研究者詳細 - 淺田　騰

論文 - 淺田　騰

分割表示 126 件中 41 - 60 件目／全件表示 >>

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

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

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

記述言語：日本語掲載種別：研究論文（学術雑誌）

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

DOI： 10.11406/rinketsu.66.81

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Oral Inflammation and Microbiome Dysbiosis Exacerbate Chronic Graft-versus-host Disease. 査読国際誌

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

Blood 145 ( 8 ) 881 - 896 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1182/blood.2024024540

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

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 121 ( 2 ) 232 - 243 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1007/s12185-024-03888-9

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Pericardial artery lymphoma in a patient with dermatomyositis: A case report. 国際誌

Kei Hirose, Takayuki Katsuyama, Natsuki Kubota, Yuya Terajima, Kazuya Matsumoto, Kenta Shidahara, Takato Nakadoi, Shoichi Nawachi, Yu Katayama, Yoshia Miyawaki, Eri Katsuyama, Mariko Narazaki-Takano, Yoshinori Matsumoto, Noboru Asada, Ken-Ei Sada, Jun Wada

Modern rheumatology case reports 9 ( 1 ) 100 - 103 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

A woman in her 60s presented with erythema on both elbows, dyspnea on exertion, discomfort, and swelling of the left upper extremity, followed by swelling and myalgia of the right upper and lower extremities. She was diagnosed with anti-TIF1γ antibody-positive dermatomyositis with interstitial pneumonia. The initial screening tests for malignant diseases including contrast-enhanced CT, upper and lower endoscopy, and gynecological examination did not reveal any obvious abnormalities. The patient experienced two recurrent episodes of muscle weakness and dysphagia during treatment with intravenous glucocorticoids and cyclophosphamide. Five months after diagnosis, a bone marrow biopsy and positron emission tomography- computed tomography (PET-CT) scan revealed a coronary malignant lymphoma with suspected systemic metastasis. Although chemotherapy was initiated, the patient ultimately succumbed to alveolar hemorrhage. Coronary lymphoma is very rare and there has been no report of a cases associated with myositis. PET-CT may be useful for searching malignancy in anti-TIF1γ antibody-positive dermatomyositis cases of recurrent relapse.

DOI： 10.1093/mrcr/rxae065

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Reappraising the prognostic relevance of cytogenetic risk in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. 査読国際誌

Shohei Mizuno, Hiroki Hosoi, Akiyoshi Takami, Takahito Kawata, Noriko Doki, Wataru Takeda, Masatsugu Tanaka, Tetsuya Nishida, Naoyuki Uchida, Yuta Hasegawa, Masashi Sawa, Shuichi Ota, Makoto Onizuka, Hirohisa Nakamae, Noboru Asada, Takahiro Fukuda, Makoto Yoshimitsu, Yoshinobu Kanda, Marie Ohbiki, Yoshiko Atsuta, Takaaki Konuma, Masamitsu Yanada

Annals of hematology 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

This study aimed to investigate the prognostic relevance of cytogenetic risk in 9826 adults with acute myeloid leukemia (AML) who underwent allogeneic hematopoietic cell transplantation (HCT) during the first or second complete remission. The 5-year probabilities of overall survival (OS) were 66%, 61%, and 47% (P < 0.001), the cumulative incidences of relapse were 14%, 19%, and 32% (P < 0.001), and the cumulative incidences of non-relapse mortality (NRM) were 23%, 23%, and 25% (P = 0.208) in patients with favorable (n = 1418), intermediate (n = 6747), and poor cytogenetic risk (n = 1661), respectively. The significant effect of cytogenetic risk on OS was strong in all subgroups stratified by age, sex, performance status, disease status, donor type, conditioning intensity, graft-versus-host disease prophylaxis, and transplantation period (P < 0.001 for all). The evaluation of trends in posttransplant outcomes for patients in each cytogenetic risk category indicated that the risk of relapse declined in patients with favorable and intermediate cytogenetics and that the risk of NRM decreased in those with intermediate and poor cytogenetics. Therefore, patients with intermediate cytogenetics experienced the best OS improvement. These results confirm cytogenetic risk as a universal prognostic factor in patients with AML undergoing allogeneic HCT while highlighting the requirement for further improvements in posttransplant OS by reducing NRM in patients with favorable cytogenetics and by reducing relapse in patients with poor cytogenetics.

DOI： 10.1007/s00277-024-06094-z

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

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

日本血液学会学術集会 86回 O3 - 2 2024年10月

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

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

Internal medicine (Tokyo, Japan) 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.2169/internalmedicine.3998-24

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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 査読

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

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

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 査読

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

eJHaem 2024年6月

掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

Abstract

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

DOI： 10.1002/jha2.962

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造血幹細胞移植後の難治性腸管合併症に対して腸管切除術を施行した2症例

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

臨床血液 65 ( 5 ) 454 - 454 2024年5月

難治性下腿潰瘍の精査により診断したKlinefelter症候群の1例

川本雅也, 三宅智子, 神野泰輔, 高須賀琴巳, 別木祐介, 松本真理, 澤井希望, 川上佳夫, 森実真, 淺田騰, 戸田洋伸

日本皮膚科学会雑誌 134 ( 6 ) 1711 - 1711 2024年5月

HAVCR2ホモ接合型変異を有し家族内発症した皮下脂肪織炎様T細胞リンパ腫

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

臨床血液 65 ( 5 ) 465 - 466 2024年5月

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1007/s12185-024-03711-5

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A phase 1/2 study of NS-87/CPX-351 (cytarabine and daunorubicin liposome) in Japanese patients with high-risk acute myeloid leukemia. 査読

Kensuke Usuki, Toshihiro Miyamoto, Takuji Yamauchi, Kiyoshi Ando, Yoshiaki Ogawa, Masahiro Onozawa, Takahiro Yamauchi, Hitoshi Kiyoi, Akira Yokota, Takayuki Ikezoe, Yuna Katsuoka, Satoru Takada, Nobuyuki Aotsuka, Yasuyoshi Morita, Takayuki Ishikawa, Noboru Asada, Shuichi Ota, Atsushi Dohi, Kensaku Morimoto, Shunji Imai, Umi Kishimoto, Koichi Akashi, Yasushi Miyazaki

International journal of hematology 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: NS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML. METHODOLOGY: This open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60-75 years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351. RESULTS: In the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100 units/m2 during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7 h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7-74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated. OUTCOMES: NS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML.

DOI： 10.1007/s12185-024-03733-z

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

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

Transfusion 2024年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1111/trf.17765

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

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

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

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

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.2169/internalmedicine.2799-23

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

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

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

記述言語：日本語掲載種別：研究論文（学術雑誌）

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

DOI： 10.11406/rinketsu.65.622

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Alpha-Pinene As a Novel Therapeutic Agent for T-Cell Tumors

Masaya Abe, Noboru Asada, Maiko Kimura, Chie Fukui, Daisuke Yamada, Ziyi Wang, Masayuki Miyake, Takeshi Takarada, Mitsuaki Ono, Michinori Aoe, Wataru Kitamura, Masayuki Matsuda, Takashi Moriyama, Akifumi Matsumura, Yoshinobu Maeda

Blood 142 ( Supplement 1 ) 1441 - 1441 2023年11月

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

T-cell acute leukemia and lymphoma have poor prognoses, necessitating the development of novel therapeutic agents. In this study, we investigated the antitumor activity of α-pinene, a monoterpene compound, against T-cell tumors. We evaluated the effects of α-pinene on cell growth inhibition in vitro using the murine T-cell tumor cell line EL-4 and the human-derived T-cell tumor cell line Molt-4. In addition, we assessed the effects of limonene, another monoterpene with reported tumor-suppressive effects, as a comparative agent.

Both α-pinene and limonene demonstrated concentration- and time-dependent inhibition of cell growth in both the EL-4 and Molt-4 cell lines (Figure 1). Moreover, α-pinene exhibited greater potency than limonene in inhibiting the growth of various hematologic malignancies. Importantly, α-pinene and limonene had minimal effects on the growth of normal murine spleen T cells. Further investigation of the mechanisms of action of α-pinene revealed its ability to induce apoptosis and cell cycle arrest in EL-4 and Molt-4 cells. Transcriptomic profiling of α-pinene-treated EL-4 cells using RNA-seq identified differentially expressed genes associated with cellular damage and mitochondrial dysfunction. Increased intracellular ROS levels and mitochondrial impairment were observed in the T-cell tumors treated with α-pinene. The activation of intrinsic apoptotic pathways involving EGR1, p53, BCL-2, and BAX was found to contribute to α-pinene-induced apoptosis in T-cell tumors. Moreover, α-pinene inhibited the NF-κB signaling pathway, resulting in the reduced nuclear translocation of NF-κB p65 and decreased total intracellular NF-κB p65 levels in EL-4 cells. Additionally, we discovered that α-pinene induced ferroptosis, a newly identified programmed cell death process, in EL-4 cells through lipid peroxidation and iron accumulation. Activation of the system x c−/GSH/GPX4 axis and upregulation of iron transporters, such as Slc39a8 and TfR1, were observed in α-pinene-induced ferroptosis. Treatment with the ferroptosis inhibitor Fer-1 partially reversed the tumor-inhibiting effect of α-pinene in EL-4 cells. Finally, we administrated α-pinene to mice subcutaneously injected with luciferase-expressing EL-4 to evaluate the efficacy of α-pinene in vivo. The tumor growth was significantly inhibited by α-pinene treatment (vehicle: 1055 ± 101 mm 3; α-pinene: 701 ± 82 mm 3, p &lt; 0.01, Figure 2) without adverse effects on body weight or behavior. Immunohistochemistry analyses revealed a significant increase of CD8 + T-cells (vehicle: 8.1 ± 2.7 cells / field of view; α-pinene: 43.1 ± 12.2 cells / field of view , p &lt; 0.05) and NK1.1 + cells (vehicle: 5.1 ± 1.0 cells / field of view ; α-pinene: 41.1 ± 9.8 cells / field of view , p &lt; 0.01) in the tumors, suggesting that α-pinene may have an indirect antitumor effect by recruiting immune cells into tumors.

Overall, our findings demonstrate the antitumor activity of α-pinene against T-cell tumors through the induction of apoptosis, cell cycle arrest, and ferroptosis. α-Pinene shows promise as a potential therapeutic agent for T-cell tumors and warrants further investigation for its clinical application.

DOI： 10.1182/blood-2023-181447

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CDK4/6 signaling attenuates the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer. 査読国際誌

Naofumi Hara, Eiki Ichihara, Hirohisa Kano, Chihiro Ando, Ayako Morita, Tatsuya Nishi, Sachi Okawa, Takamasa Nakasuka, Atsuko Hirabae, Masaya Abe, Noboru Asada, Kiichiro Ninomiya, Go Makimoto, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Translational lung cancer research 12 ( 10 ) 2098 - 2112 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and exon 21 L858R, are driver oncogenes of non-small cell lung cancer (NSCLC), with EGFR tyrosine kinase inhibitors (TKIs) being effective against EGFR-mutant NSCLC. However, the efficacy of EGFR-TKIs is transient and eventually leads to acquired resistance. Herein, we focused on the significance of cell cycle factors as a mechanism to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC before the emergence of acquired resistance. METHODS: Using several EGFR-mutant cell lines, we investigated the significance of cell cycle factors to attenuate the effect of EGFR-TKIs in EGFR-mutant NSCLC. RESULTS: In several EGFR-mutant cell lines, certain cancer cells continued to proliferate without EGFR signaling, and the cell cycle regulator retinoblastoma protein (RB) was not completely dephosphorylated. Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models. Furthermore, residual RB phosphorylation without EGFR signaling was maintained by extracellular signal-regulated kinase (ERK) signaling, and the ERK inhibition pathway showed further RB dephosphorylation. CONCLUSIONS: Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.

DOI： 10.21037/tlcr-23-99

PubMed

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