8) (q15;q22)

TAKATA S

Cancer Genet Cytogenet 140 167 - 169 2003.4

A novel fusion variant of the MORF and CBP genes detected in therapy-related myelodysplastic syndrome with t(10;16)(q22;p13) Reviewed

K Kojima, K Kaneda, C Yoshida, H Dansako, N Fujii, T Yano, K Shinagawa, M Yasukawa, S Fujita, M Tanimoto

BRITISH JOURNAL OF HAEMATOLOGY 120 ( 2 ) 271 - 273 2003.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING LTD

We report a case of therapy-related myelodysplastic syndrome (t-MDS) with t(10;16)(q22;p13), in which novel fusion transcripts of the MORF and CBP genes were detected. In one MORF-CBP fusion transcript, exon 15 of the MORF gene was fused in frame with exon 5 of the CBP gene. In a reciprocal CBP-MORF transcript, exon 4 of the CBP gene was fused in frame with exon 16 of the MORF gene. This is the first reported case of t-MDS associated with t(10;16), and provides molecular evidence that the novel MORF-CBP and/or CBP-MORF fusion protein(s) might play an important role in the development of t-MDS.

Predictive value of circulating immature cell counts in peripheral blood for timing of peripheral blood progenitor cell collection after G-CSF plus chemotherapy-induced mobilization Reviewed

T Kozuka, K Ikeda, T Teshima, K Kojima, K Matsuo, A Bessho, K Sunami, Y Hiramatsu, Y Maeda, T Noguchi, K Yamamoto, N Fujii, T Imai, K Takenaka, K Shinagawa, F Ishimaru, K Niiya, N Koide, M Tanimoto, M Harada

TRANSFUSION 42 ( 11 ) 1514 - 1522 2002.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC BLOOD BANKS

Background: Enumeration of CD34+ cells in peripheral blood (PB) before apheresis predicts the number of CD34+ cells collected, although flow cytometric techniques used are complex and expensive. In an attempt to determine the optimal timing for peripheral blood progenitor cell (PBPC) collection, the usefulness of circulating immature cell (CIC) counts in PB was evaluated.
Study design and methods: CIC counts in PB and CD34+ cell counts in the apheresis product from 249 collections were assessed, and the relationship between these two parameters was evaluated by with the Pearson rank correlation analysis, the Fisher exact test, and the U-test.
Results: CIC counts were correlated significantly with the number of CD34+ cells per kg of patient's body weight in the apheresis product (Pearson rank correlation analysis: r=0.635, p<0.0001). When a level of 1x10(9) CICs per L was selected as a cutoff value, the sensitivity and specificity for collecting more than 1x10(6) CD34+ cells per kg of body weight were 75.7 and 85.5 percent, respectively.
Conclusion: The present study strongly suggests that the number of CICs in PB may estimate the number of CD34+ cells collected. The data indicate that CIC counts above 1x10(9) per L can be used as a good predictor for PBPC collections containing more than 1x10(6) CD34+ cells per kg of body weight in a single apheresis procedure.

Other Link： http://orcid.org/0000-0003-1761-6314

Tandem high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation for recurrent soft tissue sarcoma Reviewed

Teruhiko Kozuka, Katsuyuki Kiura, Hideki Katayama, Nobuharu Fujii, Fumihiko Ishimaru, Kazuma Ikeda, Hiroshi Ueoka, Shuuji Hamasaki, Tadashi Yoshino, Yoshio Kashihara, Hiroshi Date, Mitsune Tanimoto, Mine Harada

Anticancer Research 22 ( 5 ) 2939 - 2944 2002.9

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

Background: Patients with recurrent soft tissue sarcoma (STS) are seldom curable, with 5-year survival rates of less than 10% in all large series. The role of high-dose chemotherapy (HDC) with hematopoietic stem cell support in this disease has not been established. Case Report: We report on two patients with recurrent STS who were treated with tandem HDC supported by autologous peripheral blood stem cell transplantation (PBSCT). One patient with malignant fibrous histiocytoma recurred with multiple lung metastases. This patient achieved a partial response after two cycles of induction chemotherapy consisting of ifosfamide and epirubicin. During four cycles of induction chemotherapy, peripheral blood stem cells (PBSCs) were harvested. Tandem high-dose ICE regimen (ifosfamide 3 g/m2 on days - 7 to - 3, carboplatin 400 mg/m2 on days - 7, - 5 and 3, etoposide 500 mg/m2 on days - 7, - 5 and 3) supported by autologous PBSCT gave rise to further regression of the tumors. Another patient with malignant hemangiopericytoma was treated by tandem high-dose ICE regimen supported by autologous PBSCT after the 3rd removal of abdominal tumors. Relapse-free intervals until the 1st, 2nd and 3rd relapses were 40, 19 and 22 months, respectively. Tandem high-dose ICE regimen might delay the relapse. Conclusion: These observations suggest that a tandem high-dose ICE regimen with autologous PBSCT is feasible with some clinical efficacy in the control of refractory STS.

固形腫瘍におけるマイナー組織適合性抗原HA-1の発現の検討

平木章夫, 藤井伸治, 池田和眞, 木浦勝行, 田端雅弘, 上岡博, 原田実根, 谷本光音

日本癌学会総会記事 60回 243 - 243 2001.9

Genetics of Epstein-Barr virus infection

A. Hiraki, N. Fujii, K. Masuda, K. Ikeda, M. Tanimoto

Biomedicine and Pharmacotherapy 55 ( 7 ) 369 - 372 2001

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Masson SAS

Epstein-Barr (EBV) virus is a member of the human herpesvirus family. EBV is the etiologic agent of acute infectious mononucleosis and is closely associated with the genesis of Burkitt's lymphoma and undifferentiated nasopharyngeal carcinoma. EBV is also implicated in a variety of other diseases, such as X-linked lymphoproliferative syndrome, T-cell non-Hodgkin's lymphoma, Hodgkin's disease, and NK-cell granular lymphoproliferative disorder. Recently, lymphoepithelial carcinoma of the stomach, gastric carcinoma, pyothorax-associated lymphoma, and smooth muscle tumors were also recognized as EBV-associated diseases. It is therefore important to review the genetics and immunological response of EBV infection. In this review we summarize the genetics of EBV, immunological responses and clinical findings of EBV-associated diseases, which would help us to understand the pathophysiology of EBV-associated disease and develop specific treatments. © 2001 Éditions scientifiques et médicales Elsevier SAS.

DOI： 10.1016/S0753-3322(01)00084-1

Retrospective Analysis on Time Requirements and Cost Effectiveness of Collection and Cryopreservation of Autologous Blood Stem Cells.

Hiramatsu Yasushi, Sunami Kazutaka, Maeda Yoshinobu, Fujii Nobuharu, Bessho Akihiro, Asano Naomi, Ogo Hiroaki, Takenaka Katsuto, Shinagawa Katsuji, Ikeda Kazuma, Harada Mine

Japanese Journal of Transfusion and Cell Therapy 46 ( 1 ) 1 - 6 2000

Language：Japanese Publisher：The Japan Society of Transfusion Medicine and Cell Therapy

Autologous blood stem cell transplantation (auto-PBSCT) has increasingly been incorporated into the treatment of various malignancies. Auto- PBSCT provides several advantages over auto-BMT, but sometimes requires several collections of PBSC. We have retrospectively analyzed the time requirements and cost effectiveness of PBSC collection in Okayama University Hospital between 1994 and 1997, in which PBSCs were mobilized by chemotherapy and granulocyte colony-stimulating factor in 85 patients. During the 1994-1995 period, PBSCs were collected by apheresis, which was timed by leukocyte count and carried out by attending physicians, and cryopreserved at<5×10⁷cells/ml concentrations. During 1996-1997, PBSC harvests, in which the number of apheresis was adjusted by the number of CD34⁺ cells collected at each harvest, were predicted by circulating immature myeloid cell count, and carried out by personnel of the Division of Blood Transfusion. Collected cells were cryopreserved at<1×10⁸cells/ml. From the 1994-1995 to 1996-1997 periods, the average number of apheresis, the number of cryopreserved bags, and the time and cost required for aphereses and cryopreservation decreased from 3.5 to 1.4 aphereses, from 12.1 to 4.5 bags, from 13.6 to 7.1 hours and from 317 to 113 thousand yen per patient, respectively. Our experience suggests that the time requirements and cost effectiveness of PBSC harvest may be improved with precisely timed apheresis by skilled personnel and with appropriately defined cryopreservation.

DOI： 10.3925/jjtc1958.46.1

492 ヒト末梢血幹細胞培養好塩基球におけるsuperoxide産生能の検討

濱田昇, 谷本安, 高尾和志, 藤井誠, 藤井伸治, 金廣有彦, 原田実根, 池田和真, 片岡幹男, 今城健二, 高橋清

アレルギー 49 ( 9 ) 1015 - 1015 2000

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