研究等業績 - その他 - 髙橋 直人
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Kuroki W.
British Journal of Haematology ( British Journal of Haematology ) 206 ( 6 ) 1615 - 1626 2025年
Multiple myeloma (MM) with chromosome 1q21 gain/amplification (1q+) has been reported to respond poorly to daratumumab. We aimed to explore the mechanism of daratumumab resistance in 1q+ MM. Our findings revealed significantly lower CD38 expression in patients with 1q+ MM than in those with 1q wild type (WT) MM. Next, we focused on the interleukin-6 receptor (IL6R) located in the 1q21 region because a previous report shows that interleukin-6 (IL-6) reduces CD38 expression via the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway activation in MM. Indeed, IL6R expression was significantly higher in 1q+ MM than in 1q WT MM. We verified that the 1q+ human myeloma cell lines (HMCLs) expressed higher IL6R levels than the 1q WT HMCLs. IL-6 treatment induced CD38 downregulation in both the 1q+ HMCLs and primary bone marrow (BM) samples but not in their 1q WT HMCLs and BM samples. IL-6 also resulted in the upregulation of phosphorylated STAT3 in 1q+ HMCLs but not in the 1q WT HMCLs. Furthermore, inhibition of the IL-6/JAK/STAT pathway by treatment with ruxolitinib or tocilizumab restored CD38 expression in the 1q+ HMCLs and BM samples. These findings elucidate the mechanisms underlying daratumumab resistance in 1q+ MM and provide insights for future therapeutic strategies.
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Fujishima Takashi, Kobayashi Takahiro, Kobayashi Isuzu, Kitadate Akihiro, Kameoka Yoshihiro, Takahashi Naoto
Internal Medicine ( 一般社団法人 日本内科学会 ) advpub ( 0 ) 3020 - 3026 2025年
<p>We herein present the case of a 73-year-old man with IgM multiple myeloma (IgM-MM) and t(11;14). The tumor cells showed a small lymphoplasmacytic morphology and dim expression of CD38 and CD138. The MYD 88<sup>L265P</sup> mutation was found to be negative. After plasma exchange, bortezomib and dexamethasone treatments were refractory. Subsequent daratumumab, lenalidomide, and dexamethasone therapy failed to respond despite the standard therapy for non-IgM MM. Subsequently, pomalidomide, cyclophosphamide, and dexamethasone therapies demonstrated a good response, and a stringent complete response was therefore achieved. This case highlights the need for different treatment strategies for IgM-MM compared with non-IgM-MM because the biological features of IgM-MM and non-IgM-MM are different. </p>
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Ikeda Sho, Kobayashi Takahiro, Kitadate Akihiro, Yamashita Takaya, Watanabe Atsushi, Fujishima Naohito, Yoshioka Tomoko, Kume Masaaki, Kameoka Yoshihiro, Kitabayashi Atsushi, Kuroki Jun, Takahashi Naoto
Internal Medicine ( 一般社団法人 日本内科学会 ) advpub ( 0 ) 1106 - 1114 2025年
<p><b>Objective </b>In the real-world clinical setting of transplant-eligible patients with multiple myeloma (MM), a certain proportion of patients switch from induction therapy to other regimens because of insufficient response or adverse events. However, the prognostic benefits of these changes remain unclear. This retrospective study investigated the impact of pre-transplant induction therapy switches on the prognosis. </p><p><b>Methods </b>We analyzed the treatment course, patient background, risk classification, and post-transplantation event-free survival (EFS) of 35 patients who achieved partial response (PR) or better with triplet therapy and underwent autologous stem cell transplantation (ASCT) at our institution between January 2017 and July 2023. </p><p><b>Results </b>Induction therapy included VRd therapy in 11 patients and switching therapy in 20 patients (7 due to intolerance and 13 due to insufficient treatment effects). Among the 13 patients who switched treatment due to insufficient treatment effects, 10 showed an improved response, leading to a trend towards a better EFS. Nevertheless, high-risk chromosomal abnormalities, particularly t(4;14), were associated with a significantly poorer EFS, regardless of the treatment received. </p><p><b>Conclusion </b>Even with a response-guided induction treatment switch, maintaining long-term remission after ASCT in high-risk patients remains challenging. A careful risk assessment using fluorescence <i>in situ</i> hybridization or a genomic analysis may improve the prognosis of patients with MM in the future. </p>
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Dismal Outcome of EBV-Positive Nodal T/NK-Cell Lymphoma: A Multicenter Retrospective Study
Ichikawa S.
Clinical Lymphoma Myeloma and Leukemia ( Clinical Lymphoma Myeloma and Leukemia ) 26 ( 3 ) e376 - e384 2025年
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Takahashi Y.
Cancer Science ( Cancer Science ) 117 ( 2 ) 407 - 417 2025年
Histone deacetylase inhibitors, such as vorinostat, show promise as treatment for T-cell lymphomas including cutaneous T-cell lymphoma. However, the emergence of resistance ultimately leads to disease relapse. To elucidate the underlying mechanisms and identify potential countermeasures, we established histone deacetylase inhibitor-resistant cutaneous T-cell lymphoma cell lines by prolonged exposure to vorinostat. We then comprehensively profiled gene expression in these cell lines by using microarrays and in silico analytical approaches. We identified 83 genes that were significantly upregulated in the resistant cell lines. Subsequent enrichment analyses using ChIP-Atlas and Enrichr revealed that these genes are regulated by particular transcription factors, including RELA/p65, GATA3, and EP300, of which RELA (p65) exhibited the highest composite score. RELA is a key subunit of the NF-κB complex, which is involved in inflammation, cell survival, and proliferation. We demonstrated marked upregulation and nuclear enrichment of p65 and pronounced NF-κB pathway activation in the histone deacetylase inhibitor-resistant cells. The mechanism involved acetylation-mediated inhibition of p65 ubiquitination, which resulted in protein stabilization and enhanced transcriptional activity. Histone deacetylase inhibitor-resistant cell lines displayed heightened sensitivity to inhibition of the NF-κB pathway by bortezomib and dimethyl fumarate. These findings implicate aberrant NF-κB activation as a central driver of the emergence of histone deacetylase inhibitor resistance in cutaneous T-cell lymphoma. Ultimately, our results provide a strong rationale for exploring NF-κB inhibition as a therapeutic strategy to restore or enhance the efficacy of histone deacetylase inhibitor-based therapies, overcome histone deacetylase inhibitor resistance, and improve outcomes for patients with cutaneous T-cell lymphoma.
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医師と薬剤師との連携によるTDMを用いたCMLの外来治療【JST機械翻訳】|||
ABUMIYA Maiko, TAKAHASHI Naoto, MIURA Masatomo
日本血液学会学術集会抄録(Web) 87th 2025年
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慢性骨髄性白血病患者におけるアシミニブの薬物動態【JST機械翻訳】|||
TAKAHASHI Naoto, MIURA Masatomo
日本血液学会学術集会抄録(Web) 87th 2025年
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LINC00887はHDAC3との結合を介して多発性骨髄腫細胞の薬剤耐性を誘導する
長田 直希, 松岡 紗恵, 池田 翔, 高橋 直人, 安井 寛, 古川 雄祐, 菊池 次郎, 仲宗根 秀樹
日本血液学会学術集会 ( (一社)日本血液学会 ) 86回 O1 - 1 2024年10月
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SETD7はt(11;14)陽性多発性骨髄腫に対する新たな治療標的分子となる
松岡 紗恵, 長田 直希, 池田 翔, 高橋 直人, 安井 寛, 古川 雄祐, 菊池 次郎, 仲宗根 秀樹
日本血液学会学術集会 ( (一社)日本血液学会 ) 86回 O1 - 4 2024年10月
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Imamura K.
BMJ Open ( BMJ Open ) 14 ( 10 ) 2024年10月
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膜性腎症を合併し多彩な自己抗体陽性を認めた全身性強皮症
橋本 眞子, 阿部 史人, 齋藤 綾乃, 坂口 舞, 金澤 達郎, 齋藤 雅也, 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 ) 34回 84 - 84 2024年10月
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LINC00887はHDAC3との結合を介して多発性骨髄腫細胞の薬剤耐性を誘導する
長田 直希, 松岡 紗恵, 池田 翔, 高橋 直人, 安井 寛, 古川 雄祐, 菊池 次郎, 仲宗根 秀樹
日本血液学会学術集会 ( (一社)日本血液学会 ) 86回 O1 - 1 2024年10月
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SETD7はt(11;14)陽性多発性骨髄腫に対する新たな治療標的分子となる
松岡 紗恵, 長田 直希, 池田 翔, 高橋 直人, 安井 寛, 古川 雄祐, 菊池 次郎, 仲宗根 秀樹
日本血液学会学術集会 ( (一社)日本血液学会 ) 86回 O1 - 4 2024年10月
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TFR後の晩期再発は免疫の調節不全を背景にしている
藤岡 優樹, 植木 重治, 高橋 直人
日本血液学会学術集会 ( (一社)日本血液学会 ) 86回 O1 - 5 2024年10月
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小児白血病におけるチロシンキナーゼ阻害剤の薬物血中濃度モニタリング
田村 真一, 内藤 優樹, 友安 千紘, 矢野 未央, 三浦 昌朋, 高橋 直人, 石田 宏之
日本血液学会学術集会 ( (一社)日本血液学会 ) 86回 P1 - 6 2024年10月
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Minami Y.
International Journal of Hematology ( International Journal of Hematology ) 120 ( 3 ) 305 - 313 2024年09月
Asciminib is a first-in-class BCR::ABL1 inhibitor that Specifically Targets the ABL1 Myristoyl Pocket (STAMP). It is approved worldwide and in Japan for chronic myeloid leukemia in chronic phase (CML-CP) with resistance or intolerance to previous tyrosine kinase inhibitor (TKI) therapy. In the Phase 3 ASCEMBL study, patients with CML-CP who received ≥ 2 prior ATP-competitive TKIs were randomized (2:1) to asciminib 40 mg twice-daily or bosutinib 500 mg once-daily. Here, we report the 96-week results of the subgroup analysis of Japanese patients (asciminib, n = 13; bosutinib, n = 3) in the ASCEMBL study. The MMR rate at Week 96 was 46.2% in asciminib-treated patients, increasing from Weeks 24 and 48. Patients who achieved MMR at Week 24 remained in MMR up to the Week 96 cutoff. While a high proportion of patients treated with asciminib remained on treatment at cutoff, none randomized to bosutinib were on treatment at Week 96. Despite the longer duration of exposure to asciminib, its safety and tolerability continued to be favorable with no new or worsening safety findings. Overall, the efficacy and safety outcomes in the Japanese subgroup were comparable with the ASCEMBL global study population, which supports the use of asciminib in Japanese patients with previously treated CML-CP.
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ネフローゼ症候群を呈する巣状分節性糸球体硬化症を併発した糖原病Ia型の一例
坂口 舞, 齋藤 雅也, 橋本 眞子, 齋藤 綾乃, 阿部 史人, 野口 篤子, 金澤 達郎, 熊谷 拓哉, 高橋 直人
日本腎臓学会誌 ( (一社)日本腎臓学会 ) 66 ( 6-E ) 953 - 953 2024年09月
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Takahashi N.
Japanese Journal of Clinical Oncology ( Japanese Journal of Clinical Oncology ) 54 ( 8 ) 930 - 938 2024年08月
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保存期CKDにおける赤血球分布幅とESA初期治療抵抗性の関連
金澤 達郎, 齋藤 雅也, 齋藤 綾乃, 阿部 史人, 橋本 眞子, 高橋 直人
日本腎臓学会誌 ( (一社)日本腎臓学会 ) 66 ( 4 ) 630 - 630 2024年06月