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Maiko Abumiya, Ayano Saito, Yuki Fujioka, Masatomo Miura, Naoto Takahashi
International journal of hematology ( International Journal of Hematology ) 2025年02月
研究論文（学術雑誌）
Bosutinib is known to increase serum creatinine levels, and its mechanism of action is believed to involve a decrease in tubular creatinine excretion due to inhibition of tubular transporters and organic cation transporter 2. This study aimed to determine whether discontinuation of bosutinib could reverse bosutinib-induced elevation of serum creatinine levels. Serum creatinine levels were compared immediately before and after bosutinib administration and after bosutinib discontinuation in 11 patients with chronic myeloid leukemia. The median serum creatinine concentration significantly increased from 0.66 mg/dL before bosutinib to 0.76 mg/dL after bosutinib (P = 0.003) and decreased from 0.79 mg/dL before discontinuation of bosutinib to 0.66 mg/dL after discontinuation of bosutinib at 3 months (P = 0.005). This study revealed that bosutinib-induced elevation of serum creatinine, which was more pronounced in patients with the SLC22A2 808G/G genotype, does not indicate chronic kidney disease, but rather is simply a laboratory abnormality. If bosutinib-induced chronic kidney disease is suspected, renal function should be assessed by urinalysis and cystatin C levels to differentiate from simple elevation of serum creatinine.
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Toshinori Ezawa, Riku Otomo, Yumi Kariya, Kyoko Nozawa, Sonosuke Kyoya, Chikako Furutani, Keiichi Noguchi, Masafumi Yohda, Masafumi Odaka, Hirotoshi Matsumura, Ayano Saito, Masaya Saito, Fumito Abe, Yuki Fujioka, Akihiro Kitadate, Hideki Wakui, Naoto Takahashi
FASEB journal : official publication of the Federation of American Societies for Experimental Biology ( FASEB Journal ) 39 ( 1 ) e70296 2025年01月
研究論文（学術雑誌）
Various tubular diseases in patients with multiple myeloma (MM) are caused by monoclonal immunoglobulin light chains (LCs). However, the physicochemical characteristics of the disease-causing LCs contributing to the onset of MM-associated tubular diseases remain unclear. We herein report a rare case of MM-associated combined tubulopathies: non-crystalline light chain proximal tubulopathy (LCPT) and crystalline light chain cast nephropathy (LCCN). The patient's urinary κ-LC (Bence-Jones proteins, BJP-κ PT-CN) was detected through immunofixation. Renal biopsy revealed cytoplasmic vacuoles in swollen proximal tubular cells and distal tubular casts. Immunohistochemistry showed proximal tubular reabsorption granules and distal tubular casts positively stained with an anti-κ-LC antibody. Electron microscopy identified vacuolation and an increased number of lysosomes in proximal tubular epithelial cells without crystalline structures. Distal tubular casts comprised numerous crystals with both rod-shaped and needle-like configurations and tube-shaped materials. To elucidate the molecular mechanisms underlying tubular toxicity, we performed the following physicochemical analyses of BJP-κ PT-CN: N-terminal amino acid sequencing, cDNA cloning, size-exclusion chromatography, thermal shift assays, and X-ray crystallography. The variable segment of BJP-κ PT-CN was derived from the IGKV1-39 gene. The characteristic features of BJP-κ PT-CN were a positively charged surface patch, concentration-dependent monomer-dimer equilibrium, and the R61G mutation. This is the first biochemical and structural characterization of disease-causing BJPs in MM-associated LCPT and crystalline LCCN. The results obtained suggest that these characteristic features enhance protein binding to negatively charged sites on brush-border membranes in proximal tubules and promote the formation of organized casts in distal tubular lumens.
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Eline Zwiers, Daphne Montizaan, Annemarie Kip, Kelsy Waaijenberg, Paul S Fichtinger, Sameer K Mathur, Yuki Fujioka, Shigeharu Ueki, Helmuth van Es, Renato G S Chirivi, Eric Meldrum, Maarten van der Linden
Frontiers in immunology ( Frontiers in Immunology ) 16 1533407 - 1533407 2025年
研究論文（学術雑誌）
Eosinophils are a subset of granulocytes that protect the host against fungal and parasitic infection through secretion of their granular contents. In response to specific stimuli, eosinophils also undergo a type of lytic cell death, referred to as eosinophil extracellular trap (EET)-associated cell death (EETosis), where histone citrullination facilitates chromatin decondensation, cell rupture and release of pro-inflammatory, decondensed chromatin into the extracellular environment as EETs. In this study, we show the abundant presence of eosinophils and citrullinated histones in nasal polyp tissue of patients with eosinophilic chronic rhinosinusitis (ECRS). Using live imaging microscopy on purified human eosinophils, we demonstrate that physiologically relevant stimuli induce release of citrullinated EETs and the marker of eosinophil activation galectin-10. While the kinetics of release of EETs and galectin-10 are similar, inhibitors of citrullination block EETosis in a dose dependent manner but fail to inhibit galectin-10 release. The importance of citrullination is further exemplified with CIT-013, a monoclonal antibody specific for citrullinated histones H2A and H4. CIT-013 potently inhibits release of EETs (half-maximal inhibitory concentration of 2.5 nM) without inhibiting other eosinophil functions such as degranulation, adhesion, superoxide production and induction of chemokine expression. Together, this study provides new insights into the requirement of protein arginine deiminase 4 (PAD4) for EETosis, differentiates requirements of EETosis from galectin-10 release, and identifies a novel therapeutic approach for EETosis inhibition by targeting citrullinated histones in eosinophil-driven diseases such as ECRS.
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Comparison of Transient and Persistent Adverse Events After COVID-19 Vaccination: A Retrospective Analysis.
Haruka Hikichi, Yuki Fujioka, Akiko Saga, Ken Watanabe, Ryo Hasegawa, Yuki Moritoki, Shigeharu Ueki
Cureus 16 ( 6 ) e63410 2024年06月
研究論文（学術雑誌）
OBJECTIVE: Most reported adverse events following COVID-19 vaccination have been transient. However, persistent adverse events may occur with some frequency. This study aimed to analyze patient background characteristics and trends, with a focus on whether adverse events following COVID-19 vaccination were transient or persistent. METHODS: A retrospective study was performed at a single institution in Japan. PATIENTS: The study cohort included 47 patients who presented with symptoms after COVID-19 vaccination between May 2021 and September 2023. The patients were classified into two groups based on the duration of symptoms: transient group, less than four weeks; persistent group, greater than or equal to four weeks. Data on age, sex, body mass index, smoking history, underlying conditions, type of COVID-19 vaccination, number of doses, onset, symptoms, and treatments were collected retrospectively. RESULTS: The median age was 51.0 years and 74.5% were females, with a particularly high proportion of women in their 40s. The use of the bivalent omicron-containing booster vaccine (BA.1) was significantly more common in the persistent group than in the transient group (p = 0.0267). Onset in the transient group was more common after the first vaccination, whereas onset in the persistent group was more common after the second and subsequent vaccinations (p = 0.003). Regarding symptoms, pain was more frequent in the persistent group than in the transient group (60% vs. 13.6%; p = 0.001). CONCLUSIONS: This study investigated the presence of persistent symptoms, especially pain, after COVID-19 vaccination. Persistent symptoms were frequently reported after the second vaccination. It should be noted that the study does not negate the usefulness of COVID-19 vaccines.
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Ponatinib Improved the Prognosis of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Japanese Single-Center Cohort Study.
Nagi Tozawa, Takaya Yamashita, Miho Nara, Yuki Fujioka, Sho Ikeda, Takahiro Kobayashi, Isuzu Kobayashi, Akihiro Kitadate, Yoshihiro Kameoka, Naoto Takahashi
Cureus 15 ( 12 ) e50416 2023年12月
研究論文（学術雑誌）
Introduction The overall survival (OS) of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the combination of tyrosine kinase inhibitor (TKI) with intensive chemotherapy. In recent years, there has been increased interest in the possibility of long-term survival without allogeneic hematopoietic stem cell transplantation (HSCT) or maintenance therapy. The aim of this study was to determine the effectiveness of treatment and the resultant outcomes in Ph+ALL patients using real-world data. Methods We performed a single-center retrospective analysis utilizing Akita University Hospital data (Akita, Japan) from November 2000 to June 2023 to evaluate the outcomes of TKI with intensive chemotherapy for Ph+ALL. Results Twenty-three patients with Ph+ALL were treated with intensive chemotherapy combined with TKI, including six imatinib, four dasatinib, and 13 ponatinib. The median patient age was 53 years (range; 28-67). Eighteen patients (78%) achieved complete molecular remission (CMR) within three months. HSCT was performed in 16 patients (70%), all of whom did not receive post-transplant TKI maintenance therapy. Six of the seven patients who did not undergo HSCT received maintenance therapy with ponatinib after intensive chemotherapy. The three-year OS was 81%. Ponatinib treatment resulted in a much higher OS rate than imatinib/dasatinib (100% vs. 60%; P=0.011). CMR within three months was identified as a prognostic factor for molecular relapse-free survival (hazard ratio (HR)=0.22; P=0.027). CD20 positivity was identified as a risk factor for hematological relapse (HR=5.2, P=0.032). Conclusion Even in a single-center cohort study, ponatinib, as a combination TKI with intensive chemotherapy or maintenance therapy, may improve the prognosis of Ph+ALL. Patients with CMR within three months might not necessarily need to receive HSCT, but a subsequent treatment-free status could have been achieved only by HSCT. Furthermore, CD20 positivity may be a useful biomarker for future treatment decisions in patients with Ph+ALL.
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症例からひもとく疾患 慢性骨髄性白血病
藤岡 優樹, 永沼 綾子, 齊藤 由紀子, 植木 重治, 髙橋 直人
検査と技術 ( 株式会社医学書院 ) 53 ( 4 ) 446 - 452 2025年04月
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急速に進行した線溶亢進型DICを伴うAMLの一例
荒井 杏子, 藤岡 優樹, 菊地 優子, 永沼 綾子, 齊藤 由紀子, 菅原 直央, 高橋 智映, 植木 重治
日臨技北日本支部医学検査学会抄録集 ( 日臨技北日本支部医学検査学会 ) 12回 103 - 103 2024年12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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好酸球ETosisにおける細胞構造の経時的変化
小玉 早穂子, 藤岡 優樹, 守時 由起, 長谷川 諒, 植木 重治
日本臨床検査医学会誌 ( (一社)日本臨床検査医学会 ) 72 ( 補冊 ) 233 - 233 2024年10月
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慢性骨髄性白血病における無治療寛解バイオマーカーとしての制御性T細胞の表現型に関する検討
藤岡 優樹, 菅原 直央, 山本 梨絵, 高橋 智映, 守時 由起, 植木 重治
日本臨床検査医学会誌 ( (一社)日本臨床検査医学会 ) 72 ( 補冊 ) 160 - 160 2024年10月
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Galectin-10の測定に関する基礎的検討
藤岡優樹, 山本梨絵, 達子瑠美, 富谷陽子, 守時由起, 植木重治
第70回日本臨床検査医学会学術集会 2023年12月 - 2023年12月
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Mechanism of Late Recurrences of Chronic Myeloid Leukemia after Discontinuation of TKI Therapy: BCR::ABL1Ins35bp Loss-of-Function Splicing Mutation and Regulatory T cells
Yuki Fujioka, Junichiro Yuda, Naoto Takahashi
65th ASH Annual Meeting & Exposition 2023年12月 - 2023年12月
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RCPC1（意識消失のために救急車にて来院した20歳代女性）
常川勝彦, 森本麻衣, 藤岡優樹, 松本剛 [招待有り]
第70回日本臨床検査医学会学術集会 2023年12月 - 2023年12月
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Kinetics of Treg after TKI discontinuation as a TFR biomarker
Yuki Fujioka, Takaaki Ono, Hiroyoshi Nishikawa, Shigeki Ohtake, Yoshiko Atsuta, Yosuke Minami, Yoshinori Iriyama, Hitoshi Kiyoi, Yasushi Miyazaki, Itaru Matsumura, Naoto Takahashi
第85回日本血液学会 2023年10月 - 2023年10月
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Transient Elevation of Regulatory T cells as a predictive marker of successful TFR after Bostinib Discontinuation
Yuki Fujioka, Takaaki Ono, Naoto Takahashi
24th Annual John Goldman Conference on Chronic Myeloid Leukemia: Biology and Therapy 2023年10月 - 2023年10月