13 results on '"Yasuhiro Nakashima"'
Search Results
2. A Prospective Comparison Analysis of Blood Biomarkers for the Diagnosis and Prediction of Sinusoidal Obstruction Syndrome
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Yosuke Makuuchi, Hideo Koh, Mika Nakamae, Masayuki Hino, Mitsutaka Nishimoto, Teruhito Takakuwa, Masatomo Kuno, Naonori Harada, Hiroshi Okamura, Asao Hirose, Yasuhiro Nakashima, Hirohisa Nakamae, and Nao Tanizawa
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medicine.medical_specialty ,business.industry ,Blood biomarkers ,Internal medicine ,Immunology ,medicine ,Cell Biology ,Hematology ,business ,Biochemistry ,Gastroenterology - Abstract
Background: Sinusoidal obstruction syndrome (SOS) remains a significant, potentially lethal complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although a liver biopsy is required to diagnose SOS accurately, it is not considered a mandatory evaluation due to its invasiveness. Therefore, the Seattle and Baltimore criteria with minor revisions have been widely used. However, the diagnostic accuracy of those criteria is insufficient. A noninvasive and more accurate diagnostic strategy is necessary. A number of studies have reported several candidate blood biomarkers for the diagnosis and prediction of SOS. However, which biomarkers or combination thereof are most useful for the diagnosis and prediction of SOS is unclear. We explored the best diagnostic and predictive biomarkers/combination among previously reported biomarkers for SOS using a stringent definition based on a liver biopsy. Methods: We performed this single-center prospective observational study in patients who received allo-HCT from April 2014 to February 2019. Seven biomarkers (PAI-1, P3P, ferritin, total bilirubin [T-bil], direct bilirubin [D-bil], brain natriuretic peptide [BNP], and protein C activity) were examined at pre-conditioning, at days 5 and 30, and at the onset of CTCAE grade ≥2 liver disorder after allo-HCT. We described how to diagnose definitive SOS (Fig. 1). A logistic regression (LR) model and the area under the receiver operating characteristic curves (AUC) were used to compare the seven biomarkers in the diagnosis and prediction of definitive SOS. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for the SOS diagnosis and prediction were also calculated by the best cut-off values, using the Youden index. Results of statistical tests with a p < 0.05 were considered significant. Results: A total of 180 patients were included. The median age was 48 (range: 16-68) years old. Forty-eight patients developed CTCAE grade ≥2 liver disorders. Of these, 10 were diagnosed with definitive SOS. The results of LR and AUC analyses of the SOS diagnosis and prediction are shown in the Table. PAI-1, P3P, ferritin, T-bil, and D-bil were found to be significant diagnostic markers for SOS. Among these, PAI-1 showed the highest AUC (0.85; 95% confidence interval [CI], 0.67-1.00). Furthermore, PAI-1, P3P, ferritin, T-bil, D-bil, and BNP were significant predictors for SOS. Among these biomarkers, P3P showed the highest AUC (0.82; 95% CI, 0.67-0.97). To perform further comparisons using multivariable models in SOS prediction, we first constructed a base model including the times of allo-HCT, disease status, and conditioning intensity. The AUC of the base model was 0.66 (95% CI, 0.48-0.84). After adding P3P to the base model, the AUC significantly improved to 0.88 (95% CI, 0.76-1.00) (p = 0.049). In the kinetics analysis of biomarkers, notably, PAI-1 and P3P increased over the peri-transplant period only in patients with definitive SOS (Fig. 2). In contrast, those values in patients with liver disorders other than SOS or without liver disorders did not show significant kinetic characteristics in the allo-HCT period. Discussion: SOS is attributed to toxic injury of the sinusoidal endothelial cells. PAI-1 is a known endothelial factor, released when the endothelial cells are damaged. This could be why PAI-1 was considered useful for the SOS diagnosis. P3P has been shown to be a sensitive biomarker for liver fibrosis. Furthermore, fibrous alterations in the hepatic remodeling process are well-known significant features for patients with SOS. Thus, liver fibrosis may pathophysiologically be a risk factor for SOS, and P3P may allow clinicians to detect SOS-high-risk patients with high accuracy, even at the time of allo-HCT when preclinical liver fibrosis can exist. Conclusion: We demonstrated that PAI-1 and P3P were the most useful biomarkers for the diagnosis and prediction of SOS, respectively. Figure 1 Figure 1. Disclosures Okamura: NIPPON SHINYAKU CO.,LTD.: Honoraria. Koh: AstraZeneca: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; MSD: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Novartis: Honoraria; NIHON PHARMACEUTICAL CO., LTD: Honoraria; Asahi Kasei Corporation:: Research Funding; IQVIA Services Japan K.K.:: Research Funding. Takakuwa: Takeda Pharmaceutical Company Limited.: Honoraria; Bristol-Myers Squibb Comapany: Honoraria; Sanofi K.K.: Honoraria; Celgene Corporation: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis: Honoraria; AbbVie GK: Research Funding; Celgene Corporation: Research Funding. Nakamae: Novartis: Honoraria. Nishimoto: Otsuka Pharmaceutical Co., Ltd.: Honoraria; CSL Behring: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; "Bayer Yakuhin, Ltd ": Research Funding; Janssen Pharmaceutical K.K.: Research Funding. Nakashima: Amgen Astellas BioPharma K.K.: Honoraria; Amgen Inc: Honoraria; Novartis: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Eisai Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; SymBio Pharmaceuticals Limited.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Celgene Corporation: Research Funding; AbbVie GK: Research Funding. Nakamae: Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Simon-Kucher & Partners: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria, Research Funding; Alexion: Research Funding; PPD-SNBL K.K: Research Funding; CMIC HOLDINGS Co., Ltd: Research Funding. Hino: Novartis: Honoraria, Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AstraZeneca: Honoraria; Astellas Pharma Inc.: Honoraria; MSD: Honoraria, Research Funding; CSL Behring: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Meiji Seika Pharma Co., Ltd.: Honoraria; Eisai Co., Ltd: Honoraria, Research Funding; Kyowa Kirin Co., Ltd: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria, Research Funding; Bristol-Myers Squibb Comapany: Honoraria; Janssen Pharmaceutical: Honoraria; JCR Pharmaceuticals Co., Ltd.: Research Funding; ARKRAY: Research Funding; Asahi Kasei Corporation:: Research Funding; Abbott: Research Funding; TEIJIN PHARMA LIMITED.: Research Funding; SEKISUI MEDICAL CO., LTD.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Research Funding; TOSOH CORPORATION: Research Funding.
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- 2021
3. Pretransplant Risk Factors for Calcineurin Inhibitor-Induced Encephalopathy and Limbic Encephalitis Following Allogeneic Hematopoietic Cell Transplantation
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Mitsutaka Nishimoto, Masayuki Hino, Mika Nakamae, Nao Tanizawa, Koh Shiro, Hiroshi Okamura, Asao Hirose, Takahiko Nakane, Satoru Nanno, Hideo Koh, Hirohisa Nakamae, and Yasuhiro Nakashima
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business.industry ,medicine.medical_treatment ,Viral encephalitis ,Immunology ,Limbic encephalitis ,Encephalopathy ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Tacrolimus ,Transplantation ,Calcineurin ,Medicine ,business ,Encephalitis - Abstract
Background: Central nervous system (CNS) complications after allogeneic hematopoietic cell transplantation (allo-HCT) can be fatal. Although numerous studies have reported risk factors for CNS complications after allo-HCT, most defined CNS complication events as a composite endpoint, for example, composed of cerebrovascular disease, infection, posterior reversible encephalopathy syndrome (PRES), and metabolic encephalopathy. For a more precise and targeted approach, risk factor analyses for each individual CNS event are needed. Few studies have reported risk factor analyses for individual CNS complications. They have included analyses for cerebrovascular disease, viral encephalitis, HHV6 encephalitis, and noninfectious neurologic complications. To our knowledge, no pretransplant risk factor analysis for calcineurin inhibitor-induced encephalopathy (CNIE) and limbic encephalitis (LE) has yet been reported. Method: We retrospectively examined consecutive patients who underwent allo-HCT at our institute between January 2005 and November 2017. CNIE was defined as a patient who exhibited clinical symptoms of PRES or neurological manifestations of thrombotic microangiopathy during cyclosporin A (CSA) or tacrolimus (TAC) administration. LE was defined as a patient who displayed selective medial temporal lobe involvement in brain MRIs. As a rule, HHV-6 DNA polymerase chain reaction was performed on cerebrospinal fluid (CSF) for LE cases. Results: A total of 485 patients between 16- and 69-years-old (median, 46 years) were eligible for this study. They received myeloablative (n = 292) or reduced-intensity conditioning (n = 193) for allo-HCT. Diagnoses included AML/ALL (n = 292), MDS (n = 59), NHL (n = 93), and others (n = 41). HLA allele typing was performed at HLA-A, -B, -C, and -DRB1. Donor sources consisted of HLA-matched or -one allele mismatched sibling peripheral blood (PB) or bone marrow (BM) (n = 98)/HLA matched unrelated donors (n = 93) (hereafter referred to as HLA-matched donors), HLA-mismatched unrelated BM (uBM; n = 36), umbilical cord blood (uCB; n = 110), haploidentical PB (n = 118), and allele unknown uBM (n = 30). A total of 33 CNS events were identified: 11 CNIE (33 %), 14 LE (42 %), 3 transverse myelitis (9.0 %), 2 drug encephalopathy (6.0 %), 1 aseptic meningitis (3.0 %), 1 fungal brain abscess (3.0 %), and 1 acute epidural hematoma (3.0 %). The median follow-up time among the survivors was 1836 days (range, 45-4860 days) after allo-HCT. By landmark time analysis, the prognosis of those with any CNS complications within 30 days was significantly worse than those who did not (1-year OS, 37.5 % vs. 55.4 %, Log-rank p = 0.011). A multivariable time-dependent Cox model revealed that CNS complications were an independent prognostic factor for overall survival (Hazard ratio (HR) 4.49, 95 % CI, 2.30-8.76, p < 0.001), adjusted for age and disease risk index. CNIE cases included 6 CSA-induced and 3 TAC-induced cases, of which 4 patients (44 %) were alive. In the multivariable Cox models, MDS (HR 9.4 (vs. AML/ALL), 95 % CI, 2.2-40, p = 0.002) and HLA-mismatched uBM (HR 16 (vs. HLA-matched donors), 95 % CI, 3.0-81, p = 0.001) were significantly associated with CNIE development. LE included 7 HHV6-negative (2 alive), 5 HHV6-positve (1 alive), and 2 unknown cases (1 alive). Eleven of these patients were treated by methylprednisolone pulse therapy; all patients responded partially or effectively and four patients (36 %) achieved complete remission. In the multivariable Cox models, HLA-mismatched uBM (HR 7.5 (vs. HLA-matched donors), 95 % CI, 1.2-45, p = 0.028) was significantly associated with LE development. Conclusion: CNS complications were found to be an independent risk factor for OS after allo-HCT, as reported previously. MDS and HLA-mismatched uBM were risk factors for CNIE; the former may be partly explained by the fact that a subset of MDS may be predisposed to vascular endothelial damage (e.g. vasculitis), since CNIE may be triggered by endothelial dysfunction caused by CNI. Moreover, HLA-mismatched uBM was a risk factor for LE. Experimental data revealed that major histocompatibility complex class 1 protein was expressed in hippocampal neurons; thus, the limbic system may be targeted by alloimmune reactions more frequently in HLA-mismatched uBM settings, regardless of whether HHV-6 reactivation occurs. Disclosures Koh: Alexion: Honoraria; DAIICHI SANKYO COMPANY: Honoraria; MSD K.K: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; NIHON PHARMACEUTICAL: Honoraria; Takeda Science Foundation: Research Funding; Chugai Pharmaceutical: Research Funding; Amgen Astellas BioPharma: Research Funding; Asahi Kasei Corporation: Research Funding; IQVIA Services Japan: Research Funding. Okamura:Eisai Co., Ltd: Honoraria; MSD K.K: Honoraria. Shiro:Bristol-Myers Squibb: Honoraria. Nanno:Eisai Co., Ltd.: Honoraria; MSD K.K: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Nakamae:Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Japan Blood Products Organization: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire Japan KK.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Nakashima:Novartis: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Eisai Co.,Ltd: Honoraria, Research Funding; Celgene Corporation: Research Funding; Amgen Astellas BioPharma K.K.: Honoraria, Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Bristol-Myers Squibb: Honoraria. Nakane:Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.,: Honoraria; Mundipharma K.K.: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Research Funding; MSD K. K,: Research Funding; Pfizer Japan Inc.: Research Funding; Bayer Yakuhin, Ltd: Research Funding. Hino:MSD: Honoraria, Research Funding; Mundipharma: Honoraria; Nihon Pharmaceutical Co., Ltd: Research Funding; Sumitomo Dainippon Parma: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ono Pharmaceutical: Honoraria, Other: Consulting fee, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Pfizer Japan Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Shire Japan KK: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee, Research Funding; Mochica Pharmaceutical Co., Ltd: Honoraria; Eisai: Research Funding; Janssen: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria, Research Funding; Daichi-Sankyo: Honoraria, Research Funding; Astellas Pharma Inc: Honoraria, Research Funding; Astellas Amgen BioPharma: Honoraria; Bristol-Myers Squibb: Honoraria; Taiho Pharama: Research Funding; Takeda Pharmaceutical Co., Ltd: Honoraria, Research Funding; Teijin: Research Funding; Alexion: Honoraria; Abbott: Research Funding. Nakamae:Takeda Pharmaceutical Co., Ltd.: Honoraria; Skire Japan KK.: Honoraria; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceutical: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Kwowa-Hakko kirin Co., Ltd.: Honoraria; Japan blood Products Organization: Honoraria; Janssen: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria.
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- 2019
4. Impact of Donor KIR and HLA Genotypes on Clinical Outcomes According to Pre-Transplant Remission Status after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide
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Asao Hirose, Hideo Koh, Shiro Koh, Yasuhiro Nakashima, Mika Nakamae, Hiroshi Okamura, Hirohisa Nakamae, Kentaro Ido, Mitsutaka Nishimoto, Takahiko Nakane, Masayuki Hino, and Satoru Nanno
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Oncology ,medicine.medical_specialty ,Haploidentical transplantation ,Cyclophosphamide ,business.industry ,Post transplantation cyclophosphamide ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,medicine.disease ,Biochemistry ,Transplantation ,Leukemia ,Internal medicine ,Genotype ,Medicine ,business ,medicine.drug - Abstract
INTRODUCTION HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using post-transplantation cyclophosphamide (PT/Cy-haplo) can be a standard of care in patients suffering from poor prognostic hematological malignancies without conventional donors. Regarding killer cell immunoglobulin-like receptor (KIR) and HLA information on optimal donor selection in PT/Cy-haplo settings, the following factors associated with improved survival have been reported: HLA-DR/HLA-DP mismatch, KIR receptor-ligand mismatch, KIR B/x haplotype with KIR2DS2, and inhibitory KIR gene mismatch (Willem 2019, Solomon 2018, Symons 2010). However, the results were still inconclusive. In addition, it remains unknown whether the graft-versus-leukemia/tumor (GVL) effect of donor KIRs or HLAs is modified by residual tumor burden at PT/Cy-haplo. METHODS We retrospectively examined consecutive patients who received PT/Cy-haplo at our institution between June 2009 and December 2018. In both patients and donors, 16 KIR genes were genotyped using KIR SSO Genotyping Test (One Lambda, Inc.) and HLA allele typing was performed at HLA-A, -B, -C, and -DRB1. Cumulative incidence of relapse (CIR) was estimated using a cumulative incidence curve with nonrelapse mortality as a competing risk and compared using the Gray's test. RESULTS A total of 91 patients with available KIR typing data were eligible. Of these, HLA typing data were unavailable for 5 patients (5.5%). In this cohort, 76 HLA-C mismatched transplants (88%) were included, and the frequencies of donor KIR ligand were 78 (90.7%) in C1/C1, 8 (9.3%) in C1/C2, and 0 in C2/C2. The median age was 48 years (range, 17 - 68 years). Median follow-up time among survivors was 1,271 days (range, 242 - 3,135 days) after PT/Cy-haplo. This study included 54 AML, 6 MDS, 2 CML, 13 ALL, and 16 NHL patients. Thirty-four patients (37%) showed complete remission (CR) at PT/Cy-haplo, and 37 on the secondor third transplant (40.7%). In CR population at PT/Cy-haplo, the patients who underwent PT/Cy-haplo from a KIR2DS1-positive donor had significantly lower rates of CIR than those from a KIR2DS1-negative donor (2-year CIR, 9.2% vs 42%; P = 0.037; Figure 1A). Due to unavailability of cases, we were unable to perform the subgroup analysis based on donor C1 or C2 status. In PT/Cy-haplo from a KIR3DS1- or KIR2DL5-positive donor, similar results were obtained, most likely due to genetic linkage disequilibrium among these genes. No other donor KIR genes were associated with CIR. Furthermore, PT/Cy-haplo from a KIR2DS1-positive donor was significantly associated with improved OS (2-year OS, 83% vs 34%; P = 0.01; Figure 1C). Also, PT/Cy-haplo from a B/x donor significantly increased OS (2-year OS, 77% vs 35%; P = 0.019), but did not decrease CIR (2-year CIR, 16% vs 40%; P = 0.122). These results suggested that donor KIR2DS1 could have a more crucial role in prevention of leukemia relapse than donor B/x haplotype. In non-complete remission (NCR) population at PT/Cy-haplo, however, PT/Cy-haplo from a KIR2DS1-positive donor and a B/x donor did not significantly improve CIR (Figure 1B) or OS (Figure 1D). Although we investigated the following previously reported models: KIR mismatch with ligand incompatibility model, receptor-ligand model, missing ligand model, inhibitory KIR gene model, and HLA-DRB1 disparity of graft-versus-host direction, none was found to be associated with significantly improved CIR or OS. CONCLUSION We found that in PT/Cy-haplo settings, with donor-recipient HLA-C mismatch in almost all cases, a KIR2DS1-positive donor significantly contributed to decreased CIR and increased OS in CR population at PT/Cy-haplo, but not in NCR population. These results were consistent with the 2012 NEJM data by Venstrom et al in patients undergoing allo-HCT from HLA-matched or one-allele mismatched unrelated donors. Although the exact mechanism remains unclear, activating KIR2DS1, known as a player in the activation and tolerance of NK cells, could mediate NK-cell function and enhance GVL effect through NK alloreactivity in low tumor burden status at PT/Cy-haplo also in the PT/Cy-haplo setting. Our results may contribute to the establishment of an optimal donor selection algorithm. In future, elucidating the detailed mechanism of our findings could lead to the development of a novel preventive or therapeutic strategy for leukemia relapse. Disclosures Ido: MSD K.K.: Honoraria. Koh:Alexion: Honoraria; DAIICHI SANKYO COMPANY: Honoraria; MSD K.K: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; NIHON PHARMACEUTICAL: Honoraria; Takeda Science Foundation: Research Funding; Chugai Pharmaceutical: Research Funding; Amgen Astellas BioPharma: Research Funding; Asahi Kasei Corporation: Research Funding; IQVIA Services Japan: Research Funding. Okamura:MSD K.K: Honoraria; Eisai Co., Ltd: Honoraria. Koh:Bristol-Myers Squibb: Honoraria. Nanno:Eisai Co., Ltd.: Honoraria; MSD K.K: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Nakamae:Novartis: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria; Japan Blood Products Organization: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Astellas Pharma Inc.: Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Nippon Shinyaku: Honoraria; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire Japan KK.: Honoraria. Nakashima:Novartis: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Eisai Co.,Ltd: Honoraria, Research Funding; Celgene Corporation: Research Funding; Bristol-Myers Squibb: Honoraria; Astellas Pharma Inc.: Research Funding; Amgen Astellas BioPharma K.K.: Honoraria, Research Funding; AbbVie Inc.: Research Funding. Nakane:Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.,: Honoraria; Mundipharma K.K.: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Research Funding; MSD K. K,: Research Funding; Pfizer Japan Inc.: Research Funding; Bayer Yakuhin, Ltd: Research Funding. Hino:Taiho Pharama: Research Funding; Takeda Pharmaceutical Co., Ltd: Honoraria, Research Funding; Astellas Amgen BioPharma: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria, Research Funding; Daichi-Sankyo: Honoraria, Research Funding; Eisai: Research Funding; Janssen: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Kyowa-Hakko Kirin Co.,Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee, Research Funding; Mochica Pharmaceutical Co., Ltd: Honoraria; Pfizer Japan Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Shire Japan KK: Honoraria; Sumitomo Dainippon Parma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Other: Consulting fee, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teijin: Research Funding; Nihon Pharmaceutical Co., Ltd: Research Funding; Astellas Pharma Inc: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Mundipharma: Honoraria; Abbott: Research Funding; Alexion: Honoraria. Nakamae:Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceutical: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Kwowa-Hakko kirin Co., Ltd.: Honoraria; Japan blood Products Organization: Honoraria; Janssen: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Skire Japan KK.: Honoraria.
- Published
- 2019
5. Pre-Transplant Serum Beta-2 Microglobulin Level Is a Potential Novel Prognostic Marker for Overall Survival after Allogeneic Hematopoietic Stem Cell Transplantation
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Hiroshi Okamura, Takahiko Nakane, Mika Nakamae, Masayuki Hino, Naonori Harada, Hideo Koh, Asao Hirose, Mitsutaka Nishimoto, Yasuhiro Nakashima, Hirohisa Nakamae, Yasunobu Takeoka, and Satoru Nanno
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medicine.medical_specialty ,Univariate analysis ,Performance status ,business.industry ,Proportional hazards model ,Beta-2 microglobulin ,medicine.medical_treatment ,Immunology ,Hazard ratio ,Renal function ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Gastroenterology ,Transplantation ,Internal medicine ,Medicine ,business - Abstract
Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for hematologic malignancies. In addition to hematopoietic cell transplantation-comorbidity index (HCT-CI) and disease risk index (DRI), age, performance status (PS), conditioning regimen intensity, and donor source are used to assess the transplant outcome in patients. Recently, several serum markers, such as ferritin and albumin, have also been reported as additional useful prognostic markers. Beta-2 microglobulin (BMG) is a component of major histocompatibility complex class 1 molecules in all nucleated cells, and serum BMG levels reflect renal function, tumor burden, and inflammatory conditions. Although elevated serum BMG levels are reportedly markers for poor prognosis of several hematological malignancies, no study has assessed the prognostic significance of pre-transplant serum BMG levels for allo-HSCT. Methods: We retrospectively registered consecutive patients who underwent allo-HSCT from April 2010 to September 2017 with available pre-transplant serum BMG levels at our institute. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals in the univariate and multivariate analyses. In this study, the variables analyzed were age, sex, disease, HCT-CI, PS, DRI, number of times HSCT was performed, conditioning regimen intensity, donor source, cytomegalovirus (CMV) serostatus, and pre-transplant serum BMG level in each patient. Predictors with borderline significance (p Result: A total of 288 patients were identified during the study period. The median age was 47 (range: 17-48) years. The clinical characteristics are shown in Table 1. The median follow-up period of survivors (192 patients) was 674.5 (range: 15-2642) days. The median pre-transplant BMG level was 2.1 (range: 0.9-11.6) mg/mL. When stratified into quartiles of pre-transplant BMG levels, the 2-year OS rates were 89.2%, 62.8%, 64.3%, and 33.7% in quartiles 1 (0.9-1.6), 2 (1.7-2.0), 3 (2.1-2.9), and 4 (3.0-11.6), respectively. Because quartiles 2 and 3 showed almost the same OS rates, we combined these two groups and assessed the association between major transplant outcomes (OS, Rel/Prog, NRM, acute GVHD, and chronic GVHD) and the following three groups of BMG levels: 0.9-1.6 mg/mL (lower BMG group), 1.7-3.0 mg/mL (intermediate BMG group as the reference), and >3.0 mg/mL (higher BMG group). In the univariate analysis, the lower BMG group was significantly associated with an increased probability of OS (HR: 0.29, p=0.002) and decreased probability of Rel/Prog and NRM (HR: 0.58, p=0.048 and HR: 0.19, p=0.02, respectively) compared with those of the intermediate BMG group. The higher BMG group was significantly associated with a decreased probability of OS (HR: 2.4, p Conclusions: The study results suggest that pre-transplant serum BMG level is a potential prognostic marker for survival after allo-HSCT, which is independent of other prognostic factors, including well-known prognostic systems, such as HCT-CI and DRI. Disclosures Nakamae: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding. Hino:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Novartis: Research Funding. Nakamae:Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding.
- Published
- 2018
6. The Proportional Association between WT1 mRNA Level in Peripheral Blood before Allogeneic Hematopoietic Cell Transplantation and Risk of Mortality in Acute Myeloid Leukemia Not in Remission
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Takahiko Nakane, Yoshinori Hashimoto, Kentaro Ido, Hideo Koh, Mika Nakamae, Mitsutaka Nishimoto, Asao Hirose, Satoru Nanno, Hiroshi Okamura, Hirohisa Nakamae, Yasunobu Takeoka, Masayuki Hino, and Yasuhiro Nakashima
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Umbilical Cord Blood Transplantation ,business.industry ,medicine.medical_treatment ,Immunology ,Preleukemia ,Myeloid leukemia ,Cell Biology ,Hematology ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,Biochemistry ,Transplantation ,medicine.anatomical_structure ,medicine ,Risk of mortality ,Bone marrow ,business - Abstract
INTRODUCTION The prognosis for allogeneic hematopoietic cell transplantation (allo-HCT) is relatively poor in patients with acute myeloid leukemia (AML) who are not in remission (non-CR). Wilms' tumor-1 gene messenger ribonucleic acid (WT1 mRNA), which is overexpressed in almost all AML, has been used as an indicator of monitoring minimal residual disease (MRD) and has been regarded as one of the prognostic factors in AML patients with complete remission (CR). However, the association between the expression levels of WT1 mRNA in peripheral blood (WT1) before allo-HCT and risk of mortality in AML patients in non-CR remains quite elusive. We therefore assessed the effect of the pre-transplant WT1 level on survival after allo-HCT in AML patients in non-CR. METHODS We retrospectively analyzed data from consecutive patients undergoing allo-HCT at our institution between November 2007 and January 2017. We excluded patients who did not have an available WT1 value within 28 days before the start of conditioning. RESULTS A total of 125 AML patients, including 46 non-CR patients (36.8 %), were eligible for this study. The median age was 48 years (range: 17-68 years) and the number of males was 69 (55.2%). Forty-two patients (33.6%) had AML with myelodysplasia-related changes. This study included 34 patients (27.2%) who had undergone multiple transplantation. Myeloablative and reduced-intensity conditioning were used in 73 (58.4%) and 52 (41.6%) patients, respectively. In 63 patients who received transplants from either a related peripheral blood stem cell or bone marrow (BM) donor, four pairs (6.3%) were serologically mismatched for one antigen of HLA and 45 pairs (71.4%) received transplants from HLA haploidentical donors. In 32 patients who received transplants from an unrelated BM donor, seven pairs (21.9%) were serologically mismatched for one HLA antigen. Twenty-nine patients (23.2%) received unrelated cord blood transplantation. Among 46 non-CR patients, the median follow-up period among survivors was 1,092 days (range: 688-2,607 days) following allo-HCT. Receiver operating characteristic analysis for prediction of composite events including any cause of death or subsequent transplantation indicated that the best cutoff value for WT1 was 5,000 copies/ μg RNA in non-CR AML patients. Estimated two-year, event-free survival of non-CR patients with WT1 levels of less than 5,000 copies/ μg RNA was significantly higher than that of those with WT1 levels of 5,000 copies/ μg RNA or more (41.2% [95% confidence interval (CI), 18.6-62.6] vs 10.3% [95% CI, 2.6-24.3]; P=0.006). On multivariate analysis of the non-CR patients, WT1 5,000 copies/ μg RNA or more was significantly associated with increased risk of mortality (hazard ratio (HR), 2.7; 95% CI, 1.3-5.5; P=0.008). Log10-transformed WT1 (continuous scale) was also significantly related to increased risk of mortality (HR, 1.5; 95% CI, 1.0-2.1; P=0.037). In the entire cohort, log10-transformed WT1 (divided into four categories) before allo-HCT was found to be the most powerful prognostic factor of survival among remission status, cytogenetic risk group, and revised disease risk index, applying Akaike's information criterion. Moreover, under the assumption of a non-linear model, as the log10-transformed WT1 level rose, the HR of mortality increased monotonically; a non-linear fit was obtained using a restricted cubic spline function (three knots; Figure 1). CONCLUSION Our data showed that WT1 levels obtained before allo-HCT monotonically increased HR of mortality in a non-linear manner regardless of CR status. Of importance is the finding that WT1 levels before allo-HCT were proportionally correlated with probability of survival after allo-HCT in non-CR AML patients. This suggests that the level of expression of WT1 mRNA in peripheral blood might reflect tumor burden and that there may be a WT1 threshold in non-CR patients for benefiting from allo-HCT. Further prospective studies of WT1 are necessary to determine acceptable or feasible levels of disease activity for receiving allo-HCT in relapsed or refractory AML patients. Disclosures Nakamae: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding. Hino:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Novartis: Research Funding. Nakamae:Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding.
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- 2018
7. Noninvasive Diagnostic Approach By per Rectal Portal Scintigraphy for Sinusoidal Obstruction Syndrome after Allogeneic Hematopoietic Cell Transplantation
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Joji Kawabe, Hiroshi Okamura, Teruhito Takakuwa, Takahiko Nakane, Yosuke Makuuchi, Masao Hamuro, Hideo Koh, Kentaro Ido, Akira Yamamoto, Satoru Nanno, Masayuki Hino, Atsushi Jogo, Shigeaki Higashiyama, Atsushi Yoshida, Shoji Ine, Kohei Kotani, Masahiko Ohsawa, Hirohisa Nakamae, Yasuhiro Nakashima, and Susumu Shiomi
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medicine.medical_specialty ,Hepatic veno-occlusive disease ,medicine.diagnostic_test ,Receiver operating characteristic ,business.industry ,Portal venous pressure ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Scintigraphy ,Biochemistry ,Transplantation ,Liver biopsy ,Ascites ,medicine ,Portal hypertension ,Radiology ,medicine.symptom ,business - Abstract
Background Sinusoidal obstruction syndrome (SOS) is a significant, potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). In particular, severe SOS frequently causes multiple organ failure and results in poor prognosis. Although early and accurate diagnosis of SOS is vital to intervene early and improve its prognosis, the diagnostic accuracy of clinical criteria, such as the Seattle criteria and Baltimore criteria, is unsatisfactory. Liver biopsy is a gold standard for SOS diagnosis and should be considered to confirm the diagnosis. However, this procedure confers the risk of major bleeding, potentially leading to fatal outcomes, due to low platelet counts or coagulation disorders in patients with SOS. Therefore, a novel, noninvasive diagnostic approach for SOS is needed. The hepatic venous pressure gradient (HVPG) representing portal pressure has been reported to be the most accurate for SOS diagnosis, but its measurement procedure is invasive. Per rectal portal scintigraphy (PRPS), which is a nuclear medicine examination, can estimate portal pressure safely using the portal shunt index (SI) calculated from radioactivity curves of the liver and heart. Only one case report has shown that PRPS was useful to detect portal hypertension in a patient with SOS after allo-HCT (Okamura H, et al. Acta Haematol 2013). To investigate the usefulness of PRPS for SOS diagnosis, we retrospectively analyzed patients who had hepatic disorder and/or ascites after allo-HCT and underwent transjugular liver biopsy and PRPS. Methods We examined consecutive patients who underwent transjugular liver biopsy with HVPG measurement and were assessed using PRPS around the same time at our institution between April 2011 and May 2017. When performing transjugular liver biopsy, we also measured the HVPG. All causes of hepatic disorder and/or ascites were pathologically determined based on liver biopsy, if applicable, with autopsy or needle necropsy findings. In PRPS, 370 MBq of Tc-99m pertechnetate was administered to the upper rectum. The SI was calculated using the ratio of liver to heart counts integrated for 24 seconds immediately after the appearance of the liver or heart time-activity curve. We assessed the diagnostic performances of the HVPG and SI for SOS using receiver-operating characteristic (ROC) curves and calculated the optimal cutoff points using the Youden index. Analyses were performed using GraphPad Prism® version 5.02 and SPSS® version 24. Results Eleven cases were evaluable. The median onset of liver damage and/or ascites was on day 27 after allo-HCT: early-phase (within 30 days) in 7 cases and late-phase (after 30 days) in 4 cases. All patients were histologically diagnosed: 5 with SOS and 6 with non-SOS. The median interval from PRPS to transjagular liver biopsy was +4 days (range, -13 to 15 days). SI values from PRPS correlated with HVPG values in 11 pairs of the measurements (Spearman correlation coefficient 0.92, P < 0.001, Figure 1A). The areas under the ROC curves of the HVPG and SI for SOS diagnosis were 0.85 (95% confidence interval (CI), 0.61-1.0) and 0.77 (95% CI, 0.45-1.0), respectively. The best cutoff values of the HVPG and SI were calculated as 10 mmHg and 56%, respectively. Table 1 shows the sensitivity, specificity, and positive and negative predictive values for the HVPG, SI, and Seattle criteria for SOS diagnosis among all 11 cases. As a subgroup analysis, in 7 patients who developed hepatic disorder and/or ascites in the early phase after allo-HCT, both HVPG and SI were significantly higher in patients with SOS than in those without SOS (mean HVPG: 13.3 mmHg in SOS vs. 4.3 mmHg in non-SOS, P = 0.01, Figure 1B; mean SI: 58% in SOS vs. 26% in non-SOS, P = 0.03, Figure 1C). Furthermore, in these 7 patients, both the HVPG and SI made it possible to completely discriminate between SOS and non-SOS using cutoff points calculated based on the Youden index (8 mmHg for the HVPG and 44% for the SI). Conclusion We found that the SI from PRPS represented portal pressure, even in patients after allo-HCT, and that the diagnostic accuracy of PRPS for SOS was not only superior to that of the Seattle criteria, but also comparable to that of the HVPG. In addition, especially in the early phase after allo-HCT, SI may be useful to discriminate between SOS and non-SOS. This noninvasive examination could offer a new diagnostic strategy, along with SOS clinical criteria. Disclosures Hino: Otsuka Pharmaceutical Co., Ltd.: Research Funding; Novartis: Research Funding. Nakamae:Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding.
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- 2018
8. Prophylactic Use of a Combination of an Anticoagulant and Ursodeoxycholic Acid for Sinusoidal Obstruction Syndrome after Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation
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Hirohisa Nakamae, Asao Hirose, Hideo Koh, Takahiko Nakane, Yasuhiro Nakashima, Yasunobu Takeoka, Mitsutaka Nishimoto, Hiroshi Okamura, Masayuki Hino, and Mika Nakamae
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medicine.medical_specialty ,medicine.drug_class ,business.industry ,Gemtuzumab ozogamicin ,medicine.medical_treatment ,Immunology ,Anticoagulant ,Danaparoid ,Retrospective cohort study ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Biochemistry ,Ursodeoxycholic acid ,Internal medicine ,medicine ,Cumulative incidence ,business ,Busulfan ,medicine.drug - Abstract
Introduction: Sinusoidal obstruction syndrome (SOS) is one of the potentially fatal complications of hematopoietic stem cell transplantation (HSCT). In particular, severe SOS frequently leads to multiple organ failure, and a worse prognosis. Thus, prophylaxis against development of SOS could contribute improved survival after HSCT. Previous reports demonstrated the effectiveness of the prophylactic use of ursodeoxycholic acid (UDCA) or certain anticoagulants, including unfractionated and low-molecular-weight heparin, for SOS. In two randomized controlled trials and two meta-analyses it was reported that UDCA, a hydrophilic bile acid, was an effective and safe drug for prophylaxis against SOS. The usefulness and feasibility of prophylactic use of anticoagulants after allogeneic HSCT are however still controversial. In addition, to our knowledge no study has evaluated the feasibility of usage of UDCA combined with an anticoagulant for SOS prevention after allogeneic HSCT in adult patients. To assess the efficacy and safety of use of UDCA combined with an anticoagulant as SOS prophylaxis, we performed a retrospective cohort study to examine the occurrences of SOS and hemorrhagic events in patients who underwent myeloablative allogeneic HSCT at our institution. We examined use of any anticoagulant together with simultaneous administration of UDCA, in comparison with UDCA alone for the prevention of SOS. Patients and methods: We reviewed the charts of consecutive adult patients in whom myeloablative allogeneic HSCT was performed at our hospital from November 1994 to May 2014, and who received either unfractionated heparin or dalteparin (low-molecular-weight heparin) with UDCA (group 1), danaparoid with UDCA (group 2), or UDCA only (group 3), used for prophylaxis against SOS. Results: A total of 280 patients (group 1: n=52; group 2: n=33; and group 3: n=195) were investigated. The proportions of patients with risk factors for SOS-including non-remission at the time of HSCT, a second or subsequent HSCT, high aspartate aminotransferase (AST) levels before HSCT, high ferritin levels before HSCT, a history of receiving gemtuzumab ozogamicin, and HLA disparity-were similar across the three groups. In group 1, a conditioning regimen containing busulfan was used less frequently (P = 0.002). SOS occurred in seven patients (13.7%) in group 1, five patients (15.2%) in group 2, and 28 patients (14.4%) in group 3, all meeting the Seattle criteria. None of the patients in group 1, two (6.1%) in group 2, and nine (4.6%) in group 3 had SOS diagnosed according to the Baltimore criteria. There was no significant difference in the incidence of SOS among the three groups. In addition, with regard to the cumulative incidence of severe SOS, no statistically significant difference was present among the three groups. The incidence of hemorrhagic events within 30 and 100 days following allogeneic HSCT was not significantly different across the three groups (30 days; 5.8%, 3.0%, 5.1%, P = 0.843, 100 days; 17.6%, 15.2%, 14.4%, P=0.843, respectively). Furthermore, the probabilities of OS and NRM until day 100 after allogeneic HSCT were similar among the three groups (P = 0.733 and P = 0.637, respectively). In a univariate model, a history of gemtuzumab ozogamicin treatment, high serum ferritin levels before HSCT, an HLA mismatched donor, and non-complete remission of disease at the time of allogeneic HSCT were found to be significant risk factors for SOS. Multivariate analysis revealed that a history of gemtuzumab ozogamicin therapy, a mismatched HLA donor, and non-complete remission of disease at the time of allogeneic HSCT were significant and independent risk factors for SOS. In the multivariate as well as univariate analyses, combined administration of UDCA and any anticoagulant for SOS prophylaxis did not have a significant effect on the incidence SOS, when compared to prophylaxis with UDCA alone. Conclusion: Our study results suggest that the combined use of UDCA and an anticoagulant for SOS prophylaxis after myeloablative allogeneic HSCT in adult patients was not beneficial. Establishment of an optimal strategy for prophylaxis against SOS after HSCT is still needed. Disclosures Nakane: Mundipharma KK: Research Funding. Koh:Pfizer: Consultancy, Honoraria. Hino:Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Speakers Bureau; Alexion: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding.
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- 2016
9. Short-Term Fasting Induces Cell Cycle Arrest of Immature Hematopoietic Cells and Increases the Number of Naive T Cells in the Bone Marrow of Mice
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Hideo Koh, Masayuki Hino, Teruhito Takakuwa, Takahiko Nakane, Hirohisa Nakamae, and Yasuhiro Nakashima
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medicine.medical_specialty ,Immunology ,Calorie restriction ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Haematopoiesis ,medicine.anatomical_structure ,Endocrinology ,Immune system ,White blood cell ,Internal medicine ,medicine ,Bone marrow ,Progenitor cell ,Stem cell ,CD8 - Abstract
Calorie restriction has long been studied not only as a way to prolong longevity but also as an approach to improve cancer prevention and treatment. Dietary restriction may prevent senescence of the immune and hematopoietic systems. In addition, short-term fasting before chemotherapy can reduce hematological toxicity in cancer patients. We studied the influence of fasting on immune cells, hematopoietic stem cells, and progenitor cells in the bone marrow and spleen of mice. Six-to-twelve-week old C57BL/6 mice were starved for 48 hours before analysis. We collected bone marrow and splenic cells from starved and control mice. After 48 hours of fasting, the body weight significantly decreased by an average of 24.1% compared to that of normal control mice. Calorie restriction caused a significant decrease in peripheral white blood cell count by an average of 48.3%, but hemoglobin level and platelet count were less affected. The averaged total number of bone marrow cells in the fasting group was significantly lower than that in the normal control group (2.45×107 versus 3.14×107, P < 0.01). In fasted mice there was a significant reduction in the hematopoietic stem cell count, using detection based on the lineage- c-kit+ Sca-1+, compared to control mice (0.83×105 versus 1.24×105, P < 0.05). In contrast, there was no significant difference for progenitor cells detected based on the lineage- c-kit+ Sca-1- (6.81×105 versus 7.75×105, P = 0.11). We performed colony assays with bone marrow cells from fasted and control mice. There was no difference between the two groups for not only the primary colony assay but also for the secondary and tertiary assays. Annexin V and 7-AAD analysis by flow cytometry showed that the rates of early and late apoptosis were almost identical in hematopoietic stem cells and progenitor cells, on comparing fasted and control mice. Furthermore, DNA cell cycle analysis of progenitor cells showed that short-term fasting caused a significant increase in the percentage in G0/G1 phase (83.1% versus 70.7%, P < 0.05) and decreases in the S and G2/M phases. These results imply that immature bone marrow cells retained their proliferative capacity by maintaining cell cycle arrest after short-term fasting, a finding that may account for the protective effect of starvation against chemotherapy in cancer patients. Calorie restriction caused a significant decrease in B cells in bone marrow (5.38×106 versus 8.1×106, P < 0.05) and especially in the spleen (6.65×106 versus 33.0×106, P < 0.001), and also significantly decreased T cells in the spleen (3.91×106 versus 14.5×106, P < 0.01). To our surprise, we detected a remarkable increase in the number of T cells in the bone marrow of fasted mice (1.25×106 versus 0.91×106, P < 0.01). Of greatest significance CD44- naive CD8+ T cells were dramatically increased in fasted bone marrow (1.74×106 versus 0.47×106, P < 0.01), and CD44- naive CD4+ T cells were also increased (0.23×106 versus 0.07×106, P < 0.05). In contrast, the numbers of CD62L- CD44+ effector memory and CD62L+ CD44+central memory T cells were not substantially changed after starvation. The increased naive T cells had no activated markers and appear to have migrated into bone marrow in a resting state without proliferating there. Short-term fasting decreased the number of hematopoietic stem cells but progenitor cells remained in a relatively quiescent state, with a prolonged DNA cell cycle and retention of colony-forming capabilities. The number of T cells in the bone marrow of fasted mice also increased dramatically, especially naive CD8+ T cells which probably migrated in from other lymphoid tissues. These findings imply that immature hematopoietic cells and some lymphoid cells can survive starvation while maintaining their function. The mechanisms by which T lymphoid cells promptly accumulate in bone marrow during starvation are under investigation. Disclosures Koh: Pfizer: Consultancy, Honoraria. Nakane:Mundipharma KK: Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding. Hino:Nippon Shinyaku: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding; Alexion: Honoraria, Research Funding.
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- 2016
10. Pre-Transplant Autonomic Nervous System Malfunction Is a Powerful Predictor for Survival after Allogeneic Hematopoietic Cell Transplantation
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Takahiko Nakane, Hideo Koh, Hirohisa Nakamae, Asao Hirose, Mitsutaka Nishimoto, Mika Nakamae, Yasuhiro Nakashima, Masayuki Hino, and Yoshiki Hayashi
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medicine.medical_specialty ,Univariate analysis ,business.industry ,Proportional hazards model ,Immunology ,Lymphoblastic lymphoma ,Hazard ratio ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Comorbidity ,Gastroenterology ,Surgery ,Transplantation ,Autonomic nervous system ,Internal medicine ,medicine ,Aplastic anemia ,business - Abstract
Background: Autonomic nerve function can be affected by various factors such as patient activity of daily living, disease status, treatment history and/or comorbidity. Indeed, autonomic nervous system dysfunction, as indexed by heart rate variability (HRV), has shown prognostic value for various disease outcomes, but its influence on outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) is unclear. We therefore conducted a prospective observational study to determine the impact of autonomic nervous system dysfunction on outcomes following allo-HCT. Methods: From July 2011 to July 2013, we prospectively registered patients who had received allo-HCT in our institute. We also applied well-established examination of HRV as a surrogate maker of the autonomic nervous system. HRV data were collected from 24-hour ambulatory ECG recordings within 28 days of the starting day of the conditioning regimen for allo-HCT. Obtained data were analyzed with RR data analysis software (MemCalc/CHIRAM version 3, GMS Co., LTD., Tokyo, Japan). The following parameters were employed as markers of HRV: standard deviation of NN interval (SDNN) and the squares of the differences between adjacent normal-to-normal RR intervals (r-MSSD) in time domain analysis, and low-frequency (LF) and high-frequency (HF) power in frequency domain analysis. Δ Akaike's information criterion (Δ AIC) was used to compare the HRV components-added model to the basic model by the Pre-transplantation Assessment of Mortality (PAM) score, HCT-specific comorbidity index (HCT-CI), or disease risk index (DRI) in a Cox proportional hazards model. Results: We registered 112 consecutive allo-HCTs (103 patients) who agreed to participate in this study. The median age of the patients was 45.5 years (range: 18-66) and the median follow-up period for survivors (76 patients) was 961 days (range: 159-1654). Diagnoses included acute myeloid leukemia (n=55, 49%), acute lymphoid leukemia/lymphoblastic lymphoma (n=13, 12%), mixed phenotype acute leukemia (n=3, 3%), myelodysplastic syndrome (n=15, 13%), adult T cell leukemia/lymphoma (n=7, 6%), aggressive lymphomas (n=6, 5%), indolent lymphoma/chronic lymphoid leukemia (n=3, 3%), chronic myeloid leukemia/other myeloproliferative neoplasms (n=5, 4%), aplastic anemia (n=2, 2%), and others (n=3, 3%). Stem cell sources consisted of HLA-matched related donors for 18 transplants (16%), mismatched related donors for 24 transplants (22%), matched unrelated donors for 32 transplants (29%), mismatched unrelated donors for 8 transplants (7%), and cord blood for 30 transplants (27%). Myeloablative conditioning was employed for 84 transplants (75%). Median value of LF, HF, SDNN, and r-MSSD was 409 msec2 (range: 27-1279), 103 msec2 (range: 5-1309), 122 msec (range: 48-231), and 20 msec (range: 4-95), respectively.From univariate analysis, the reduction of LF, HF, SDNN, or r-MSSD was significantly associated with decreased probability of OS (hazard ratio (HR): 0.7 for LF per 100 msec2 (p Conclusions: Pre-transplant autonomic nervous system dysfunction is a powerful predictor of survival likely because it reflects the comprehensive physiological or pathological status of the patient. Of note, LF was a powerful predictor for survival and statistically independent from well-known prognostic indexes or scoring systems such as PAM, HCT-CI, and DRI. Disclosures Nakane: Otsuka: Honoraria. Nakamae:Otsuka: Other: My spouse receives research funding from Otsuka; Kyowa Kirin: Other: My spouse receives research funding from Kyowa Kirin. Nishimoto:Otsuka: Honoraria. Hino:Celgene: Honoraria. Nakamae:Otsuka: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding.
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- 2015
11. The V50/V25 Ratio, a Marker of Small Airway Disease, Is Highly Predictive of Survival after Allogeneic Hematopoietic Cell Transplantation
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Mika Nakamae, Hideo Koh, Yasuhiro Nakashima, Mariko Yamashita, Takahiko Nakane, Masayuki Hino, Hirohisa Nakamae, Yoshiki Hayashi, Asao Hirose, and Mitsutaka Nishimoto
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medicine.medical_specialty ,business.industry ,Proportional hazards model ,Immunology ,Cell Biology ,Hematology ,respiratory system ,Airway obstruction ,medicine.disease ,Biochemistry ,Surgery ,Pulmonary function testing ,Transplantation ,FEV1/FVC ratio ,DLCO ,Internal medicine ,Diffusing capacity ,Cardiology ,Medicine ,Lung volumes ,business - Abstract
Some studies that evaluated the predictive value of lung function prior to allogeneic hematopoietic stem cell transplant (allo-SCT) showed a statistically significant relationship between pulmonary function test (PFT) parameters and outcome. However, patients infrequently display significant abnormalities in lung function before allo-SCT, specifically forced expiratory volume in one second (%FEV1.0) and vital capacity (%VC). In addition, the underlying mechanism for the abnormalities in PFT parameters present before allo-SCT remains elusive. V50/V25 ratio is known to be a sensitive marker of small airway obstruction and an abnormal V50/V25 ratio often becomes detectable even in patients in whom %FEV 1.0 and/or %VC are normal. To our knowledge, nobody has reported the effect of the V50/V25 ratio on outcome in patients undergoing allo-SCT. We here comprehensively evaluate the effect of PFT parameters determined before allo-SCT on survival and outcomes. We also address the causes of deterioration in PFT indicators. We retrospectively studied 159 evaluable patients who received allo-SCT at our institute between June in 2004 and December in 2012, and who had available PFT data acquired before allo-SCT (median age 46). The median follow-up duration for survivors was 875 days. We evaluated PFT indicators including %VC, %FEV1.0, MMF, %RV, RV/TLC, FVC, FEV1.0/FVC, DLco/VA, V25 and V50/V25 ratio. Analysis using a univariate Cox proportional hazard model showed that %VC, %FEV1.0, DLco/VA, RV/TLC, and V50/V25 ratio (all P< 0.05) were significantly compromised in patients who died. On multivariate analysis, %VC, DLco/VA and V50/V25 retained statistical significance (all P-3.0) pre allo-SCT, whereas in just 12% and 11% respectively were the %FEV1.0 (< 80%) and %VC (< 80%) abnormal. Moreover, the V50/V25 determined before allo-SCT was significantly correlated with age (P Next, we established a scoring system for lung function by applying three independently significant parameters. Importantly, the three indicators for which statistical significance was detected have distinct physiological implications. V50/V25 is a marker of obstruction, %VC, a measure of lung capacity, and diffusing capacity for carbon monoxide/alveolar volume (DLco/VA), a measure of diffusing capacity. We assigned a separate score (%VC; < 80% = 1 and > 80% = 0, DLco/VA; < 80% = 1 and > 80% = 0, V50/V25; >3.25=1 and < 3.25 = 0) and stratified all patients into the four group by total score. The scoring system consisting of %VC, DLco/VA and V50/V25 represented a significant discriminating variable for prediction of survival after allo-SCT (Figure 1). In the current study, our data demonstrate the predictive value of a sensitive small-airway disease indicator, V50/V25, for survival. Although we cannot exclude the presence of other potential factors affecting V50/V25 in hematological patients, our results demonstrate that V50/V25 might be significantly compromised by age, and/or smoking before allo-SCT. In addition a scoring system that incorporates V50/V25 instead of %FEV1.0 may be a potentially useful clinical tool for prediction of survival after allo-SCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2014
12. Effectiveness of Antibacterial Prophylaxis with Non-Absorbable Polymyxin B Compared to Levofloxacin after Allogeneic Hematopoietic Stem Cell Transplantation
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Hideo Koh, Asao Hirose, Yoshiki Hayashi, Mitsutaka Nishimoto, Hirohisa Nakamae, Hiroshi Kakeya, Koichi Yamada, Takahiko Nakane, Yasuhiro Nakashima, Masayuki Hino, Shiro Koh, and Mika Nakamae
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Administration, Topical ,medicine.medical_treatment ,Immunology ,Antibiotics ,Levofloxacin ,Hematopoietic stem cell transplantation ,Opportunistic Infections ,Neutropenia ,Biochemistry ,Gastroenterology ,Immunocompromised Host ,Young Adult ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Survival rate ,Aged ,Polymyxin B ,Retrospective Studies ,Transplantation ,Neutrophil Engraftment ,business.industry ,Mortality rate ,Hematopoietic Stem Cell Transplantation ,Bacterial Infections ,Cell Biology ,Hematology ,Antibiotic Prophylaxis ,Middle Aged ,medicine.disease ,Anti-Bacterial Agents ,Infectious Diseases ,Graft-versus-host disease ,Bacteremia ,Female ,business ,Follow-Up Studies ,medicine.drug - Abstract
Introduction: Bacterial infection is a major cause of early mortality after hematopoietic stem cell transplantation (HSCT). Currently, fluoroquinolones are widely used as prophylaxis against bacterial infection during neutropenia in HSCT. This strategy was established based on the results of several meta-analyses which showed that fluoroquinolones improved survival outcomes in patients receiving chemotherapy including HSCT when compared to placebo or no treatment. However, there was no evidence that the sole use of fluoroquinolones decreased mortality rates compared to other antibiotics. Intestinal flora has been investigated as a possible source of systemic infection during neutropenia through bacterial translocation from the intestinal tract. Some recent reports have shown that enterobacterial flora might be associated with bacteremia or graft-versus-host disease (GVHD) in HSCT. It was also shown in early trials that non-absorbable antibiotics which target intestinal flora improve the survival rate through decreased incidence of infection events in patients with neutropenia. However, it has been not sufficiently elucidated whether fluoroquinolones are able to reduce the infection rate more effectively than non-absorbable antibiotics, particularly in HSCT. Here we retrospectively compared systemic levofloxacin (LVFX) with non-absorbable polymyxin B (PB) in allogeneic HSCT. Patients and methods: This was a retrospective cohort study. We reviewed the charts of patients who underwent allogeneic HSCT where prophylaxis against bacterial infection was given using LVFX or PB from the start of conditioning until neutrophil engraftment. The study was conducted at our institute between 2005 and 2013. Results: A total of 226 (86 patients with PB and 140 patients with LVFX) patients were analyzed. Median age was 46 years (range: 16-69) with a 52:48 female/male ratio. The percentages for disease diagnosis, disease risk, and conditioning intensity were statistically similar. In the latter part of the study, significantly more patients were given LVFX. With the recent developments in HSCT procedure, cord blood or an HLA-mismatched donor was used as a stem cell source and drug combinations other than the classical combination, i.e., calcineurin+ short-term MTX, were used as GVHD prophylaxis in the LVFX group more frequently than in PB group. Median duration until neutrophil engraftment after HSCT was 16 days (range, 8-40) in the LVFX group and 15.5 days (range, 7-47) in the PB group (P= 0.74). The duration of prophylaxis was 11 days (range, 0-27) in the LVFX group and 12 days (range, 0-31) (P= 0.41) in the PB group. The type of antibiotic was changed in 96% of patients in the LVFX group and 94% in the PB group before engraftment, which was defined as failure of prophylaxis in this study (P=0.51). There was no significant difference in the incidence of clinically documented infection between the LVFX group (13%) and the PB group (17%) (P= 0.34). Microbiologically documented infection rates were 17% in the PB group and 11% in the LVFX group. The rate of resistance of etiological bacteria to LVFX was 100% in the LVFX group and 79% in the PB group (P=0.51). No significant difference was observed between the two groups in the cumulative incidences of prophylaxis failure (P= 0.36), clinically documented infection (P= 0.26), GVHD (P=0.50) and non-relapse mortality within the first 100 days after HSCT (P= 0.62). Furthermore, there was also no significant difference in overall survival between the two groups (P=0.72). Similar results were obtained in multivariate analysis adjusted for following factors: sex, age, transplant source, disease risk, donor type, HLA disparity, intensity of conditioning, type of GVHD prophylaxis, use of TBI or ATG. Conclusion: Our results indicate that prophylaxis against bacterial infection even with PB, a topical antimicrobial agent, might be as effective as LVFX in the early phase after allogeneic HSCT, suggesting the importance of inhibiting pathogenic bacteria in the intestine to prevent systemic infection probably due to the bacterial translocation. Antibacterial prophylaxis with PB might be a feasible strategy to preserve quinolone as an option for later use. Further optimization of oral prophylaxis against bacterial infection and/or a better understanding of influence of enterobacterial flora on after-transplant immunity are required. Disclosures Nakamae: Pfizer Inc.: Research Funding. Hayashi:Pfizer Inc.: Honoraria. Kakeya:Daiichi sankyo: Honoraria, Research Funding; Pfizer Inc.: Honoraria, Research Funding. Hino:Pfizer Inc.: Research Funding.
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- 2014
13. HLA Haplo-Identical Peripheral Blood Stem Cell Transplantation Using High-Dose Cyclophosphamide Post-Transplantation For Poor Prognosis Or Refractory Acute Leukemia and Myelodysplastic Syndrome: A Prospective Pilot Study At a Single Center
- Author
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Takahiko Nakane, Jyoji Nagasaki, Satoru Nanno, Mitsutaka Nishimoto, Asao Hirose, Hirohisa Nakamae, Takuro Yoshimura, Shiro Koh, Hideo Koh, Masayuki Hino, Yasuhiro Nakashima, Hiroshi Okamura, and Mika Nakamae
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medicine.medical_specialty ,Acute leukemia ,Thymoglobulin ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Surgery ,Fludarabine ,Transplantation ,Graft-versus-host disease ,Internal medicine ,Medicine ,business ,Busulfan ,medicine.drug - Abstract
Recently nonmyeloablative, haplo-identical T-cell replete bone marrow transplantation using high-dose cyclophosphamide (CY) post-BMT to control GVHD and prevent graft rejection by inducing bi-directional tolerance was reported. This strategy resulted in promising outcomes with low transplantation-related mortality (TRM) due to a low incidence of GVHD and infectious disease. However, the high relapse rate remained a major problem in high-risk hematological disease. We therefore planned a prospective pilot study of myeloablative or reduced intensity HLA haplo-identical allogeneic hematopoietic cell transplantation (HCT) using reduced doses of CY post-transplantation, followed by administration of peripheral blood stem cells (PBSC) instead of bone marrow, for those with a poor-prognosis or refractory leukemia and MDS. As of 30 June 2013, 17 patients had been enrolled in this prospective pilot study. Patients with a poor prognosis or refractory leukemia and MDS requiring prompt HCT were eligible for this study if they lacked a donor who was serologically HLA-identical or had a single antigen mismatch. The conditioning regimen consisted of fludarabine 15 mg/m2 and cytarabine 2.0 g/ m2 twice a day on days -11 and -10, thymoglobulin 2.0 mg/kg on days -8 and -7, and fludarabine 30 mg/ m2/day with intravenous busulfan 3.2 mg/kg/day on days -6 to -3 (n=11) or melphalan 100 mg (n=6) on day -2. Nine patients received a single dose of 25 mg/kg CY on day 3 and eight patients, double doses of 25 mg/kg CY on days 3 and 4 post-peripheral blood stem cell transplantation (PBSCT). Tacrolimus and oral mycophenolate mofetil was started after the completion of high-dose CY post-HCT. The median age of patients was 42 years (range 18–65). Disease diagnoses included AML (n=14), ALL (n=2) and MDS (n=1). In 12 (71%) of 17 patients, disease status was non-remission, with active disease at the time of PBSCT. Eight (47%) of 17 patients had a history of prior HCT. Donors were partially HLA-mismatched (haplo-identical) first degree relatives of the patients and differed from the patients at a median of 3/8 HLA loci in both the HVG and GVH directions. All patients received G-CSF-mobilized, unmanipulated PBSC containing a median of 3.0 x 106 CD34+cells/kg and 1.4 x 108CD3+T-cells/kg. Non-infectious fever due to PBSC infusion occurred in 14 (82%) patients and persisted until day 2 in most patients. Except for one patient who died soon after PBSCT due to disease progression, full donor T-cell chimerism was achieved at day 30 following PBSCT in all patients. Nine of 17 developed grade II-III acute GVHD. None developed grade IV acute GVHD. Three of nine patients receiving a single dose of CY, but only one of eight patients receiving double doses of CY developed grade III acute GVHD. In 12 of 16 evaluable patients, CMV reactivation was observed by day 100. Three patients developed CMV disease. BK virus cystitis occurred in four of eight patients receiving double doses of CY, however, none receiving a single dose of CY post-PBSCT developed BK virus cystitis. The cumulative incidence of TRM at one year was 13%. At one year, the overall survival of all patients, and the percentages of patients in remission and those with active disease were 43%, 75% and 31%, respectively. The results of our study demonstrated that our HLA haplo-identical transplantation using high-dose CY post-PBSCT resulted in a low incidence of TRM and was feasible even in patients with high-risk acute leukemia and MDS as an alternative stem cell source. Of note, the dose of CY post-PBSCT affected the incidence of both BKV cystitis and severe GVHD. The optimal dose of CY following HLA haplo-identical PBSCT and preparative regimen should be further explored to establish a standard regimen. Disclosures: Nakamae: Otsuka Pharmaceutical Co., Ltd.: Honoraria, Travel/accommodations/meeting expenses, Travel/accommodations/meeting expenses Other; Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses Other. Off Label Use: Mycophenolate mofetil was used as one of drugs for acute GVHD prophylaxis. Koh:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nishimoto:Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakashima:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nagasaki:Kyowa Hakko Kirin Pharma, Inc.: Travel/accommodations/meeting expenses Other. Nakane:Otsuka Pharmaceutical Co., Ltd.: Honoraria, Speakers Bureau; Kyowa Hakko Kirin Pharma, Inc.: Speakers Bureau, Travel/accommodations/meeting expenses Other. Nakamae:Kyowa Hakko Kirin Pharma, Inc.: Research Funding, Travel/accommodations/meeting expenses Other. Hino:Sanofi K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria, Research Funding; Kyowa Hakko Kirin Pharma, Inc.: Honoraria, Research Funding, Travel/accommodations/meeting expenses Other.
- Published
- 2013
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