研究等業績 - その他 - 髙橋 直人
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半月体を形成する糖尿病性腎症の臨床病理学的検討
齋藤 綾乃, 加賀 一, 齋藤 雅也, 阿部 史人, 奈良 瑞穂, 富樫 賢, 小松田 敦, 涌井 秀樹, 高橋 直人
秋田腎不全研究会誌 ( 秋田腎不全研究会 ) 20 43 - 47 2017年11月
腎生検で診断した糖尿病性腎症患者を対象とし、半月体形成を伴う群20例(男性16例、女性4例、36.0〜81.0歳)、伴わない群43例(男性31例、女性12例、18.5〜40.8歳)であった。腎生検時の年齢、BMI、血圧、尿蛋白、尿潜血、eGFR、HbA1c、総コレステロール値、C-reactive protein、糖尿病性網膜症の有無、降圧薬内服の有無、および腎予後について調査した。腎予後は透析導入をエンドポイントとした。臨床データは全ての項目で2群間に有意差を認めなかった。病理学的所見では糸球体病変がClass III(結節病変を伴う糸球体)の割合が半月体形成群で有意に高く、糸球体基底膜のIgG沈着も半月体形成群で有意に高かった。腎生存率は2群間で有意差を認めなかった。
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Niioka T.
Therapeutic Drug Monitoring ( Therapeutic Drug Monitoring ) 39 ( 5 ) 514 - 521 2017年10月
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Relationship Between the CYP2C19 Phenotype Using the Voriconazole-to-Voriconazole N-Oxide Plasma Concentration Ratio and Demographic and Clinical Characteristics of Japanese Patients With Different CYP2C19 Genotypes
Takenori Niioka, Naohito Fujishima, Maiko Abumiya, Takaya Yamashita, Kumi Ubukawa, Miho Nara, Masumi Fujishima, Naoto Takahashi, Masatomo Miura
THERAPEUTIC DRUG MONITORING ( LIPPINCOTT WILLIAMS & WILKINS ) 39 ( 5 ) 514 - 521 2017年10月
Background: Although voriconazole (VRCZ) is metabolized to VRCZ N-oxide principally by CYP2C19, VRCZ clearance is affected by multiple factors. In this study, we investigated the relationship between the CYP2C19 phenotype using the VRCZ-to-VRCZ N-oxide plasma concentration ratio (VRCZ/N-oxide) and demographic and clinical characteristics of Japanese patients taking VRCZ.
Methods: A total of 65 Japanese patients taking VRCZ for prophylaxis or treatment of fungal infection were enrolled in this study. Stepwise selection multiple linear regression analysis was performed to investigate the effect of factors on the VRCZ/N-oxide ratio.
Results: In patients not undergoing concurrent treatment with a drug influencing CYP2C19 activity (n = 54), the VRCZ/N-oxide ratio with definite thresholds for CYP2C19 genotypes, CYP2C19*1/ *1, *1/*2 + *1/*3 + *2/*17, and *2/*2 + *2/*3, was specifically identified in patients taking VRCZ (<0.48, >= 0.48, and <0.82 and >= 0.82). However, the VRCZ/N-oxide ratio could not be predicted based solely on the CYP2C19 genotype (R-2 = 0.053). The route of VRCZ administration, C-reactive protein concentration determined on the same day as VRCZ plasma concentration measurement, CYP2C19 extensive metabolizer, and patient age were independent factors influencing the VRCZ/N-oxide ratio (R-2 = 0.489, standard-ized regression coefficient = 0.385, 0.380, 20.231, and 0.231; P = 0.001, 0.001, 0.032, and 0.036, respectively).
Conclusions: It is possible to comprehensively evaluate CYP2C19 activity using the actual measured value of the VRCZ/N-oxide ratio in patients taking VRCZ. The predictive performance of the VRCZ/ N-oxide ratio was improved by including the route of administration, C-reactive protein level, and patient age in addition to the CYP2C19 genotype as predictive factors. -
Doki N.
Annals of Hematology ( Annals of Hematology ) 96 ( 9 ) 1517 - 1523 2017年09月
Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2 weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (<2), intermediate (2, 3), and high (>3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, p = 0.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, p = 0.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (p < 0.01) and a lower tendency for Bacteroidetes (p = 0.106) than non-aGVHD patients. Maintenance of Bacteroidetes throughout allo-HSCT may be a strategy to prevent aGVHD.
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Takahashi N.
International Journal of Hematology ( International Journal of Hematology ) 106 ( 3 ) 398 - 410 2017年09月
This long-term follow-up of a completed phase 1/2 study assessed the safety and efficacy of bosutinib in Japanese Philadelphia chromosome-positive, chronic phase (CP) or advanced phase (ADV) chronic myeloid leukemia patients who were resistant/refractory or intolerant to prior tyrosine kinase inhibitor treatment. This analysis included 63 patients with a median bosutinib follow-up of 132 weeks (range 3aEuro'372). In the CP second-line (2L) cohort, the cumulative major cytogenetic response (MCyR) and major molecular response (MMR) rates throughout the study were 73 and 53%, respectively. In the CP third-line (3L) cohort, the cumulative MCyR and MMR rates throughout the study were 70 and 40%, respectively. Of the eight ADV patients, MCyR was attained or maintained by 50% of patients, and complete hematologic response was attained or maintained by 25% of patients. Progression-free survival rate and overall survival rate at 96 weeks were, respectively, 91 and 98% in CP2L, 88 and 100% in CP3L, and 33 and 50% in ADV patients. The most common adverse events (> 50%) reported were diarrhea (95%), nasopharyngitis (57%), and rash (57%). Bosutinib demonstrated durable efficacy and a manageable tolerability profile over long-term use in Japanese patients.
ClinicalTrials.gov: NCT00811070. -
Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study
Tojo A.
International Journal of Hematology ( International Journal of Hematology ) 106 ( 3 ) 385 - 397 2017年09月
In this ongoing Phase 1/2 study (NCT01667133), we evaluated ponatinib and assessed its recommended dose in Japanese patients with chronic myeloid leukemia (CML) resistant/intolerant to dasatinib or nilotinib, or with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) resistant/intolerant to ≥1 tyrosine kinase inhibitor (TKI). The primary endpoints were safety of the recommended dose (Phase 1) and major cytogenetic response (MCyR) by 12 months in chronic-phase CML (CP-CML) patients or major hematologic response (MaHR) by 6 months in patients with advanced phase disease (Phase 2). MCyR was achieved/maintained by 12 months in 65% of CP-CML patients
MaHR was achieved by 6 months in 61% of patients with advanced phase disease. The most common nonhematologic grade 3/4 treatment-emergent adverse event (AE) was hypertension (37%)
common hematologic grade 3/4 AEs were thrombocytopenia (57%), neutropenia (34%), and leukopenia (26%). Overall, five (14%) patients experienced arterial occlusive events (AOEs)
no grade 5 AOEs were reported. The steady-state accumulation ratio of ponatinib (based on area under the curve) ranged from 2.6 (15 mg/day) to 1.3 (45 mg/day). In summary, ponatinib demonstrated efficacy in Japanese patients with CML and Ph+ALL resistant/intolerant to prior TKI treatment
safety data support a recommended starting dose of 45 mg/day in these patients. -
Nara M.
American Journal of Nephrology ( American Journal of Nephrology ) 46 ( 3 ) 187 - 194 2017年09月
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T細胞リンパ腫においてHDAC阻害剤はCCR4発現を減少させモガムリズマブの作用を減弱させる
北舘 明宏, 池田 翔, 阿部 史人, 手島 和暁, 高橋 直人, 末永 孝生, 田川 博之
日本癌学会総会記事 ( 日本癌学会 ) 76回 E - 2025 2017年09月
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低酸素環境における骨髄腫細胞の生存はH3K9脱メチル化酵素KDM3Aに依存する
池田 翔, 北舘 明宏, 阿部 史人, 高橋 直人, 田川 博之
日本癌学会総会記事 ( 日本癌学会 ) 76回 J - 3036 2017年09月
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悪性リンパ腫におけるイノシトールリン脂質プロファイル
阿部 史人, 中西 広樹, 北舘 明宏, 池田 翔, 亀岡 吉弘, 高橋 直人, 佐々木 雄彦, 田川 博之
日本癌学会総会記事 ( 日本癌学会 ) 76回 P - 2236 2017年09月
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早期LCDDに対してVRD療法が奏功した一例
齋藤 綾乃, 池田 翔, 伊藤 香里, 阿部 史人, 奈良 瑞穂, 奥山 慎, 涌井 秀樹, 小松田 敦, 高橋 直人
日本腎臓学会誌 ( (一社)日本腎臓学会 ) 59 ( 6 ) 893 - 893 2017年09月
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Ph陽性ALLに対するチロシンキナーゼ阻害剤の役割と臨床効果 (特集 急性リンパ芽球性白血病(ALL)の病態と診療 : 最近の展開)
山下 鷹也, 髙橋 直人
血液内科 = Hematology ( 科学評論社 ) 75 ( 3 ) 287 - 293 2017年09月
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Honma M.
Applied Optics ( Applied Optics ) 56 ( 21 ) 5849 - 5856 2017年07月
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同種造血幹細胞移植前にruxolitinibで脾腫のコントロールを行った多血症線維化期から移行した急性骨髄性白血病
藤島 眞澄, 藤島 直仁, 北舘 明宏, 郭 永梅, 渡部 敦, 鵜生川 久美, 奈良 美保, 吉岡 智子, 亀岡 吉弘, 高橋 直人
臨床血液 ( (一社)日本血液学会-東京事務局 ) 58 ( 7 ) 743 - 748 2017年07月
症例は64歳女性(移植時年齢)。移植の7年前に真性多血症(JAK2 V617F変異陽性)と診断,2年前に脾腫が増悪しruxolitinibを開始した。汎血球減少のためruxolitinibを中止したところ,脾臓の増大と骨髄線維化を伴う白血化を認め,多血症後線維化期から移行した急性骨髄性白血病と診断した。寛解導入療法により完全寛解が得られたが,脾臓は季肋下8横指触知する状態であった。地固め療法2コース後にruxolitinibを再投与し,脾臓が縮小した時点で非血縁ドナーから末梢血幹細胞移植を行った。Ruxolitinibは移植前日まで継続した。Day 13に好中球生着が得られた後,withdrawal symptomと考えられる脾臓の再増大がみられたが一時的であった。脾腫は同種造血幹細胞移植における生着不全・移植関連死のリスク因子となるが,移植前の摘脾や照射は侵襲性が問題となる。Ruxolitinibは脾腫を非侵襲的に改善するため,移植前まで継続することにより,脾臓の縮小による生着率の向上が期待される。(著者抄録)
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Tajima K.
Leukemia and Lymphoma ( Leukemia and Lymphoma ) 58 ( 6 ) 1509 - 1511 2017年06月
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虚血性持続勃起症(Priapism)を契機に発見された急性骨髄性白血病とWaldenstrom's-macroglobulinemiaの重複例
永沼 綾子, 菊地 優子, 長谷山 佳菜, 小野 杏子, 小林 毅, 小林 則子, 北舘 明宏, 亀岡 吉弘, 高橋 直人, 廣川 誠
日本検査血液学会雑誌 ( (一社)日本検査血液学会 ) 18 ( 学術集会 ) S182 - S182 2017年06月
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Yokoyama H.
International Journal of Hematology ( International Journal of Hematology ) 105 ( 5 ) 606 - 613 2017年05月
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Drug interaction between tacrolimus and nilotinib in a patient with chronic myeloid leukemia after renal transplant.
Takashi Onaka, Naoto Takahashi, Masatomo Miura, Akihito Yonezawa
Clinical case reports 5 ( 5 ) 605 - 607 2017年05月
Nilotinib, a BCR-ABL tyrosine kinase inhibitor, is a known inhibitor of CYP3A4 and could increase the concentration of drugs metabolized by CYP3A4. An immunosuppressive drug for nilotinib-treated patients following transplant should be administered with careful pharmacokinetic monitoring because of its interaction with nilotinib.
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Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma
Sho Ikeda, Akihiro Kitadate, Fumito Abe, Hirobumi Saitoh, Yoshihiro Michishita, Yoshiaki Hatano, Yoshinari Kawabata, Atsushi Kitabayashi, Kazuaki Teshima, Masaaki Kume, Naoto Takahashi, Hiroyuki Tagawa
Cancer Science ( Blackwell Publishing Ltd ) 108 ( 4 ) 641 - 652 2017年04月
Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti-apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 (IRF4), an essential transcription factor in myeloma oncogenesis. To identify essential microRNAs and their targets regulated under hypoxic conditions, we undertook microRNA and cDNA microarray analyses using hypoxia-exposed primary MM samples and myeloma cell lines. Under hypoxia, only miR-210 was highly upregulated and was accompanied by direct downregulation of an 18S rRNA base methyltransferase, DIMT1. This inverse expression correlation was validated by quantitative RT-PCR for primary MM samples. We further determined that DIMT1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia-inducible microRNA-210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM.
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Long-term prognosis of AL and AA renal amyloidosis: a Japanese single-center experience
Ozawa M.
Clinical and Experimental Nephrology ( Clinical and Experimental Nephrology ) 21 ( 2 ) 212 - 227 2017年04月
Few studies have been conducted on the long-term prognosis of patients with amyloid light chain (AL) and amyloid A (AA) renal amyloidosis in the same cohort.
We retrospectively examined 68 patients with biopsy-proven renal amyloidosis (38 AL and 30 AA). Clinicopathological findings at the diagnosis and follow-up data were evaluated in each patient. We analyzed the relationship between clinicopathological parameters and survival data.
Significant differences were observed in several clinicopathological features, such as proteinuria levels, between the AL and AA groups. Among all patients, 84.2 % of the AL group and 93.3 % of the AA group received treatments for the underlying diseases of amyloidosis. During the follow-up period (median 18 months in AL and 61 months in AA), 36.8 % of the AL group and 36.7 % of the AA group developed end-stage renal failure requiring dialysis, while 71.1 % of the AL group and 56.7 % of the AA group died. Patient and renal survivals were significantly longer in the AA group than in the AL group. eGFR of > 60 mL/min/1.73 m(2) at biopsy and an early histological stage of glomerular amyloid deposition were identified as low-risk factors. A multivariate analysis showed that cardiac amyloidosis and steroid therapy significantly influenced patient and renal survivals.
Our results showed that heart involvement was the major predictor of poor outcomes in renal amyloidosis, and that the prognosis of AA renal amyloidosis was markedly better than that in previously reported cohorts. Therapeutic advances in inflammatory diseases are expected to improve the prognosis of AA amyloidosis.