Publications by authors named "Shigeyoshi Makino"

41 Publications

Cord blood index predicts engraftment and early non-relapse mortality in adult patients with single-unit cord blood transplantation.

Bone Marrow Transplant 2021 Jul 15. Epub 2021 Jul 15.

Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan.

How to select optimal cord blood (CB) remains an important clinical question. We developed and validated an index of CB engraftment, the cord blood index (CBI), which uses three weighted variables representing cell doses and HLA mismatches. We modeled the neutrophil engraftment time with competing events by random survival forests for competing risks as a function of the predictors: total nucleated cells, CD34, colony-forming units for granulocytes/macrophages, and the number of HLA mismatches at the antigen and allele levels. The CBI defined three groups that had different neutrophil engraftment rates at day 30 (High, 83.7% [95% CI, 79.2-88.1%]; Intermediate, 77.0% [95% CI, 73.7-80.2%]; Low, 68.4% [95% CI, 63.6-73.2%]), platelet engraftment rates at day 60 (High, 70.4% [95% CI, 64.9-75.9%]; Intermediate, 62.3% [95% CI, 58.5-66.0%]; Low, 49.3% [95% CI, 44.2-54.5%]), and non-relapse mortality at day 100 (High, 14.1% [95% CI, 9.9-18.3%]; Intermediate, 16.4% [95% CI, 13.5-19.3%]; Low, 21.3% [95% CI, 17.1-25.5%]). This novel approach is clinically beneficial and can be adopted immediately because it uses easily obtained pre-freeze data of CB.
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http://dx.doi.org/10.1038/s41409-021-01406-7DOI Listing
July 2021

The impact of graft cell source on bloodstream infection in the first 100 days after allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 07 19;56(7):1625-1634. Epub 2021 Feb 19.

Department of Hematology, Toranomon Hospital, Tokyo, Japan.

Bloodstream infection (BSI) is a major infectious complication after allogeneic hematopoietic cell transplantation (HCT). To clarify the impact of graft cell source on the incidence of BSI after transplantation, we retrospectively examined 782 adult patients receiving their first allogeneic HCT: 122 recipients of related peripheral blood stem cells or bone marrow, 215 recipients of unrelated bone marrow, and 445 recipients of unrelated umbilical cord blood (U-CB). The cumulative incidence of BSI was 42.5% at 100 days after transplantation (95% confidence interval, 39.0-46.0). Gram-positive cocci were present in 64.2% of detected isolates. Among the pre-transplant factors including age, performance status, primary disease, disease status, graft cell source, sex and ABO blood type matching, and the intensity of conditioning regimen, U-CB use was identified as the most significant risk factor for BSI by multivariate analysis (hazard ratio, 1.76; 95% confidence interval, 1.40-2.22; p < 0.00001). Among the U-CB recipients, those who are not in remission at the time of transplantation were at the greatest risk of BSI (hazard ratio, 1.69; 95% confidence interval, 1.14-2.50; p < 0.01). The study makes it clear that graft cell source has an impact on BSI development after allogeneic HCT.
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http://dx.doi.org/10.1038/s41409-021-01229-6DOI Listing
July 2021

Transfusion-associated circulatory overload and high blood pressure: A multicentre retrospective study in Japan.

Vox Sang 2021 Aug 2;116(7):785-792. Epub 2021 Feb 2.

Division of Cell Transplantation and Transfusion, Jichi Medical University Hospital, Tochigi, Japan.

Background: Transfusion-associated circulatory overload (TACO) is an adverse reaction associated with a high risk of mortality. The actual incidence of TACO and hypertension associated with transfusion in Japan is unknown.

Methods: A multicentre retrospective observational study was conducted across 23 institutions during the 1-year period of 2016. Patients were included if they developed TACO or their blood pressure (either systolic or diastolic) increased by at least 30 mmHg during the transfusion. TACO was confirmed by the primary physicians and transfusion medicine teams and recorded in the data on passive surveillance, and additional data were extracted from electronic medical records.

Results: In our patient cohort of 31 384 patients who underwent transfusion, the incidence of TACO and hypertension was 0·03% and 0·2%, respectively. However, 43% of the participating institutions didn't report any cases. When comparing risk factors between the TACO and hypertension groups, there were significant differences in comorbidities, such as abnormal findings on chest x-ray. Significant differences between the two groups were observed post-transfusion pulse rate, body temperature and oxygen saturation (P < 0·01). In the group of patients with hypertension, the level of BNP increased significantly after transfusion in 45% (5/11) of the patients. We identified 4 patients in the hypertension group who met the new ISBT's TACO criteria.

Conclusion: Our study suggests that more attention should be given to TACO in Japan, particularly in terms of improving surveillance systems. For the early diagnosis of TACO, it is crucial to carefully monitor vital signs including blood pressure.
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http://dx.doi.org/10.1111/vox.13063DOI Listing
August 2021

Prognostic Impact of Cytogenetic Evolution on the Outcome of Allogeneic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in Nonremission: A Single-Institute Analysis of 212 Recipients.

Biol Blood Marrow Transplant 2020 12 29;26(12):2262-2270. Epub 2020 Aug 29.

Department of Hematology, Toranomon Hospital, Tokyo, Japan; Okinaka Memorial Institute for Medical Research, Tokyo, Japan.

Recent progress in genetic analysis technology has helped researchers understand the pathogenesis of acute myeloid leukemia (AML). Considering this progress, AML karyotype is still one of the most significant prognostic factors that provides risk-adapted treatment approaches. Karyotype changes during treatment have been observed at times, but their prognostic impact is sparse, especially on allogeneic stem cell transplantation (allo-SCT). Here, we retrospectively investigated the effect of chromosomal changes between diagnosis and pretransplantation on the prognosis of allo-SCT by analyzing the outcomes of 212 consecutive patients who underwent allo-SCT for the first time at Toranomon Hospital, Tokyo, Japan, between 2008 and 2018. Cytogenetic abnormalities at diagnosis and pretransplantation were categorized based on the 2017 European Leukemia Net risk stratification. Genetic abnormalities such as FLT3-ITD and NPM1 were not considered in this study due to lack of genetic information in most patients. We defined cytogenetic evolution as chromosomal changes classified from lower category to higher category. Seventeen patients (8%) had cytogenetic evolution between diagnosis and pretransplantation, and they showed a significantly worse relapse rate than those who were categorized in the intermediate group based on the karyotype at diagnosis (3-year confidence interval [CI] of relapse, 57.4% versus 24.9%; P < .01). In multivariate analysis, cytogenetic evolution before allo-SCT had a significant impact on the CI of relapse (hazard ratio [HR], 3.89; CI, 1.75 to 8.67; P < .01), as well as the high score of the hematopoietic cell transplantation-specific comorbidity index (HR, 0.54; CI, 0.31 to 0.94; P = .03), but had no significant impact on overall survival or nonrelapse mortality. These results indicate that cytogenetic evolution has a significant impact after allo-SCT and should be considered during AML treatment.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.026DOI Listing
December 2020

Differences among hemoglobin thresholds for red blood cell transfusions in patients with hematological diseases in teaching hospitals: a real world data in Japan.

Int J Hematol 2020 Oct 18;112(4):535-543. Epub 2020 Jul 18.

Clinical Study Supporting Committee, The Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan.

A hemoglobin (Hb) threshold level of 7 g/dL has been proposed for red blood cell (RBC) transfusion in patients with chronic anemia in the Japanese guideline since 2005. However, Hb thresholds for hematological diseases in clinical practice and factors responsible for higher Hb thresholds remain unclear. Hb thresholds were collected for patients with hematological diseases from 32 Japanese teaching hospitals. Uni- and multivariate analyses were used to analyze relationships between Hb threshold level and various patient and hospital factors. In total, 4996 units of RBC were transfused to 1054 patients with hematological diseases in 2421 transfusions. Median age was 68 years. Myelodysplastic syndrome was the most frequent diagnosis. Overall median Hb threshold level was 6.9 g/dL. Multivariate linear regression analysis detected the following variables associated with Hb threshold level: hospital; cardiovascular disease; symptomatic anemia; and hematopoietic stem cell transplantation. Hospital was the most significant factor. Collectively, median Hb threshold level in clinical practice in Japan was similar to the guidelines. Higher Hb threshold level depended on the hospitals at which the transfusions were performed as well as patient condition. Educational approaches directed toward hospitals may be useful to promote transfusion guidelines.
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http://dx.doi.org/10.1007/s12185-020-02937-3DOI Listing
October 2020

Splenomegaly Negatively Impacts Neutrophil Engraftment in Cord Blood Transplantation.

Biol Blood Marrow Transplant 2020 09 4;26(9):1689-1696. Epub 2020 Jun 4.

Department of Hematology, Toranomon Hospital, Tokyo, Japan; Okinaka Memorial Institute for Medical Research, Tokyo, Japan.

Delayed neutrophil engraftment (NE) has been reported in cord blood transplantation (CBT) compared with other stem cell transplantation methods. The numbers of total nucleated cells (TNCs), CD34 cells (generally ≥ 1 × 10/kg), and granulocyte/macrophage colony-forming units (CFU-GM) significantly impact NE. Splenomegaly exerts negative effects on NE, but the appropriate cell dose for the patients with splenomegaly has not yet been determined, especially in CBT. We retrospectively investigated the effect of splenomegaly and number of CD34 cells infused on NE through the analysis of outcomes of 502 consecutive patients who underwent single CBT for the first time at Toranomon Hospital between 2011 and 2018. Spleen index, L × H (SI L × H), was defined as maximal length at any transverse section, (L) × vertical height (H), and splenomegaly was defined as SI L × H ≥ 115 cm. Our results show that splenomegaly (hazard ratio [HR], .60; P < .01) and low dose of infused CD34 cells (HR, .58; P < .01) had significant negative impact on NE, whereas neither CFU-GM dose nor TNC dose had any impact on NE in multivariate analysis. Other factors with a significant negative impact on NE in multivariate analysis were myeloid disease (HR, .62; P < .01), nonremission status at CBT (HR, .71; P < .01), low Eastern Cooperative Oncology Group Performance Status (HR, .68; P < .01), and graft-versus-host disease prophylaxis (other than tacrolimus alone) (HR, .76; P < .01). Without splenomegaly, even patients infused with < .8 × 10/kg CD34 cells achieved up to 94.3% NE, with the median value observed at 21 days post-CBT. This study shows that splenomegaly has a significant negative impact on NE after CBT. Cord blood units with < .8 × 10/kg CD34 cells may still be a suitable choice for patients without splenomegaly.
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http://dx.doi.org/10.1016/j.bbmt.2020.05.018DOI Listing
September 2020

Feasibility of autologous fibrin glue in general thoracic surgery.

J Thorac Dis 2020 Mar;12(3):484-492

Department of Transfusion Medicine, Toranomon Hospital, Tokyo, Japan.

Background: Fibrin glue effectively controls air leakage in lung surgery; however, allogenic fibrin glue cannot eliminate the risks of infection and allergy despite current sterilization methods. Autologous fibrin glue (AFG) could be a good alternative, but is not commonly used worldwide because of its limited availability and lack of evidence. Herein, we report clinical outcomes of AFG in thoracic surgery.

Methods: We retrospectively analyzed patients who underwent lobectomies or segmentectomies between November 2016 and September 2017 in our institution. We used two types of AFGs. One was a partially-autologous fibrin glue (PAFG), the components of which are largely autologous but which contains allogenic thrombin. The other was a completely-autologous fibrin glue (CAFG) which has no allogenic components. PAFG was used in the first half of the study period, after which CAFG was used from March 2017 onward. Patients who did not undergo AFG generation were categorized as the non-AFG group. The perioperative outcomes of the three groups were evaluated.

Results: A total of 207 patients underwent lung surgery, including 118 lobectomies and 89 segmentectomies. Among them, 83 patients received PAFG, 94 received CAFG, and 30 received non-AFG. The mean postoperative drainage period was within a few days in each group (PAFG CAFG . non-AFG: 3.23±3.91 . 3.16±4.04 . 3.17±4.16 days, respectively; P=0.405), and the incidence of postoperative prolonged air leakage was within an acceptable range (PAFG . CAFG non-AFG: 13.3% . 12.8% . 16.7%, respectively; P=0.821).

Conclusions: The use of AFG is clinically feasible for patients who undergo lobectomies or segmentectomies. AFGs could be a viable alternative to conventional allogenic fibrin glues.
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http://dx.doi.org/10.21037/jtd.2020.01.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139074PMC
March 2020

Clinical significance of autologous blood transfusions in bone marrow harvest from unrelated donors.

Int J Hematol 2020 Jun 14;111(6):833-839. Epub 2020 Mar 14.

Division of Cell Transplantation and Transfusion, Jichi Medical University Hospital, Shimotsuke, Japan.

In the Japan Marrow Donor Program (JMDP), autologous blood is collected from most unrelated bone marrow (BM) donors. We retrospectively evaluated 5772 donors who underwent BM harvest between 2010 and 2015 through the JMDP. Autologous blood was collected in 96.8% of the donors; the wastage rate was 0.6%. Allogeneic blood transfusion was not required. The mean hemoglobin (Hb) levels were 12.1 g/dL after the BM harvest (mean 891 mL) together with autologous blood transfusion (mean 596 mL). Propensity-score matching was used to adjust the backgrounds. Among donors with harvested BM of 100-400 mL, autologous blood transfusion had no impact on Hb levels or complications after BM harvest. Among donors with harvested BM of > 400 mL, more autologous blood transfusion followed by a bleeding volume of ≤ 100 mL did not confer clinical benefit to donors compared with less autologous blood transfusion followed by a bleeding volume of > 300 mL. The findings of the present study suggest that autologous blood transfusion to BM donors is excessive in terms of Hb changes and post-harvest outcomes.
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http://dx.doi.org/10.1007/s12185-020-02851-8DOI Listing
June 2020

Utility of autologous fibrin glue and polyglycolic acid sheet for preventing delayed bleeding associated with antithrombotic therapy after gastric ESD.

Endosc Int Open 2019 Nov 11;7(11):E1542-E1548. Epub 2019 Nov 11.

Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan.

 Delayed bleeding is one of the most serious adverse events of gastric endoscopic submucosal dissection (ESD), especially in patients taking antithrombotic therapy. This study aimed to evaluate the utility and safety of a shielding method with autologous fibrin glue and polyglycolic acid (PGA) sheets for patients undergoing gastric ESD who are receiving antithrombotic therapy.  One hundred twenty-three patients who were treated with gastric ESD while receiving antithrombotic therapy between December 2014 and September 2017 were enrolled in this study. Patients who received the shielding method were classified into the shielding group. Others were classified into the conventional group. Various clinico-pathological factors were retrospectively compared between the two groups.  The shielding group consisted of 38 patients, and the conventional group consisted of the remaining 85 patients. In the shielding group, the rate of continuation of antithrombotic therapy was significantly higher (68.4 % vs 41.2 %). Incidence of delayed bleeding was lower in the shielding group (2.6 %, 1/38) than in the conventional group (14.1 %, 12/85). In the propensity score-adjusted logistic regression analysis, the delayed bleeding rate in the shielding group tended to be lower than in the conventional group (  = 0.070). Allogeneic transfusion was performed in eight patients (8/85, 9.4 %) in the conventional group and none in the shielding group (  = 0.047). No adverse event associated with endoscopic shielding were observed in the shielding group.  This study suggests that a shielding method with autologous fibrin glue and PGA sheet effectively prevents delayed bleeding after gastric ESD in patients receiving antithrombotic therapy.
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http://dx.doi.org/10.1055/a-1007-1694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6847688PMC
November 2019

Released washed platelet concentrates are effective and safe in patients with a history of transfusion reactions.

Transfus Apher Sci 2018 Dec 7;57(6):746-751. Epub 2018 Sep 7.

Division of Hematology, Jichi Medical University Hospital, Shimotsuke, Japan; Division of Cell Transplantation and Transfusion, Jichi Medical University Hospital, Shimotsuke, Japan.

Background: Plasma removal by washing is an effective approach to prevent transfusion reactions by platelet concentrates (PCs). Recently, washed PCs were released by the Japanese Red Cross Society (JRCS).

Materials And Methods: This retrospective multicenter study evaluated the efficacy and safety of released washed PCs (RWPCs) between September 2016 and January 2017 in Japan. The RWPCs were prepared by washing leukoreduced apheresis PCs with the platelet additive solution, BRS-A, using automated cell processors.

Results: Clinical data were obtained from 91 patients and 1210 RWPC transfusions at 50 institutions. The median number of RWPC transfusions per patient was 8 (range, 1-91). RWPCs were used in 94.5% of the patients with a history of recurrent or severe transfusion reactions for preventing such reactions. Responses of RWPCs were evaluated as complete response (91.6%), partial response (8.2%), no-change (0.2%), and progression (0%) and overall response was equal across subgroups divided by patients' profiles. The median corrected count increment (CCI) at 1 and 24 h post-transfusion were 13.5 (range, 1.9-35.4) × 10/L and 3.5 (range, -13 to 53.6) × 10/L, respectively, and median CCI at 24 h was 5.5 (range, -13 to 53.6) × 10/L in patients without risk factors associated with platelet transfusion refractoriness. Transfusion reactions to RWPCs were observed in only nine transfusions (0.7%), all of which were mild allergic reactions.

Conclusion: This study demonstrated that RWPCs were effective and safe in patients with a history of transfusion reactions. Further prospective studies on efficacy together with cost-benefit analysis in RWPCs are needed.
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http://dx.doi.org/10.1016/j.transci.2018.09.001DOI Listing
December 2018

Feasibility of Autologous Fibrin Glue and Polyglycolic Acid Sheets to Prevent Delayed Bleeding after Endoscopic Submucosal Dissection of Gastric Neoplasms in Patients Receiving Antithrombotic Therapy.

Gastroenterol Res Pract 2018 4;2018:2174957. Epub 2018 Mar 4.

Department of Gastroenterology, Toranomon Hospital, Minato-ku, Tokyo, Japan.

Background/aims: Delayed bleeding is one of the most serious complications following gastric endoscopic submucosal dissection (ESD) under antithrombotic therapy. As a safety measure, for patients receiving antithrombotic therapy, we covered the ESD ulcer with autologous fibrin glue (prepared using autologous blood) alone or with polyglycolic acid (PGA) sheets.

Methods: From July 2014 to November 2015, 20 patients with gastric neoplasms who were receiving antithrombotic therapy were enrolled in this study. After ESD, the ESD ulcers were covered with autologous fibrin glue alone or with PGA sheets. We prospectively evaluated the feasibility of this safety measure.

Results: In total, 22 lesions in 20 patients were resected en bloc by ESD. The mean specimen size and tumor size were 31.5 ± 9.5 mm and 14.0 ± 8.8 mm, respectively. There were no cases of delayed bleeding or adverse events in this study. Attachment of autologous fibrin glue was observed in 81.8% (18/22) and 68.2% (15/22) of lesions at endoscopy performed 1 day and 7 days after ESD, respectively.

Conclusion: No patient in this study had delayed bleeding or adverse events. This suggests that this measure may facilitate the safety of gastric ESD in patients receiving antithrombotic therapy. This trial is registered with UMIN000019386.
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http://dx.doi.org/10.1155/2018/2174957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857318PMC
March 2018

A national survey of premedication for transfusion reactions in Japan.

Transfus Apher Sci 2017 Oct 11;56(5):708-712. Epub 2017 Sep 11.

Division of Hematology, Jichi Medical University Hospital, Shimotsuke, Japan; Division of Cell Transplantation and Transfusion, Jichi Medical University Hospital, Shimotsuke, Japan.

Background: Premedication before transfusion is commonly administered in clinical practice despite a lack of evidence for its efficacy. The aim of this study was to clarify the status of premedication and evaluate expert opinions regarding its use in Japanese medical institutions.

Method: Between May and July 2016, we conducted a questionnaire survey on premedication before transfusion in 252 medical institutes that were certified by an academic society or employed transfusion experts.

Results: A total of 141 institutes (54.2%) responded, and hematologists (n=113) comprised the most frequent respondents. The purpose of premedication was to prevent urticaria, pruritus, and fever, and washed blood products were used for anaphylactic shock or refractory transfusion reactions before. Drugs for premedication were intravenously administered either just before or 30min before transfusion. Both inpatients and outpatients were premedicated in a similar manner, and institutional guidelines were not established. More than half of the experts recognized premedication as efficient and necessary, and premedication for previous transfusion reactions was frequently implemented, particularly for platelet transfusion or in patients with hematological diseases. Some institutions administered one or more drugs for premedication from the first transfusion. Antihistamines and hydrocortisone were the most frequently used as premedication.

Conclusion: Our study reports the current status of premedication for transfusion in Japan. Antihistamines and hydrocortisone were most commonly used for premedication despite a lack of evidence of their use. These findings may help clarify the indications for premedication and the use of washed blood products.
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http://dx.doi.org/10.1016/j.transci.2017.07.024DOI Listing
October 2017

Successful Treatment of Pulmonary Mucormycosis Caused by Cunninghamella bertholletiae with High-Dose Liposomal Amphotericin B (10 mg/kg/day) Followed by a Lobectomy in Cord Blood Transplant Recipients.

Mycopathologia 2017 Oct 2;182(9-10):847-853. Epub 2017 Jun 2.

Department of Hematology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan.

Infection caused by Cunninghamella bertholletiae carries one of the highest mortality rates among mucormycosis, and there are no reported cases that survived from the infection in allogeneic hematopoietic stem cell transplantation recipients occurring before neutrophil engraftment. Here, we present two cases of pulmonary mucormycosis caused by C. bertholletiae occurring before neutrophil engraftment after cord blood transplantation. Both were successfully treated with high-dose liposomal amphotericin B (10 mg/kg/day) combined with micafungin, which was then followed by neutrophil recovery, reduction in immunosuppressive agents, and a subsequent lobectomy. The intensive antifungal therapy immediately administered upon suspicion of mucormycosis greatly suppressed the infection in its early stage and was well tolerated despite its prolonged administration and simultaneous use of nephrotoxic agents after transplantation. Although the synergic effect of micafungin remains unclear, these cases highlight the importance of prompt administration of high-dose lipid polyene when suspecting mucormycosis in highly immunocompromised patients, which enables subsequent diagnostic and therapeutic interventions, resulting in a favorable outcome.
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http://dx.doi.org/10.1007/s11046-017-0149-1DOI Listing
October 2017

Transfusion medicine in practice.

Rinsho Ketsueki 2016 ;57(10):2232-2240

Department of Transfusion Medicine, Toranomon Hospital.

The safety and stability of the supply of blood products must be ensured for appropriate blood transfusion therapy. Various security measures need to be taken and a balanced blood donation system should be maintained by the Japanese Red Cross Society. Based on such a system, each institute needs to establish a proper management protocol and to assure adequate use of blood products, as well as creating measures to deal with adverse events associated with blood transfusion. The system for preventing transfusion errors is particularly essential. For appropriate use of blood products, the "Guideline for the Use of Blood Products" should be followed, and unnecessary use should be avoided. These are prerequisites for error-free treatment of patients. In this educational lecture, major points in performing blood transfusion in clinical practice, such as proper indications for the use of blood products associated with patient conditions or trigger levels, and important points as well as contraindications when using blood products, such as the speed of administration, will be discussed.
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http://dx.doi.org/10.11406/rinketsu.57.2232DOI Listing
February 2017

A Novel Reduced-Toxicity Myeloablative Conditioning Regimen Using Full-Dose Busulfan, Fludarabine, and Melphalan for Single Cord Blood Transplantation Provides Durable Engraftment and Remission in Nonremission Myeloid Malignancies.

Biol Blood Marrow Transplant 2016 10 21;22(10):1844-1850. Epub 2016 Jun 21.

Department of Hematology, Toranomon Hospital, Tokyo, Japan; Okinaka Memorial Institute for Medical Research, Tokyo, Japan.

A pilot study of a novel, reduced-toxicity, myeloablative conditioning regimen using intravenous busulfan 12.8 mg/kg, fludarabine 180 mg/m(2), and melphalan 80 mg/m(2) for single cord blood transplantation (CBT) was conducted at our institution. Fifty-one patients with myeloid malignancies not in remission were included in this study. Their median age was 59 years (range, 19 to 70 years), with a median hematopoietic cell transplantation-specific comorbidity index score of 3. With a median observation period of 39.6 months (range, 24.3 to 90.8 months) among the survivors, overall survival and progression-free survival at 2 years were both 54.9%. Forty-six of 51 achieved neutrophil engraftment at a median of 19.5 days (range, 13 to 38 days) after transplantation, with a cumulative incidence of 90.2%. No patient developed graft rejection in this study. All patients who achieved engraftment showed hematological complete remission with complete donor chimerism. Eleven patients relapsed at a median of 4.9 months (range, .5 to 26.7 months). Cumulative incidences of nonrelapse mortality (NRM) at 100 days and 2 years were 11.8% and 25.5%, respectively. In conclusion, the present results show that the novel conditioning regimen for single CBT provided durable engraftment and remission with acceptable NRM leading to excellent survival, even for a relatively older population with myeloid malignancies not in remission.
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http://dx.doi.org/10.1016/j.bbmt.2016.06.017DOI Listing
October 2016

Anti-HLA antibodies other than against HLA-A, -B, -DRB1 adversely affect engraftment and nonrelapse mortality in HLA-mismatched single cord blood transplantation: possible implications of unrecognized donor-specific antibodies.

Biol Blood Marrow Transplant 2014 Oct 24;20(10):1634-40. Epub 2014 Jun 24.

Department of Hematology, Toranomon Hospital, Tokyo, Japan; Okinaka Memorial Institute for Medical Research, Tokyo, Japan.

The impact of anti-HLA antibodies, except for donor-specific anti-HLA-A, -B, -DRB1 antibodies, on engraftment was retrospectively evaluated in 175 single cord blood transplantations (CBT). Patients and donors had been typed at HLA-A, -B, and -DRB1 antigens, and anti-HLA antibodies had been screened before transplantation to avoid the use of cord blood (CB) units with corresponding antigens. The median age was 59 (range, 17 to 74) years. Overall, 61% were male, 89% had high-risk disease status, 77% received myeloablative conditioning regimens, and over 80% were heavily transfused patients. Sixty-nine of the 175 (39.4%) were positive for anti-HLA antibodies. Thirty-nine patients had antibodies only against HLA-A, -B, or -DRB1, 13 had antibodies only against HLA-C, -DP, -DQ, or -DRB3/4/5, and 17 had antibodies both against HLA-C, -DP, -DQ, or -DRB3/4/5 and against HLA-A, -B, or -DRB1. Because CB units had not been typed at HLA-C, -DP, -DQ, or -DRB3/4/5, it was possible that antibodies against them were unrecognized donor-specific antibodies. Patients with antibodies only against HLA-A, -B, or -DRB1 showed comparable neutrophil engraftment rates to those without antibodies (89.7% versus 83%, P = .65), whereas patients having antibodies against C, DP, DQ, or -DRB3/4/5 showed lower engraftment rate (66.7%, P = .12), which became statistically significant in a subgroup of HLA-mismatched donor-recipient pairs (50%, P = .01). Our results demonstrated that the presence of donor nonspecific anti-HLA-A, -B, -DRB1 antibodies had no significant influence on engraftment, whereas anti-HLA-C, -DP, -DQ, or -DRB3/4/5 antibodies adversely affect engraftment, possibly because of unrecognized donor-specific anti-HLA antibodies against them, especially in HLA-mismatched CBT.
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http://dx.doi.org/10.1016/j.bbmt.2014.06.024DOI Listing
October 2014

[The current state of transfusion medicine in Japan].

Gan To Kagaku Ryoho 2014 Apr;41(4):410-5

Dept. of Transfusion Medicine, Toranomon Hospital.

In Japan, transfusion medicine, which is supported by the voluntary blood donation system, is facing a risk of blood shortage. This is due to reduced donations by the younger generation as well as the falling birth rate and the aging of the population, with a consequent increase in the elderly population that depends on blood transfusions for conditions such as cancer and hematological and cardiovascular diseases. Therefore, to guarantee stable provision of blood products, in addition to implementing measures to promote blood donation, healthcare professionals must, as a policy, strictly follow the rules for appropriate use of blood products as defined in the "Criteria for the Use of Blood Products". Additionally, measures such as the use of autologous blood to reduce allogeneic blood usage and the implementation of adequate internal control systems to reduce blood wastage should be considered. Further, although this is not presently covered by the Japanese Health Insurance System, cryoprecipitate or fibrinogen products, which are used as alternative therapies in cases of hypofibrinogenemia due to massive bleeding, are effective not only for reducing the blood transfusion volume, but also for alleviating bleeding in patients. Additionally, the use of erythropoietin to treat chemotherapy-induced anemia is an effective measure to improve patients' quality of life, and its prompt approval by the Health Insurance System is desired.
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April 2014

A prospective feasibility study of primary prophylaxis against invasive fungal disease with voriconazole following umbilical cord blood transplantation with fludarabine-based conditioning.

Int J Hematol 2014 25;99(5):652-8. Epub 2014 Mar 25.

Department of Hematology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan,

Despite the recent introduction of a new class of anti-Aspergillus agents, no standard regimen for the prevention of invasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation has been shown to be superior to fluconazole. The present prospective, single-arm study investigated the feasibility of voriconazole (VOR) administration as primary prophylaxis in 52 recipients of umbilical cord blood transplantation (CBT) with fludarabine-based conditioning, who had no previous IFD episodes. Proven or probable IFD was determined using the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group, and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria were considered as breakthrough infections. VOR was administered as prophylaxis for a total of 6884 patient-days following CBT. The mean duration of VOR administration after transplantation was 132 days (range, 1-769); 44 patients (85 %) had advanced disease, 15 (29 %) had a history of allogeneic HSCT, and 29 (56 %) received systemic corticosteroid therapy for allogeneic immune-mediated complications. Under the prophylaxis with VOR, one patient developed probable invasive aspergillosis on day 71, and the cumulative incidence of IFD was 4.5 % at day 180. None of the patients developed breakthrough candida or zygomycetes infections. Under the extensive therapeutic dose monitoring, VOR was safely administered with a calcineurin inhibitor and was well tolerated. These results suggest that VOR represents a feasible primary prophylactic agent for IFD after CBT with fludarabine-based conditioning.
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http://dx.doi.org/10.1007/s12185-014-1529-7DOI Listing
April 2015

Questionnaire-based survey on chemotherapy-induced anemia.

Int J Clin Oncol 2014 8;19(3):411-20. Epub 2014 Mar 8.

Transfusion Medicine, Clinical Laboratory Medicine, Hachioji Medical Center of Tokyo Medical University, 1163 Tate-machi, Hachioji, Tokyo, 193-0998, Japan,

A questionnaire-based survey on chemotherapy-induced anemia (CIA) in cancer patients was conducted between September and November 2010. The number of patients treated with chemotherapy, rate of blood transfusion, volume of blood transfused, severity of anemia, and factors affecting blood transfusion were analyzed according to the type of cancer, in an attempt to clarify the current status of CIA in Japan. During the survey period, among the eight types of cancer analyzed (breast, lung, stomach, colorectal, liver, gynecologic cancer, urologic cancer, and malignant lymphoma), chemotherapy was given to 5.4-13.6 % (mean 9.2 %) of patients, among whom 1.6-24.0 % (mean 7.5 %) required blood transfusion. The number of units of red blood cells transfused was 3.9-7.3 units (mean 5.9 units) per patient. According to a nationwide patient survey conducted by the Ministry of Health, Labour and Welfare, it is estimated that approximately 146,000 units of red blood cells, which account for 2.2 % of the annual total supply of red blood cell products, are transfused to cancer patients with CIA yearly. In addition, it is estimated that annually approximately 172,000 cancer patients with CIA, accounting for 40 % of patients receiving chemotherapy, have hemoglobin (Hb) levels below 10 g/dL. Possible factors affecting blood transfusion include a history of chemotherapy and radiotherapy, as well as the use of platinum agents. In patients who received red blood cell transfusions, the average Hb level prior to chemotherapy was 9.5 g/dL, and the average lowest Hb level after starting chemotherapy was 6.9 g/dL. By contrast, in patients who did not receive transfusion, these values were 11.6 and 10.4 g/dL, respectively. Furthermore, in all cancer types, almost no red blood cell transfusion was performed in patients with an Hb level of 8.0 g/dL or higher, but also many patients with an Hb level of 6.9 g/dL or lower did not receive red blood cell transfusions. There was no significant difference in the ratio of adverse events following blood transfusion in this survey compared with that in the nationwide survey. The present results demonstrate the strict restriction of red blood cell transfusion to cancer patients with CIA. Therefore, there is a need to consider the use of alternative therapies to allogeneic blood transfusion, such as erythropoiesis-stimulating agents, to increase Hb levels, and consequently improve the quality of life in cancer patients with CIA.
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http://dx.doi.org/10.1007/s10147-014-0677-3DOI Listing
May 2015

Clinical characteristics and outcomes of 11 patients with pure red cell aplasia at a single institution over a 13-year period.

Intern Med 2013 ;52(18):2025-30

Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Japan.

Objective: Pure red cell aplasia (PRCA) is a rare clinical entity characterized by anemia due to severe suppression of erythroid precursors, where the other cell lineages in the bone marrow remain morphologically normal. A standard treatment has not yet been established for PRCA due to the rarity of this condition. Recently, however, the administration of either cyclosporine (CSP) or prednisolone (PSL) has been reported to be an effective treatment for PRCA.

Methods: To clarify the clinical characteristics of PRCA, 11 PRCA cases were retrospectively analyzed over a 13-year period at our institution. Since acute PRCA was found to be self-limiting, we administered the immunosuppressive treatment of CSP or PSL after providing supportive care for 4 weeks.

Results: The causes of PRCA were as follows: idiopathic (3), acute parvovirus infection (1), chronic parvovirus infection (3), thymic tumor (3), and end-stage renal disease with hemodialysis (1). Complete remission (CR) was achieved for 4 of the 5 patients treated with CSP, for 2 of the 3 patients with chronic parvovirus infection treated by immunoglobulin (Ig), and for all 3 patients treated with PSL. During the follow-up periods, 4 of the 11 patients relapsed. Complete remission was achieved a second time in all 4 cases by therapies that were more intensive and had longer administration periods than those provided during initial treatment. Consequently, 9 of the 11 patients were still alive (80%) after 5 years.

Conclusion: Depending on the cause of the PRCA, treatment with CSP, PSL, or Ig was found to be effective in most PRCA cases.
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http://dx.doi.org/10.2169/internalmedicine.52.8291DOI Listing
April 2014

Therapeutic modality of 11 patients with TTP in a single institution in Miyazaki from 2000 to 2011.

Intern Med 2013 ;52(17):1883-91

Department of Internal Medicine, Miyazaki Prefectural Hospital, Japan.

Objective: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disease with pathological features that are termed thrombotic microangiopathies. Since the discovery of the von Willebrand factor-cleaving protease [a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13)], it is widely known that approximately two-thirds of TTP patients have a severe deficiency of ADAMTS13 activity due to gene mutations or acquired autoantibodies to this enzyme. However, the remaining one-third of TTP patients have only moderately reduced or almost normal ADAMTS13 activity. To elucidate the clinical characteristics and outcomes of these two types of TTP, we have retrospectively analyzed the cases of acquired TTP patients treated in a single institution from 2000 to 2011.

Methods: Our case studies include 11 TTP patients, of which 5 were considered idiopathic and 6 had cases of TTP associated with underlying diseases such as non-Hodgkin lymphoma or connective tissue diseases.

Results: These patients were treated with a combination therapy of plasma exchange and steroids and with several adjunctive therapeutic regimens including the on-label use of cyclophosphamide and cyclosporine and the off-label use of high-dose steroid or immunoglobulin with rituximab. Splenectomies were not performed. As a result of these treatments, 6 out of the 7 patients with ADAMTS13 activity deficient TTP achieved a complete remission without relapse, but the remaining 4 patients with non-ADAMTS13 activity deficient TTP all died without complete remission.

Conclusion: We present herein the detailed clinical courses of 11 patients with TTP and address our experiences with the efficacy of various therapeutic regimens. This case-oriented study should be helpful to the physicians who directly care for TTP patients, and may provide a future direction for developing a more efficient treatment modality.
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http://dx.doi.org/10.2169/internalmedicine.52.8253DOI Listing
April 2014

The current state of transfusion medicine and cell therapy.

Japan Med Assoc J 2012 Sep;55(5):413-5

2 The Japan Society of Transfusion Medicine and Cell Therapy, Tokyo, Japan.

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September 2012

Acute myeloid leukemia in clinical practice: a retrospective population-based cohort study in Miyazaki Prefecture, Japan.

Int J Hematol 2012 Sep 24;96(3):342-9. Epub 2012 Jul 24.

Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.

We performed a retrospective population-based cohort study of acute myeloid leukemia (AML) in Miyazaki Prefecture, Japan. Over 6 years, we diagnosed 221 patients (211 adults and 10 children) with AML, indicating an incidence of AML in Miyazaki Prefecture of 3.2 per 100,000 per year. In 193 adult patients with non-acute promyelocytic leukemia (APL), the proportion of patients with myelodysplasia, unfavorable risk karyotypes, antecedent hematologic diseases, prior chemotherapy for other malignancies, and small proportion of blasts in the marrow was higher in patients ≥65 years, and patients with poor performance status (PS) and higher WBC counts at diagnosis were more prevalent among patients ≥75 years. One-third of the adult non-APL patients met the inclusion criteria usually applied in clinical trials: de novo AML, age ≤64 years with PS 0-2 and no key organ dysfunction. The 5-year overall survival (OS) rate of adult non-APL patients was 21.1 % (patients ≤64 years, 33.8 %; 65-74 years, 21.6 %; ≥75 years, 0 %). Multivariate analysis revealed that French-American-British subtypes M0, M6, and M7, poor PS (3, 4), unfavorable risk karyotypes, and higher WBC counts at diagnosis were independent adverse prognostic factors associated with OS. This analysis provides real world data.
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http://dx.doi.org/10.1007/s12185-012-1146-2DOI Listing
September 2012

Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone.

Transplantation 2011 Aug;92(3):366-71

Department of Hematology, Toranomon Hospital, Minato-Ku, Tokyo, Japan.

Background: The optimal graft-versus-host disease (GVHD) prophylaxis after umbilical cord blood transplantation has not been established. Our previous observation using single calcineurin inhibitors revealed a high incidence and severity of early immune-mediated complications, especially for older patients or those with poor performance status.

Methods: We conducted a single institute pilot study assessing the safety and effectiveness of mycophenolate mofetil (MMF) and tacrolimus (FK) combination as a GVHD prophylaxis for 29 patients (FK+MMF), and the results were compared with matched-pairs extracted from our historical database who received FK alone as GVHD prophylaxis (control).

Results: FK+MMF group showed superior engraftment rate compared with control group (cumulative incidence until day 60 posttransplant; 90%±0% vs. 69%±1%, P=0.02). A cumulative incidence of severe type preengraftment immune reactions was significantly decreased in FK+MMF group (16%±1%) compared with that of control group (52%±2%, P=0.03), and, remarkably, there was no nonrelapse mortality (NRM) observed up to day 30 posttransplant in FK+MMF group, whereas 21%±1% of NRM was observed in the control group. However, the incidences of acute and chronic GVHD, estimated overall and progression-free survivals were comparable between two groups.

Conclusions: MMF and FK in combination was well tolerated and decreased early NRM possibly by better control of preengraftment immune reactions. Subsequent NRM or disease progression needs to be overcome to further improve survival.
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http://dx.doi.org/10.1097/TP.0b013e318223d7acDOI Listing
August 2011

[Optimal therapeutic concentration of tacrolimus in adult patients undergoing reduced-intensity cord blood transplantation].

Gan To Kagaku Ryoho 2011 Feb;38(2):249-53

Dept. of Pharmacy, Tokyo Metropolitan Geriatric Hospital.

To investigate the effectiveness and safety of GVHD prophylaxis using FK506 alone as a continuous infusion, 104 patients who underwent reduced-intensity cord blood transplantation were retrospectively reviewed. The respective incidence of acute GVHD was 25 grade 1(24. 1%), 19 grade2(18. 3%), 15 grade3(14. 4%), and 4 grade4(3. 8%), which are comparable to that in the literature. The incidences of grade 2 and greater acute GVHD were 32 out of 69(46. 4%)for those whose wholeblood concentration of FK506 werele ss than 13 ng/mL, whereas 6 out of 35(17. 1%)for those FK5 06 were greater than 13 ng/mL. The differenceies between above and below 13 ng/mL were statistically significant(p=0. 008). There were 19 cases(18. 3%)of renal dysfunction, although none required hemodialysis. There were only 4 patients who discontinued FK506, which further confirmed the safety of FK506 alone. Together with our previous report on the upper limit of FK506(17 ng/mL)and these results, we recommend the optimal serum concentration of FK506 to range from 13 to 17 ng/ mL.
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February 2011

Successful sustained engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with severe aplastic anemia.

Blood 2011 Mar 13;117(11):3240-2. Epub 2011 Jan 13.

Department of Hematology, Toranomon Hospital, Tokyo, Japan.

We retrospectively analyzed 12 consecutive adult severe aplastic anemia patients who received unrelated umbilical cord blood transplantation after a reduced-intensity conditioning regimen (RI-UCBT). The conditioning regimen consisted of 125 mg/m² fludarabine, 80 mg/m² melphalan, and 4 Gy of total body irradiation. The median infused total nucleated cell number and CD34(+) cell number were 2.50 × 10⁷/kg and 0.76 × 10⁵/kg, respectively. Eleven of the 12 patients achieved primary neutrophil and platelet engraftment. All patients who achieved engraftment had complete hematologic recovery with complete donor chimerism, except for one patient who developed late graft failure 3 years after RI-UCBT. Two of the 12 patients died of idiopathic pneumonia syndrome, and the remaining 10 patients are alive, having survived for a median of 36 months. Our encouraging results indicate that RI-UCBT may become a viable therapeutic option for adult severe aplastic anemia patients who lack suitable human leukocyte antigen-matched donors and fail immunosuppressive therapy.
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http://dx.doi.org/10.1182/blood-2010-08-295832DOI Listing
March 2011
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