研究等業績 - その他 - 髙橋　直人

Serial evaluation of the pharmacokinetics of ponatinib in patients with CML and Ph + ALL

Kawano N.

International Journal of Hematology ( International Journal of Hematology )  114 ( 4 ) 509 - 516   2021年10月

Although tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), intolerance and resistance to TKIs have been serious problems. Due to a lack of research, the importance of the pharmacokinetics (PK) of TKIs is currently unclear. We examined the PK of the third-generation TKI ponatinib to monitor side effects and efficacy during treatments for one patient with CML-chronic phase (CP-CML) and two who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), one for CML-blastic crisis (BC-CML) and one for Ph + ALL. The patient with CP-CML was intolerant to multiple TKIs (dasatinib, nilotinib, imatinib, and bosutinib) and thus was switched to ponatinib (15 mg/day). The patients who received allo-HSCT for BC-CML and Ph + ALL received ponatinib (15 mg/day) as maintenance therapy. Notably, serial evaluation of the PK of ponatinib showed that the median trough values (ng/ml) were 17.2 (12.2–34.5), 33.1 (21.2–40.3) and 27.7 (13.6–29.9) in patients 1, 2, and 3, respectively. These values were around the target concentration (23 ng/ml). All patients are maintaining complete remission without side effects. In conclusion, serial evaluation of PK of ponatinib may yield meaningful information about its safety and efficacy.

DOI PubMed

Multiple myeloma with t(11;14)-associated immature phenotype has lower CD38 expression and higher BCL2 dependence

Kitadate A.

Cancer Science ( Cancer Science )  112 ( 9 ) 3645 - 3654   2021年09月

DOI

IGL/MYC再構成を有し、かつCD138の発現を伴うB細胞性リンパ芽球性白血病(Precursor B-lymphoblastic leukemia with IGL/MYC rearrangement and CD138 expression)

倉橋 保奈実, 山下 鷹也, 北舘 明宏, 道下 吉広, 川端 良成, 北林 淳, 松本 奈津美, 齋藤 雅也, 小林 敬宏, 藤島 直仁, 亀岡 吉弘, 高橋 直人

日本血液学会学術集会 ( (一社)日本血液学会 )  83回   OS3 - 3   2021年09月

MYCの転座相手が非IgHと考えられるdouble hit lymphoma

安田 拓人, 亀岡 吉弘, 橋本 眞子, 藤岡 優樹, 斎藤 雅也, 鵜生川 久美, 高橋 直人

臨床血液 ( (一社)日本血液学会-東京事務局 )  62 ( 9 ) 1417 - 1418   2021年09月

慢性リンパ性白血病に合併したmonoclonal immunotactoid glomerulopathy

齋藤 綾乃, 亀岡 吉弘, 小松田 敦, 鵜生川 久美, 今泉 ちひろ, 齋藤 雅也, 阿部 史人, 加賀 一, 奈良 瑞穂, 大谷 浩, 涌井 秀樹, 高橋 直人

日本腎臓学会誌 ( (一社)日本腎臓学会 )  63 ( 6-E ) 685 - 685   2021年09月

原発性マクログロブリン血症の経過観察中にMYD88陽性のびまん性大細胞型B細胞リンパ腫を発症した1例

高橋 照子, 倉橋 保奈実, 山下 鷹也, 齋藤 雅也, 小林 敬宏, 藤島 直人, 亀岡 吉弘, 高橋 直人

臨床血液 ( (一社)日本血液学会-東京事務局 )  62 ( 9 ) 1418 - 1418   2021年09月

皮膚T細胞性リンパ腫においてmiR-26aの抑制はIL-22の過剰発現を介して転移に寄与する

松田 悠佳, 池田 翔, 北舘 明宏, 高橋 祐斗, 阿部 滉, 阿部 史人, 高橋 直人, 涌井 秀樹, 田川 博之

日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [J14 - 5]   2021年09月

高腫瘍量濾胞性リンパ腫における治療前PET/CTを用いたTLGの予後予測因子としての有用性(Prognostic value of baseline total lesion glycolysis in high-tumor-burden follicular lymphoma)

黒木 航, 北舘 明宏, 山下 鷹也, 小林 敬宏, 池田 翔, 奈良 美保, 鵜生川 久美, 藤島 直仁, 吉岡 智子, 石山 公一, 亀岡 吉弘, 高橋 直人

日本血液学会学術集会 ( (一社)日本血液学会 )  83回   OS1 - 1   2021年09月

再発難治性ホジキンリンパ腫に対する免疫チェックポイント阻害薬治療の後方視的解析(Retrospective analysis of ICI therapy for relapsed or refractory classical Hodgkin's lymphoma: THF26)

前田 峻大, 小宅 達郎, 久保 恒明, 高畑 武功, 玉井 佳子, 亀岡 吉弘, 高橋 直人, 宮入 泰郎, 村井 一範, 下瀬川 健二, 吉田 こず恵, 菅原 健, 猪倉 恭子, 福原 規子, 張替 秀郎, 佐藤 諒, 石澤 賢一, 田嶋 克史, 齊藤 宗一, 深津 真彦, 池添 隆之, 角田 三郎, 神林 裕行, 三田 正行, 森 甚一, 古和田 周吾, 伊藤 薫樹

日本血液学会学術集会 ( (一社)日本血液学会 )  83回   OS2 - 2   2021年09月

成人初期前駆T細胞性急性リンパ性白血病の臨床的特徴と予後に関する後方視的研究 THF-24(Clinical features and prognosis of adult early T-cell precursor acute lymphoblastic leukemia: THF-24)

古川 瑛次郎, 大西 康, 遠宮 靖雄, 原崎 頼子, 深津 真彦, 池添 隆之, 亀岡 吉弘, 高橋 直人, 八田 俊介, 勝岡 優奈, 濱田 宏之, 村井 一範, 小宅 達郎, 伊藤 薫樹, 甲斐 龍幸, 助川 真純, 中嶌 真治, 柳谷 稜, 石澤 賢一, 山口 公平, 高橋 太郎, 張替 秀郎

日本血液学会学術集会 ( (一社)日本血液学会 )  83回   OS3 - 5   2021年09月

Il-6 generated from human hematopoietic stem and progenitor cells through tlr4 signaling promotes emergency granulopoiesis by regulating transcription factor expression

Sasaki Y.

Journal of Immunology ( Journal of Immunology )  207 ( 4 ) 1078 - 1086   2021年08月

Emergency granulopoiesis, also known as demand-adapted granulopoiesis, is defined as the response of an organism to systemic bacterial infections, and it results in neutrophil mobilization from reservoir pools and increased myelopoiesis in the bone marrow. Indirect and direct initiating mechanisms of emergency granulopoiesis have been hypothesized. However, the detailed mechanism of hyperactive myelopoiesis in the bone marrow, which leads to granulocyte left shift, remains unknown. In this study, we report that TLR4 is expressed on granulo-monocytic progenitors, as well as mobilized human peripheral blood CD34+ cells, which account for 0.2% of monocytes in peripheral blood, and ∼ 10% in bone marrow. LPS, a component of Gram-negative bacteria that results in a systemic bacterial infection, induces the differentiation of peripheral blood CD34+ cells into myelocytes and monocytes in vitro via the TLR4 signaling pathway. Moreover, CD34+ cells directly responded to LPS stimulation by activating the MAPK and NF-κB signaling pathways, and they produced IL-6 that promotes emergency granulopoiesis by phosphorylating C/EBPα and C/EBPβ, and this effect was suppressed by the action of an IL-6 receptor inhibitor. This work supports the finding that TLR is expressed on human hematopoietic stem and progenitor cells, and it provides evidence that human hematopoietic stem and progenitor cells can directly sense pathogens and produce cytokines exerting autocrine and/or paracrine effects, thereby promoting differentiation.

DOI PubMed

血液形態診断のためのケースカンファレンス Cryptic translocationを認めたPML-RARA陽性微細顆粒型急性前骨髄球性白血病

菊地 優子, 山下 鷹也, 小林 敬宏, 永沼 綾子, 齊藤 由紀子, 安保 綾奈, 荒井 杏子, 富谷 陽子, 高橋 直人, 植木 重治

日本検査血液学会雑誌 ( (一社)日本検査血液学会 )  22 ( 2 ) 263 - 269   2021年07月

症例は50歳代男性。職場の健診にて白血球増多を指摘され当院紹介となった。受診の2日前より発熱、頭痛あり、また最近誘因無く四肢に紫斑が出現することを自覚していた。受診時の血液検査所見として、白血球著増、貧血、血小板減少、線溶亢進型播種性血管内凝固症候群を認めた。末梢血液像は、核網繊細で核形不整が顕著な単球様細胞で占められており、僅かにアズール顆粒が豊富な細胞やファゴット細胞を認めた。骨髄像は末梢血と同様の異常細胞で占められており、細胞表面マーカーでは、CD2、CD13、CD33、CD117、MPOが陽性、CD34、CD56、HLA-DRが陰性であった。染色体検査は正常核型であったが、遺伝子検査ではPML-RARA融合遺伝子を認めたことから、cryptic translocationを認めたPML-RARA陽性微細顆粒型急性前骨髄球性白血病の診断に至った。本症例のように線溶亢進型播種性血管内凝固症候群と白血病細胞の増多を認めるが、典型的な急性前骨髄球性白血病細胞をほとんど認めない場合は、微細顆粒型急性前骨髄球性白血病を鑑別に挙げ、全トランス型レチノイン酸による治療を遅滞なく行うことが重要である。(著者抄録)

抗がん剤起因性の肝類洞閉塞症候群に対し、デフィブロチドが著効したB細胞性リンパ腫

倉橋 保奈実, 山下 鷹也, 齋藤 雅也, 藤島 直仁, 亀岡 吉弘, 高橋 直人

臨床血液 ( (一社)日本血液学会-東京事務局 )  62 ( 4 ) 323 - 323   2021年04月

Successful Pregnancies in a Patient with Childhood-onset Steroid-dependent Nephrotic Syndrome during Rituximab Maintenance Therapy.

Mizuho Nara, Hajime Kaga, Masaya Saito, Fumito Abe, Ayano Saito, Chihiro Imaizumi, Atsushi Komatsuda, Hideki Wakui, Naoto Takahashi

Internal medicine (Tokyo, Japan) ( 一般社団法人 日本内科学会 )    2021年03月

There are an increasing number of reports on the safe use of rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, in pregnant women with hematological malignancies or refractory autoimmune diseases. In 2014, the use of RTX for patients with complicated steroid-dependent nephrotic syndrome (SDNS) was approved in Japan. We herein report a woman with childhood-onset complicated SDNS due to focal and segmental glomerulosclerosis, who had two successful pregnancies while receiving RTX maintenance therapy. No adverse complications were observed during the pregnancies, and she delivered healthy newborns. This case suggested that RTX may be used safely in pregnant women complicated with SDNS.

DOI PubMed

Tocilizumab治療中に健常児を得た妊娠中期発症成人Still病

今泉 ちひろ, 阿部 史人, 加賀 一, 齋藤 綾乃, 齋藤 雅也, 奈良 瑞穂, 高橋 直人

日本リウマチ学会北海道・東北支部学術集会抄録集 ( (一社)日本リウマチ学会-北海道・東北支部 )  30回   54 - 54   2021年02月

Correlation between increased immune checkpoint molecule expression and refractoriness to blinatumomab evaluated by longitudinal T cell analysis

Kobayashi T.

International Journal of Hematology ( International Journal of Hematology )    2021年

国内共著

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Long-term treatment-free remission in patients with chronic myeloid leukemia after second-line nilotinib: ENESTop 5-year update

Hughes T.P.

Leukemia ( Leukemia )  35 ( 6 ) 1631 - 1642   2021年

The ENESTop study evaluated treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in chronic phase who had received ≥3 years of tyrosine kinase inhibitor therapy and achieved sustained deep molecular response only after switching from imatinib to nilotinib. After 1-year nilotinib consolidation, 126 patients attempted TFR. At 48 weeks (primary analysis), 57.9% (73/126) were in TFR. In the present analysis at 5 years, 42.9% (54/126) were in TFR. Since the 48-week analysis, among patients who left the TFR phase, 58% (11/19) did not have a loss of molecular response and discontinued for other reasons. Of the 59 patients who reinitiated nilotinib upon loss of major molecular response (MMR) or confirmed loss of MR4, 98.3% regained MMR, 94.9% regained MR4, and 93.2% regained MR4.5. Overall adverse event rates decreased over the 5 years of TFR. In patients reinitiating nilotinib, there was a cumulative increase in cardiovascular events with longer nilotinib exposure. No disease progression or CML-related deaths were reported. Overall, these results confirm the durability and safety of TFR for patients receiving second-line nilotinib. Cardiovascular risk should be carefully managed, particularly when reinitiating treatment after TFR.

DOI PubMed

Efficacy and safety of ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a case series from a single institute

Kidoguchi K.

International Journal of Hematology ( International Journal of Hematology )    2021年

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長期間完全奏効を維持している高齢男性乳腺原発びまん性大細胞型B細胞リンパ腫

野口 晋佐, 斎藤 宏文, 佐々木 英人, 鎌田 収一, 榎本 克彦, 高橋 直人

臨床血液 ( 一般社団法人 日本血液学会 )  62 ( 5 ) 341 - 345   2021年

<p>乳腺原発びまん性大細胞型B細胞リンパ腫（DLBCL）は稀な非ホジキンリンパ腫であり，殆どは女性に発症する。今回，自己免疫疾患や女性ホルモンの関与がない高齢男性に発症し，長期寛解が得られている胚中心B細胞型乳腺原発DLBCLを経験したので報告する。症例は65歳，男性。徐々に増大する右胸のしこりと右腋窩リンパ節腫脹を主訴として近医を受診した。右乳がんおよび右腋窩リンパ節転移疑いで針生検を行い悪性リンパ腫の診断となった。組織型確定に至らなかったため右乳腺腫瘤摘出術を施行され，乳腺原発DLBCL，胚中心B細胞型（Hans分類），臨床病期IIAの診断となり治療目的で当科紹介となった。R-CHOP療法6コースに加えCNS浸潤予防のため髄腔内注射を併用した。5年間完全寛解を維持している。稀ではあるが男性にも乳腺リンパ腫が生じ得るため組織学的早期診断とCNS再発予防への対応が重要である。</p>

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VEGF-VEGFR2 inhibitor-associated hyaline occlusive glomerular microangiopathy: a Japanese single-center experience

Ozawa M.

Clinical and Experimental Nephrology ( Clinical and Experimental Nephrology )  25 ( 11 ) 1193 - 1202   2021年

Background: Inhibitors of vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling, such as bevacizumab (Bmab), are used for the treatment of various advanced cancers. However, these inhibitors induce renal thrombotic microangiopathy (TMA). Recently, two European cohort studies showed a distinctive histopathological pseudothrombotic pattern different from TMA in Bmab-treated patients. Methods: We analyzed 9 renal biopsies from proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors in our Japanese cohort. Clinical and laboratory features were also assessed in these patients. Results: All 9 patients had moderate to heavy proteinuria with normal or slightly elevated serum creatinine levels. On light microscopy, a patchy pattern of hemispherical/spherical lesions along glomerular capillary walls was a characteristic finding. On immunofluorescence microscopy, staining for immunoglobulins (IgM dominant) at varying intensities was observed mainly along glomerular capillary walls. Especially, hemispherical/spherical positive staining for immunoglobulins was a characteristic pattern. Immunohistochemical studies showed positive staining for immunoglobulins and negative staining for CD61-positive platelets in capillary hemispherical/spherical lesions and positive VEGF staining in podocytes. On electron microscopy, variably electron-dense material in dilated glomerular capillaries and partial effacement of podocyte foot processes were observed. After the withdrawal of VEGF-VEGFR2 inhibitors, proteinuria improved without any specific treatment in 8 patients. Conclusions: Histopathological findings in our patients treated with VEGF-VEGFR2 inhibitors were consistent with those observed in the recently described new form of Bmab-associated hyaline occlusive glomerular microangiopathy. This form should be considered in proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors. Discontinuing VEGF-VEGFR2 inhibitors may lead to improvement of glomerular microangiopathy induced by these drugs.

DOI PubMed