Kooperativer Bibliotheksverbund

In: Neurobiology of Disease, Elsevier BV, Vol. 19, No. 3 ( 2005-08), p. 378-385

Type of Medium: Online Resource

ISSN: 0969-9961

URL: Article

DOI: 10.1016/j.nbd.2005.01.021

Language: English

Publisher: Elsevier BV

Publication Date: 2005

detail.hit.zdb_id: 1471408-5

SSG: 12

In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)

Abstract: Introduction: Atrial fibrillation (AF) activates coagulation system leading to hypercoagulation of the blood. However, it is still unknown whether rapid atrial excitation per se affects gene expression remotely in the liver, the major source of coagulation factors and other prothrombotic molecules. Methods and Results: The AF model was created by rapid atrial pacing at the frequency of 1200 bpm in anesthetized 10-week-old Sprague-Dawley rats. The livers and peripheral blood cells were collected and analyzed after the pacing of 12 hours. Sham-operated rats underwent the identical procedure without electrical stimulation. DNA microarray revealed marked changes in hepatic gene expression after 12 hours atrial pacing. Hierarchical clustering with 13871 filtered genes or genes related to coagulation including fibrinogen, demonstrated clusters for the pacing or sham. The quantitative RT-PCR focused on prothrombotic molecules revealed that rapid atrial pacing significantly augmented the hepatic mRNA expressions of fibrinogen α, β, γ-chain, prothrombin, antithrombin-III, plasminogen, and coagulation factor X. The increase of fibrinogen protein in the liver was also confirmed by Western blotting (Figure A). We further investigated the mechanism of enhanced fibrinogen production and identified increased IL-6 mRNA expression in the peripheral blood cells by rapid atrial pacing (Figure B). IL-6 was also prominent in CD11b positive cells infiltrated in the liver, and possibly promoted STAT3 phosphorylation in the nuclei of hepatocytes (Figure C). Conclusions: The rapid atrial excitation mimicking paroxysmal AF altered the hepatic gene expressions of prothrombotic molecules. Increased fibrinogen expression in the liver was accompanied by activation of IL-6/STAT3 signaling pathway in the peripheral blood and the liver. These findings might imply the cardio-hepatic interaction in AF and provide new insight into the prevention of AF-related thromboembolism.

Type of Medium: Online Resource

ISSN: 0009-7322 , 1524-4539

URL: Article

DOI: 10.1161/circ.130.suppl_2.12559

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2014

detail.hit.zdb_id: 1466401-X

In: Journal of Cardiovascular Electrophysiology, Wiley, Vol. 29, No. 12 ( 2018-12), p. 1616-1623

Abstract: A novel real‐time lesion size index (LSI) that incorporates contact force (CF), time, and power has been developed for safe and effective catheter ablation. The optimal LSI was evaluated to eliminate gap formation during pulmonary vein isolation (PVI). Methods and Results Consecutive patients were enrolled, who underwent their first PVI using a fiber‐optic CF‐sensing catheter for atrial fibrillation between December 2016 and October 2017. The CF parameters, force‐time integral (FTI), and LSI for 3095 ablation points in 34 patients were evaluated. The FTI and LSI in the lesions with gaps or dormant conduction (gaps/DC) were significantly lower than those in the lesion without gaps/DC (FTI: 140.5 ± 54.5 and 232.4 ± 121.4 g s, P   〈  0.0001; LSI: 4.0 ± 0.6 and 4.7 ± 0.9, P   〈  0.0001, respectively). On receiver operating characteristic curve analysis, the optimal LSI threshold was 4.05 (sensitivity, 63.4%; specificity, 76.3%). The LSI of 〈 5.25 predicted a gap or DC with a high sensitivity (sensitivity, 97.6%; specificity, 25.7%). In the posterior wall, which was 37% thinner than the nonposterior wall, a lower LSI of 〈 3.95 showed a relatively high sensitivity (92.3%) and specificity (65.6%). Conclusions The LSI can be used to predict gaps/DC during the PVI procedure. An LSI of 5.2 may be a suitable target for effective lesion formation. An LSI of 4.0 may be acceptable in the posterior wall, especially in areas adjacent to the esophagus.

Type of Medium: Online Resource

ISSN: 1045-3873 , 1540-8167

URL: Issue

URL: Article

DOI: 10.1111/jce.2018.29.issue-12

DOI: 10.1111/jce.13727

Language: English

Publisher: Wiley

Publication Date: 2018

detail.hit.zdb_id: 2037519-0

In: Journal of the Atomic Energy Society of Japan / Atomic Energy Society of Japan, Atomic Energy Society of Japan, Vol. 43, No. 1 ( 2001), p. 56-66

Type of Medium: Online Resource

ISSN: 0004-7120

Uniform Title: ｀２４´Ｎａの体内放射能測定とモニタリングデータを用いたＪＣＯ臨界事故における従業員等の被ばく線量評価

URL: Article

DOI: 10.3327/jaesj.43.56

Language: Japanese , Japanese

Publisher: Atomic Energy Society of Japan

Publication Date: 2001

detail.hit.zdb_id: 3000154-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 438-438

Abstract: Background: Recent advance in genetic analysis has revealed that many mutations are associated with the development, progression and/or prognosis of core-binding factor acute myeloid leukemia (CBF-AML). Although KIT mutation is the most frequently identified in CBF-AML, its prognostic relevance remains controversial. We conducted the prospective, multicenter cooperative study (JALSG CBF-AML209-KIT, UMIN Clinical Trials Registry UMIN000003434, http://www.umin.ac.jp/ctr/) to evaluate the prognostic impact of KIT mutation, the incidence and clinical relevance of the other gene mutations and prognostic impact of the minimal residual disease (MRD) in CBF-AML. Methods: A total of 199 patients 16 to 64 years of age with newly diagnosed de novo AML were enrolled in this study if they had a RUNX1-RUNX1T1 or CBFB-MYH11 chimeric transcript and achieved complete remission within 2 courses of the standard induction therapies consisting of cytarabine and either daunorubicin or idarubicin. All patients were to be received 3 courses of high-dose cytarabine therapy (2 g/m2 by 3-hour infusion every 12 hours for 5 days) and no further chemotherapy until relapse. MRD level was evaluated in BM after the completion of the 3-course of consolidation therapy by the quantitation of RUNX1-RUNX1T or CBFB-MYH11 transcript in 112 patients. Target sequencing of 56 genes frequently identified in myeloid malignancies including exons 8, 10, 11 and 17 of the KIT gene were analyzed using the preserved DNA extracted from AML cells at diagnosis. Results: A total of 68 KIT mutations were identified in 63 of 199 patients (31.7%); 42 of 132 (31.8%) and 21 of 67 (31.3%) patients with RUNX1-RUNX1T1 and CBFB-MYH11, respectively. Mutation in exon 17 was the most frequently identified (73.5%), followed by in exon 8 (20.6%) and in exon 10-11 (5.9%). Mutation in exon 8 was more frequent in AML with CBFB-MYH11 (37.5%) than that with RUNX1-RUNX1T1 (11.4%, P=0.014). Although mutation at N822 residue in exon 17 was identified in 13/44 (29.5%) KIT mutations of the patients with RUNX1-RUNX1T1, no patient with CBFB-MYH11 had this mutation (P=0.008); however, mutation at the D816 residue was equally identified in patients with RUNX1-RUNX1T1 (21/44, 47.7%) and CBFB-MYH11 (13/24, 54.1%). The median BM blast percentage of the KIT mutation positive-patients (73.5%) was significantly higher than that of negative-patients (53.8%, P 〈 0.0001). The median follow-up time was 1556 days (range, 356 - 2453 days). There was no significant difference in RFS and OS between the patients with RUNX1-RUNX1T1 and CBFB-MYH11. The 2-year RFS rate was 67.1% in KIT mutation negative-patients and 48.6% in positive-patients (P=0.0033). The 2-year OS rate was 91.0% in KIT mutation negative-patients and 74.6% in positive-patients (P=0.0005). In the patients with CBFB-MYH11, KIT mutations did not affect either RFS or OS. However, in the patients with RUNX1-RUNX1T1, KIT mutations had a strong impact both on 2-year RFS (72.8% vs. 39.5%, P 〈 0.0001) and OS rates (89.7% vs. 63.5%, P 〈 0.0001) in KIT mutation negative- and positive-patients, respectively. Among 3-types of KIT mutations, only the mutation in exon 17 had a worse prognostic impact on CBF-AML, which was also observed in the patients with RUNX1-RUNX1T1 (P 〈 0.001), but not in those with CBFB-MYH11 (P=0.724). Furthermore, mutations at the D816 and N822 residues showed a worse prognostic impact (P 〈 0.0001). In addition to KIT mutations, NRAS (21.7%), FLT3 (12.1%) and ASXL2 (12.0%) genes were frequently identified in CBF-AML. ASXL1 mutation was a favorable factor for RFS in RUNX1-RUNX1T1 and NRAS mutation was a poor prognostic factor for RFS in CBFB-MYH11. The 2-year RFS rate of the patients without MRD was significantly higher than that of those with MRD (81.3% vs. 55.4%, P=0.0075). Notably, the presence of the MRD was associated with worse RFS in the patients with CBFB-MYH11 (P=0.0144), but not in those with RUNX1-RUNX1T1 (P=0.1018). Conclusions: This large-scale prospective study demonstrated that KIT mutation has an adverse effect for OS and RFS only on AML with RUNX1-RUNX1T1 but not on AML with CBFB-MYH11. Notably, we demonstrated that only mutations in the exon 17 of KIT gene had an adverse effect both on the RFS and OS of the patients with RUNX1-RUNX1T1, and the presence of MRD was a poor factor for RFS in AML with CBFB-MYH11. Figure 1 Figure 1. Disclosures Sawa: Celgene Corporation: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis International AG: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Mundipharma K.K.: Honoraria. Dobashi:Pfizer Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Celgene Co.: Research Funding; Sysmex Co.: Research Funding. Asou:Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Yakult Honsha Co., Ltd.: Speakers Bureau; SRL Inc.: Consultancy; Eisai Co., Ltd.: Research Funding; Asahi Kasei Pharma Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Naoe:Pfizer Japan Inc.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding. Kiyoi:Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding; Bristol-Myers Squibb: Honoraria; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Celgene Corporation: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Phizer Japan Inc.: Research Funding; FUJIFILM Corporation: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113931

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cancer Science, Wiley, Vol. 111, No. 7 ( 2020-07), p. 2472-2481

Abstract: In this phase II multicenter study (JALSG AML209‐FLT3‐SCT), we aimed to prospectively elucidate the role of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) at first complete remission (CR1) for FLT3 ‐internal tandem duplication (ITD)‐positive AML. Newly diagnosed de novo AML patients with FLT3 ‐ITD were enrolled at the achievement of CR1 and received allo‐HSCT as soon as possible after the first consolidation therapy. Mutations of 57 genes in AML cells at diagnosis were also analyzed. Among 48 eligible patients with a median age of 38.5 (17‐49) years, 36 (75%) received allo‐HSCT at a median of 108 days after CR1. The median follow‐up was 1726 days. The primary end‐point, 3‐year disease‐free survival (DFS) based on an intent to treat analysis, was 43.8% (95% confidence interval [CI], 30%‐57%), suggesting the efficacy of this treatment because the lower limit of the 95% CI exceeded the threshold response rate of 20%. The 3‐year overall survival, post‐transplant DFS, and non‐relapse mortality rates were 54.2% (95% CI, 39%‐67%), 58.3% (95% CI, 41%‐72%), and 25.0% (95% CI, 12%‐40%), respectively. The median ITD allelic ratio (AR) was 0.344 (0.006‐4.099). Neither FLT3 ‐ITD AR nor cooccurring genetic alterations was associated with a poor DFS. This prospective study indicated the efficacy and safety of allo‐HSCT for FLT3‐ ITD AML patients in CR1. This study was registered at: www.umin.ac.jp/ctr/ as #UMIN000003433.

Type of Medium: Online Resource

ISSN: 1347-9032 , 1349-7006

URL: Issue

URL: Article

DOI: 10.1111/cas.v111.7

DOI: 10.1111/cas.14448

Language: English

Publisher: Wiley

Publication Date: 2020

detail.hit.zdb_id: 2115647-5

detail.hit.zdb_id: 2111204-6

In: Oncogene, Springer Science and Business Media LLC, Vol. 24, No. 36 ( 2005-08-25), p. 5637-5647

Type of Medium: Online Resource

ISSN: 0950-9232 , 1476-5594

URL: Article

DOI: 10.1038/sj.onc.1208720

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2005

detail.hit.zdb_id: 2008404-3

In: SSRN Electronic Journal, Elsevier BV

Type of Medium: Online Resource

ISSN: 1556-5068

URL: Article

DOI: 10.2139/ssrn.3343673

Language: English

Publisher: Elsevier BV

Publication Date: 2019

In: Blood Advances, American Society of Hematology, Vol. 4, No. 1 ( 2020-01-14), p. 66-75

Abstract: KIT exon 17 mutation is a poor prognostic factor in AML patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11. NRAS mutation is a poor prognostic factor in AML patients with CBFB-MYH11.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2019000709

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 2876449-3

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1328-1328

Abstract: Background: Since FLT3-ITD is a poor prognostic factor for acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is practically performed. However, clinical usefulness of allo-HSCT at the first remission (CR1) has not been fully evaluated by the prospective study. To prospectively elucidate the role of allo-HSCT at CR1 in younger adult patients with FLT3-ITD positive AML and explore the prognostic impacts of clinical and genetic features, we conducted a phase II multicenter study (JALSG AML209-FLT3-SCT, UMIN Clinical Trials Registry UMIN000003433, http://www.umin.ac.jp/ctr/). Methods: A total of 49 patients 16 to 49 years of age with newly diagnosed de novo AML were enrolled in this study if they had a FLT3-ITD mutation and achieved complete remission within 2 courses of the standard induction therapies consisting of cytarabine and either daunorubicin or idarubicin. All patients were to be received allo-HSCT as soon as possible while continuing 4 courses of consolidation therapy combining cytarabine plus mitoxantrone, daunorubicin, aclarubicin or etoposide, vincristine, and vindesine. Patients received no further chemotherapy until allo-HSCT or relapse. Conditioning was selected according to each institutional standard from myeloablative regimens except for reduced intensity conditioning only in patients older than 40 years old or with higher HCT-CI than 1 point. GvHD prophylaxis was according to each institutional standard based on cyclosporine A or tacrolimus combined with short-term MTX. Targeted sequencing of 57 genes frequently identified in myeloid malignancies were analyzed using the preserved DNA extracted from AML cells at diagnosis. FLT3-ITD allelic ratio (AR) was quantified using DNA fragment analysis. Primary endpoint was 3-year disease-free survival (DFS). Results: Among 48 eligible patients with the median age of 38.5 (range, 17-49) years, 36 (75%) maintained CR1 to receive allo-HSCT at the median of 108 (range, 54-228) days after the achievement of CR1. Median follow-up was 1,726 (range, 983-2,974) days. The 3-year DFS rate was 43.8% (95% confidence interval [CI], 30-57%, Figure 1). The lower limit of 95% CI exceeded threshold response rate of 20%, concluding the treatment was effective. The 3-year overall survival, post-transplant DFS and non-relapse mortality rates were 54.2% (95%CI, 39-67%), 58.3 % (95%CI, 41-72%) and 25.0% (95%CI, 12-40%), respectively. There was no significant difference in DFS post allo-HSCT according to donor sources (related BM 64.6% vs. related PB 50.0% vs. unrelated BM 63.6% vs. UCB 60.0% at 3 years, P= .881). Neutrophil recovery was achieved in 94.3%. Cumulative incidences of grade II to IV and III to IV acute GvHD at day 100 were 21.2% (95%CI, 9-37%) and 9.1% (95%CI, 2-22%), respectively. Cumulative incidence of chronic GvHD at 1 year was 25.0% (95%CI, 12-40%). Mutations in NPM1 gene (65%) and genes associated with DNA methylation were frequently identified including DNMT3A (36%), IDH1 (6%), IDH2 (17%) and TET2 (17%, Figure 2). Median ITD AR was 0.344 (range, 0.006-4.099). There was no significant overlap of genetic alterations with high ITD-AR (≥ 0.5). No significant impact on DFS was observed by high ITD AR (≥0.5) (Hazard ratio [HR], 1.53; 95%CI, 0.58-4.06; P= .39) or other co-occurring genetic alterations including NPM1 mutations (HR, 0.78; 95%CI, 0.28-2.20; P= .64). Conclusions: This prospective study demonstrated the efficacy and safety of proceeding faster to allo-HSCT in CR1 for younger adult patients with FLT3-ITD positive AML, whose graft sources were not limited to HLA identical donors and the first available donor should be considered. Beyond FLT3-ITD mutations, no significant prognostic factor was identified in their genetic background or high ITD AR. Further study is required to improve the prognosis of AML patients with FLT3-ITD by establishment of an adequate therapeutic strategy using FLT3 inhibitors and allo-HSCT. Disclosures Atsuta: Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Sawa:Asahi-Kasei: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Nippon Shinyaku: Honoraria; Pfizer Japan Inc.: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Otsuka Pharmaceutical: Honoraria; Shire: Honoraria; Mundi Pharma: Honoraria. Ozawa:Kyowa-Hakko Kirin: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria. Tomita:Taiho Pharma: Research Funding; Kyowa Kirin: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Maeda:Nippon Shinyaku Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K..: Honoraria. Usuki:Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Astellas Pharma Inc: Research Funding, Speakers Bureau. Matsuoka:Takeda Pharmaceutical: Research Funding; Novartis: Research Funding; Astellas Amgen Biopharma: Consultancy. Asou:SRL Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharm Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Asahi Kasei Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd: Research Funding; Novartis Pharmaceuticals: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Miyazaki:Kyowa-Kirin: Honoraria; Dainippon-Sumitomo: Honoraria; Chugai: Research Funding; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria. Kiyoi:Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Zenyaku Kogyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-124394

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7