105 results on '"Mika Nakamae"'
Search Results
2. A Prospective Study of an HLA-Haploidentical Peripheral Blood Stem Cell Transplantation Regimen Based on Modification of the Dose of Posttransplant Cyclophosphamide for Poor Prognosis or Refractory Hematological Malignancies
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Hirohisa Nakamae, Hiroshi Okamura, Asao Hirose, Hideo Koh, Yasuhiro Nakashima, Mika Nakamae, Mitsutaka Nishimoto, Yosuke Makuuchi, Masatomo Kuno, Naonori Harada, Teruhito Takakuwa, and Masayuki Hino
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Medicine - Abstract
The optimal dose of posttransplant cyclophosphamide (PTCy) for use in patients undergoing HLA-haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (PTCy-haplo) has not been sufficiently examined. This study evaluates the safety and efficacy of HLA-haploidentical hematopoietic cell transplantation with a reduced dose of PTCy for patients with a poor prognosis or those with refractory hematological malignancies. We conducted a prospective clinical study of PTCy-haplo with peripheral blood stem cells (PBSCs) using a modified PTCy dosage regimen consisting of 50 mg/kg on day 3 posttransplantation and a reduced dose of 25 mg/kg on day 4. The cumulative incidences of grades II to III and IV acute graft-versus-host disease (GVHD) at day 100 posttransplantation were 30% and 0%, respectively. The cumulative incidence of moderate-to-severe chronic GVHD after transplantation was 7.0%. The cumulative incidence of nonrelapse mortality at 1 year posttransplantation was 6.1%. Overall survival (OS) at 1 year was 66%. In addition, the restricted cubic-spline Cox regression analysis showed nonlinear relationship between the number of infused CD34 + cells and CD3 + cells, and OS. A graft composition of >4.54 × 10 6 /kg CD34 + cells and >1.85 × 10 8 /kg but ≤3.70 × 10 8 /kg CD3 + cells was significantly associated with better survival, irrespective of the disease status (hazard ratio, 0.13; 95% confidence interval, 0.04–0.41; P < 0.001). These results suggest that PTCy-haplo with PBSCs using a de-escalated dose of 50 mg/kg on day 3 and 25 mg/kg on day 4 posttransplantation is a feasible option.
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- 2022
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3. Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy
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Hiroshi Okamura, Hirohisa Nakamae, Takero Shindo, Katsuki Ohtani, Yoshihiko Hidaka, Yasufumi Ohtsuka, Yosuke Makuuchi, Masatomo Kuno, Teruhito Takakuwa, Naonori Harada, Mitsutaka Nishimoto, Yasuhiro Nakashima, Hideo Koh, Asao Hirose, Mika Nakamae, Nobutaka Wakamiya, Masayuki Hino, and Norimitsu Inoue
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allogeneic hematopoietic stem cell transplantation ,transplantation associated-thrombotic microangiopathy ,complement ,alternative pathway ,Ba ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation via the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA.
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- 2021
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4. Post-Treatment M2BPGi Level and the Rate of Autotaxin Reduction are Predictive of Hepatocellular Carcinoma Development after Antiviral Therapy in Patients with Chronic Hepatitis C
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Kazuya Takemura, Etsuko Takizawa, Akihiro Tamori, Mika Nakamae, Hiroshi Kubota, Sawako Uchida-Kobayashi, Masaru Enomoto, Norifumi Kawada, and Masayuki Hino
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autotaxin ,direct-acting antivirals ,hepatocellular carcinoma ,hepatitis C virus ,sustained viral response ,Wisteria floribunda agglutinin positive Mac-2 binding protein ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Patients with chronic hepatitis C virus (HCV) develop hepatocellular carcinoma (HCC) regardless of achieving a sustained viral response (SVR). Because advanced liver fibrosis is a powerful risk factor for HCC, we analyzed the association between autotaxin (ATX), a liver fibrosis marker, and post-SVR HCC development within 3 years after antiviral treatment. We included 670 patients with HCV who received direct-acting antivirals, achieved SVR and were followed up for at least 6 months (270 of them were followed up for 3 years or more). We measured serum ATX levels before treatment and 12/24 weeks after treatment. The diagnosis of HCC was based on imaging modalities, such as dynamic computed tomography and dynamic magnetic resonance imaging and/or liver biopsy. The present study revealed that high levels of serum ATX predicted post-SVR HCC development (area under the receiver operating characteristic: 0.70–0.76). However, Wisteria floribunda agglutinin positive Mac-2 binding protein (M2BPGi), another liver fibrosis marker, was a more useful predictive marker especially post-treatment according to a multivariate analysis. Patients with a high rate of ATX reduction before and after antiviral treatment did not develop HCC regardless of high pretreatment ATX levels. In conclusion, post-treatment M2BPGi level and the combination of pretreatment ATX levels and rate of ATX reduction were useful predictive markers for post-SVR HCC development in patients with chronic HCV infection.
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- 2020
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5. Sinusoidal obstruction syndrome associated with disseminated toxoplasmosis involving the liver after allogeneic hematopoietic stem cell transplantation: A case report
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Yosuke Makuuchi, Sayaka Tanaka, Hideo Koh, Makoto Niki, Kazumi Norose, Yosuke Nakaya, Kentaro Ido, Kazuki Sakatoku, Masatomo Kuno, Naonori Harada, Teruhito Takakuwa, Asao Hirose, Hiroshi Okamura, Mitsutaka Nishimoto, Yasuhiro Nakashima, Mika Nakamae, Kenji Hikosaka, Hiroshi Kakeya, Masahiko Ohsawa, Masayuki Hino, and Hirohisa Nakamae
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Microbiology (medical) ,Infectious Diseases ,Pharmacology (medical) - Published
- 2023
6. Time-Sequential Change of the Predictive Power of Peripheral Blood WT1mRNA Levels after Allogeneic Stem Cell Transplantation for Myeloid Neoplasm Relapse and Development of a Dynamic Relapse Prediction Model
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Soichiro Nakako, Hiroshi Okamura, Isao Yokota, Yukari Umemoto, Yosuke Makuuchi, Masatomo Kuno, Teruhito Takakuwa, Mitsutaka Nishimoto, Asao Hirose, Mika Nakamae, Yasuhiro Nakashima, Hideo Koh, Masayuki Hino, and Hirohisa Nakamae
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
7. Clinical characteristics of Japanese patients with polycythemia vera: results of the JSH-MPN-R18 study
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Yoko Edahiro, Tomoki Ito, Akihiko Gotoh, Mika Nakamae, Fumihiko Kimura, Michiaki Koike, Keita Kirito, Hideho Wada, Kensuke Usuki, Takayuki Tanaka, Takehiko Mori, Satoshi Wakita, Toshiki I. Saito, Akiko Kada, Akiko M. Saito, Kazuya Shimoda, Yuka Sugimoto, Toshiro Kurokawa, Akihiro Tomita, Yoshinori Hashimoto, Koichi Akashi, Itaru Matsumura, Katsuto Takenaka, and Norio Komatsu
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Japan ,Mutation ,Humans ,Thrombosis ,Hematology ,Janus Kinase 2 ,Polycythemia Vera ,Retrospective Studies - Abstract
The presence of a JAK2 V617F or JAK2 exon 12 mutation is one of the three major criteria listed for the diagnosis of polycythemia vera (PV) in the 2017 World Health Organization Classification. However, a nationwide study has not yet been conducted in Japan since the discovery of JAK2 mutations. Therefore, the Japanese Society of Hematology (JSH) retrospectively analyzed the clinical characteristics of 596 Japanese patients with PV diagnosed between April 2005 and March 2018. Among the 473 patients with complete data on JAK2 mutations available, 446 (94.3%) and 10 (2.1%) were positive for the JAK2 V617F and JAK2 exon 12 mutations, respectively. During a median follow-up of 46 months (range: 0-179 months), 47 (7.9%) deaths occurred. The major causes of death were secondary malignancies (23.4%), acute leukemia (12.8%), non-leukemic progressive disease (10.6%) and thrombotic (6.4%) and hemorrhagic complications (6.4%). Thrombotic and hemorrhagic events occurred during the clinical course in 4.0% (n = 24) and 3.5% (n = 21) of patients, respectively. These results show that the international PV prognostic score (age, venous thrombosis and leukocytosis) is applicable to Japanese patients with PV.
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- 2022
8. Immunomodulatory and direct activities of ropeginterferon alfa‐2b on cancer cells in mouse models of leukemia
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Kazuki Sakatoku, Yasuhiro Nakashima, Joji Nagasaki, Mitsutaka Nishimoto, Asao Hirose, Mika Nakamae, Hideo Koh, Masayuki Hino, and Hirohisa Nakamae
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Cancer Research ,Leukemia ,Myeloproliferative Disorders ,antitumor effector cells ,interferon-alpha ,General Medicine ,CD8-Positive T-Lymphocytes ,Recombinant Proteins ,Immunomodulation ,Mice ,Oncology ,Neoplasms ,immunomodulatory effect ,Animals ,ropeginterferon alfa-2b ,adoptive immunity ,ロペグインターフェロン - Abstract
研究グループは、白血病マウスモデルを使用した実験において、ロペグインターフェロンが生体内でがん細胞に作用するメカニズムを明らかにしました。ロペグインターフェロンが血液がんの治療で有望な結果が出ているとの報告が近年増加しています。しかし、そのメカニズムは明らかではありませんでした。本研究では、ロペグインターフェロンが腫瘍細胞に対して、直接的な細胞傷害作用をもたらしているのか、もしくは細胞そのものではなく間接的に免疫調整作用をもたらしているのかを検証しました。その結果、優れた抗腫瘍免疫作用を確認し、中でもT細胞の活性化が重要な役割を担っていることが分かりました。これは、幅広いがん種での応用の可能性も示唆しています。加えて、白血病細胞が体内から消失したマウスに再び白血病細胞株を注入しても再発しなかったことから、免疫記憶が獲得され、再発率の低下につながる可能性があると考えられます。, Although ropeginterferon alfa-2b has recently been clinically applied to myeloproliferative neoplasms with promising results, its antitumor mechanism has not been thoroughly investigated. Using a leukemia model developed in immunocompetent mice, we evaluated the direct cytotoxic effects and indirect effects induced by ropeginterferon alfa-2b in tumor cells. ...
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- 2022
9. Clinical characteristics of Japanese patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis
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Yoko Edahiro, Tomonori Ochiai, Yoshinori Hashimoto, Soji Morishita, Shuichi Shirane, Tadaaki Inano, Chiho Furuya, Michiaki Koike, Masaaki Noguchi, Kensuke Usuki, Motoaki Shiratsuchi, Kei Nakajima, Eiichi Ohtsuka, Hiroaki Tanaka, Eri Kawata, Mika Nakamae, Yasunori Ueda, Yasuo Aota, Yasumasa Sugita, Shin Ohara, Satoshi Yamasaki, Kohsuke Asagoe, Shuro Yoshida, Jun Yamanouchi, Sayaka Suzuki, Toshinori Kondo, Yuji Kanisawa, Kohtaro Toyama, Hiromi Omura, Daisuke Mizuchi, Sumio Sakamaki, Miki Ando, and Norio Komatsu
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Hematology - Published
- 2023
10. [Warm autoimmune hemolytic anemia and IgM-monoclonal gammopathy following BNT162b2 COVID-19 vaccine in a patient with splenic marginal zone lymphoma]
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Nobuhiro, Sogabe, Masatomo, Kuno, Yu, Nakagama, Yosuke, Makuuchi, Naonori, Harada, Teruhito, Takakuwa, Hiroshi, Okamura, Asao, Hirose, Mitsutaka, Nishimoto, Yasuhiro, Nakashima, Hideo, Koh, Mika, Nakamae, Yasutoshi, Kido, Hirohisa, Nakamae, and Masayuki, Hino
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Male ,COVID-19 Vaccines ,Lymphoma, B-Cell ,Immunoglobulin M ,SARS-CoV-2 ,Splenic Neoplasms ,Paraproteinemias ,Humans ,COVID-19 ,Anemia, Hemolytic, Autoimmune ,Leukemia, Lymphocytic, Chronic, B-Cell ,BNT162 Vaccine ,Aged - Abstract
There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient's symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient's serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.
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- 2022
11. A phase II study of post-transplant cyclophosphamide combined with tacrolimus for GVHD prophylaxis after HLA-matched related/unrelated allogeneic hematopoietic stem cell transplantation
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Hirohisa Nakamae, Takahiko Nakane, Hiroshi Okamura, Hideo Koh, Yasuhiro Nakashima, Asao Hirose, Mika Nakamae, Mitsutaka Nishimoto, Masatomo Kuno, Yosuke Makuuchi, Naonori Harada, Teruhito Takakuwa, and Masayuki Hino
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Adult ,Male ,Postoperative Care ,Calcineurin Inhibitors ,Hematopoietic Stem Cell Transplantation ,Patient Acuity ,Graft vs Host Disease ,Hematology ,Middle Aged ,Tacrolimus ,Survival Rate ,HLA Antigens ,Chronic Disease ,Humans ,Transplantation, Homologous ,Drug Therapy, Combination ,Female ,Cyclophosphamide ,Immunosuppressive Agents ,Aged - Abstract
A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).
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- 2021
12. Pretransplant plasma brain natriuretic peptide and N-terminal probrain natriuretic peptide are more useful prognostic markers of overall survival after allogeneic hematopoietic cell transplantation than echocardiography
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Hideo Koh, Hiroshi Okamura, Satoru Nanno, Yasuhiro Nakashima, Shiro Koh, Naonori Harada, Hirohisa Nakamae, Mitsutaka Nishimoto, Masayuki Hino, Mika Nakamae, Takahiko Nakane, and Asao Hirose
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medicine.medical_specialty ,medicine.drug_class ,Immunology ,Pharmacology ,Biochemistry ,Text mining ,Internal medicine ,Natriuretic Peptide, Brain ,Natriuretic peptide ,Overall survival ,Medicine ,In patient ,Multivariable model ,Transplantation ,Hematopoietic cell ,business.industry ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Prognosis ,Brain natriuretic peptide ,Peptide Fragments ,Echocardiography ,business ,Biomarkers ,Comorbidity index ,N-terminal pro-Brain Natriuretic Peptide - Abstract
Background: There are several prognosis prediction models about allogeneic hematopoietic cell transplantation (allo-HCT) such as the hematopoietic cell transplantation specific comorbidity index (HCT-CI) and the refined disease risk index (R-DRI). Although HCT-CI and R-DRI are valuable and commonly used, further improvement of these models is desirable because the prognostic predictive abilities for post-allo-HCT survival remain suboptimal. Both brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP), are released from the ventricular and atrial walls, in response to the walls stretch into the blood. Plasma BNP and NT-proBNP levels are well-known biomarkers of the predictors of death in patients with cancer and heart disease. However, it is unclear whether these biomarkers are useful predictors for prognosis after allo-HCT. The main aim of our study was to evaluate the potential role of plasma BNP and NT-proBNP levels in predicting the mortality in allo-HCT patients. Methods: We retrospectively registered consecutive patients who underwent allo-HCT from January 2011 to December 2018. Plasma BNP and NT-proBNP examinations and echocardiography within 1 month from the start of conditioning regimen were performed in all transplant candidates as pretransplant work-up in our institution. Cox regression models were used to estimate the hazard ratios (HRs) with 95% confidence intervals (95% CI) in the univariate and multivariate analyses. Relapse/progression (Rel/Prog) and non-relapse mortality (NRM) were considered competing events. The Fine-Gray proportional hazard regression model was used for the univariate and multivariate analyses with competing risks. A p value < 0.050 was considered statistically significant. We estimated the two models using c-statistics on the basis of time to event, using the total follow-up period to compare the predictive accuracy of R-DRI or HCT-CI with BNP or NT-proBNP added models. Standard errors (SEs) for the c-statistics were estimated by applying a bootstrap procedure using 1000 bootstrap samples to confirm the reproducibility. The SEs for the difference in c-statistics between these two models were compared with the above bootstrap samples and used to compute a z-score and a p value for the difference, similar to that in several previous studies. Results: We enrolled 174 consecutive patients. The median age was 49 (range: 16-68) years. During the follow-up period, 64 patients died (36.8%). Both plasma BNP and NT-proBNP levels showed a significant association with OS and NRM, but not Rel/Prog in the univariate analysis. Next, we conducted multivariable analysis to evaluate the independence of plasma BNP and NT-proBNP levels by adjusting for not only those variables that were reported as prognostic factors in the previous research for OS, but also diastolic dysfunction that can be associated with plasma BNP and NT-proBNP levels. We constructed each two and three multivariable model, including either BNP or NT-proBNP to assess the effects of these biomarkers on OS and NRM according to the one-in-ten rule 6 to avoid overfitting (Table 1). The adjusted models for OS showed that higher plasma BNP and NT-proBNP levels were significantly associated with poorer outcomes. Moreover, the adjusted models for NRM showed that a higher plasma BNP level was significantly associated with the outcome. We also evaluated the prognostic significance of BNP, NT-proBNP, HCT-CI, or echocardiographic parameters, including ejection fraction (EF) and diastolic dysfunction, by adding to R-DRI via computation of the c-statistic. BNP or NT-proBNP showed significantly higher c-statistic estimates for OS as compared with R-DRI alone (c-statistic estimate 0.741, 0.759, and 0.674, respectively), but not EF or diastolic dysfunction (Table 2). Both plasma BNP and NT-proBNP levels had higher HRs for OS [HR per standard deviation (SD) 2.57 (95% CI: 1.75-3.76), p < 0.001, and HR per SD 1.95 (95% CI: 1.39-2.73), p < 0.001] and NRM [HR per SD 2.10 (95% CI: 1.11-3.97), p < 0.024, and HR per SD 2.57 (95% CI: 1.92-3.44), p < 0.001] even in the normal heart function group. Conclusion: Plasma BNP and NT-proBNP levels are easy to perform and cost-effective; thus, these could be useful independent biomarkers for predicting allo-HCT prognosis than echocardiography. They enable clinical decision regarding allo-HCT. Disclosures Okamura: NIPPON SHINYAKU CO.,LTD: Honoraria. Nakane:Pfizer Japan Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Bayer Yakuhin, Ltd: Research Funding; Novartis: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED: Honoraria; Mundipharma K.K: Honoraria. Nanno:Otsuka Pharmaceutical Co., Ltd: Honoraria. Nishimoto:Bayer Yakuhin, Ltd:: Research Funding; Janssen Pharmaceutical K.K.:: Research Funding. Nakamae:Shire Japan KK: Honoraria; Celgene Corporation: Honoraria; DAIICHI SANKYO COMPANY, LIMITED: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria; Japan Blood Products Organization: Honoraria; NIPPON SHINYAKU CO.,LTD: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Amgen Astellas BioPharma K.K: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria. Nakashima:Amgen Astellas BioPharma K.K: Honoraria; Novartis: Honoraria, Research Funding; Eisai Co., Ltd: Honoraria, Research Funding; Amgen Inc: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; JCR Pharmaceuticals Co., Ltd: Honoraria; Pfizer Japan Inc: Honoraria; Astellas Pharma Inc: Research Funding; SymBio Pharmaceuticals Limited: Research Funding; Celgene Corporation: Research Funding; AbbVie GK: Research Funding; M S D K. K: Research Funding. Koh:Takeda Pharmaceutical Company Limited: Honoraria, Research Funding; Sumitomo Dainippon Pharma Co., Ltd: Honoraria; M S D K. K: Honoraria; NIHON PHARMACEUTICAL CO., LTD: Honoraria; Chugai Pharmaceutical Co., Ltd: Research Funding; Asahi Kasei Corporation: Research Funding; Amgen Astellas BioPharma K.K: Research Funding; IQVIA Services Japan K.K.: Research Funding; Takeda Science Foundation: Research Funding. Hino:Kyowa-Kirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Taiho: Research Funding; Teijin: Research Funding; MSD: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Daiichisankyo: Honoraria, Research Funding; Eisai: Research Funding; Jansenn: Honoraria; Celgene: Honoraria; Mochida: Honoraria; Ono: Honoraria; Sanofi: Honoraria; Japan Blood Products Organization: Research Funding; Nippon Shinyaku: Honoraria; Nihon Pharmaceutical: Research Funding; Mundi Pharma: Honoraria; Alexion: Honoraria. Nakamae:Pfizer Japan Inc: Honoraria, Research Funding; Astellas Pharma Inc: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen Astellas BioPharma K.K: Honoraria; ONO PHARMACEUTICAL CO., LTD: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Shire Japan KK: Honoraria; Celgene Corporation: Honoraria; DAIICHI SANKYO COMPANY, LIMITED: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria; Japan Blood Products Organization: Honoraria; NIPPON SHINYAKU CO.,LTD: Honoraria; Novartis: Honoraria; PPD-SNBL K.K: Research Funding.
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- 2021
13. Association of serum autotaxin levels with liver fibrosis in patients pretreatment and posttreatment with chronic hepatitis C
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Masayuki Hino, Hiroshi Kubota, Norifumi Kawada, Masaru Enomoto, Sawako Uchida-Kobayashi, Kazuya Takemura, Mika Nakamae, Akihiro Tamori, and Etsuko Takizawa
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Liver Cirrhosis ,Male ,Chronic hepatitis C virus ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Gastroenterology ,Antiviral Agents ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,medicine ,Humans ,In patient ,Risk factor ,Stage (cooking) ,Aged ,Hepatology ,Receiver operating characteristic ,medicine.diagnostic_test ,business.industry ,Phosphoric Diester Hydrolases ,Liver fibrosis stage ,Liver Neoplasms ,Hepatitis C, Chronic ,Middle Aged ,medicine.disease ,慢性C型肝炎ウイルス ,Sustained virological response ,Autotaxin ,オートタキシン ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Immunoassay ,030211 gastroenterology & hepatology ,Female ,business ,Biomarkers ,Serum liver fibrosis marker - Abstract
Background and aim The evaluation of liver fibrosis in patients with chronic hepatitis C virus (HCV) infection is important as it is a risk factor for hepatocellular carcinoma. In the recent years, autotaxin (ATX) has been established as a new noninvasive biomarker to predict liver fibrosis. However, antiviral treatment has been reported to decrease serum ATX, but it is unclear whether posttreatment ATX levels reflect liver fibrosis. In the present study, the correlation between ATX and liver fibrosis in pretreatment and posttreatment patients with HCV infection was analyzed. Methods A total of 199 samples from 136 patients with HCV infection who had undergone hepatic biopsy before and/or after antiviral treatment at Osaka City University Hospital were used. Posttreatment patients included 38 interferon-treated patients and 80 interferon-free direct-acting antiviral-treated patients; all patients achieved a sustained virological response (SVR). Serum ATX levels were determined by enzyme immunoassay with an AIA-2000 analyzer. Results Serum ATX levels were largely correlated with liver fibrosis stage in patients with HCV infection before and after antiviral treatment. The measured values decreased even in similar liver fibrosis stages after treatment. The area under the receiver operating characteristic curve for the ability of ATX to diagnose above F2 stage before treatment was 0.81 (both male and female) and that after achieving SVR, it was 0.71 (male) and 0.72 (female). Conclusions Serum ATX levels were correlated with histological liver fibrosis stage after achieving SVR. However, separate cutoff values before and after antiviral therapy should be established.
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- 2021
14. Safety and efficacy of anti-programmed cell death-1 monoclonal antibodies before and after allogeneic hematopoietic cell transplantation for relapsed or refractory Hodgkin lymphoma: a multicenter retrospective study
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Hideyuki Nakazawa, Satoshi Yoshioka, Takanori Teshima, Tomonari Takemura, Yoshihiro Inamoto, Ritsuro Suzuki, Arata Ishii, Shinobu Tamura, Yuna Katsuoka, Takashi Tanaka, Koji Izutsu, Noriaki Kawano, Kazuto Togitani, Takahiro Fukuda, Toshiro Kawakita, Junichi Sugita, Junji Suzumiya, Makoto Onizuka, Ayumu Ito, Masafumi Fukaya, Kohei Higuchi, Ichiro Kawashima, Rika Sakai, Shin ichiro Fujiwara, Miho Nara, Tomomi Toubai, Yosuke Imai, Tadakazu Kondo, Hiroatsu Iida, Mika Nakamae, Sung-Won Kim, Ken-ichi Matsuoka, and Seitaro Terakura
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Adult ,Male ,medicine.medical_specialty ,Cyclophosphamide ,medicine.drug_class ,Programmed Cell Death 1 Receptor ,Graft vs Host Disease ,Gastroenterology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Refractory Hodgkin Lymphoma ,Humans ,Transplantation, Homologous ,Aged ,Hematology ,business.industry ,Mortality rate ,Hematopoietic Stem Cell Transplantation ,Antibodies, Monoclonal ,Retrospective cohort study ,Middle Aged ,Hodgkin Disease ,Survival Rate ,Transplantation ,Treatment Outcome ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Toxicity ,Corticosteroid ,Female ,Neoplasm Recurrence, Local ,Safety ,business ,Immunosuppressive Agents ,030215 immunology ,medicine.drug - Abstract
We conducted a multicenter study on anti-programmed cell death-1 monoclonal antibodies (anti-PD-1 mAbs) before/after allogeneic hematopoietic cell transplantation (allo-HCT) for Hodgkin lymphoma. Anti-PD-1 mAbs were administered to 25 patients before allo-HCT and to 20 after allo-HCT. In pre-allo-HCT setting, the median interval from the last administration to allo-HCT was 59 days. After allo-HCT, 12 patients developed non-infectious febrile syndrome requiring high-dose corticosteroid. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGvHD) were 47.1%. Eight patients who had GvHD prophylaxis with post-transplant cyclophosphamide (PTCy) had less frequent aGvHD (grade II-IV, 14.6% versus 58.8%; P = 0.086). The 1 year overall survival (OS), relapse/progression, and non-relapse mortality rates were 81.3%, 27.9%, and 8.4%. In post-allo-HCT setting, the median interval from allo-HCT to the first administration was 589 days. The overall and complete response rates were 75% and 40%. At 100 days after anti-PD-1 therapy, the cumulative incidences of grade II-IV aGvHD, moderate-to-severe chronic GvHD, and grade 3-4 immune-related toxicity were 15.0%, 30.0%, and 30.0%. While the 1 year relapse/progression rate was 47.4%, the 1 year OS probability was 89.7%. In conclusion, immune-related complications were frequent despite modifications of GvHD prophylaxis or anti-PD-1 mAb dosing. In anti-PD-1-mAb-pretreated patients, PTCy-based GvHD prophylaxis may be effective.
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- 2020
15. Acquired Gray Platelet Syndrome Associated with Primary Myelofibrosis
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Hiroshi Okamura, Kentaro Ido, Asao Hirose, Yasuhiro Nakashima, Masayuki Hino, Shiro Koh, Satoru Nanno, Yosuke Makuuchi, Mitsutaka Nishimoto, Hideo Koh, Hirohisa Nakamae, Nao Tanizawa, Mika Nakamae, and Takahiko Nakane
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Male ,Light transmission ,Pathology ,medicine.medical_specialty ,Platelet dysfunction ,Case Report ,myeloproliferative neoplasms (MPNs) ,Hemorrhage ,Platelet Transfusion ,030204 cardiovascular system & hematology ,Gray Platelet Syndrome ,Gray platelet syndrome ,03 medical and health sciences ,primary myelofibrosis (PMF) ,0302 clinical medicine ,Internal Medicine ,medicine ,Humans ,In patient ,Platelet ,Myelofibrosis ,Abnormal Platelet ,business.industry ,Platelet Count ,acquired platelet dysfunction ,General Medicine ,Middle Aged ,medicine.disease ,Treatment Outcome ,Primary Myelofibrosis ,030211 gastroenterology & hepatology ,business ,Calreticulin ,Uncontrolled bleeding - Abstract
A 53-year-old man presented with uncontrolled bleeding caused by acquired platelet dysfunction accompanied by calreticulin-mutated primary myelofibrosis. Based on the detection of abnormal platelets, including large gray platelets, under light microscopy and the loss of the second wave of aggregation observed by light transmission aggregometry, the patient was diagnosed with platelet dysfunction accompanied by myeloproliferative neoplasms (MPNs). In addition, the absence of platelet α-granules was confirmed by electron microscopy. Therefore, this condition may be termed "acquired gray platelet syndrome." Acquired platelet dysfunction must be ruled out when abnormal platelets are observed in patients with MPNs.
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- 2020
16. Donor KIR2DS1-Mediated Decreased Relapse and Improved Survival Depending on Remission Status at HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide
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Masayuki Hino, Yasuhiro Nakashima, Satoru Nanno, Kentaro Ido, Mitsutaka Nishimoto, Mika Nakamae, Hideo Koh, Shiro Koh, Hiroshi Okamura, Hirohisa Nakamae, Takahiko Nakane, and Asao Hirose
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Male ,medicine.medical_specialty ,シクロホスファミド ,予後 ,Cyclophosphamide ,Survival ,キラー細胞免疫グロブリン様受容体 ,CD34 ,Graft vs Host Disease ,Human leukocyte antigen ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Receptors, KIR ,Recurrence ,Internal medicine ,medicine ,Humans ,Complete remission ,Cumulative incidence ,再発 ,Post-transplantation cyclophosphamide ,Relapse ,Genotyping ,Retrospective Studies ,Killer-cell immunoglobulin-like receptor genotyping ,Transplantation ,寛解 ,business.industry ,Donor selection ,Hematopoietic Stem Cell Transplantation ,KIR2DS1 ,Hematology ,medicine.disease ,Prognosis ,HLA-haploidentical allogeneic hematopoietic cell transplantation ,Leukemia ,HLA半合致移植 ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Transplantation, Haploidentical ,Female ,business ,030215 immunology ,medicine.drug - Abstract
HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using post-transplantation cyclophosphamide (PT/Cy-haplo) is becoming the standard of care for patients without an HLA-matched related or unrelated donor. PT/Cy-haplo can give more patients the opportunity to undergo allo-HCT, because most patients have multiple available HLA-haploidentical related donor candidates. The optimal donor selection algorithm in the PT/Cy-haplo setting has not yet been established, however. To contribute to the establishment of a donor selection formula based on disease status and killer-cell immunoglobulin-like receptor (KIR) genotype, we retrospectively analyzed 91 patients who underwent PT/Cy-haplo at our institution. In both patients and donors, HLA allele genotyping was performed for HLA-A, -B, -C, and -DRB1, and 16 KIR genes were genotyped. Patients in complete remission (CR) who underwent PT/Cy-haplo from a KIR2DS1-positive donor had a significantly lower cumulative incidence of relapse (CIR) than those who underwent PT/Cy-haplo from a KIR2DS1-negative donor (1-year CIR: 0% versus 32.6%, P = .037; 2-year CIR: 9.2% versus 42%, P = .037). Moreover, PT/Cy-haplo from a KIR2DS1-positive donor was significantly associated with improved overall survival (OS) (1-year OS: 91.7% versus 58.7%, P = .010; 2-year OS: 83% versus 34%, P = .010). In contrast, in non-CR individuals, PT/Cy-haplo from KIR2DS1-positive donors did not significantly improve CIR or OS (1-year CIR: 56.5% versus 64.7%, P = .973; 2-year CIR: not reached versus 64.7%, Pnot evaluable; 1-year OS: 25.4% versus 20.6%, P = .418; 2-year OS: 5.1% versus 20.6%, P = .418). In addition, lower infused CD34+ cell dose, female-to-male transplantation, and acute myelogenous leukemia were significantly associated with increased risk of relapse and mortality. This study demonstrates that graft-versus-leukemia/tumor effects were exerted through donor KIR2DS1 at PT/Cy-haplo when patients have low tumor burdens. It would be worth examining the inclusion of donor KIR genotyping and disease status assessment in establishing optimal donor selection criteria for PT/Cy-haplo.
- Published
- 2020
17. Prospective evaluation of alternative donor from unrelated donor and cord blood in adult acute leukemia and myelodysplastic syndrome
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Tomoyuki Endo, Koichi Miyamura, Yachiyo Kuwatsuka, Masashi Sawa, Makoto Onizuka, Yoshiko Atsuta, Noriko Fukuhara, Hiroatsu Iida, Kotaro Miyao, Akio Kohno, Atsumi Yanagisawa, Shingo Kurahashi, Hisayuki Yokoyama, Tatsunori Goto, Seitaro Terakura, Masanobu Kasai, Mika Nakamae, Makoto Murata, Nobuhiro Kanemura, Yasuo Tomiya, Nobuharu Fujii, Hiroatsu Ago, Yasushi Onishi, Tomonori Kato, Tetsuya Nishida, Yuichiro Nawa, Yasuyuki Nagata, Ritsuro Suzuki, Satoshi Iyama, Nagoya Blood, Yukiyasu Ozawa, and Kazutaka Ozeki
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Transplantation ,medicine.medical_specialty ,Acute leukemia ,Multivariate analysis ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Hematology ,Hematopoietic stem cell transplantation ,Internal medicine ,Cord blood ,Medicine ,Stem cell ,business ,Prospective cohort study - Abstract
A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.
- Published
- 2020
18. Clinical characteristics, prognostic factors, and outcomes of patients with essential thrombocythemia in Japan: the JSH-MPN-R18 study
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Yoko Edahiro, Mika Nakamae, Toshiki Saito, Michiaki Koike, Yoshinori Hashimoto, Kensuke Usuki, Akihiko Gotoh, Hideho Wada, Satoshi Wakita, Yuka Sugimoto, Katsuto Takenaka, Norio Komatsu, Toshiro Kurokawa, Akiko Kada, Kazuya Shimoda, Takayuki Tanaka, Itaru Matsumura, Koichi Akashi, Akiko Saito, Tomoki Ito, Fumihiko Kimura, Akihiro Tomita, Takehiko Mori, and Keita Kirito
- Subjects
Adult ,Male ,medicine.medical_specialty ,World health ,Young Adult ,Japan ,Risk Factors ,Internal medicine ,Medicine ,Humans ,Risk factor ,Aged ,Retrospective Studies ,Aged, 80 and over ,Acute leukemia ,Hematology ,Thrombocytosis ,business.industry ,Essential thrombocythemia ,Incidence (epidemiology) ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Female ,business ,Thrombocythemia, Essential - Abstract
We conducted a large-scale, nationwide retrospective study of Japanese patients who were diagnosed with essential thrombocythemia based on the diagnostic criteria in the World Health Organization classification. We investigated clinical characteristics, survival rates, and the incidence of thrombohemorrhagic events as well as risk factors for these events. A total of 1152 patients were analyzed in the present study. Median age at diagnosis was 65 years, the median platelet count was 832 × 109/L, and the positive mutation rates of JAK2V617F, CALR, and MPL were 62.8, 25.1, and 4.1%, respectively. Compared with European and American patients, Japanese patients were more likely to have cardiovascular risk factors and less likely to have systemic symptoms including palpable splenomegaly. Thrombocytosis was identified as a risk factor for hemorrhagic events and prognosis, but not for thrombotic events. The prognostic factors and risk classifications reported in Europe and the United States were generally applicable to Japanese patients. Regarding transformations, secondary myelofibrosis progressed in a time-dependent manner, but progression to acute leukemia was low in "true" ET patients. Skin cancers were less common and gastrointestinal cancers more common as secondary malignancies in Japanese patients, suggesting ethnic differences.
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- 2021
19. Mosquito allergy: a novel strong prognostic symptom of outcome after allogeneic hematopoietic transplantation
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Mika Nakamae, Satoru Nanno, Hideo Koh, Takahiko Nakane, Masayuki Hino, Shiro Koh, Asao Hirose, Yasuhiro Nakashima, and Hirohisa Nakamae
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Oncology ,Transplantation ,medicine.medical_specialty ,Mosquito allergy ,business.industry ,Hematopoietic Stem Cell Transplantation ,MEDLINE ,Hematology ,Prognosis ,Outcome (game theory) ,Haematopoiesis ,Culicidae ,Treatment Outcome ,Internal medicine ,Hypersensitivity ,medicine ,Animals ,Humans ,Transplantation, Homologous ,business ,Retrospective Studies - Published
- 2019
20. The Proportional Relationship Between Pretransplant WT1 mRNA Levels and Risk of Mortality After Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Not in Remission
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Yasuhiro Nakashima, Hideo Koh, Yoshinori Hashimoto, Yasunobu Takeoka, Satoru Nanno, Kentaro Ido, Asao Hirose, Hirohisa Nakamae, Mika Nakamae, Takahiko Nakane, Hiroshi Okamura, Mitsutaka Nishimoto, and Masayuki Hino
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Myeloid ,Adolescent ,Kaplan-Meier Estimate ,030230 surgery ,Disease-Free Survival ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Reference Values ,hemic and lymphatic diseases ,Internal medicine ,Biomarkers, Tumor ,Risk of mortality ,medicine ,Humans ,Transplantation, Homologous ,RNA, Messenger ,Young adult ,WT1 Proteins ,Aged ,Retrospective Studies ,Transplantation ,Hematopoietic cell ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Retrospective cohort study ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,surgical procedures, operative ,medicine.anatomical_structure ,Preoperative Period ,Female ,030211 gastroenterology & hepatology ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
The relationship between the expression levels of Wilms' tumor-1 gene (WT1) mRNA in peripheral blood before allogeneic hematopoietic cell transplantation (allo-HCT) and risk of mortality in acute myeloid leukemia (AML) patients in noncomplete remission (non-CR) remains quite elusive.We retrospectively assessed the impact of the pretransplant WT1 mRNA level on survival after allo-HCT in non-CR AML patients.A total of 125 AML patients, including 46 non-CR patients (36.8%), were analyzed. On multivariate analysis of non-CR AML patients, WT1 mRNA ≥5000 copies/μg RNA was significantly related to increased risk of mortality (hazard ratio, 2.7; 95% confidence interval, 1.3-5.5; P = 0.008). Furthermore, in the entire cohort, log10-transformed WT1 mRNA before allo-HCT was found to be significantly associated with the increased risk of mortality irrespective of whether the disease status was CR or non-CR, using Akaike's information criterion. As the pretransplant WT1 mRNA level elevated, the hazard ratio of mortality monotonically increased in a nonlinear manner regardless of remission status, suggesting that WT1 mRNA level in peripheral blood might reflect tumor burden.This study demonstrated that the pretransplant WT1 mRNA level was a powerful prognostic factor in allo-HCT even for non-CR AML patients, and there may be a WT1 mRNA threshold in non-CR patients for benefiting from allo-HCT.
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- 2019
21. Phase I study of graft-versus-host disease prophylaxis including bortezomib for allogeneic hematopoietic cell transplantation from unrelated donors with one or two HLA loci mismatches in Japanese patients
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Masayuki Hino, Hirohisa Nakamae, Shiro Koh, Hiroshi Okamura, Satoru Nanno, Takuro Yoshimura, Yasuhiro Nakashima, Mika Nakamae, Yumi Tagaito, Takahiko Nakane, Asao Hirose, Yosuke Makuuchi, and Hideo Koh
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,Premedication ,Graft vs Host Disease ,Human leukocyte antigen ,Tacrolimus ,Bortezomib ,Japan ,HLA Antigens ,immune system diseases ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Neutrophil Engraftment ,Hematology ,Dose-Response Relationship, Drug ,business.industry ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,medicine.disease ,Transplantation ,Regimen ,Methotrexate ,surgical procedures, operative ,Graft-versus-host disease ,Histocompatibility ,Female ,Unrelated Donors ,business ,medicine.drug - Abstract
This phase I study was designed for graft-versus-host disease (GVHD) prophylaxis including bortezomib in allogeneic hematopoietic cell transplantation (allo-HCT) from human leukocyte antigen (HLA)-mismatched unrelated donors in Japanese patients. Patients were administered bortezomib on days 1, 4, and 7, with short-term methotrexate and tacrolimus. Three bortezomib dose levels were prepared (1.0, 1.3, and 1.5 mg/m2). A dose of 1.3 mg/m2 was planned for administration to the initial six patients, and was adjusted if dose-limiting toxicity developed. Five of six patients enrolled for the initial dose had bone marrow donors. Two cases had single-antigen and single-allele mismatches; four had single-antigen mismatch at the A, B, C, and/or DRB1 loci in the GVH direction. All patients achieved neutrophil engraftment and complete donor chimerism. Three patients developed grade II acute GVHD, and none developed grade III–IV GVHD or any dose-limiting toxicity attributable to bortezomib by day 100. Two patients developed late-onset acute GVHD, and two developed chronic GVHD, but all cases were manageable. All patients were alive without relapse after a median follow-up period of 52 months. The optimal dose of bortezomib was determined to be 1.3 mg/m2. Prophylaxis against GVHD using a regimen including bortezomib thus seems feasible for HLA-mismatched unrelated allo-HCT.
- Published
- 2019
22. Risk Factor and Long-Term Outcome Analyses for Acute Limbic Encephalitis and Calcineurin Inhibitor-Induced Encephalopathy in Adults following Allogeneic Hematopoietic Cell Transplantation
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Asao Hirose, Keiichi Yamamoto, Hirohisa Nakamae, Yosuke Makuuchi, Yasuhiro Nakashima, Teruhito Takakuwa, Takahiko Nakane, Mitsutaka Nishimoto, Satoru Nanno, Nao Tanizawa, Hiroshi Okamura, Masayuki Hino, Mika Nakamae, Masatomo Kuno, Shiro Koh, and Hideo Koh
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Adult ,endocrine system ,medicine.medical_specialty ,genetic structures ,Encephalopathy ,Calcineurin Inhibitors ,Long-term prognosis ,Disease ,Gastroenterology ,Risk Factors ,hemic and lymphatic diseases ,Internal medicine ,Limbic Encephalitis ,medicine ,Immunology and Allergy ,Humans ,Risk factor ,Calcineurin inhibitor-induced encephalopathy ,Aged ,Retrospective Studies ,Acute limbic encephalitis ,Transplantation ,biology ,business.industry ,Limbic encephalitis ,Hematopoietic Stem Cell Transplantation ,Human herpesvirus-6 ,Cell Biology ,Hematology ,Allogeneic hematopoietic cell transplantation ,Middle Aged ,biology.organism_classification ,medicine.disease ,Calcineurin ,nervous system ,Methylprednisolone ,Molecular Medicine ,Human herpesvirus 6 ,sense organs ,business ,medicine.drug - Abstract
Post-transplantation acute limbic encephalitis (PALE) is a rare, severe inflammatory disorder in the bilateral limbic system, including the hippocampus. To date, only a few studies have reported details, including risk factors for PALE; however, further clinical evidence of PALE, especially in cerebrospinal fluid human herpesvirus 6-negative cases, is warranted. In addition, data are sparse regarding the risk factors for calcineurin inhibitor (CNI)-induced encephalopathy (CNIE) following allogeneic hematopoietic cell transplantation (allo-HCT) in adults. Therefore, we examined the risk factors for and clinical details of PALE and CNIE. We retrospectively analyzed consecutive patients who underwent allo-HCT between January 2005 and November 2017. A total of 485 patients age 46 years (median) were eligible. In total, 14 PALE cases and 11 CNIE cases were identified. Multivariable analyses identified older age, use of an HLA-mismatched unrelated donor (URD), graft-versus-host disease (GVHD) prophylaxis with CNI and mycophenolate mofetil, and grade II-IV acute GVHD as significantly associated with an increased risk of PALE. In 13 patients who received high-dose methylprednisolone (mPSL) therapy, 6 (46%) responded to mPSL therapy, and 3 (23%) achieved complete remission at day 90 after mPSL administration. Furthermore, myelodysplastic syndrome (MDS), HLA-mismatched URD, and grade II-IV acute GVHD were significantly associated with an increased risk of CNIE. The 5-year nonrelapse mortality rate was 50% in PALE and 63% in CNIE, suggesting a very poor prognosis. In conclusion, this study provides evidence that HLA-mismatched URD and acute GVHD may independently contribute to the development of PALE, possibly in part through HLA-mismatch-derived alloimmune responses. Other than acute GVHD, we have identified MDS and HLA-mismatched URD as novel predictors of CNIE after allo-HCT.
- Published
- 2020
23. [Erythrocytosis following allogeneic hematopoietic stem cell transplantation]
- Author
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Hiroe, Kawahara, Teruhito, Takakuwa, Mika, Nakamae, Hiroshi, Kubota, Hiroshi, Okamura, Satoru, Nanno, Yasuhiro, Nakashima, Takahiko, Nakane, Hideo, Koh, Asao, Hirose, Masayuki, Hino, and Hirohisa, Nakamae
- Subjects
Mutation ,Hematopoietic Stem Cell Transplantation ,Humans ,Polycythemia ,Polycythemia Vera - Abstract
Post-transplant erythrocytosis (PTE) following allogeneic hematopoietic stem cell transplantation (alloHSCT) is rare, and the clinical characteristics of this condition remain unknown. In this study, we examined the clinical characteristics of three PTE cases among 321 patients who received allo HSCT from January 1992 to December 2011 at our institution. All three patients exhibited normal levels of white blood cell and platelet counts when their hemoglobin levels reached their peak. Two patients exhibited normal levels of erythropoietin. No thrombosis or hemorrhage was observed in any of the three patients without cytoreductive therapy or an antiplatelet agent. All three patients tested negative for JAK2V617F mutations. Two patients had high levels of IL-13, an upstream signal for the JAK/STAT pathway. JAK2 is known to significantly contribute to the pathology of polycythemia vera; however, this pathology may differ from that of PTE. We believe that it is necessary to construct a more appropriate management structure for PTE by analyzing more case data in the future.
- Published
- 2020
24. Interactive Web Application for Plotting Personalized Prognosis Prediction Curves in Allogeneic Hematopoietic Cell Transplantation Using Machine Learning
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Takahiko Nakane, Hirohisa Nakamae, Asao Hirose, Masayuki Hino, Yasuhiro Nakashima, Satoru Nanno, Shiro Koh, Mika Nakamae, Hiroshi Okamura, and Hideo Koh
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Prognosis prediction ,Time Factors ,Adolescent ,MEDLINE ,Objective data ,030230 surgery ,Risk Assessment ,Decision Support Techniques ,Machine Learning ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Predictive Value of Tests ,Recurrence ,Risk Factors ,Internal medicine ,Cause of Death ,Computer Graphics ,Medicine ,Web application ,Humans ,Transplantation, Homologous ,Nonrelapse mortality ,Cumulative incidence ,Aged ,Retrospective Studies ,Transplantation ,Internet ,Hematopoietic cell ,business.industry ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Training cohort ,Progression-Free Survival ,Cohort ,Disease Progression ,030211 gastroenterology & hepatology ,Female ,business - Abstract
BackgroundAllogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for malignant hematological disorders. Transplant clinicians estimate patient-specific prognosis empirically in clinical practice based on previous studies on similar patients. However, this approach does not provide objective data. The present study primarily aimed to develop a tool capable of providing accurate personalized prognosis prediction after allo-HCT in an objective manner.MethodsWe developed an interactive web application tool with a graphical user interface capable of plotting the personalized survival and cumulative incidence prediction curves after allo-HCT adjusted by eight patient-specific factors, which are known as prognostic predictors, and assessed their predictive performances. A random survival forest model using the data of patients who underwent allo-HCT at our institution was applied to develop this application.ResultsWe succeeded in showing the personalized prognosis prediction curves of 1-year overall survival (OS), progression-free survival (PFS), relapse/progression, and non-relapse mortality (NRM) interactively using our web application (https://predicted-os-after-transplantation.shinyapps.io/RSF_model/). To assess its predictive performance, the entire cohort (363 cases) was split into a training cohort (70%) to develop the predictive model and test cohort (30%) to confirm its performance time-sequentially. The areas under the receiver-operating characteristic curves for 1-year OS, PFS, relapse/progression, and NRM in test cohort were 0.70, 0.72, 0.73, and 0.77, respectively.ConclusionsThe new web application could allow transplant clinicians to inform a new allo-HCT candidate of the objective personalized prognosis prediction and facilitate decision-making.
- Published
- 2020
25. [High-dose polyclonal intravenous immunoglobulin therapy for refractory viral infections including viremia after allogeneic hematopoietic cell transplantation]
- Author
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Kentaro, Ido, Takahiko, Nakane, Hiroshi, Okamura, Satoru, Nanno, Mitsutaka, Nishimoto, Asao, Hirose, Mika, Nakamae, Yasuhiro, Nakashima, Hideo, Koh, Masayuki, Hino, and Hirohisa, Nakamae
- Subjects
Hematopoietic Stem Cell Transplantation ,Parvovirus B19, Human ,Humans ,Immunoglobulins, Intravenous ,Pilot Projects ,Viremia - Abstract
Refractory viremia/viral disease is a major life-threatening complication that may arise among patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to clarify the therapeutic effect of high-dose polyclonal intravenous immunoglobulin (IVIG) against viremia/viral diseases after allo-HCT. We conducted a pilot study to investigate the therapeutic effect of 400 mg/kg of IVIG given for 5 consecutive days against refractory viremia/viral disease after allo-HCT. Overall, 7 patients were drug-resistant and the other 7 had not previously received any drug for their viremia/viral disease. All patients completed the 5-day therapy regimen of IVIG. A complete response at Day 56 was observed for 8 of 14 patients (57.1%). Additionally, 10 of 14 patients (71.4%) were alive at Day 56, although only one death occurred due to the viremia/viral disease. Remarkably, all 3 cases who developed exogenous viremia/viral diseases including respiratory syncytial virus pneumonia/bronchitis and human parvovirus B19 viremia achieved a complete response, suggesting that high-dose polyclonal IVIG may be more effective against exogenous viruses rather than endogenous ones. Congestive heart failure was observed in 1 patient. High-dose polyclonal IVIG could be an effective and feasible therapy for refractory viremia/viral disease after allo-HCT.
- Published
- 2020
26. Effect of Donor NKG2D Polymorphism on Relapse after Haploidentical Transplantation with Post-Transplantation Cyclophosphamide
- Author
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Teruhito Takakuwa, Masatomo Kuno, Masayuki Hino, Toshiyuki Seto, Kentaro Ido, Yosuke Makuuchi, Hideo Koh, Satoru Nanno, Asao Hirose, Yasuhiro Nakashima, Mitsutaka Nishimoto, Hirohisa Nakamae, Hiroshi Okamura, and Mika Nakamae
- Subjects
Oncology ,Adult ,Male ,endocrine system ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,Adolescent ,Graft vs Host Disease ,Polymorphism, Single Nucleotide ,Young Adult ,Polymorphism (computer science) ,Recurrence ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,Cumulative incidence ,HLA-haploidentical transplantation with post-transplantation cyclophosphamide ,Aged ,Retrospective Studies ,Transplantation ,Donor selection ,business.industry ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Tissue Donors ,Leukemia ,Leukemia, Myeloid ,NK Cell Lectin-Like Receptor Subfamily K ,NKG2D gene polymorphism ,Transplantation, Haploidentical ,Molecular Medicine ,Female ,Hematologic malignancies ,Gene polymorphism ,Graft-versus-leukemia/tumor effect ,business ,medicine.drug - Abstract
NKG2D-mediated cytotoxicity is regulated by the single nucleotide polymorphism rs1049174, and its antitumor effect has been observed in various clinical settings. There are no previously published data on the influence of donor rs1049174 polymorphism on HLA-haploidentical allogeneic hematopoietic cell transplantation using post-transplantation cyclophosphamide (PTCy-haplo). We aimed to investigate the effect of donor NKG2D gene polymorphism on PTCy-haplo recipients. We retrospectively reviewed 91 consecutive PTCy-haplo recipients at our institution, and genotyped rs1049174 of the NKG2D gene in both donors and patients. In the patients who received PTCy without antithymocyte globulin (ATG) as graft-versus-host disease prophylaxis, the 2-year cumulative incidence of relapse/progression (RI) of PTCy-haplo from rs1049174 CC donors was lower than that from rs1049174 CG/GG donors (25.0% versus 52.4%; P = .041), and rs1049174 CC donors were associated with a decreased risk of relapse/progression (adjusted hazard ratio, 0.2; 95% confidence interval, 0.0 to 0.6; P = .007). Furthermore, a beneficial effect of rs1049174 CC donor on OS and RI was observed in non-acute myelogenous leukemia patients. This study demonstrates that receipt of PTCy-haplo from rs1049174 CC donors was associated with a decreased risk of relapse/progression in the patients who underwent PTCy-haplo without ATG. Future large-scale validation studies are needed to test the significance of donor NKG2D polymorphism in the development of a new donor selection algorithm for PTCy-haplo.
- Published
- 2022
27. A Prospective Comparison Analysis of Blood Biomarkers for the Diagnosis and Prediction of Sinusoidal Obstruction Syndrome
- Author
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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
- Subjects
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.
- Published
- 2021
28. Correction to: A phase II study of post‑transplant cyclophosphamide combined with tacrolimus for GVHD prophylaxis after HLA‑matched related/unrelated allogeneic hematopoietic stem cell transplantation
- Author
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Masayuki Hino, Teruhito Takakuwa, Takahiko Nakane, Asao Hirose, Mitsutaka Nishimoto, Yosuke Makuuchi, Hideo Koh, Yasuhiro Nakashima, Hirohisa Nakamae, Naonori Harada, Masatomo Kuno, Mika Nakamae, and Hiroshi Okamura
- Subjects
medicine.medical_specialty ,Hematology ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Phases of clinical research ,Hematopoietic stem cell transplantation ,Gastroenterology ,Tacrolimus ,Calcineurin ,Transplantation ,Clinical trial ,surgical procedures, operative ,immune system diseases ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II–IV and III–IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT. Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).
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- 2021
29. Kinetics of IgG subclasses and their effects on the incidence of infection after allogeneic hematopoietic stem cell transplantation
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Asao Hirose, Masayuki Hino, Hideo Koh, Shiro Koh, Satoru Nanno, Yasuhiro Nakashima, Hirohisa Nakamae, Mika Nakamae, and Hiroshi Okamura
- Subjects
Adult ,Male ,Adolescent ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,030230 surgery ,Infections ,Young Adult ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Immune system ,hemic and lymphatic diseases ,parasitic diseases ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,Medicine ,Cord blood transplantation ,Aged ,Transplantation ,business.industry ,Incidence ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Igg subclasses ,Middle Aged ,Immunity, Humoral ,Immunoglobulin Isotypes ,surgical procedures, operative ,Immunoglobulin G ,Cord blood ,Female ,Cord Blood Stem Cell Transplantation ,Stem cell ,business ,030215 immunology - Abstract
Background The impact of the reconstitution of IgG subclasses after allogeneic hematopoietic cell transplantation (allo-HCT) on the outcomes is unclear. Methods We investigated the effects of stem cell source on the levels of serum IgG subclasses and their influence on the infection risk and prognosis. The levels of serum IgG, IgG2 and IgG4 were measured chronologically in 100 patients who underwent allo-HCT at our institute. Results The median levels of serum IgG, IgA and IgM and the number of total B-cells were determined up to one year after allo-HCT. The serum IgG2 levels decreased within one year. A multiple linear regression analysis identified lymphoid malignancy, cord blood, and days after allo-HCT as significant risk factors for low serum IgG2 levels. There were no significant differences in the level of IgG or IgG2 at 90 days after allo-HCT between the late bacterial infection group (≥90 days following allo-HCT) and the control group (P = 0.34 and 0.45, respectively). There was no significant impact of the IgG, IgG2 or IgG4 levels on the survival or non-relapse mortality. Conclusion The results suggest that cord blood transplantation might affect humoral immune reconstitution, including the IgG2 level, after allo-HCT.
- Published
- 2021
30. Drug interactions and safety profiles with concomitant use of caspofungin and calcineurin inhibitors in allogeneic haematopoietic cell transplantation
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Hiroshi Okamura, Masayuki Hino, Teruhito Takakuwa, Takahiko Nakane, Satoru Nanno, Mika Nakamae, Yosuke Makuuchi, Hideo Koh, Asao Hirose, Masatomo Kuno, Atsushi Tokuwame, Takuro Yoshimura, Yasuhiro Nakashima, Mitsutaka Nishimoto, Hirohisa Nakamae, and Shiro Koh
- Subjects
0301 basic medicine ,Pharmacology ,medicine.medical_specialty ,business.industry ,030106 microbiology ,Drug interaction ,Gastroenterology ,Tacrolimus ,Calcineurin ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Pharmacokinetics ,chemistry ,Internal medicine ,Cyclosporin a ,Concomitant ,medicine ,Pharmacology (medical) ,Caspofungin ,business ,Adverse effect - Abstract
Aim Small-scale clinical studies have reported on drug interactions between caspofungin (CPFG) and calcineurin inhibitors in healthy subjects; however, little is known about these interactions in allogeneic haematopoietic cell transplantation (allo-HCT) patients. Methods We retrospectively assessed the drug interactions and safety profiles in allo-HCT recipients treated concomitantly with CPFG and calcineurin inhibitors. Results Ninety-one consecutive cases were evaluated. There were no statistically significant differences in the plasma concentration/dose (C/D) ratios of tacrolimus (TAC) in 34 patients before and after co-administration with CPFG (median: 575.6–672.4, P = 0.200). In contrast, the median C/D ratio of cyclosporin A (CsA) in 16 patients was significantly elevated after co-administration with CPFG (median: 62.8–74.9, P = 0.016). There were no serious adverse effects on liver or renal function associated with the therapy. Conclusions Our data show that CPFG did not affect the pharmacokinetics of TAC and that it could mildly increase CsA blood concentrations in allo-HCT patients.
- Published
- 2017
31. Diagnostic usefulness of plasma presepsin (soluble CD14-subtype) for diagnosing hemophagocytic syndrome in hematological malignancies
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Satoru Nanno, Masayuki Hino, Takako Katayama, Mika Nakamae, Asao Hirose, Hirohisa Nakamae, and Hideo Koh
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,diagnosis ,CD14 ,Lipopolysaccharide Receptors ,MEDLINE ,presepsin (soluble CD14-subtype) ,血球貪食症候群 ,Gastroenterology ,Lymphohistiocytosis, Hemophagocytic ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Internal medicine ,可溶性CD14サブタイプ ,medicine ,Humans ,Young adult ,Aged ,business.industry ,Follow up studies ,Case-control study ,Hematology ,Middle Aged ,Prognosis ,Peptide Fragments ,ROC Curve ,Oncology ,Case-Control Studies ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,プレセプシン ,Female ,business ,Hemophagocytic syndrome ,Biomarkers ,Follow-Up Studies ,030215 immunology - Abstract
Secondary hemophagocytic syndrome (HPS) develops predominantly in adults and is triggered by a number of factors; it is a persistent hyper-inflammatory condition associated with activated macrophag...
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- 2017
32. Diagnostic value of serum ferritin and the risk factors and cytokine profiles of hemophagocytic syndrome following allogeneic hematopoietic cell transplantation
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Hirohisa Nakamae, Takahiko Nakane, Hiroshi Okamura, Asao Hirose, Yoshiki Hayashi, Yasuhiro Nakashima, Takuro Yoshimura, Satoru Nanno, Shiro Koh, Mika Nakamae, Takako Katayama, Mitsutaka Nishimoto, Masayuki Hino, and Hideo Koh
- Subjects
Cancer Research ,medicine.medical_treatment ,serum cytokine profile ,血球貪食症候群 ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Young adult ,Risk factor ,Serum ferritin ,Survival analysis ,allogeneic hematopoietic cell transplantation ,Hematopoietic cell ,business.industry ,serum ferritin ,Retrospective cohort study ,Hematology ,Transplantation ,Cytokine ,risk factor ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,business ,Hemophagocytic syndrome ,030215 immunology - Abstract
To examine the diagnostic value of serum ferritin, the associated risk factors, and cytokine profiles of hemophagocytic syndrome (HPS) following allogeneic hematopoietic cell transplantation (allo-HCT), we retrospectively analyzed data from patients undergoing allo-HCT between 2006 and 2012. Of 223 eligible patients, 18 patients developed HPS. A serum ferritin level above 30,000 μg/l was highly specific for the detection of HPS (specificity, 93%). The one-year survival rate for ......
- Published
- 2016
33. Pretransplant serum beta-2 microglobulin level is a potential novel prognostic marker of overall survival after allogeneic hematopoietic cell transplantation - a retrospective observational study
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Asao Hirose, Yoshinori Hashimoto, Naonori Harada, Yasuhiro Nakashima, Takahiko Nakane, Satoru Nanno, Hirohisa Nakamae, Mitsutaka Nishimoto, Masayuki Hino, Hideo Koh, Hiroshi Okamura, and Mika Nakamae
- Subjects
Transplantation ,Prognostic variable ,medicine.medical_specialty ,Hematopoietic cell ,business.industry ,Beta-2 microglobulin ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,030230 surgery ,Prognosis ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Overall survival ,Humans ,Transplantation, Homologous ,030211 gastroenterology & hepatology ,Neoplasm Recurrence, Local ,business ,Serum beta 2 microglobulin level ,Retrospective Studies - Abstract
Although elevated serum beta-2 microglobulin (BMG) has been reported as a poor prognostic marker for various hematological malignancies, no study has assessed its prognostic significance in allogenec hematopoietic cell transplantation (allo-HCT). Therefore, we conducted this retrospective observational study in 227 consecutive patients with available pretransplant serum BMG levels between April 2010 and September 2017 at our institute. We also collected and retrospectively analyzed various pretransplant variables likely related to transplant outcomes. Multivariable analysis, including major prognostic variables, such as the disease risk index and the hematopoietic cell transplant-comorbidity index, showed a significant association between higher serum BMG levels and poorer overall survival (OS) in all three adjusted models [hazard ratio (HR) per its standard deviation (SD) (SD = 1.094): 1.67 (1.35-2.03; P < 0.001), HR per SD: 1.46 (1.14-1.86; P = 0.002), HR per SD: 2.03 (1.62-2.55; P < 0.001)], respectively, due to the significant association between higher serum BMG levels and relapse/progression [HR 1.52 (1.20-1.94; P < 0.001)] instead of nonrelapse mortality [HR 1.06 (0.70-1.60; P = 0.780)]. Moreover, DRI and serum BMG had statistically significantly higher c-statistic estimates for OS compared with DRI alone (c-index 0.74 and 0.68, respectively; P < 0.001). In conclusion, pretransplant serum BMG level may serve as a useful prognostic marker and help clinical decision in allo-HCT.
- Published
- 2019
34. Clinical Impacts of Using Serum IL-6 Level as an Indicator of Cytokine Release Syndrome after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide
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Asao Hirose, Satoru Nanno, Mitsutaka Nishimoto, Masayuki Hino, Takahiko Nakane, Mika Nakamae, Hideo Koh, Hiroshi Okamura, Yasuhiro Nakashima, and Hirohisa Nakamae
- Subjects
Adult ,Male ,medicine.medical_specialty ,Cyclophosphamide ,Adolescent ,Human leukocyte antigen ,Gastroenterology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,Clinical significance ,Interleukin 6 ,Aged ,Transplantation ,biology ,business.industry ,Surrogate endpoint ,Interleukin-6 ,Hematology ,Middle Aged ,medicine.disease ,Cytokine release syndrome ,030220 oncology & carcinogenesis ,Cohort ,Transplantation, Haploidentical ,biology.protein ,Female ,business ,Cytokine Release Syndrome ,Immunosuppressive Agents ,030215 immunology ,medicine.drug - Abstract
HLA-haploidentical allogeneic hematopoietic cell transplantation with post-transplantation cyclophosphamide (PT/Cy-haplo) is widely used because of such advantages as low procedure cost, high probability of finding a suitable donor, and donor availability at short notice. Cytokine release syndrome (CRS), resulting from bidirectional alloreaction between host and donor, occurs frequently in recipients of PT/Cy-haplo, especially when peripheral blood is used. Severe and life-threatening instances of CRS have been reported. The clinical significance of CRS remains unclear, however. Here we used serum IL-6 level as a surrogate marker of CRS to evaluate the impact of outcomes in 65 consecutive patients receiving PT/Cy-haplo at our institution. Our results indicate that active disease status, high Hematopoietic Cell Transplantation-Specific Comorbidity Index score, and very severe CRS are significantly related to peak serum IL-6 level. In our cohort, high peak serum IL-6 level and severe CRS were significantly associated with the development of grade III or IV acute graft-versus-host disease (GVHD). High peak serum IL-6 level was identified a significant risk factor for poor 3-year overall survival. Our results suggest that even transient CRS following PT/Cy-haplo may contribute to poor survival owing to an increase in severe acute GVHD.
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- 2019
35. [The Foundation of Allogeneic Hematopoietic Stem Cell Transplantation and the Role of Clinical Laboratory Tests in This Field]
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Mika, Nakamae
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Hematologic Neoplasms ,Hematopoietic Stem Cell Transplantation ,Quality of Life ,Humans ,Clinical Laboratory Services - Abstract
Despite the marked progress in the procedure of allogeneic hematopoietic stem cell transplantation (allo- HCT) as a curative therapy for hematological malignancy, we still need to resolve issues in clinical laboratory testing for the assessment of transplant patients. For example, minimal residual disease (MRD) negativity before transplantation is known to be associated with good survival, but the widespread use of the multi-color flow cytometry system is needed for the routine assessment of MRD. In addition, we should apply an appropriate testing system for counting harvested bone marrow cells with careful consideration of the meas- urement principle of testing equipment because bone marrow is different from peripheral blood in its compo- sition of cells and components. It is also a problem that the short tandem repeat-polymerase chain reaction (PCR) for the evaluation of donor chimerism is not covered by Japanese national health insurance. Tissue biopsy is useful for the diagnosis of graft-versus-host disease, transplantation-associated microangi- opathy, and sinusoidal obstruction syndrome. It is, however, potentially dangerous for patients who have thrombocytopenia after allo-HCT to undergo a biopsy. Non-invasive tests including surrogate makers for the diagnosis of those complications are highly desirable, but they have been not established. Moreover, limitations in the diagnosis of infection after allo-HCT by laboratory tests include the poor clinical utility of the viral antibody test after allo-HCT and the fact that quantitative virus PCR tests after allo-HCT are not covered by Japanesehational health insurance. The number of long-term transplant survivors has increased in recent years. We therefore need to focus on treatment strategies against long-term complications after allo-HCT and the improvement of the quality of life. Further progress in laboratory medicine in the allo-HCT field may contribute to the prevention of late complications and/or improvement of the quality of life. I.
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- 2019
36. Effect of Prophylactic Post-transplant Ponatinib Administration on Outcomes in Patients With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia
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Hirohisa Nakamae, Hideo Koh, Kana Matsumoto, Mitsutaka Nishimoto, Hiroshi Okamura, Yasuhiro Nakashima, Masayuki Hino, Mika Nakamae, Satoru Nanno, Takahiko Nakane, Asao Hirose, and Kunihiko Morita
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Antineoplastic Agents ,Hematopoietic stem cell transplantation ,Neutropenia ,Gastroenterology ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Maintenance therapy ,Internal medicine ,medicine ,Humans ,Adverse effect ,Aged ,Retrospective Studies ,Philadelphia Chromosome Positive ,business.industry ,Ponatinib ,Imidazoles ,Retrospective cohort study ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Pyridazines ,Treatment Outcome ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Acute Disease ,business ,Tyrosine kinase ,030215 immunology - Abstract
Background The objective of the present retrospective study was to evaluate the effect of ponatinib administration as maintenance therapy on the outcomes after allogeneic hematopoietic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Patients and Methods We retrospectively analyzed the data from 34 consecutive patients treated at our institution from January 2008 to June 2019. We had administered post-transplant tyrosine kinase inhibitors preemptively before December 2017. Thereafter, we had initiated the prophylactic use of post-transplant ponatinib. The initial ponatinib dose was 15 mg/d. Ponatinib plasma trough levels were measured using the liquid chromatography-tandem mass spectrometry method 8 days after the first administration and subsequently. Results Nine patients received ponatinib maintenance. The 2-year overall survival and leukemia-free survival in the ponatinib maintenance group tended to be better than that in the non–ponatinib group (100% vs. 70.5%, P = .10; and 100% vs. 50.8%, P = .02, respectively). In the first 7 of the 9 consecutive patients, the median plasma concentration after ponatinib administration (15 mg/d) was 15.6 ng/mL (range, 4.8-23.3 ng/mL). Although the treatment schedule for 1 patient was altered because of adverse effects (elevation of serum amylase and neutropenia), ponatinib administration was continued for all the patients, except for 1 patient with molecular relapse. One patient developed a transient elevation of serum lipase. No patient presented with any arterial occlusive events. Conclusion Our results have indicated that the strategy of ponatinib maintenance after allogeneic hematopoietic stem cell transplantation is safe, efficacious, and promising.
- Published
- 2020
37. Combinational approach using in situ hybridization targeting 23S ribosomal RNA genes and blood cultures for bacterial identification in patients with neutropenia and fever
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Hirohisa Nakamae, Takuro Yoshimura, Hiroshi Okamura, Mika Nakamae, Takako Katayama, Mitsutaka Nishimoto, Yasuhiro Nakashima, Mizuki Aimoto, Satoru Nanno, Masayuki Hino, Akio Matsuhisa, Shiro Koh, Takahiko Nakane, Hideo Koh, Asao Hirose, and Shin-ichi Inoue
- Subjects
Male ,0301 basic medicine ,Leukocyte Count ,Ascites ,Pharmacology (medical) ,Blood culture ,Prospective Studies ,Chemotherapy-Induced Febrile Neutropenia ,Fever of unknown origin ,Bacterial identification ,medicine.diagnostic_test ,Bacterial Infections ,Middle Aged ,RNA, Bacterial ,RNA, Ribosomal, 23S ,Infectious Diseases ,Blood cultures ,Female ,medicine.symptom ,In situ hybridization ,Adult ,Calcitonin ,DNA, Bacterial ,Microbiology (medical) ,Febrile neutropenia ,030106 microbiology ,Antineoplastic Agents ,Neutropenia ,Biology ,Sensitivity and Specificity ,Sepsis ,Young Adult ,03 medical and health sciences ,Spontaneous bacterial peritonitis ,23S ribosomal RNA genes ,medicine ,Humans ,Aged ,Bacteria ,Interleukin-6 ,Interleukin-8 ,Genes, rRNA ,medicine.disease ,Virology ,Blood Culture ,Immunology ,Biomarkers - Abstract
Background A new 23S ribosomal RNA genes-targeted in situ hybridization (ISH) probe to detect global bacterial genomic DNA (59 species from 35 genera; referred to as the GB probe) phagocytized in leukocytes was recently developed. This method provided early and direct evidence of bacterial infection with high sensitivity and specificity in spontaneous bacterial peritonitis ascites. However, the utility of this method in febrile neutropenia (FN) is unknown. Methods We prospectively evaluated the utility of the ISH approach using the GB probe and previously reported probes in patients with neutropenia and fever undergoing chemotherapy at our institution between June 2011 and July 2013. Blood samples for culture analysis and ISH tests were collected simultaneously at the onset of fever; the latter were performed repeatedly. Results Fifty febrile episodes were evaluated. In 24 episodes of fever of unknown origin and 15 episodes of local infection (all negative for blood cultures), ISH tests identified causal bacteria in 21% and 13% of cases, respectively, at the onset of fever. In seven sepsis cases (all positive for blood culture), positive ISH test results at fever onset were achieved in 71%; for two patients with neutrophil counts of 0/μl and 171/μl, respectively, negative results were obtained. Conclusions This new ISH approach could prove useful for early detection of bacteria in patients with neutropenia and blood culture-negative, with fever of unknown etiology after chemotherapy. Using this method in combination with blood culture, even in cases with extremely low neutrophil counts, might contribute to better management of FN.
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- 2016
38. Diagnostic value of levels of presepsin (soluble CD14-subtype) in febrile neutropenia in patients with hematological disorders
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Mizuki Aimoto, Hiroshi Okamura, Mika Nakamae, Hirohisa Nakamae, Teruto Takakuwa, Ayumi Sato, Asao Hirose, Masatomo Kuno, Masayuki Hino, Masamichi Hashiba, Takako Katayama, Yosuke Makuuchi, and Hideo Koh
- Subjects
Male ,Lipopolysaccharide Receptors ,Gastroenterology ,Procalcitonin ,Cohort Studies ,0302 clinical medicine ,Pharmacology (medical) ,030212 general & internal medicine ,Prospective Studies ,Fever of unknown origin ,Prospective cohort study ,biology ,Bacterial Infections ,Middle Aged ,Infectious Diseases ,030220 oncology & carcinogenesis ,Female ,hormones, hormone substitutes, and hormone antagonists ,Microbiology (medical) ,Adult ,Calcitonin ,medicine.medical_specialty ,Neutropenia ,Adolescent ,Febrile neutropenia ,C-reactive protein ,03 medical and health sciences ,Young Adult ,Internal medicine ,parasitic diseases ,medicine ,Humans ,Aged ,Presepsin (soluble CD14-subtype) ,Septic shock ,business.industry ,Interleukin-6 ,Interleukin-8 ,medicine.disease ,bacterial infections and mycoses ,Hematologic Diseases ,Peptide Fragments ,Bacteremia ,Immunology ,biology.protein ,business ,Biomarkers - Abstract
Background Whether presepsin (soluble CD14-subtype) is better than other markers including procalcitonin (PCT), has not been adequately investigated in febrile neutropenia (FN). Methods We prospectively examined the utility of presepsin in FN in Cohort 1 (C1) and 2 (C2), between November 2010 and February 2012, and between November 2013 and January 2014, respectively. The purpose of this study was to investigate 1) the relative value of serum presepsin over serum PCT in C1, and 2) the relative value of plasma presepsin as compared with serum PCT, C-reactive protein, interleukin-6 and interleukin-8 with frequent, repeated sampling in C2. Results Seventy-nine FN episodes (C1, 75; C2, 4) were evaluable. In C1, when compared with control values, presepsin was significantly higher at onset of FN (P = 0.004), while PCT was not significantly higher (P = 0.54). The median value of serum presepsin within 72 h of onset of FN in subjects with fever of unknown origin, local infection, bacteremia and septic shock was 680 (reference 314) pg/ml, 763, 782 and 1359, respectively. In C2, the mean levels of plasma presepsin from onset of FN to 72 h were classified as negative in the two patients with no suspected site of infection, and those of the remaining two patients with clinically probable infections were positive (175, 131, 346 and 329 pg/ml, respectively). In contrast, the other markers did not discriminate between this two groups. Conclusions In FN, presepsin may be an earlier and more sensitive indicator of bacterial infection than PCT.
- Published
- 2016
39. 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
40. 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
41. Prospective Evaluation of Alternative Donor from Unrelated Volunteer Donor and Cord Blood in Adult Acute Leukemia and Myelodysplastic Syndrome: No Difference between Unrelated Donor and Cord Blood
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Yachiyo Kuwatsuka, Kazutaka Ozeki, Tomoyuki Endo, Koichi Miyamura, Yasuyuki Nagata, Yasuo Tomiya, Nobuharu Fujii, Yoshiko Atsuta, Satoshi Iyama, Hiroatsu Iida, Mika Nakamae, Masanobu Kasai, Kotaro Miyao, Akio Kohno, Makoto Murata, Tatsunori Goto, Tomonori Kato, Yuichiro Nawa, Hisayuki Yokoyama, Shingo Kurahashi, Ritsuro Suzuki, Seitaro Terakura, Makoto Onizuka, Tetsuya Nishida, Noriko Fukuhara, Nobuhiro Kanemura, Hiroatsu Ago, Atsumi Yanagisawa, Yasushi Onishi, Masashi Sawa, and Yukiyasu Ozawa
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medicine.medical_specialty ,Acute leukemia ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Comorbidity ,Tacrolimus ,Transplantation ,Graft-versus-host disease ,Internal medicine ,Cord blood ,medicine ,Methotrexate ,business ,medicine.drug - Abstract
Background: Among HLA-well-matched unrelated donor (UD) and umbilical cord blood (CB), HLA-8/8 allele-matched UD transplantation (UDT) showed superior overall survival (OS) to 7/8 allele-matched UDT and CBT, while a similar OS has been demonstrated between the HLA-7/8 allele-matched UDT and the CBT. However, a fair comparison between UDT and CBT is difficult, because graft availability and time required for donor-search is completely different. Once patients relapsed during UD-search period, most of those patients would choose immediate CBT. This means that patients who maintained CR in UD group may have more favorable characteristics, because those patients have been longer in remission and selected as a group of patients who maintained CR. Thus we thought that the factor of "donor-search duration" is important upon conducting a comparative study between UDT and CBT. We planned a clinical study that also taken "donor-search duration" into consideration to compare CBT outcomes with HLA well-matched UDT in a prospective trial setting. Purpose: The purpose of the current study is to compare the transplant outcomes of HLA-well-matched UDT with those of CBT in a prospective trial. Patients and Methods: From 2007 to 2015, 231 patients were provisionally registered for a single-arm phase 2 study of CBT (manuscript submitted). All provisionally registered patients were subjects of current study (Figure 1). After provisional registration, we attempted to find appropriate UD within a decent time period. After approximately 180 days of donor-search, patients received CBT if an appropriate UD was not available. In total, 91 patients received UDT, and 119 patients received CBT. Six patients withdrew and three died before transplantation. Twelve patients did not receive either UDT or CBT, but five received HLA-mismatched SCT from family donor (seven chose not to receive allogeneic SCT). Of 119 CBT recipients, 62 patients were eligible and registered to a phase 2 clinical trial reported elsewhere. Herein we analyzed transplant outcomes of 91 UDT and 119 CBT (UDT group; 49 AML, 37 ALL, 5 MDS: CBT group; 68 AML, 38 ALL, 13 MDS). Risk factors were analyzed by cox proportional hazard model, and survival estimates were depicted by Kaplan-Meier estimation and tested by log-rank test. Results: Patient age was median 39 yrs in both UDT and CBT (p=0.80). Patient body weight was median 59kg (37-90kg) in UDT, and median 55kg (35-90kg) in CBT (p=0.10). Sixty-six of 91 (72.5%) in UDT and 114 of 119 (95.8%) in CBT received myeloablative conditioning. More than 90% of patients received Tacrolimus and short-term methotrexate as GVHD prophylaxis in both UDT and CBT. Days from provisional registration to transplant were median 126 days (range, 77-261 days) in UDT, and median 99 days (8-286 days) in CBT (p Conclusion: Taken donor-search period into consideration, OS after UDT and CBT were similar in a prospective clinical study. CB may be the comparable alternative donor source to UDT. Disclosures Terakura: Novartis: Honoraria; Astellas Pharma Inc.: Honoraria; Amgen Astellas BioPharma K.K.: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Yakult Honsha, Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria. Nishida:Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; MSD K.K.: Consultancy, Honoraria; Amgen Astellas BioPharma K.K.: Honoraria. Sawa:Mundi Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanofi: Honoraria; Astellas Pharma Inc.: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Otsuka Pharmaceutical: Honoraria; Kyowa-Hakko Kirin: Honoraria; Novartis: Honoraria; Shire: Honoraria; Eisai: Honoraria; Mochida: Honoraria; Pfizer Japan Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku: Honoraria; MSD: Honoraria; Asahi-Kasei: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Miyao:Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria; Novartis: Honoraria. Ozawa:Pfizer Japan Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis: Honoraria. Goto:Celgene Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Onishi:Sumitomo Dainippon Pharma: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Nippon Shinyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma: Honoraria; Takeda Pharmaceutical Co., Ltd.: Research Funding; MSD: Honoraria, Research Funding. Fukuhara:Janssen Pharma: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; AbbVie: Research Funding; Celgene Corporation: Honoraria, Research Funding; Zenyaku: Honoraria; Bayer: Research Funding; Nippon Shinkyaku: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Mundi: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Fujii:Novartis Pharma Co., Ltd.: Honoraria; Kyowa-Hakko Kirin Co., Ltd.: Honoraria. Iida:Chugai Pharmaceutical Co., Ltd.: Research Funding. Endo:Ono: Research Funding. Onizuka:Sumitomo Dainippon Pharma: Research Funding; Astellas: Research Funding; Novartis: Research Funding; pfizer: Research Funding; Chugai Pharma: Research Funding; Bristol-Myers Squibb: Research Funding. Iyama:Otsuka Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Factory: Honoraria; Astellas Pharma: Honoraria; Daiichi Sankyo: Honoraria; Allexion Pharma: Honoraria; CSL Behring: Honoraria. Nakamae:Japan Blood Products Organization: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Nippon Shinyaku: Honoraria; Bristol-Myers Squibb: Honoraria; Shire Japan KK.: Honoraria; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria. Nagata:Janssen Pharmaceutical K.K.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Novartis Pharma K.K.: Honoraria; Celgene K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kurahashi:Novartis Pharma Co., Ltd.: Honoraria; Bristol-Myers Squibb, Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd: Honoraria. Suzuki:Celgene: Honoraria; Eisai: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Atsuta:Mochida Pharmaceutical Co. Ltd: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Miyamura:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria; Kyowa-Hakko Kirin Co., Ltd: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria. Murata:Bristol-Myers Squibb, Ltd.: Honoraria; Kyowa-Hakko Kirin Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Consultancy, Honoraria; GSK Co., Ltd.: Consultancy; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria; MSD Co., Ltd.: Honoraria.
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- 2019
42. Validation of previous prognostic models for thrombosis and exploration of modified models in patients with essential thrombocythemia
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Masayuki Hino, Mika Nakamae, Atsuko Mugitani, Takayuki Tanaka, Takuro Yoshimura, Yoshinori Hashimoto, Hiromi Omura, Hirohisa Nakamae, Mirei Horiuchi, Teruhito Takakuwa, Asao Hirose, and Hideo Koh
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Oncology ,Adult ,Male ,Risk ,medicine.medical_specialty ,Population ,Kaplan-Meier Estimate ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,In patient ,Young adult ,education ,Prognostic models ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,education.field_of_study ,business.industry ,Proportional hazards model ,Essential thrombocythemia ,Thrombosis ,Hematology ,General Medicine ,Janus Kinase 2 ,Middle Aged ,medicine.disease ,Prognosis ,030220 oncology & carcinogenesis ,Female ,business ,Risk classification ,Biomarkers ,030215 immunology ,Thrombocythemia, Essential - Abstract
Objective We examined the prognostic factors to validate previous prognostic models for survival and thrombosis with large-scale data on Japanese patients with essential thrombocythemia (ET). Method We conducted a study in 352 patients with ET to validate previous prognostic models and search for new prognostic factors. Results The International Prognostic Score for essential thrombocythemia (IPSET), the conventional risk classification and the International Prognostic Score for thrombosis in essential thrombocythemia (IPSET-T) were confirmed to be reproducible in Japanese patients. However, no significant difference was observed between the low-risk and intermediate-risk categories according to the revised IPSET-T, which does not allow direct comparison of the four risk groups. We reevaluated the risk using a modified revised IPSET-T, which was derived from the revised IPSET-T by scoring the factors as follows: one point for age > 60 years, two points for past history of thrombosis, two points for JAK2 gene mutation-positive; total points of 0 = very low risk, 1 = low risk, 2 = intermediate risk, 3 and above = high risk, with significantly different thrombosis-free survival. Conclusion The modified revised IPSET-T has been useful for 4-group stratification to predict a population that requires therapeutic intervention, irrespective of the treatment regimens.
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- 2018
43. Allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia with 11q23 abnormality: a retrospective study of the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)
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Hirohisa Nakamae, Ishikazu Mizuno, Yoshiko Atsuta, Takaaki Konuma, Hiroki Yamaguchi, Mika Nakamae, Tadakazu Kondo, Yuho Najima, Yasushi Onishi, Shohei Mizuno, Heiwa Kanamori, Satoshi Takahashi, Akira Yokota, Junichi Sugita, Yoshinobu Kanda, Shingo Yano, Naoyuki Uchida, Shuichi Ota, Takahiro Fukuda, and Tatsuo Ichinohe
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Japan ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Humans ,Cumulative incidence ,Registries ,Societies, Medical ,Aged ,Retrospective Studies ,Chromosome Aberrations ,Hematology ,business.industry ,Chromosomes, Human, Pair 11 ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Adult Acute Myeloid Leukemia ,Retrospective cohort study ,General Medicine ,Middle Aged ,Allografts ,Minimal residual disease ,Transplantation ,Survival Rate ,Leukemia, Myeloid, Acute ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Female ,Abnormality ,business ,030215 immunology - Abstract
An 11q23 abnormality presents in approximately 5% of adults with acute myeloid leukemia (AML) and is associated with adverse outcomes even after allogeneic hematopoietic cell transplantation (allo-HCT). To evaluate the outcomes and prognostic factors following allo-HCT for adult AML with 11q23 abnormality, we retrospectively analyzed the Japanese registration data of 322 adult AML patients with 11q23 abnormality who had received allo-HCT between 1990 and 2014. In total, the disease status at HCT was first complete remission (CR1) in 159 (49%) patients. The probability of overall survival and the cumulative incidence of relapse at 3 years were 44 and 44%, respectively. In the multivariate analysis, disease status beyond CR1 at the time of HCT was significantly associated with a higher overall mortality and relapse. The 11q23 fusion partner did not have a significant impact on survival. We also evaluated the prognostic value of minimal residual disease (MRD) status at HCT on transplant outcomes among hematological CR patients. MRD status at HCT was the significant prognostic indicator for hematological relapse and survival. These data suggested that allo-HCT offered a curative option for adult AML with 11q23 abnormality. Pretransplant MRD status was the significant prognostic indicator for relapse and survival in CR patients.
- Published
- 2018
44. PB1932 PREDICTIVE POWERS OF VARIOUS CARDIOVASCULAR EXAMINATIONS FOR CARDIOVASCULAR OCCLUSION EVENTS IN CML PATIENTS RECEIVING TYROSINE KINASE INHIBITORS
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M. Hino, Hirohisa Nakamae, Hideo Koh, Takahiko Nakane, Yasuhiro Nakashima, M. Hashimoto, Mika Nakamae, Asao Hirose, and J. Yoshikawa
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medicine.medical_specialty ,Cardiovascular occlusion ,business.industry ,Internal medicine ,Cardiology ,medicine ,Hematology ,business ,Tyrosine kinase - Published
- 2019
45. Prognostic Value and Clinical Implication of Serum Ferritin Levels following Allogeneic Hematopoietic Cell Transplantation
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Shiro Koh, Mitsutaka Nishimoto, Masayuki Hino, Hirohisa Nakamae, Hideo Koh, Mika Nakamae, Asao Hirose, Yasuhiro Nakashima, and Takahiko Nakane
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Adult ,Male ,Epstein-Barr Virus Infections ,medicine.medical_specialty ,Neutropenia ,Adolescent ,Red Blood Cell Transfusion ,Infections ,Gastroenterology ,Disease-Free Survival ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Prospective cohort study ,Serum ferritin ,Aged ,Hematopoietic cell ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,General Medicine ,Middle Aged ,Allografts ,medicine.disease ,Hematologic Diseases ,Survival Rate ,Transplantation ,surgical procedures, operative ,Chronic Disease ,Ferritins ,Immunology ,Female ,Erythrocyte Transfusion ,business ,Febrile neutropenia - Abstract
Little research has been done on changes in serum ferritin (s-ferritin) levels and clinical implications following allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated the correlation of s-ferritin levels after HCT with survival in 203 patients. The s-ferritin level was significantly elevated, with 75% of the patients showing peak levels 90 days after HCT. The level was >10,000 ng/ml in a total of 43% of the patients, a finding that was associated with febrile neutropenia or infection. The s-ferritin level at day 30 and at 1 year after HCT was significantly associated with prognosis. However, this statistically significant relationship was lost after adjusting for acute-phase reactants. We conclude that hyperferritinemia is very common and the degree of influence of a red blood cell transfusion will vary depending on the phase after HCT. A prospective study is needed to determine if iron load in and of itself contributes to a worse prognosis after HCT. © 2014 S. Karger AG, Basel
- Published
- 2014
46. Autonomic Nervous System Pretransplant Malfunction Is a Powerful Predictor of Survival After Allogeneic Hematopoietic Cell Transplantation
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Mika Nakamae, Mitsutaka Nishimoto, Masayuki Hino, Hirohisa Nakamae, Takahiko Nakane, Hideo Koh, Asao Hirose, and Yasuhiro Nakashima
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Comorbidity ,030204 cardiovascular system & hematology ,Autonomic Nervous System ,Risk Assessment ,Disease-Free Survival ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Postoperative Complications ,Japan ,Heart Rate ,Risk Factors ,Internal medicine ,Heart rate ,Medicine ,Heart rate variability ,Humans ,Transplantation, Homologous ,Prospective Studies ,Aged ,Proportional Hazards Models ,Transplantation ,Univariate analysis ,business.industry ,Proportional hazards model ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Heart ,Middle Aged ,Autonomic nervous system ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunology ,Multivariate Analysis ,Cardiology ,Female ,business - Abstract
BACKGROUND Autonomic nervous system function indexed by heart rate variability (HRV) has shown prognostic value for mortality in various cardiovascular and noncardiovascular diseases including cancer. The purpose of this study was to evaluate an association between HRV and outcomes of allogeneic hematopoietic cell transplantation (allo-HCT). METHODS We prospectively measured HRV as a surrogate pretransplant marker of autonomic nervous system activity in consecutive allo-HCTs with hematological diseases. RESULTS We analyzed 112 allo-HCTs performed between July 2011 and July 2013 in our center. Univariate analysis showed that increased values of HRV components (low-frequency [LF] and high-frequency [HF] spectral component), SD of normal-to-normal RR interval (SDNN), and squares of the differences between adjacent normal-to-normal RR intervals (r-MSSD) were significantly associated with decreased probability of overall mortality (hazard ratio = 0.3 for LF, P < 0.001; hazard ratio = 0.3 for HF, P = 0.001; hazard ratio = 0.6 for SDNN, P = 0.004; and hazard ratio = 0.5 for r-MSSD, P = 0.014). Among these 4 indicators, the LF-added pretransplantation assessment of mortality, hematopoietic cell transplantation-comorbidity index, and disease risk index models showed the highest values of ΔAkaike information criterion (16.5, 22.2, and 11.4, respectively). When stratified into quartiles of LF groups, 2-year overall survival was 92.9, 84.5, 59.7, and 33.2%, respectively (P < 0.001). LF alone represented a better discriminating variable for the prediction of mortality when compared with pretransplantation assessment of mortality, hematopoietic cell transplantation-comorbidity index, and disease risk index. In addition, from bivariate analyses, decreased LF was an independent and significant factor for higher overall mortality in all models. CONCLUSIONS Indicators reflective of autonomic nervous system function might be a powerful predictor of survival after allo-HCT.
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- 2017
47. PF190 PLASMA LEVELS AND OUTCOMES OF PROPHYLACTIC POST-TRANSPLANT PONATINIB ADMINISTRATION IN PATIENTS WITH PHILADELPHIA CHROMOSOME-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH+ALL)
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Mika Nakamae, K. Morita, Takahiko Nakane, Hiroshi Okamura, Yasuhiro Nakashima, Hideo Koh, Asao Hirose, M. Hino, Hirohisa Nakamae, Satoshi Nanno, and K. Matsumoto
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Oncology ,medicine.medical_specialty ,Philadelphia Chromosome Positive ,business.industry ,Lymphoblastic Leukemia ,Ponatinib ,Hematology ,Plasma levels ,Post transplant ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,In patient ,business - Published
- 2019
48. 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.
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- 2018
49. 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
- Subjects
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
50. Response-guided therapy for steroid-refractory acute GVHD starting with very-low-dose antithymocyte globulin
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Takahiko Nakane, Asao Hirose, Mika Nakamae, Yasuhiro Nakashima, Hirohisa Nakamae, Masayuki Hino, Mitsutaka Nishimoto, Hideo Koh, and Yoshiki Hayashi
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Globulin ,Anti-Inflammatory Agents ,Drug Resistance ,Graft vs Host Disease ,Drug resistance ,Gastroenterology ,Drug Administration Schedule ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Survival analysis ,Aged ,Antilymphocyte Serum ,Retrospective Studies ,Dose-Response Relationship, Drug ,biology ,business.industry ,Incidence (epidemiology) ,Low dose ,Retrospective cohort study ,Cell Biology ,Hematology ,Middle Aged ,Survival Analysis ,Surgery ,Dose–response relationship ,biology.protein ,Prednisone ,Female ,Rabbits ,Steroid refractory ,business ,Immunosuppressive Agents - Abstract
Treatment for steroid-refractory acute graft-versus-host disease (GVHD) has not been established yet. In this article, we report a single-center experience with rabbit antithymocyte globulin (ATG) for the treatment of steroid-refractory acute GVHD. We retrospectively analyzed 11 consecutive patients between December 2009 and December 2013. ATG was given at an initial dose of 1.0 mg/kg for all but one patient with gradual dose escalation while assessing responses. The overall improvement at day 28 was 55% after a median of two treatments (range: 1-5), and a median dose of 3 mg/kg (range: 1.0-11.75 mg/kg) of ATG. Patients with skin (100%, 3/3) and gut (83%, 5/6) responded favorably, whereas the cases with liver involvement showed poor responses (25%, 1/4). The overall survival and transplant-related mortality at 1 year were 55% and 45%, respectively. There were no patients who had developed a post-transplant lymphoproliferative disorder. We suggest that response-guided ATG therapy could be an option for patients with steroid-refractory GVHD, without increasing the incidence of opportunistic infections.
- Published
- 2015
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