研究等業績 - 原著論文 - 髙橋 直人
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Ezawa T.
FASEB Journal ( 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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Abumiya M.
International Journal of Hematology ( International Journal of Hematology ) 2025年
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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Ureshino H.
International Journal of Hematology ( International Journal of Hematology ) 120 ( 4 ) 492 - 500 2024年10月
研究論文（学術雑誌）
Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.
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Matsumura I.
Blood Advances ( Blood Advances ) 8 ( 20 ) 5237 - 5247 2024年10月
研究論文（学術雑誌）
Treatment-free remission (TFR) is a new therapeutic goal for chronic myeloid leukemia in chronic phase (CML-CP). Deep molecular response (DMR) is a prerequite condition for TFR. The Japan Adult Leukemia Study Group (JALSG) conducted a multicentral prospective randomized phase 3 CML212 study for de novo CML-CP to compare the cumulative achievement of MR4.5 (international scale [IS] BCR::ABL1≤0.0032%) by 18 months between nilotinib and dasatinib as a primary endpoint. A total of 454 patients were randomly assigned to the nilotinib 300 mg, bid arm or dasatinib 100 mg, qd arm (both, n=227). BCR::ABL1 mRNA levels were monitored every three months. Study treatment was stopped if the patients were judged as failure by the European LekemiaNet (ELN) 2009 criteria or showed intolerance. The cumulative achievement rates of MR4.5 by 18 months were 32.6% (95% confidence interval [CI]: 26.5-39.1%) in the nilotinib arm and 30.8% (95% CI: 24.9-37.3%) in the dasatinib arm with no significant difference (p=0.66). Also, the cumulative achievement rates of early molecular response (EMR), complete cytogenetic response (CCyR) and major molecular response (MMR), MR4.0 by 12, 18, 24, and 36 months were almost the same between the two arms. At 36 months, 66.5% and 65.0% patients continued nilotinib and dasatinib, respectively (p=0.76). There was no significant difference in progression-free survival (PFS) or overall survival (OS) between the two arms by log-rank tests (PFS, p=0.58; OS, p=0.64). These results suggest that nilotinib and dasatinib would be equally effective for de novo CML-CP patients with similar continuity. UMIN Clinical Trials Registry (#UMIN000007909).
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Ayano Saito, Yoshihiro Kameoka, Kumi Ubukawa, Hiroshi Ohtani, Fumito Abe, Masaya Saito, Mako Hashimoto, Tatsuro Kanazawa, Atsushi Komatsuda, Naoto Takahashi
Internal medicine (Tokyo, Japan) ( 一般社団法人 日本内科学会 ) advpub ( 0 ) 1388 - 1392 2024年10月
研究論文（学術雑誌）
A 71-year-old woman developed nephrotic syndrome during 10-year follow-up for chronic lymphocytic leukemia. A renal biopsy sample analysis revealed IgG1-lambda-positive monoclonal immunotactoid glomerulopathy (mITG). The patient was treated with ibrutinib, a Bruton tyrosine kinase inhibitor, and complete renal remission was achieved after 24 months. ITG is a rare disease that is characterized by glomerular deposition. In particular, mITG, which presents immune deposits that exhibit light-chain restriction, is often associated with hematologic disorders. Most patients with mITG receive immunosuppressive therapy and/or chemotherapy; however, to our knowledge, there have been no reports of treatment with ibrutinib.
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Yamada M.
International Journal of Hematology ( International Journal of Hematology ) 120 ( 3 ) 325 - 336 2024年09月
研究論文（学術雑誌）
Basic research to expand treatment options for multiple myeloma is greatly needed due to the refractory nature of the disease. Histone deacetylase (HDAC) inhibitors, which are epigenetic regulators, are attractive but have limited applications. MicroRNAs (miRNAs), which are also epigenetic regulators, are important molecules that may lead to future therapeutic breakthroughs. In this study, we comprehensively searched for miRNAs that are altered by HDAC inhibitors in myeloma cells. We identified miR-7-5p (miR-7) as a miRNA downregulated by HDAC inhibitors. Transfection of myeloma cell lines with miR-7 suppressed cell proliferation, induced apoptosis, and enhanced the effects of the HDAC inhibitor panobinostat. Expression of miR-7 was downregulated by c-Myc inhibition, but upregulated by bortezomib. Comprehensive examination of miR-7 targets revealed four candidates: SLC6A9, LRRC59, EXOSC2, and PSME3. Among these, we focused on PSME3, an oncogene involved in proteasome capacity in myeloma cells. PSME3 knockdown increases myeloma cell death and panobinostat sensitivity. In conclusion, miR-7, which is downregulated by HDAC inhibitors, is a tumor suppressor that targets PSME3. This miR-7 downregulation may be involved in HDAC inhibitor resistance. In addition, combinations of anti-myeloma drugs that complement changes in miRNA expression should be considered.
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OA-35 Discovery of a Novel Class MMSET Inhibitor With Specificity for t(4; 14)-Positive Multiple Myeloma
Sae Matsuoka, Naoki Osada, Hirokazu Kubota, Ko Kikuzato, Hiroo Koyama, Takeshi Sonoda, Akiko Ide, Minoru Yoshida, Masaki Kikuchi, Takashi Umehara, Chiduru Watanabe, Teruki Honma, Hiroshi Yasui, Sho Ikeda, Naoto Takahashi, Hideki Nakasone, Jiro Kikuchi, Yusuke Furukawa
Clinical Lymphoma Myeloma and Leukemia ( Elsevier BV ) 24 S22 - S23 2024年09月
研究論文（学術雑誌）
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Kobayashi T.
Cancer Chemotherapy and Pharmacology ( Cancer Chemotherapy and Pharmacology ) 94 ( 2 ) 285 - 296 2024年08月
研究論文（学術雑誌）
PURPOSE: An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy. METHODS: The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML. RESULTS: Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8-46 days). Area under the concentration-time curve (AUC0-24) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC0-24 was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007). CONCLUSION: Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.
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Kobayashi T.
Xenobiotica ( Xenobiotica ) 55 ( 1 ) 1 - 6 2024年
研究論文（学術雑誌）
The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C0) of venetoclax and the fluconazole C0 were obtained from plasma samples on day 7 later after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C0 values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC0-24 and C0 of venetoclax were not associated with fluconazole C0; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C0 and fluconazole C0 (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C0. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C0 is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.
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Oyake T.
Journal of Clinical and Experimental Hematopathology ( Journal of Clinical and Experimental Hematopathology ) 64 ( 3 ) 191 - 202 2024年
研究論文（学術雑誌）
Immune checkpoint inhibitors (ICI) are promising therapeutic agents for relapsed or refractory classical Hodgkin's lymphoma (RRcHL). This retrospective study evaluated patients with RRcHL registered in the clinical research program Tohoku-Hematology-Forum-26, between 2016 and 2020, and treated with ICI in 14 centers in Northeast Japan. We analyzed the usage, efficacy, and safety of ICI therapy (ICIT). Among a total of 27 patients with RRcHL, 21 and nine were treated with nivolumab and/or pembrolizumab, respectively. The best response was complete response (CR), partial response (PR), stable disease (SD), and progressive disease in 11 (40.8%), seven (25.9%), eight (29.6%), and one (3.7%) patient, respectively. In all patients undergoing ICIT, the 2-year progression-free survival and 2-year overall survival (OS) were 48.6% and 87.4%, respectively. The 2-year OS for patients with CR, PR, and SD were 100%, 68.6%, and 87.5%, respectively. A total of 36 events of immune-related adverse events (irAEs) or immune-related like adverse events (irlAEs) were observed in 19 of the 27 patients (70.4%). Two thirds of these irAEs or irlAEs were grade 1-2 and controllable. During the observation period, ICIT was discontinued in 22 of 27 (81.4%) patients due to CR, inadequate response, irAE and patient circumstances in five (22.7%), seven (31.8%), eight (36.4%) and two patients (9.1%), respectively. Therapy-related mortality-associated irAE were observed in only one patient during ICIT. These results suggest that ICIT for RRcHL is effective and safe in real-world settings. The optimal timing of induction and duration of ICIT remains to be established.
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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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Kazuaki Kameda, Ryo Yanagiya, Yuji Miyatake, Joaquim Carreras, Hiroshi Higuchi, Hiromichi Murayama, Takashi Ishida, Asahi Ito, Shinsuke Iida, Noriko Fukuhara, Hideo Harigae, Yuki Fujioka, Naoto Takahashi, Hidenori Wada, Fumihiro Ishida, Hideyuki Nakazawa, Rei Ishihara, Yuki Murakami, Hiroyuki Tagawa, Tadashi Matsuura, So Nakagawa, Sadahiro Iwabuchi, Shinichi Hashimoto, Ken-Ichi Imadome, Naoya Nakamura, Kenichi Ishizawa, Yoshinobu Kanda, Kiyoshi Ando, Ai Kotani
Blood Journal ( American Society of Hematology ) 2023年05月
研究論文（学術雑誌）
Aggressive natural killer cell leukemia (ANKL) is a rare lymphoid neoplasm frequently associated with Epstein-Barr virus, with a disastrously poor prognosis. Owing to the lack of samples from patients with ANKL and relevant murine models, comprehensive investigation of its pathogenesis including the tumor microenvironment (TME) has been hindered. Here we established three ANKL-patient-derived xenograft mice (PDXs), which enabled extensive analysis of tumor cells and their TME. ANKL cells primarily engrafted and proliferated in the hepatic sinusoid. Hepatic ANKL cells were characterized by an enriched Myc-pathway and proliferated faster than those in other organs. Interactome analyses and in vivo CRISPR-Cas9 analyses revealed transferrin (Tf)-transferrin receptor 1 (TfR1) axis as a potential molecular interaction between the liver and ANKL. ANKL cells were rather vulnerable to iron deprivation. PPMX-T003, a humanized anti-TfR1 monoclonal antibody, showed remarkable therapeutic efficacy in a preclinical setting using ANKL-PDXs. These findings indicate that the liver, a non-canonical hematopoietic organ in adults, serves as a principal niche for ANKL, and that inhibition of the Tf-TfR1 axis is a promising therapeutic strategy for ANKL.
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Abe K.
Cancer Medicine ( Cancer Medicine ) 12 ( 8 ) 9709 - 9722 2023年
研究論文（学術雑誌）
BACKGROUND: Multiple myeloma (MM) is a hematopoietic malignancy for which proteasome inhibitors have become available in recent years. However, many patients develop resistance to these drugs during treatment. Therefore, it is important to elucidate the mechanisms underlying resistance acquisition by proteasome inhibitors. Side population (SP) cells, which have a high drug efflux capacity and hypoxic responses in the microenvironment have both provided important insights into drug resistance in MM; however, little is known about the characteristics of SP cells in hypoxic microenvironments. METHODS: We performed cDNA microarray analysis for SP and non-SP obtained from RPMI-8226 and KMS-11 cell lines cultured for 48 h in normoxic and hypoxic conditions (1% O2 ). Genes specifically upregulated in hypoxic SP were examined. RESULTS: Our comprehensive gene expression analysis identified HMOX1, BACH2, and DUX4 as protein-coding genes that are specifically highly expressed in SP cells under hypoxic conditions. We have shown that HMOX1/heme oxygenase-1 (HMOX1/HO-1) is induced by hypoxia-inducible reactive oxygen species (ROS) and reduces ROS levels. Furthermore, we found that HMOX1 contributes to hypoxia-induced resistance to proteasome inhibitors in vitro and in vivo. Excessive ROS levels synergistically enhance bortezomib sensitivity. In clinical datasets, HMOX1 had a strong and significantly positive correlation with MAFB but not MAF. Interestingly, hypoxic stimulation increased MAFB/MafB expression in myeloma cells; in addition, the knockdown of MAFB under hypoxic conditions suppressed HMOX1 expression. CONCLUSION: These results suggest that the hypoxia-ROS-HMOX1 axis and hypoxia-induced MafB may be important mechanisms of proteasome inhibitor resistance in hypoxic microenvironments.
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Abumiya M.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 2 ) 382 - 387 2021年04月 [査読有り]
研究論文（学術雑誌） 国内共著
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Abumiya M.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 1 ) 219 - 222 2021年02月 [査読有り]
研究論文（学術雑誌） 国内共著
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Ito F.
International Journal of Hematology ( International Journal of Hematology ) 113 ( 1 ) 100 - 105 2021年01月 [査読有り]
研究論文（学術雑誌） 国内共著
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Teshima Kazuaki, Kume Masaaki, Kondo Rui, Shibata Kenichi, Abe Ko, Aono Hiroaki, Fushimi Susumu, Takahashi Satoshi, Takahashi Satsuki, Saito Masahiro, Takahashi Naoto
Internal Medicine ( 一般社団法人 日本内科学会 ) 2021年 [査読有り]
研究論文（学術雑誌） 国内共著
<p>A 17-year-old girl was diagnosed with acute lymphoblastic leukemia (ALL). After the administration of high-dose methotrexate (MTX) or intrathecal MTX, the patient experienced transient hemiparesis and motor aphasia. Diffusion-weighted magnetic resonance imaging showed a high-intensity lesion in the bilateral centrum semiovale, and a vasospasm was detected in the proximal segment of bilateral A1 on magnetic resonance angiography. Edaravone was administered, and leucovorin rescue treatment was continued; eventually, the patient's neurological symptoms completely resolved. This finding suggested that vasospasm might be a mechanism underlying MTX-induced transient encephalopathy in adolescent and young adult patients with ALL. </p>
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Ubukawa K.
Scientific Reports ( Scientific Reports ) 10 ( 1 ) 11806 2020年12月 [査読有り]
研究論文（学術雑誌） 国内共著
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Outcome of colorectal cancer in Diamond–Blackfan syndrome with a ribosomal protein S19 mutation
Kimura K.
Clinical Journal of Gastroenterology ( Clinical Journal of Gastroenterology ) 13 ( 6 ) 1173 - 1177 2020年12月 [査読有り]
研究論文（学術雑誌） 国内共著
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Ikeda S.
Cancer Science ( Cancer Science ) 111 ( 11 ) 4088 - 4101 2020年11月 [査読有り]
研究論文（学術雑誌） 国内共著
Multiple myeloma (MM) is an incurable hematopoietic neoplasm derived from plasma cells and existing in bone marrow region. Recent developments in the field of myeloma onco-biology enabled to use proteasome inhibitors (PIs) as key drugs for MM. PIs can increase cell sensitivity to endoplasmic reticulum stress, leading to apoptosis against myeloma cells. However, PI cannot kill all of myeloma cells. One reason of this might be activation of autophagy via hypoxic stress under bone marrow microenvironment. Hypoxia-inducible gene(s) that regulate autophagy may be novel therapeutic target(s) for PI-resistant myeloma cells. Here, we demonstrate that a hypoxia-inducible glycolytic enzyme hexokinase-2 (HK2) contributes to acquisition of the anti-apoptotic phenotype of myeloma cells via activating autophagy. We found that hypoxic stress led to autophagy activation with upregulation of HK2 in myeloma cells. Under hypoxic conditions, HK2 knockdown inhibited glycolysis and impaired autophagy, inducing apoptosis. We examined the cooperative effects of PI (bortezomib) against immunodeficient mice inoculated with HK2-knocked down myeloma cells and observed significant tumor reduction. An HK2 inhibitor, 3-bromopyruvate, also induced apoptosis under hypoxia rather than normoxic conditions. Further examination of the cooperative effects of both 3-bromopyruvate and bortezomib on myeloma cells revealed a significant increase in apoptotic myeloma cells. These results strongly suggest that HK2 regulates the activation of autophagy in hypoxic myeloma cells. Furthermore, cooperative treatment against a dominant fraction with PI and a minor fraction adapting to the bone marrow microenvironment with HK2 inhibitor may lead to deeper remission for refractory MM.
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Taniguchi Y.
Internal Medicine ( Internal Medicine ) 59 ( 21 ) 2745 - 2749 2020年11月 [査読有り]
研究論文（学術雑誌） 国内共著
<p>We recently treated a chronic myeloid leukemia (CML) patient with liver and renal dysfunction, who was undergoing hemodialysis (HD). He was treated with 50 mg dasatinib (DAS) once daily just before HD. The maximum plasma concentration of DAS was 227 ng/mL on a non-HD day and 46.9 ng/mL on a HD day. He was subsequently treated with 200 mg bosutinib (BOS) once daily. The plasma concentration of BOS changed from 74.5 ng/mL before HD to 58.8 ng/mL after HD. Our results indicate that close monitoring of the plasma tyrosine kinase inhibitor concentrations should be considered in CML patients with organ impairment. </p>
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Ono T.
Cancer Science ( Cancer Science ) 111 ( 10 ) 3714 - 3725 2020年10月 [査読有り]
研究論文（学術雑誌） 国内共著
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Shimoda K.
International Journal of Hematology ( International Journal of Hematology ) 112 ( 3 ) 268 - 291 2020年09月 [査読有り] [招待有り]
研究論文（学術雑誌） 国内共著
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Multiple Myeloma–Associated Ig Light Chain Crystalline Cast Nephropathy
Matsumura H.
Kidney International Reports ( Kidney International Reports ) 5 ( 9 ) 1595 - 1602 2020年09月 [査読有り]
研究論文（学術雑誌） 国内共著
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Comparative proteomic analysis of renal proteins from IgA nephropathy model mice and control mice
Miyakawa R.
Clinical and Experimental Nephrology ( Clinical and Experimental Nephrology ) 24 ( 8 ) 666 - 679 2020年08月 [査読有り]
研究論文（学術雑誌） 国内共著
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Saito A.
Clinical and Experimental Nephrology ( Clinical and Experimental Nephrology ) 24 ( 6 ) 509 - 517 2020年06月 [査読有り]
研究論文（学術雑誌） 国内共著
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Sakurai M.
International Journal of Hematology ( International Journal of Hematology ) 111 ( 6 ) 812 - 825 2020年06月 [査読有り]
研究論文（学術雑誌） 国内共著
We herein report the results of the New TARGET study 2nd-line, which collected data on patients with chronic-phase (CP) chronic myeloid leukemia (CML) who received a 2nd-line tyrosine kinase inhibitor (TKI) because of resistance and/or to a 1st-line TKI. A total of 98 patients were enrolled intolerance between April 2010 and March 2013, and 82 patients were analyzed. The median age was 54 years (range 22-88 years). Seventy-six patients (93%) received imatinib as the 1st-line TKI. Forty-five (55%) and 37 (45%) patients began nilotinib and dasatinib treatments at entry, respectively. First-line TKI treatment achieved complete hematological response in 79 patients (96%) and complete cytogenetic response (CCyR) in 49 patients (60%), respectively. Nine patients (11%) had BCR-ABL1 kinase domain point mutations at enrollment. The estimated 3-year progression-free-survival rate after enrollment was 98.7% (95% CI 91.1-99.8%). Overall, the probabilities of achieving CCyR and a major molecular response were 89.3% (95% CI 81.4-94.8%) and 87.2% (95% CI 78.1-93.8%), respectively. There were no new safety issues. This study demonstrated that CML-CP patients in Japan who are resistant and/or intolerant to a 1st-line TKI can achieve an extremely good outcome by 2nd-line TKI treatment.
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Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells
Tanaka A.
Journal of Experimental Medicine ( Journal of Experimental Medicine ) 217 ( 2 ) 2020年02月 [査読有り]
研究論文（学術雑誌） 国内共著
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Nara M.
Internal Medicine ( Internal Medicine ) 58 ( 24 ) 3583 - 3587 2019年12月 [査読有り]
研究論文（学術雑誌） 国内共著
<p>We herein report the first pediatric case (a 13-year-old girl) of relapsing eosinophilic granulomatosis with polyangiitis (EGPA) successfully treated with mepolizumab (anti-interleukin-5). She was classified as having EGPA based on the presence of asthma, eosinophilia, pulmonary infiltrates, and extravascular eosinophil infiltration confirmed by a biopsy. She achieved remission after initial oral prednisolone (PSL) therapy, but EGPA relapsed during PSL tapering. Subsequent combined therapy with PSL and tacrolimus did not improve the recurrent disease. Intravenous methylprednisolone pulse therapy was started, followed by oral PSL. During PSL tapering, mepolizumab was added to the treatment, which resulted in sustained remission and successful PSL tapering. </p>
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Imamura K.
BMJ Open ( BMJ Open ) 9 ( 12 ) e033131 - e033131 2019年12月 [査読有り]
研究論文（学術雑誌）
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Ikeda S.
Internal Medicine ( Internal Medicine ) 58 ( 23 ) 3461 - 3468 2019年12月 [査読有り]
研究論文（学術雑誌） 国内共著
<p>A 72-year-old man presented with a 6-month history of systemic edema. Hyperpigmentation, hemangioma, pleural effusion, IgG-kappa-type monoclonal protein, high vascular endothelial growth factor values, renal failure, and nerve conduction study abnormalities were also present. Multiparameter flow cytometry (MFC) showed 0.2% neoplastic plasma cells (CD38-, CD56-, and kappa-positive; CD19-, CD27-, and lambda-negative) in the bone marrow leading to POEMS syndrome. Cases involving kappa-type POEMS syndrome are extremely rare. A kidney biopsy revealed membranous proliferative glomerulonephritis-like changes in our case. Lenalidomide-dexamethasone therapy improved the renal function. Detection of neoplastic plasma cells by MFC was useful for the accurate diagnosis and treatment evaluation. </p>
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Thrombocytopenia caused by a Tea Beverage of Taxus yunnanensis (Chinese Yew)
Ubukawa K.
Internal Medicine ( Internal Medicine ) 58 ( 21 ) 3153 - 3156 2019年11月 [査読有り]
研究論文（学術雑誌） 国内共著
<p>A 53-year-old woman presented at our hospital due to nasal bleeding and petechiae with profound thrombocytopenia (0.4×10<sup>9</sup>/L). Her platelet count returned to the normal range immediately following a platelet transfusion. In this case, tea brewed from <i>Taxus yunnanensis</i> was the only suspected agent ingested prior to the onset of thrombocytopenia while all other etiologies for thrombocytopenia were excluded. A re-exposure test to <i>Taxus yunnanensis </i>resulted in the recurrence of acute thrombocytopenia. The association of thrombocytopenia with substances other than drugs has so far only been rarely described and to the best of our knowledge, this is the first reported case of thrombocytopenia caused by<i> Taxus yunnanensis</i>. </p>
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Guo Y.M.
Internal Medicine ( Internal Medicine ) 58 ( 20 ) 3039 - 3043 2019年10月 [査読有り]
研究論文（学術雑誌） 国内共著
<p>Severe hepatic failure is rarely a cause of death in patients with immunoglobulin light chain (AL) amyloidosis. We herein report a case of AL amyloidosis involving a bleeding tendency due to factor X deficiency and marked hepatic involvement of amyloidosis. The patient died due to severe liver dysfunction two weeks after admission. The diagnosis was confirmed histologically by AL-λ amyloidosis, with the liver and spleen as the main lesions, on an autopsy. As treatment-related toxicity is strong in advanced cases, appropriate treatments are required to improve the prognosis of AL amyloidosis with severe liver dysfunction. </p>
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Hirokawa M.
Scientific Reports ( Scientific Reports ) 9 ( 1 ) 8645 - 8645 2019年06月 [査読有り]
研究論文（学術雑誌） 国内共著
Primary immune thrombocytopenia (ITP) is an acquired form of thrombocytopenia caused by IgG anti-platelet autoantibodies and represents an organ-specific autoimmune disorder. Although the glycoprotein (GP)IIb/IIIa and GPIb/IX have been shown to be targets for autoantibodies, the antigen specificity of autoantibodies is not fully elucidated. To identify the characteristics of IgG B-cell receptor (BCR) repertoires in ITP, we took advantage of adaptor-ligation PCR and high-throughput DNA sequencing methods for analyzing the clone-based repertoires of IgG-expressing peripheral blood B cells. A total of 2,009,943 in-frame and 315,469 unique reads for IGH (immunoglobulin heavy) were obtained from twenty blood samples. Comparison of the IGHV repertoires between patients and controls revealed an increased usage of IGHV4-28 in ITP patients. One hundred eighty-six distinct IGHV4-28-carrying sequences were identified in ITP patients and the majority of these clones used an IGHJ4 segment. The IGHV4-28/IGHJ4-carrying B-cell clones were found in all ITP patients. Oligoclonal expansions of IGHV4-28/IGHJ4-carrying B cells were accompanied by multiple related clones with single amino substitution in the CDR3 region suggesting somatic hypermutation. Taken together, the expansion of IGHV4-28/IGHJ4-carrying IgG-expressing B cells in ITP may be the result of certain antigenic pressure and may provide a clue for the immune pathophysiology of ITP.
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Kobayashi T.
Medical Oncology ( Medical Oncology ) 36 ( 6 ) 55 - 55 2019年05月 [査読有り]
研究論文（学術雑誌） 国内共著
Individual diversity in plasma concentrations of lenalidomide occurs despite dosage modifications based on creatinine clearance (CCr), which can lead to unexpected toxicity. We have previously identified a cutoff value of area under the concentration-time curve (AUC0-24) for lenalidomide to avoid severe toxicity. Here, we investigated the association between ABCB1 polymorphisms and pharmacokinetics of lenalidomide in patients with multiple myeloma (MM) treated with lenalidomide and dexamethasone. Plasma concentrations of lenalidomide were analyzed using liquid chromatography-tandem mass spectrometry. Genotyping for ABCB1 1236C>T, 2677G>A/T, and 3435C>T polymorphisms was performed, and the effects of ABCB1 polymorphisms on AUC0-24 for lenalidomide were compared in 36 patients with MM who were administered lenalidomide according to the drug label based on CCr. Genotyping analysis showed that although there were no differences in AUC0-24 in 1236C>T and 2677G>A/T polymorphisms. AUC0-24 was significantly higher in patients with the T allele of 3435C>T (n = 15) than in those without (n = 21) (median 6324.6 ng h/mL vs. 2857.4 ng h/mL, p = 0.028). The AUC0-24 value exceeded the aforementioned cutoff value in 95% of the patients with the T allele of 3435C>T but in 60% with C/C genotype (p = 0.013). Multivariate logistic analysis confirmed the significance of T allele of ABCB1 3435C>T as a factor due to which the AUC0-24 cutoff value was exceeded (hazard ratio of 15.0, p = 0.019). We show that lenalidomide pharmacokinetics is influenced by the ABCB1 3435C>T polymorphism, which could be useful to individualize dosage design and reduce unexpected toxicity.
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ATP produced by anaerobic glycolysis is essential for enucleation of human erythroblasts
Goto T.
Experimental Hematology ( Experimental Hematology ) 72 14 - 26 2019年04月 [査読有り]
研究論文（学術雑誌） 国内共著
More than 2million human erythroblasts extrude their nuclei every second in bone marrow under hypoxic conditions (<7% O2). Enucleation requires specific signal transduction pathways and the local assembly of contractile actomyosin rings. However, the energy source driving these events has not yet been identified. We examined whether different O2 environments (hypoxic [5% O2] and normoxic [21% O2] conditions) affected human CD34+ cell erythroblast differentiation. We also investigated the regulatory mechanisms underlying energy production in erythroblasts during terminal differentiation under 5% or 21% O2 conditions. The results obtained revealed that the enucleation ratio and intracellular levels of adenosine triphosphate (ATP), lactate dehydrogenase (LDH) M3H, and hypoxia-inducible factor 1α in erythroblasts during terminal differentiation were higher under the 5% O2 condition than under the 21% O2 condition. We also found that the enzymatic inhibition of glyceraldehyde 3-phosphate dehydrogenase and LDH, key enzymes in anaerobic glycolysis, blocked the proliferation of colony-forming units-erythroid and enucleation of erythroblasts, and also reduced ATP levels in erythroblasts under both hypoxic and normoxic conditions. Under both conditions, phosphorylation of the Ser232, Ser293, and Ser300 residues in pyruvate dehydrogenase (inactive state of the enzyme) in erythroblasts was involved in regulating the pathway governing energy metabolism during erythroid terminal differentiation. This reaction may be mediated by pyruvate dehydrogenase kinase (PDK) 4, the major PDK isozyme expressed in erythroblasts undergoing enucleation. Collectively, these results suggest that ATP produced by anaerobic glycolysis is the main source of energy for human erythroblast enucleation in the hypoxic bone marrow environment.
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Kaga H.
Clinical and Experimental Nephrology ( Clinical and Experimental Nephrology ) 23 ( 4 ) 465 - 473 2019年04月 [査読有り]
研究論文（学術雑誌） 国内共著
BACKGROUND: The prevalence of antibodies against M-type anti-phospholipase A2 receptor (PLA2R) was reported to be ~ 70-80% in early studies on idiopathic membranous nephropathy (iMN) cohorts from Western countries, China, and Korea, and ~ 50% in recent studies on two Japanese iMN cohorts. METHODS: We developed an in-house enzyme-linked immunosorbent assay (ELISA) for the detection of anti-PLA2R antibodies, and examined sera from 217 patients with iMN, 22 patients with secondary MN (sMN), and 50 healthy individuals. All patients and healthy individuals were Japanese. The relationships between levels of anti-PLA2R antibodies and clinical parameters were analyzed. Serum samples were also tested using a standardized commercial ELISA (Euroimmun, Germany). RESULTS: In our ELISA, OD values greater than the mean + 3 standard deviation of healthy subjects were considered to be positive for anti-PLA2R antibodies. Of the patients with iMN, 33.6% (73/217) were positive, but all sMN patients were negative. Our ELISA and the Euroimmun ELISA had a high concordance (93.5%). The proportion of patients with nephrotic syndrome was significantly higher in anti-PLA2R antibody-positive patients than in antibody-negative patients (65.8 vs. 37.5%, P < 0.001). Levels of anti-PLA2R antibodies were significantly correlated with levels of urinary protein and serum albumin (P = 0.004 and P < 0.001, respectively). CONCLUSIONS: The prevalence of anti-PLA2R antibodies in our Japanese iMN cohort was lower than that in the previous studies from other countries and other Japanese institutes. The low prevalence of antibodies may be related with the characteristics of enrolled patients with mild proteinuria and undetectable antibody levels.
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Kizaki M.
International Journal of Hematology ( International Journal of Hematology ) 109 ( 4 ) 426 - 439 2019年04月 [査読有り]
研究論文（学術雑誌） 国内共著
We report the results of a multicenter observational study using the New TARGET system, in which the effectiveness and safety of tyrosine kinase inhibitors (TKIs) were evaluated in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. A total of 506 patients were enrolled between April 2010 and March 2013. Median age was 56 (range 18-92) years; 35% of patients were females. As the first-line therapy, 139 (27.9%), 169 (33.9%) and 144 (28.9%) patients were treated with imatinib, nilotinib, and dasatinib, respectively. Five-year progression-free survival (PFS) and overall survival (OS) were 93.8% and 94.5%, respectively. The OS curve was significantly superior for patients treated with second-generation TKIs than imatinib (P = 0.0068), and an early molecular response (EMR) at 3 months (BCR-ABL1 < 10%) was detected in 328 of 377 patients evaluated for molecular response. The PFS curve was significantly superior for patients with EMR than without (P < 0.0001). Although 12 patients experienced vascular adverse events, no new safety issues were observed in patients with adverse events. The results of this observational study demonstrated that treating newly diagnosed CML-CP patients with TKI results in satisfactory and reliable outcomes.
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高橋 直人
日本内科学会雑誌 ( 一般社団法人 日本内科学会 ) 108 ( 3 ) 547 - 550 2019年03月 [査読有り] [招待有り]
研究論文（学術雑誌） 単著
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Kobayashi T.
International Journal of Hematology ( International Journal of Hematology ) 109 ( 3 ) 356 - 360 2019年03月 [査読有り]
研究論文（学術雑誌） 国内共著
Although programmed cell death (PD)-1 blockade induces immune-related adverse events (irAEs), little is known about the safety of PD-1 blockade after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we describe immune system changes during nivolumab-related myositis in a patient with Hodgkin's lymphoma after allogeneic HSCT; to our knowledge, this is the first such report in the literature. At the onset of myositis, the patient lost lower limb mobility against gravity, and had an activated immune profile with increased cytotoxic CD107a and granzyme B expression, as well as pro-inflammatory cytokines, interferon-γ, tumor necrosis factor-α, interleukin-2 in T and NK cells compared to healthy donor. Pulse steroid therapy decreased creatine kinase levels and induced PD-1 expression and regulatory T cells, but did not improve myositis; previously activated markers remained high. Four-week corticosteroid therapy decreased previously activated markers and the myositis improved. These findings provide new insights into nivolumab-induced irAE pathogenesis and suggest possible optimal treatments for irAEs.
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Sasaki T.
Prostate ( Prostate ) 79 ( 3 ) 259 - 264 2019年02月 [査読有り]
研究論文（学術雑誌） 国際共著
BACKGROUND: The tyrosine kinase inhibitors (TKI), imatinib and nilotinib, are used to treat chronic myelogenous leukemia (CML). In three CML patients being monitored for urologic diseases, we observed that switching of TKI therapy affected prostate-specific antigen (PSA) titers. Urologists and other medical professionals need to be aware of the potential side-effects of drugs that patients may be receiving for other indications to modify this important prostate diseases indicator. TKIs may affect PSA titers independent of prostate growth or volume. MATERIALS AND METHODS: We followed PSA levels in urology patients who were also undergoing TKI treatment for CML. We determined the effects of nilotinib and imatinib on proliferation, AR and PSA expression in the LNCaP and 22Rv1 prostate cancer (PCa) cell lines using real-time PCR and Western blotting. RESULTS: Clinically, nilotinib and dasatinib reversibly reduced PSA titers compared to imatinib. At high doses nilotinib and imatinib both demonstrated antiproliferative effects in the PCa cells. At low doses expression of AR and PSA was decreased by both drugs, at mRNA and protein levels. Nilotinib exerted greater effects at lower doses than imatinib. CONCLUSIONS: Nilotinib down-regulates serum PSA in patients being treated for non-urological indications, potentially masking a clinical useful marker, we cannot exclude a similar but smaller effect of imatinib. Nilotinib and imatinib both decreased AR and PSA expression in PCa cell lines with the nilotinib effect evident at lower doses. Urologists must appreciate the effects of drugs provided for other diseases on PSA titers and be aware that sudden changes may not reflect underlying prostatic disease.
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慢性骨髄性白血病治療薬チロシンキナーゼ阻害剤の血中濃度を用いた治療マネジメントupdate
三浦 昌朋, 高橋 直人
臨床血液 ( 一般社団法人 日本血液学会 ) 60 ( 9 ) 1140 - 1147 2019年 [招待有り]
研究論文（学術雑誌） 国内共著
<p>慢性骨髄性白血病治療薬として現在5つのチロシンキナーゼ阻害剤が使用可能である。各々の薬剤において，特定の血中濃度を指標に投与量を調節する治療法の有用性が確認されている。イマチニブは特定薬剤治療管理料が算定でき，ターゲット血中トラフ濃度（C0）を1,000 ng/m<i>l</i>にすることで，1年でのMMR達成率が37％から63％に上昇している。ニロチニブは490 ng/m<i>l</i>以上にすることでMMR達成が6ヶ月早まっており，C0値900 ng/m<i>l</i>でより深い寛解が得られる。ダサチニブはC0値を4.33 ng/m<i>l</i>以下の可能な限り検出させないことで胸水発現を抑えることができ，ボスチニブはC0値62 ng/m<i>l</i>を推移させることで，治療開始1年におけるMMR達成が有意に高まる。ポナチニブは21.3 ng/m<i>l</i>をターゲットに投与量を調節することで，血管閉塞性有害事象を回避した継続的治療の可能性が考えられている。本稿では血中濃度を用いた治療戦略の導入による治療成績の変化について概説する。</p>
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Kameoka Y.
International Journal of Hematology ( International Journal of Hematology ) 108 ( 5 ) 510 - 515 2018年11月 [査読有り]
研究論文（学術雑誌） 国内共著
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is widely used as a salvage therapy for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL). To investigate the safety and efficacy of regimens including high-dose MCNU followed by ASCT for DLBCL, we analyzed the data from prospective multicenter trials. Twenty-nine patients were analyzed, and the median follow-up time for survival patients was 70 months. Fifteen patients received MCVC conditioning regimen, and fourteen patients received MEAM regimen. Major toxicities associated with these conditioning regimens included nausea (69%), anorexia (66%), febrile neutropenia (62%), diarrhea (59%), and mucositis (34%). One patient who developed severe sinusoidal obstructive syndrome and acute lung injury died without disease progression, and overall therapy-related mortality at 5 years was 3%. No patient developed therapy-related hematological malignancy. At 5 years, overall survival and progression-free survival in all patients were 82.8 and 58.2%, respectively. The 5-year OS in patients treated by the MCVC and MEAM regimens were 73.3 and 92.9%, respectively. These results suggest that regimens including high-dose MCNU followed by ASCT are feasible and effective for the treatment of relapsed or high-risk DLBCL. Further investigation is needed to evaluate of these regimens.
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Takahashi N.
Haematologica ( Haematologica ) 103 ( 11 ) 1835 - 1842 2018年11月 [査読有り]
研究論文（学術雑誌） 国内共著
The purpose of this trial was to evaluate the efficacy of 2-year consolidation therapy with nilotinib, at a dose of 300 mg twice daily, for achieving treatment-free remission in chronic myeloid leukemia patients with a deep molecular response (BCR-ABL1IS ≤0.0032%). Successful treatment-free remission was defined as no confirmed loss of deep molecular response. We recruited 96 Japanese patients, of whom 78 sustained a deep molecular response during the consolidation phase and were therefore eligible to discontinue nilotinib in the treatment-free remission phase; of these, 53 patients (67.9%; 95% confidence interval: 56.4-78.1%) remained free from molecular recurrence in the first 12 months. The estimated 3-year treatment-free survival was 62.8%. Nilotinib was readministered to all patients (n=29) who experienced a molecular recurrence during the treatment-free remission phase. After restarting treatment, rapid deep molecular response returned in 25 patients (86.2%), with 50% of patients achieving a deep molecular response within 3.5 months. Tyrosine kinase inhibitor withdrawal syndrome was reported in 11/78 patients during the early treatment-free remission phase. The treatment-free survival curve was significantly better in patients with undetectable molecular residual disease than in patients without (3-year treatment-free survival, 75.6 versus 48.6%, respectively; P=0.0126 by the log-rank test). There were no significant differences in treatment-free survival between subgroups based on tyrosine kinase inhibitor treatment before the nilotinib consolidation phase, tyrosine kinase inhibitor-withdrawal syndrome, or absolute number of natural killer cells. The results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904).
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Noguchi S.
International Journal of Hematology ( International Journal of Hematology ) 108 ( 2 ) 176 - 183 2018年08月 [査読有り]
研究論文（学術雑誌） 国内共著
The purpose of this clinical trial was to evaluate the efficacy of 2-year consolidation therapy using nilotinib (NIL) for achieving a molecular response (MR4.5, BCR-ABL1IS ≤ 0.0032% on the International Scale) in patients with chronic myeloid leukemia in the chronic phase (CML-CP) who had achieved a major molecular response (MMR, BCR-ABL1IS ≤ 0.1%) with imatinib (IM). We recruited 76 Japanese patients for this trial. Nilotinib 300 mg, twice daily, was administered for 2 years, and 74 patients were evaluated in the study. The median age was 55.0 years. The median duration of IM treatment was 69.0 months. All patients showed MMR at the time of entry into the study; the median time to MMR on IM therapy was 20.4 months. The proportion of patients who achieved MR4.5 increased over time. The rates of MR4.5 in the 74 evaluable patients were 27.0% [90% confidence interval (CI) (18.7-36.8%)] and 44.6% [90% CI (34.7-54.8%)] at 12 and 24 months, respectively. The frequency of ABCG2 421C/A + A/A was an independent predictive biomarker for achieving a 24-month MR4.5. Switching to NIL led to safer, deeper molecular responses in patients with MMR on long-term IM therapy for future treatment-free remission.
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The localization of α-synuclein in the process of differentiation of human erythroid cells
Araki K.
International Journal of Hematology ( International Journal of Hematology ) 108 ( 2 ) 130 - 138 2018年08月 [査読有り]
研究論文（学術雑誌） 国内共著
Although the neuronal protein α-synuclein (α-syn) is thought to play a central role in the pathogenesis of Parkinson's disease (PD), its physiological function remains unknown. It is known that α-syn is also abundantly expressed in erythrocytes. However, its role in erythrocytes is also unknown. In the present study, we investigated the localization of α-syn in human erythroblasts and erythrocytes. Protein expression of α-syn increased during terminal differentiation of erythroblasts (from day 7 to day 13), whereas its mRNA level peaked at day 11. α-syn was detected in the nucleus, and was also seen in the cytoplasm and at the plasma membrane after day 11. In erythroblasts undergoing nucleus extrusion (day 13), α-syn was detected at the periphery of the nucleus. Interestingly, we found that recombinant α-syn binds to trypsinized inside-out vesicles of erythrocytes and phosphatidylserine (PS) liposomes. The dissociation constants for binding to PS/phosphatidylcholine (PC) liposomes of N-terminally acetylated (NAc) α-syn was lower than that of non NAc α-syn. This suggests that N-terminal acetylation plays a significant functional role. The results of the present study collectively suggest that α-syn is involved in the enucleation of erythroblasts and the stabilization of erythroid membranes.
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Kobayashi T.
Therapeutic Drug Monitoring ( Therapeutic Drug Monitoring ) 40 ( 3 ) 301 - 309 2018年06月 [査読有り]
研究論文（学術雑誌） 国内共著
BACKGROUND: The authors conducted a phase II clinical trial of lenalidomide and dexamethasone combination therapy in Japanese elderly patients with newly diagnosed multiple myeloma to evaluate its safety and efficacy and to determine whether safety and efficacy correlate with the plasma concentration of lenalidomide. METHODS: Forty patients received oral lenalidomide on days 1-21 of a 28-day cycle in addition to weekly doses of dexamethasone. Plasma concentrations of lenalidomide were measured, and the area under the concentration-time curve from 0 to 24 hours (AUC0-24) of lenalidomide was predicted using a formula the authors previously reported in this journal. RESULTS: The median age was 75.5 years. Twenty-one patients had renal impairment severe enough to require dose adjustment of lenalidomide. The median initial doses of lenalidomide and dexamethasone were 12.5 and 20 mg, respectively. The overall response rate was 68.6%, and the 2-year overall survival rate was 88.5%. There was no correlation between the response rate and plasma concentration of lenalidomide. Grade 3-4 adverse events (AEs) were observed in 57.5% of patients. The AUC0-24 of lenalidomide was significantly higher in patients with grade 3-4 AEs than in those who did not suffer from AEs (median = 4852.0 versus 2464.9 ng·h·mL, P = 0.027). Receiver-operating characteristic curve analysis showed that the AUC0-24 of lenalidomide was a good predictor of grade 3-4 AEs, with an area under the receiver-operating characteristic curve of 0.758 (95% confidence interval, 0.572-0.943, P = 0.027). The cutoff value for best prediction of grade 3-4 AEs was 2613.5 ng·h·mL (sensitivity 86.7%, specificity 54.5%). Multivariate logistic analysis confirmed the significance of this cutoff value. CONCLUSIONS: These data suggest that overexposure to lenalidomide could contribute to toxicity. Furthermore, the predicted cutoff value of AUC0-24 can be clinically used to prevent severe AEs.
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Abumiya M.
Medical Oncology ( Medical Oncology ) 35 ( 6 ) 90 2018年05月 [査読有り]
研究論文（学術雑誌） 国内共著
We investigated the effects of polymorphisms in NR1I2 (7635A>
G, 8055C>
T), CYP3A4 (20230G>
A), ABCB1 (1199G>
A, 1236C>
T, 2677G>
T/A, 3435C>
T), and ABCG2 (421C>
A) on the mean plasma trough concentrations (C0) of bosutinib at the steady-state in 30 Japanese patients with chronic myeloid leukemia. Bosutinib C0 values were monitored using high-performance liquid chromatography. The median coefficient of variation (CV) value of the bosutinib C0 for one patient (intrapatient) during bosutinib therapy was 25.9% (range: 7.66–44.24%). During bosutinib therapy, 17 of 30 patients received 300 mg/day bosutinib. The interpatient CV value for the bosutinib C0 after administration of 300 mg/day was 45.0%. There were no significant differences in the bosutinib C0 between genotypes for ABCB1, ABCG2, and CYP3A4 polymorphisms. However, the bosutinib C0 in patients with the NR1I2 7635G/G or 8055T/T genotype was significantly lower than those in patients with the 7635A allele or 8055C allele, respectively (P = 0.050 and 0.022, respectively). In addition, the bosutinib C0 in patients with both NR1I2 7635G/G and 8055T/T genotypes was significantly lower than those in patients with other genotypes (P = 0.022). Because patients with the NR1I2 7635G/G or 8055T/T genotype may have increased activity of pregnane X receptor-regulated genes and thereafter higher intestinal expression of CYP3A4 and ABC efflux drug transporters, these patients may have a lower bosutinib C0. Therefore, information on the NR1I2 genotype may be useful for achieving optimal systemic exposure of bosutinib. -
Kurahashi H, Kawabata Y, Michishita Y, Kitabayashi A, Kobayashi T, Kitadate A, Takahashi N
[Rinsho ketsueki] The Japanese journal of clinical hematology ( 一般社団法人 日本血液学会 ) 59 ( 4 ) 420 - 425 2018年04月 [査読有り]
研究論文（学術雑誌） 国内共著
<p>症例は61歳女性。生来，出血歴はなし。左膝関節内注射後の穿刺部の止血困難とAPTT延長で当科紹介。第VIII因子活性4％，VWF抗原<10％およびVWF活性<10％と著明な低下を認め，後天性von Willebrand症候群（AvWS）と診断した。粘膜出血に対してdesmopressin acetate hydrate（DDAVP）投与で止血対応しながら基礎疾患を検索したが確定診断に至らず。発症から約15ヶ月経過してから末梢血および骨髄にCD20陽性B-cellクローンが顕在化した。全身リンパ節腫大を認めなかったものの，CD20陽性リンパ増殖性疾患として，rituximabを1週間毎に8回投与したところ，末梢血のB-cellクローンの消失とともに臨床的寛解が得られた。以後rituximabの維持投与を3ヶ月毎に行い，5年以上寛解を維持している。AvWSは，何らかの基礎疾患を有し，von Willebrand病と臨床像や検査所見が類似した病態を呈する稀な後天性出血性疾患群である。CD20陽性リンパ増殖性疾患に伴うAvWSに対しrituximabは有効な治療法の一つと考えられ，適応症例の確立など今後の症例の蓄積が期待される。</p>
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Kaga H.
Clinical and Experimental Nephrology ( Clinical and Experimental Nephrology ) 22 ( 2 ) 275 - 282 2018年04月 [査読有り]
研究論文（学術雑誌） 国内共著
Background: Several recent studies in patients with idiopathic membranous nephropathy (iMN) from Western and Asian counties showed that some single nucleotide polymorphisms (SNPs) within the PLA2R1 and HLA-DQA1 genes are significantly associated with iMN. However, there is only 1 report on analysis of PLA2R1 and HLA regions in Japanese patients with iMN. Methods: A total of 58 patients with iMN, 26 patients with secondary MN (sMN), and 50 patients with other diseases were enrolled. All patients were Japanese. We selected 6 SNPs within PLA2R1 and 1 SNP within HLA-DQA1, which were significantly associated with iMN in reported white European cohorts, and sequenced these exons using genomic DNA prepared from peripheral mononuclear cells from each patient. We then analyzed differences in PLA2R1 and HLA-DQA1 sequence variants among the 3 groups. Results: Genotypic and allelic frequency distributions for 3 out of 6 SNPs within PLA2R1, rs3749117, rs35771982, and rs2715918 were significantly different between the iMN and control groups. Allelic frequency distributions for SNP rs2187668 within HLA-DQA1 were significantly different between the iMN and control groups. There were no correlations between PLA2R1 and HLA-DQA1 sequence variants and clinical parameters in patients with iMN. There were no significant differences in genotypic or allelic frequency distributions for examined SNPs between the sMN and control groups. Conclusions: There are some differences in PLA2R1 SNP distributions between previously reported cohorts from other countries and our Japanese cohort of patients with iMN, while there is a significant association between SNP rs35771982 and iMN in most of reported cohorts.
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Saito M.
Clinical and Experimental Nephrology ( Clinical and Experimental Nephrology ) 22 ( 2 ) 365 - 376 2018年04月 [査読有り]
研究論文（学術雑誌） 国内共著
Background: Three recent studies from the United States and China reported the clinicopathological features and short-term prognosis in patients with membranous nephropathy (MN) and crescents in the absence of secondary MN, anti-glomerular basement membrane (GBM) antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). Methods: We compared clinicopathological and prognostic features in 16 MN patients with crescents (crescent group) and 38 MN patients without crescents (control group), in the absence of secondary MN, anti-GBM antibodies, and ANCA. Median follow-up periods in the crescent and control groups were 79 and 50 months, respectively. Results: Decreased estimated glomerular filtration rates (<
50 mL/min/1.73 m2), glomerulosclerosis, and moderate-to-severe interstitial fibrosis were more frequently observed in the crescent group than in the control group (P = 0.043, P = 0.004, and P = 0.035, respectively). Positive staining rates for glomerular IgG2 and IgG4 were significantly different between the 2 groups (P = 0.032, P = 0.006, respectively). Doubling of serum creatinine during follow-up was more frequently observed in the crescent group than in the control group (P = 0.002), although approximately two-thirds of patients in the crescent group were treated with immunosuppressive therapy. Crescent formation and interstitial fibrosis were risks for doubling of serum creatinine [hazard ratio (HR) = 10.506, P = 0.012
HR = 1.140, P = 0.009, respectively]. Conclusions: This is the first Japanese study demonstrating significant differences in clinicopathological and prognostic features between the 2 groups. Most patients in the crescent group may develop a long-term decline in renal function despite immunosuppressive therapy. -
Mita A.
Experimental Hematology and Oncology ( Experimental Hematology and Oncology ) 7 ( 1 ) 9 2018年04月 [査読有り]
研究論文（学術雑誌）
Purpose: To investigate the exposure-toxicity relationship of bosutinib and to identify the target trough plasma concentration (C0). Methods: The toxicity and C0 of bosutinib in Japanese chronic myeloid leukemia (CML) patients were monitored every 2 weeks for the first 3 months of treatment, and subsequently once a month during the 6 months after beginning 500 mg/day of standard dose (SD group, n = 10) or beginning 100 mg/day and increased by 100 mg every 2 weeks of dose escalation (DE group, n = 15). Results: Nine of 10 patients (90%) in the SD group were not able to continue bosutinib therapy without interruption due to adverse events, compared to 2 patients (13.5%) in the DE group. The total duration of treatment interruption was 35 and 14 days in the SD and DE groups, respectively. The median time until liver dysfunction or diarrhea was day 28 and day 1 in the SD group, and day 53.5 and day 19 in the DE group, respectively. The cumulative dose of bosutinib was comparable between the SD and DE groups (51,700 vs. 53,550 mg, respectively). At 6 months, the median C0 was 63.7 ng/mL and 63.0 ng/mL in the SD and DE groups, respectively. Liver dysfunction (all grades) and diarrhea (>
grade 2) were prevalent in quartile 4 of C0 (>
91.0 ng/mL), as alculated by the total C0 distribution. Conclusions: The DE regimen was better suited to avoid treatment interruption. The daily dose of bosutinib might be adjusted based on target C0 to avoid adverse events by therapeutic drug monitoring in general practice. -
Mahon F.X.
Annals of Internal Medicine ( Annals of Internal Medicine ) 168 ( 7 ) 461 - 470 2018年04月 [査読有り]
研究論文（学術雑誌） 国際共著
Background: Treatment-free remission (TFR) - that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response - is an emerging treatment goal in chronic myeloid leukemia (CML). Objective: To evaluate TFR after discontinuation of second-line nilotinib therapy. Design: Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905) Setting: 63 centers in 18 countries. Patients: Adults with CML in chronic phase who received TKI therapy for at least 3 years (>
4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR. Interventions: Patients received nilotinib during consolidation
those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment. Measurements: Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point). Results: 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation. Limitation: The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment. Conclusion: TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib. -
Takahashi N.
International Journal of Hematology ( International Journal of Hematology ) 107 ( 2 ) 185 - 193 2018年02月 [査読有り]
研究論文（学術雑誌） 国内共著
The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again
all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan–Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in >
100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan. -
Hypoxia-inducible KDM3A addiction in multiple myeloma
Ikeda S.
Blood Advances ( Blood Advances ) 2 ( 4 ) 323 - 334 2018年02月 [査読有り]
研究論文（学術雑誌） 国内共著
In multiple myeloma (MM), the bone marrow (BM) microenvironment may contain a myeloma cell fraction that has acquired treatment resistance by undergoing an epigenetic gene expression change. Hypoxic stress is an important factor in the BM microenvironment. Recently, we demonstrated that miR-210 was upregulated in hypoxia and downregulated IRF4, which is known as an essential factor in myeloma oncogenesis in normoxia. In the study, we demonstrated that myeloma cells still showed a strong antiapoptotic phenotype despite IRF4 downregulation, suggesting that another antiapoptotic factor might be involved under hypoxic stress. To determine the factor or factors, we conducted gene expression analysis on myeloma cells (primary samples and cell lines) that were exposed to chronic hypoxia and observed upregulation of glycolytic genes and genes encoding H3K9 demethylases in myeloma cells with hypoxia. Among these, KDM3A was most significantly upregulated in all examined cells, and its knockdown induced apoptosis of myeloma cells in chronic hypoxia. Expression of KDM3A was dependent on HIF-1α, which is a transcription factor specifically upregulated in hypoxia. We further demonstrated that an essential target of KDM3A was a noncoding gene, MALAT1, whose upregulation contributed to acquisition of an antiapoptotic phenotype by accumulation of HIF-1α, leading to upregulation of glycolytic genes under hypoxia. This process was independent from IRF4. These results led us to conclude that the hypoxia-inducible HIF-1α-KDM3A-MALAT1 axis also contributes to acquisition of the antiapoptotic phenotype via upregulation of glycolysis-promoting genes. Thus, this axis is a promising therapeutic target against myeloma cells in the BM microenvironment.
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Kaga H.
Internal Medicine ( Internal Medicine ) 57 ( 1 ) 107 - 113 2018年01月 [査読有り]
研究論文（学術雑誌） 国内共著
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic inflammatory disorder categorized as small-vessel vasculitis. We herein report an elderly Japanese man with AAV (granulomatosis with polyangiitis affecting the eyes, nose, lungs, and kidneys) who also showed periaortitis at the diagnosis and developed cranial hypertrophic pachymeningitis (HP) during steroid maintenance therapy. His consciousness disturbance caused by HP improved after steroid pulse therapy, but he died of aspiration pneumonia. Autopsy findings showed giant cells in the thickened pachymeninges and obsolete inflammatory lesions in the aortic adventitia and renal tubulointerstitium. This is the first case of AAV complicated by periaortitis and cranial HP.
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Kitadate A.
Haematologica ( Haematologica ) 103 ( 1 ) 126 - 135 2018年01月 [査読有り]
研究論文（学術雑誌） 国内共著
Histone deacetylase inhibitors are promising agents for various Tcell lymphomas, including cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia. CCR4 is an important therapeutic target molecule because mogamulizumab, an anti-CCR4 antibody, has shown promising efficacy against various T-cell lymphomas. In this study, we examined the in vitro synergistic effects of mogamulizumab and histone deacetylase inhibitors against various T-cell lymphomas. First, we examined the expression of CCR4 mRNA and surface CCR4 in various T-cell lymphoma cell lines and found that it was downregulated upon treatment with vorinostat, a pan-histone deacetylase inhibitor. Next, we used isoform-specific histone deacetylase inhibitors and short-interfering RNA to determine the histone deacetylase isoform involved in the regulation of CCR4, and demonstrated that romidepsin, a class I selective histone deacetylase inhibitor, reduced CCR4 most efficiently. Moreover, among class I histone deacetylases, histone deacetylase 2 knockdown led to a reduction of CCR4 in lymphoma cells, suggesting that CCR4 expression is mainly regulated by histone deacetylase 2. When we examined the CCR4 expression in skin samples from primary cutaneous T-cell lymphoma, obtained from the same patients before and after vorinostat treatment, we found that CCR4 expression was greatly reduced after treatment. Finally, when we conducted an antibody-dependent cellmediated cytotoxicity assay with mogamulizumab by using various lymphoma cells, we found that the efficacy of mogamulizumab was significantly reduced by pretreatment with vorinostat. Altogether, our results suggest that the primary use of histone deacetylase inhibitors before treatment with mogamulizumab might not be suitable to obtain synergistic effects. Moreover, these results have potential implications for optimal therapeutic sequences in various CCR4-positive T-cell lymphomas.
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Abumiya M.
Leukemia Research ( Leukemia Research ) 64 42 - 45 2018年01月 [査読有り]
研究論文（学術雑誌） 国内共著
A simple and highly sensitive high-performance liquid chromatography (HPLC) method was developed for the quantification of ponatinib in human plasma. The developed HPLC method was validated based on International D.S. Food and Drug Administration guidelines. This technique utilized a solid-phase extraction step and required only 200 μL plasma for a single analysis. The lower limit of quantification for ponatinib was 1.0 ng/mL. Coefficients of variation and accuracies for intra- and interday assays were less than 10.8% and within 13.7%, respectively. The precision and accuracy of our HPLC assay was suitable for pharmacokinetic studies of ponatinib. On day 8 after beginning ponatinib therapy with an initial dose of 15 mg, patients having a ponatinib C0 of less than 23 ng/mL by HPLC may require a dose adjustment to 30 mg to obtain a C0 of 23 ng/mL of more. The median ponatinib C0 in 6 Japanese patients taking a 15 mg daily dose was 24.6 ng/mL, which was greater than the target concentration of 23 ng/mL, and that of patients taking 30 mg increased to a plasma concentration of 48.0 ng/mL. This novel treatment strategy using the HPLC method developed herein may be useful for routine ponatinib therapy.
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Jiang Z.P.
Pharmacogenomics ( Pharmacogenomics ) 18 ( 1 ) 35 - 56 2017年01月 [査読有り]
研究論文（学術雑誌） 国際共著
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Correlation between imatinib pharmacokinetics and clinical response in Japanese patients with chronic-phase chronic myeloid leukemia.
Takahashi N, Wakita H, Miura M, Scott SA, et al
Clin Pharmacol Ther. 2010年01月
研究論文（学術雑誌）
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Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia.
Takahashi N, Miura M, Scott SA, et al
J Hum Genet. 2010年01月
研究論文（学術雑誌）
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Early prediction of a long-term outcome by neutrophil-FISH in patients with CML receiving imatinib mesylate.
Takahashi N, Kameoka Y, Tagawa H, et al.
Int J Hematol. 2010年01月
研究論文（学術雑誌）
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Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia.
Yamanaka Y, Tagawa H, Takahashi N, et al.
Blood 2009年01月
研究論文（学術雑誌）
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Clinical significance of a single nucleotide polymorphism and&0d0a;allelic imbalance of matrix metalloproteinase-1&0d0a;promoter region in prostate cancer
Tsuchiya N, Narita S, Kumazawa S, Inoue T, Ma Z, Tsuruta H, Saito M, Horikawa Y, Yuasa T, Satoh S, Ogawa O, Habuchi T
Oncology Rreports 22 ( 3 ) 493 - 499 2009年01月
研究論文（学術雑誌）
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Drug related genetic polymorphisms affecting adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin in patients with urothelial cancer
Tsuchiya N, Inoue T, Narita S, Kumazawa T, Saito M, Obara T, Tsuruta H, Horikawa Y, Yuasa T, Satoh S, Habuchi T
J Urol 180 ( 6 ) 2389 - 2395 2008年01月
研究論文（学術雑誌）
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RIZ1 repression is associated with insulin-like growth factor-1 signaling activation in chronic myeloid leukemia cell lines.
Oncogene 8 ( 26(11) ) 1586 - 94 2007年01月
研究論文（学術雑誌）
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Impact of IGF-I and CYP19 gene polymorphisms on the survival of patients with metastatic prostate cancer
Tsuchiya N, Wang L, Suzuki H, Segawa T, Fukuda H, Narita S, Shimbo M, Kamoto T, Mitsumori K, Ichikawa T, Ogawa O, Nakamura A, Habuchi T
J Clin Oncol 24 ( 13 ) 1982 - 1989 2006年01月
研究論文（学術雑誌）
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Association of XRCC1 gene polymorphisms with the susceptibility and chromosomal aberration of testicular germ cell tumors
Tsuchiya N, Mishina M, Narita S, Kumazawa T, Inoue T, Horikawa Y, Kakinuma H, Yuasa T, Matsuura S, Satoh S, Ogawa O, Habuchi T
Int J Oncol 28 ( 5 ) 1217 - 1223 2006年01月
研究論文（学術雑誌）
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Hand assisted retroperitoneoscopic living donor nephrectomy in elderly donors
Tsuchiya N, Satoh S, Sato K, Iinuma M, Narita S, Inoue T, Matsuura S, Habuchi T
J Urol 175 ( 1 ) 230 - 234 2006年01月
研究論文（学術雑誌）
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Hand-assisted retroperitoneoscopic nephrectomy for living kidney transplantation: initial 44 cases
Urology 64(2), 250-254 2004年01月
研究論文（学術雑誌）
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Influence of CYP3A5 and MDR1(ABCB1) Polymorphisms on Pharmacokinetics of Tacrolimus in Renal Transplant Recipients
Transplantation 78(8), 1182-1187 2004年01月
研究論文（学術雑誌）
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CA Repeat Polymorphism in the Insulin-like Growth Factor-I Gene is Associated with increased risk of prostate cancer and benign prostatic hyperplasia
International Journal of Oncology 26: 225-231 2004年01月
研究論文（学術雑誌）
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Multilineage involvement in hypereosinophilic syndrome terminating in granulocytic sarcoma and leukaemic transformation with trisomy 8.
Br J Haematol. 119: 1-4 2002年01月
研究論文（学術雑誌）
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Clinical significance of alterations of chromosome 8 detected by FISH analysis in pathologic organ-confined prostate cancer.
Genes Chromosomes Cancer 34, 363-371 2002年01月
研究論文（学術雑誌）
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Mapping and gene expression profile of the minimally overrepresented 8q23-q24 region in prostate cancer.
Am J Pathol 160, 1799-1806 2002年01月
研究論文（学術雑誌）
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A clinicopathological study of 20 patients with T/natural killer (NK)-cell lymphoma-associated hemophagocytic syndrome with special reference to nasal and nasal-type NK/T-cell lymphoma.
Int J Hematol. 74(3):303-8 2001年01月
研究論文（学術雑誌）
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A clinical analysis of 52 adult patients with hemophagocytic syndrome: the prognostic significance of the underlying diseases.
Int J Hematol. 74(2):209-13 2001年01月
研究論文（学術雑誌）
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Molecular cytogenetics of stem cells: target cells of chromosome aberrations as revealed by the application of fluorescence in situ hybridization to fluorescence-activated cell sorting.
Int J Hematol. 72(3):310-7 2000年01月
研究論文（学術雑誌）
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Involvement of natural killer cells in patients with myelodysplastic syndrome carrying monosomy 7 revealed by the application of fluorescence in situ hybridization to cells collected by means of fluorescence-activated cell sorting.
Br J Haematol. 110(4):876-9 2000年01月
研究論文（学術雑誌）
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A PML/RARA chimeric gene on chromosome 2 in a patient with acute promyelocytic leukemia (M3) associated with a new variant translocation: t(2;15;17)(q21;q22;q21).
Cancer Genet Cytogenet. 120(1):80-2 2000年01月
研究論文（学術雑誌）
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Ph-negative non-Hodgkin's lymphoma occurring in chronic phase of Ph-positive chronic myelogenous leukemia is defined as a genetically different neoplasm from extramedullary localized blast crisis: report of two cases and review of the literature.
Leukemia 14(1):169-82 2000年01月
研究論文（学術雑誌）
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Molecular heterogeneity of the NUP98/HOXA9 fusion transcript in myelodysplastic syndromes associated with t(7;11)(p15;p15).
Br J Haematol. 107(3):600-4 1999年01月
研究論文（学術雑誌）
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Fluorescence in situ hybridization of progenitor cells obtained by fluorescence-activated cell sorting for the detection of cells affected by chromosome abnormality trisomy 8 in patients with myelodysplastic syndromes.
Blood 92(8):2886-92 1998年01月
研究論文（学術雑誌）
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Lineage involvement of stem cells bearing the Philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization.
Blood 92(12):4758-63 1998年01月
研究論文（学術雑誌）
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Molecular features of a new human lymphoma cell line carrying both BCL2 and BCL6 gene rearrangements.
Oncogene 17(8):971-9 1998年01月
研究論文（学術雑誌）
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A chromosomal alteration of inv(16)(p13q22) as an additional change to t(9;11)(p22;q23) in a patient with acute monoblastic leukemia (M5a).
Int J Hematol. 67(1):95-7 1998年01月
研究論文（学術雑誌）
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A new variant translocation of t(15;17) in a patient with acute promyelocytic leukemia (M3): t(15;19;17)(q22;p13;q12).
Cancer Genet Cytogenet. 102(1):15-8 1998年01月
研究論文（学術雑誌）
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Rearrangements of the BCL6 gene and chromosome aberrations affecting 3q27 in 54 patients with non-Hodgkin's lymphoma.&0d0a;
Leuk Lymphoma 27(3-4):329-34 1997年01月
研究論文（学術雑誌）
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Translocation (8;12;21)(q22.1;q24.1;q22.1): a new masked type of t(8;21)(q22;q22) in a patient with acute myeloid leukemia.
Cancer Genet Cytogenet. 96(2):111-4 1997年01月
研究論文（学術雑誌）
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A recurring translocation, t(3;6)(q27;p21), in non-Hodgkin's lymphoma results in replacement of the 5' regulatory region of BCL6 with a novel H4 histone gene.
Cancer Res. 57(1):7-12 1997年01月
研究論文（学術雑誌）
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Translocation (9;11;22)(p22;q23;q11). A new type of complex variant translocation of t(9;11)(p22;q23) with MLL rearrangement.&0d0a;
Cancer Genet Cytogenet. 88(1):26-9 1996年01月
研究論文（学術雑誌）
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Duplication of chromosome 9 carrying a BCR/ABL chimeric gene in Philadelphia chromosome negative chronic myeloid leukemia.
Cancer Genet Cytogenet. 89(2):166-9 1996年01月
研究論文（学術雑誌）
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Translocation (3;14)(q27;q11): a new variant translocation in a patient with non-Hodgkin's lymphoma of B-cell type with BCL6 rearrangement.
Cancer Genet Cytogenet. 90(1):49-53 1996年01月
研究論文（学術雑誌）
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11q23 aberration is an additional chromosomal change in de novo acute leukemia after treatment with etoposide and mitoxantrone.
Am J Hematol. 53(4):264-6 1996年01月
研究論文（学術雑誌）
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A new non-random chromosomal translocation t(3;6)(q27;p21.3) associated with BCL6 rearrangement in two patients with non-Hodgkin's lymphoma.
Int J Hematol. 64(3-4):249-56 1996年01月
研究論文（学術雑誌）
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Bone and brain involvement in a case of diffuse large B cell lymphoma associated with t(2;3)(p12;q27).
Int J Hematol. 62(4):247-52. 1995年01月
研究論文（学術雑誌）
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Acute myelogenous leukemia associated with a mediastinal tumor.
Leuk Lymphoma 12(1-2):143-6 1993年01月
研究論文（学術雑誌）