研究等業績 - その他 - 髙橋　直人

Comparative proteomic analysis of glomerular proteins in primary and bucillamine-induced membranous nephropathy

Kaga H.

Clinical Proteomics ( Clinical Proteomics )  19 ( 1 )   2022年12月

DOI

Evaluation of protein production in rice seedlings under dark conditions

Watanabe A.

Scientific Reports ( Scientific Reports )  12 ( 1 )   2022年12月

DOI

Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial

Imamura K.

eClinicalMedicine ( eClinicalMedicine )  53   2022年11月

DOI

Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial

今村 恵子, 和泉 唯信, 永井 真貴子, 西山 和利, 渡辺 保裕, 花島 律子, 江川 斉宏, 綾木 孝, 沖 良祐, 藤田 浩司, 魚住 龍史, 森永 明子, 廣橋 朋子, 藤井 陽介, 山本 拓也, 建部 陽嗣, 徳田 隆彦, 高橋 直人, 森田 智視, 髙橋 良輔, 井上 治久

eClinicalMedicine ( Elsevier BV )  53   2022年11月

[Background] Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS. [Methods] An open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1–3 points during the 12-week, received escalating doses starting from 100 mg quaque die (QD) up to 400 mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study. [Findings] Between March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but DLTs were observed in 3/3 patients of the 400 mg QD cohort. In all patients receiving 100 mg–400 mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib. [Interpretation] This is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300 mg, not 400 mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required.

CiNii Research

High baseline total lesion glycolysis predicts early progression of disease within 24 months in patients with high-tumor-burden follicular lymphoma

Kuroki W.

International Journal of Hematology ( International Journal of Hematology )  116 ( 5 ) 712 - 722   2022年11月

Despite the introduction of rituximab-containing regimens, approximately 20% of patients with follicular lymphoma (FL) still experience progression of disease within 24 months (POD24) and have poor overall survival. Therefore, a more accurate risk assessment tool is required. We investigated the predictive value of two new volume-based parameters determined from baseline 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), baseline total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG), in 45 patients with high-tumor-burden FL who underwent baseline PET/CT. We observed that high TMTV, high TLG, and poor initial treatment response (less than complete [metabolic] response [non-CR/CMR] at the end of induction therapy) independently predicted poor PFS. Notably, POD24-positive patients were more common in the high-TLG group than in the high-TMTV group, which suggests that TLG is a stronger predictor of outcomes than TMTV. Combining baseline TLG and initial treatment response showed that patients with both high TLG and non-CR/CMR experienced significantly poorer outcomes, with a 2 year PFS of 0% (hazard ratio 60.39, P = 0.000002). This combination had 56% sensitivity and 100% specificity for detecting patients who would experience POD24. Baseline TLG and initial treatment response can precisely identify patients at high risk of POD24.

DOI PubMed

膜性腎症・V型ループス腎炎におけるExostosin1/Exostosin2の検討

今泉 ちひろ, 橋本 眞子, 阿部 史人, 加賀 一, 齋藤 綾乃, 齋藤 雅也, 奈良 瑞穂, 高橋 直人

秋田腎不全研究会誌 ( 秋田腎不全研究会 )  25   33 - 37   2022年11月

単純型血漿交換とリツキシマブが有効であったIgM・IgG型温式抗体を有するEvans症候群

藤田 菜々子, 亀岡 吉弘, 齋藤 綾乃, 齋藤 雅也, 藤岡 優樹, 鵜生川 久美, 奈良 美保, 高橋 直人

臨床血液 ( (一社)日本血液学会-東京事務局 )  63 ( 11 ) 1590 - 1590   2022年11月

膜性腎症・V型ループス腎炎におけるExostosin1/Exostosin2の検討

今泉 ちひろ, 橋本 眞子, 阿部 史人, 加賀 一, 齋藤 綾乃, 齋藤 雅也, 奈良 瑞穂, 高橋 直人

秋田腎不全研究会誌 ( 秋田腎不全研究会 )  25   33 - 37   2022年11月

当院と関連施設で1990～2020年に腎生検を施行された症例のうち、膜性腎症と診断された374例と、V型ループス腎炎と診断された66例を対象とし、Exostosin(EXT)1/2の検出率について調査した。結果、膜性腎症患者のうちPLA2R陽性例(98例)でEXT1/2が検出されたものは1例もなく、PLA2R陰性例(174例)ではEXT1/2が4例(2%)で検出された。ループス腎炎患者では19例(29%)でEXT1/2が検出された。ループス腎炎患者をEXT1/2陽性群と陰性群に分け、ネフローゼ症候群の合併率、細胞増殖性病変の合併率、腎障害の程度、抗ds-DNA抗体陽性率、低補体血症の合併率などについて群間比較した結果、いずれも有意差は認められなかった。

Quantitation of Venetoclax in Human Plasma by High-Performance Liquid Chromatography with Ultraviolet Detection

Natsuki Fukuda, Takahiro Kobayashi, Honami Sato, Yumiko Akamine, Naoto Takahashi, Masatomo Miura

Journal of Chromatographic Science ( Oxford University Press (OUP) )  62 ( 1 ) 58 - 64   2022年10月

Abstract

A simple, highly sensitive and specific method based on high-performance liquid chromatography (HPLC) with ultraviolet detection was developed for the measurement of venetoclax concentrations in plasma samples. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH2PO4 (pH 3.5) (80/20, v/v) on a CAPCELL PAK C18 UG120 column at a flow rate of 0.5 mL/min. The quantitative method was validated based on standards described in “Bioanalytical Method Validation: Guidance for Industry” published by the US Food and Drug Administration. The separation of venetoclax and the internal standard R051012 was satisfactory, and the chromatograms were free of interfering peaks from the biological matrix. The intra- and inter-day coefficients of variation for venetoclax assays were <12.9%, whereas intra- and inter-day accuracies were within 13.6%. Only 100 μL of human plasma was required to detect a lower limit of quantification of 10 ng/mL for venetoclax. The recoveries of venetoclax extracted with an Oasis HLB cartridge were between 81 and 85%. The developed HPLC method was successfully applied to the determination of venetoclax concentrations in plasma of acute myeloid leukemia patients taking venetoclax. The degree of drug interactions between venetoclax and CYP3A4 inhibitors can be determined by this HPLC assay.

DOI

コロナワクチン2回目接種直後にIgA血管炎を発症した一例

和田 邦宏, 澤村 昌人, 橋本 眞子, 阿部 史人, 加賀 一, 斉藤 綾乃, 斉藤 雅也, 小松田 敦, 高橋 直人

日本腎臓学会誌 ( (一社)日本腎臓学会 )  64 ( 6-E ) 545 - 545   2022年10月

CML-423 Trial in Progress: A Phase III Study of Asciminib vs an Investigator-Selected Tyrosine Kinase Inhibitor (TKI) in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Hughes T.P.

Clinical Lymphoma, Myeloma and Leukemia ( Clinical Lymphoma, Myeloma and Leukemia )  22   S297 - S298   2022年10月

DOI

秋田県腎生検症例におけるExostosin1/Exostosin2の検討

今泉 ちひろ, 阿部 史人, 加賀 一, 齋藤 綾乃, 齋藤 雅也, 高橋 直人

日本臨床免疫学会総会プログラム・抄録集 ( (一社)日本臨床免疫学会 )  50回   103 - 103   2022年10月

Long-term prognosis of monoclonal immunoglobulin-associated glomerular diseases with non-organized deposits: A report of 38 cases from a Japanese single center

Nara M.

Clinical Nephrology ( Clinical Nephrology )  98 ( 3 ) 135 - 146   2022年09月

Monoclonal immunoglobulin (MIg)-associated glomerular diseases with non-organized deposits are rare disorders. They have recently been categorized into light chain deposit disease (LCDD), light and heavy chain deposit disease (LHCDD), heavy chain deposit disease (HCDD), proliferative glomerulonephritis with MIg deposits (PGNMID) and its light chain only variant (PGNMID-LC), and membranous glomerulopathy with light chain-restricted deposits (MG-LC). In our Japanese cohort of more than 9,500 patients who underwent renal biopsy (1979 - 2020), we evaluated clinicopathological features and long-term outcomes in 38 patients with MIg-associated glomerular diseases with non-organized deposits: LCDD (n = 9), LHCDD (n = 8), HCDD (n = 5), PGNMID-membranoproliferative glomerulonephritis (MPGN) (n = 7), PGNMID-LC (n = 2), and MG-LC (n = 7). In patients with LCDD, a low estimated glomerular filtration rate (eGFR) at biopsy, a high detection rate of urinary MIgs, a high incidence rate of multiple myeloma, and sever tubulointerstitial and vascular lesions were significant clinicopathological characteristics. Median duration of follow-up in each group was 42 - 114 months. Most patients were treated with steroid-based therapy. Patients with LCDD, LHCDD, HCDD, and MG-LC were recently treated with bortezomib-based therapy. Renal survival rate was significantly shorter for LCDD than of PGNMID and MG-LC. Patient survival rate was significantly longer for MG-LC than HCDD and PGNMID. Major causes of death were pulmonary and cardiovascular complications. Among disease groups, significant differences were observed in eGFR at biopsy, detection rates of urinary MIgs, incidence rates of multiple myeloma, severities of tubulointerstitial and vascular lesions, and long-term outcomes.

DOI PubMed

Safe administration and pharmacokinetic monitoring of crushed venetoclax tablets with posaconazole and clarithromycin via percutaneous endoscopic gastrostomy tube in a patient with acute myeloid leukemia

Sato H.

Cancer Chemotherapy and Pharmacology ( Cancer Chemotherapy and Pharmacology )  90 ( 3 ) 279 - 284   2022年09月

PURPOSE: Leukemic stem cells in acute myeloid leukemia (AML) express high B cell lymphoma 2 (BCL2) levels, which contribute to leukemic cell survival and resistance to therapy. Venetoclax-a BCL-2 inhibitor-is indicated for the treatment of AML, which may also target leukemic stem cells; however, it is only available as a tablet. There are no reports of venetoclax use in patients who cannot take oral drugs; therefore, the efficacy, safety, and pharmacokinetics (PK) of venetoclax administered through a gastrostomy tube is unknown. CASE PRESENTATION: We report, for the first time, a case of relapsed Japanese AML patient treated with crushed venetoclax tablets through a percutaneous endoscopic gastrostomy (PEG) tube because of esophageal stricture due to complications of stem cell transplantation. The patient was also taking posaconazole and clarithromycin concomitantly. We evaluated the plasma concentrations of venetoclax administered through a PEG tube. Time to maximum concentration, maximum plasma concentration, and the area under the plasma concentration-time curve were similar to the previously reported PK parameters after oral administration of intact venetoclax tablets in Japanese patients with AML. The clinical course passed safely without the occurrence of unexpected adverse events during the administration of crushed venetoclax tablets in combination with azacitidine. CONCLUSIONS: The PK parameters of the crushed administered venetoclax via PEG tube was similar to the previously reported PK parameters of the orally administered venetoclax. Therefore, administration of crushed venetoclax tablets through a PEG tube could be an alternate route for patients who have difficulty with oral administration.

DOI PubMed

EMD originates from hyaluronan-induced homophilic interactions of CD44 variant-expressing MM cells under shear stress

Jiro Kikuchi, Nobuyuki Kodama, Masataka Takeshita, Sho Ikeda, Takahiro Kobayashi, Yoshiaki Kuroda, Michihiro Uchiyama, Naoki Osada, Bjarne Bogen, Hiroshi Yasui, Naoto Takahashi, Akiyoshi Miwa, Yusuke Furukawa

Blood Advances ( American Society of Hematology )  7 ( 4 ) 508 - 524   2022年08月

Extramedullary disease (EMD) is known to be associated with chemoresistance and poor prognosis in multiple myeloma (MM); however, the mechanisms of its development are not fully understood. Elucidating the mechanism of EMD development and its therapeutic targeting would greatly contribute to further improvement of treatment outcome in MM patients. Here, we show that bone marrow stroma cell-derived hyaluronan elicits homophilic interactions of MM cells by binding to surface CD44, especially long-stretch variants, under physiological shear stress and generates cell clusters that might develop into EMD. We recapitulated the development of EMD via administration of hyaluronan in a syngeneic murine MM model in a CD44-dependent manner. Hyaluronan-induced MM cell clusters exhibited the specific resistance to proteasome inhibitors (PIs) in vitro and in murine models via γ-secretase-mediated cleavage of the intracellular domains of CD44, which in turn transactivated PI resistance-inducible genes. Treatment of hyaluronan-injected mice with anti-CD44 antibody or γ-secretase inhibitors readily suppressed the development of EMD from transplanted MM cells and significantly prolonged the survival of recipients by overcoming PI resistance. The hyaluronan-CD44 axis represents a novel pathway to trigger EMD development and could be a target of the prediction, prevention, and treatment of EMD in MM patients.

DOI

Evaluation of a newly proposed renal risk score for Japanese patients with ANCA-associated glomerulonephritis

Saito M.

Clinical and Experimental Nephrology ( Clinical and Experimental Nephrology )  26 ( 8 ) 760 - 769   2022年08月

BACKGROUND: We determined the usefulness and prognostic ability of the renal risk score (RRS), proposed in Europe, for Japanese patients with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) and high myeloperoxidase (MPO)-ANCA positivity; these aspects remain to be verified. METHODS: This retrospective study was conducted on 86 Japanese patients with new, biopsy-confirmed AAGN. We calculated the RRS and analyzed the relationship between this classification, and clinicopathological features and prognosis. We also compared the predictive values between RRS for endpoints including renal death and conventional prognostic tools for patients with AAGN. RESULTS: There were 33, 37, and 16 patients in the low-, medium-, and high-risk groups, respectively. All patients were MPO-ANCA positive. The median follow-up period was 33 months; 16 (18.6%) patients progressed to end-stage renal disease (ESRD). In the high-risk group, 9/16 (56.3%) patients progressed to ESRD, and renal prognosis was significantly poorer than that in other groups (low-risk group, P < 0.001; medium-risk group, P = 0.004). In Cox multivariate regression analysis, RRS was an independent, poor renal prognostic factor (hazard ratio 5.22; 95% confidence interval 2.20-12.40; P < 0.001). The receiver-operating characteristic curves of the RRS for each endpoint were comparable with those of the 2010 histological classification and those of the severity classification of Japanese rapidly progressive glomerulonephritis. CONCLUSIONS: This is the first study to report the usefulness of the RRS for predicting renal outcomes among Japanese patients with AAGN. Our predictive value of the RRS was comparable with that of conventional prognostic tools.

DOI PubMed

Refractory IgG4-related disease complicated with organising pneumonia and hypertrophic pachymeningitis

Abe F.

Modern Rheumatology Case Reports ( Modern Rheumatology Case Reports )  6 ( 2 ) 278 - 281   2022年06月

IgG4-related disease (IgG4-RD) involves multiple organs, including the lungs and central nervous system. Lung lesions are frequently reported as mass lesions or non-specific interstitial pneumonia, whereas organizing pneumonia (OP) due to IgG4-RD is rare. Furthermore, limited information is currently available on hypertrophic pachymeningitis (HP). We herein report a case of IgG4-RD complicated with OP and HP. The diagnosis was confirmed based on the serum concentration of IgG4 and the results of salivary gland and transbronchial lung biopsies. HP did not respond to steroid monotherapy and was also resistant to rituximab and intravenous cyclophosphamide; however, the combination therapy of methotrexate and dexamethasone was effective.

DOI PubMed

脾臓浸潤による非外傷性脾破裂をきたし剖検で確定診断した血管内大細胞型B細胞リンパ腫

黒木 航, 小林 敬宏, 馬越 通信, 北舘 明宏, 今泉 ちひろ, 齋藤 雅也, 小林 五十鈴, 藤島 眞澄, 藤島 直仁, 吉岡 智子, 後藤 明輝, 高橋 直人

臨床血液 ( (一社)日本血液学会-東京事務局 )  63 ( 6 ) 523 - 529   2022年06月

非外傷性脾破裂(ASR)は悪性リンパ腫の致死的合併症である。血管内大細胞型B細胞リンパ腫(IVLBCL)に伴うASR(IVLBCL-ASR)の報告は過去に1例のみで,その機序は不明な点が多い。今回我々は,剖検所見からIVLBCL-ASRと診断した1例を報告する。症例は78歳男性。IVLBCLの精査中に出血性ショックのため突然死し,剖検所見で大量の血性腹水と脾破裂を認めた。全身の小血管内にCD20陽性大型異型リンパ球の浸潤を認めIVLBCLと診断し,腫瘍細胞浸潤は裂創部位を含めた脾被膜部ではわずかで脾臓中心部で著明で,脾中心部での腫瘍増殖による脾内圧亢進がASRの原因と考えられIVLBCL-ASRと確定診断した。患者は入院3ヵ月前に舌がんの精査目的で施行された18F-FDGPET/CT検査で右副腎に異常集積を認めており,病理所見では同部位に一致して腫瘍浸潤を認めた。IVLBCLの早期診断における18F-FDG PET/CT検査の有用性を再認識し,IVLBCLの進行に伴いASRの発症リスクが上昇することが示唆され,早期の全身化学療法の実施が重要であると考えられた。(著者抄録)

Relationship between achievement of major molecular response or deep molecular response and nilotinib plasma concentration in patients with chronic myeloid leukemia receiving first-line nilotinib therapy

Fukuda N.

Cancer Chemotherapy and Pharmacology ( Cancer Chemotherapy and Pharmacology )  89 ( 5 ) 609 - 616   2022年05月

DOI

ネフローゼ症候群に対するリツキシマブ維持療法の有効性と安全性の検討

加賀 一, 橋本 眞子, 阿部 史人, 齋藤 綾乃, 齋藤 雅也, 奈良 瑞穂, 涌井 秀樹, 高橋 直人

日本腎臓学会誌 ( (一社)日本腎臓学会 )  64 ( 3 ) 266 - 266   2022年05月