研究等業績 - 原著論文 - 髙橋 直人
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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.