Hiroaki Shimizu

Saiseikai Maebashi Hospital, Edo, Tōkyō, Japan

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Publications (15)34.1 Total impact

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    ABSTRACT: The incidence of chronic lymphocytic leukemia (CLL) is low in Japan. The clinical course ranges from very indolent to rapidly progressive. Recently, several reports have indicated that mutation of the splicing factor 3b, subunit 1 (SF3B1) gene in CLL is predictive of a poor prognosis. Here, we investigated the SF3B1 mutational status of Japanese CLL patients and clarified the association between SF3B1 mutational status and prognostic factors. One hundred and two patients that were referred to our institutions between 1999 and 2013 were enrolled. Mutation analysis of SF3B1 (n = 87) and of the immunoglobulin heavy chain gene (IGHV) (n = 102) was performed at diagnosis. FISH analysis of del(11)(q22) was performed for 17 patients. Seven patients have SF3B1 mutation (8.0 %: K700E, 5/7; G742D, 1/7 and Y623C, 1/7). The median survival times for patients with mutated and non-mutated SF3B1 were 53 and 130 months, respectively. Overall survival of the mutated SF3B1 group was significantly lower than that of the non-mutated group (p = 0.0187). No relationship was observed between IGHV mutational status and SF3B1 mutation. There was no patient with SF3B1 mutation in the IGHV1-69 population (0/2). In conclusion, mutation of SF3B1 at diagnosis in Japanese CLL patients is predictive of a poor prognosis.
    International journal of hematology 11/2015; DOI:10.1007/s12185-015-1912-z · 1.92 Impact Factor
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    ABSTRACT: Polymorphisms of the interluekin-10 (IL-10) gene, which alter the production of IL-10, have been implicated in many cancers. We investigated the association between gene polymorphisms of the promoter region of IL-10 (-1082 G/A, IL-10-819 C/T, and -592 C/A) and the risk to develop myelodysplastic syndrome (MDS) and clinical features of MDS. Genomic DNA was extracted from 119 patients with MDS or chronic myelomonocytic leukemia and 202 healthy controls. Genotypes were determined by PCR-restriction fragment length polymorphism. There were no statistically significant differences in the genotype, allele, and haplotype frequencies of L-10 -1082 G/A, IL-10-819 C/T, and -592 C/A between the MDS patients and the control group. However, the IL-10 -592 CC genotype group (IL-10 high-producer type) was associated with lower hemoglobin level (7.85±2.02 g/dL vs. 9.37±2.25 g/dL, p=0.027) and poorer prognosis as compared to the IL-10 -592 non CC genotype group (median survival time 50.2 M vs. not reached, p<0.0012). In addition, the IL-10 high-producer haplotype group (GCC/ACC or ACC/ACC) was also associated with lower hemoglobin level and shorter survival time. Our findings indicate that IL-10 gene polymorphisms may not contribute to susceptibility to MDS, but they may be associated with the severity and prognosis of MDS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 05/2015; DOI:10.1111/ejh.12577 · 2.07 Impact Factor
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    ABSTRACT: This prospective, multicenter phase I/II study of unmanipulated HLA-haploidentical RIST using a low dose of ATG and steroid was conducted in 5 institutes in Japan. Thirty-four patients with hematologic malignancies who were in an advanced stage or at a high risk of relapse at the time of transplantation were enrolled. Among them, 7 patients underwent transplantation as a second transplantation because of relapse after the previous allogeneic SCT. The conditioning regimen consisted of fludarabine, busulfan and anti-T-lymphocyte globulin (Fresenius, 8 mg/kg), and GVHD prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). All patients except one (97.1%) achieved donor-type engraftment. Rapid hematopoietic engraftment was achieved, with neutrophils > 0.5 x 10(9)/l on day 11 and platelets > 20 x 10(9)/l on day 17.5. Treatment was started for ≥ grade I GVHD, and the cumulative incidence of acute grade I and grade II-IV GVHDs was 27.5% and 30.7%, respectively. The incidence of chronic GVHD (extensive type) was 20%. Fourteen patients (41.2%) had a relapse. The cumulative incidence of transplantation-related mortality at 1 year after the transplantation was 26.5%. The survival rate at day 100 was 88.2%. The survival rates at 1 year for patients with CR/CP (n=8) and non-CR (n=26) status before transplantation were 62.5% and 42.3%, respectively. In the multivariate analysis, non-CR status before transplantation was the only factor significant prognostic factor of increased relapse (p=0.0424), which tended to have a lower survival rate (p=0.0524). This transplant protocol is safe and feasible, if a suitable donor is not available in a timely manner. As the main cause of death was relapse but not GVHD, more intensified conditioning or attenuation of GVHD prophylaxis and/or DLI may be desirable for patients with non-CR status. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 04/2015; 21(8). DOI:10.1016/j.bbmt.2015.04.012 · 3.40 Impact Factor
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    ABSTRACT: Adult mixed phenotype acute leukemia (MPAL) patients have a poor prognosis, and the therapeutic role of allogeneic stem cell transplantation (allo-SCT) for MPAL remains to be elucidated. Thus, we retrospectively assessed the efficacy of allo-SCT for MPAL. Eighteen patients with MPAL were identified from the transplant outcome database of KSGCT. We also selected 215 patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) as control cohorts using an optimal matching method. The 5-year overall survival (OS) rate of patients with MPAL was 48.1%, and patients in remission at the time of transplant showed significantly better survival than those not in remission (5-year OS: 71.8% vs. 0%, p = 0.001). No significant differences were seen in OS when stratifying patients according to immunophenotype, cytogenetic abnormalities, or the type of induction therapy. The 5-year OS rate of MPAL patients was not significantly different compared with AML control patients (48.1% vs. 48.1%; p = 0.855) or ALL control patients (48.1% vs. 37.8%; p = 0.426). These results suggested that allo-SCT is an effective treatment for MPAL, especially early in the disease course, and innovative transplant approaches are warranted to improve the transplant outcome of MPAL patients who are not in remission. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 01/2015; 95(5). DOI:10.1111/ejh.12516 · 2.07 Impact Factor

  • Thrombosis and Haemostasis 10/2014; 112(4):831-833. DOI:10.1160/TH14-04-0323 · 4.98 Impact Factor
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    ABSTRACT: Although the introduction of imatinib dramatically improved the outcomes for patients with Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+BCP-ALL), the survival benefit of imatinib has not been assessed in the context of Ph+ mixed phenotype acute leukemia (Ph+MPAL). To clarify this important issue, we studied 42 Ph+ acute leukemia (Ph+AL) patients who received intensive chemotherapy and concurrent administration of imatinib. Of the 42 Ph+AL patients, 13 (31%) patients were categorized as Ph+MPAL (positive for both myeloid and B-cell lineage), 27 (64%) were categorized as Ph+BCP-ALL, and two (5%) were categorized as Ph+ acute myeloid leukemia. The complete remission rates after the initial induction therapy were not significantly different when comparing Ph+MPAL and Ph+BCP-ALL patients (100% vs. 85%, respectively, p = 0.14). Likewise, there were no significant differences in the 5-year overall survival (OS) or disease-free survival (DFS) rates when comparing the MPAL and BCP-ALL groups (OS: 55% vs. 53%, respectively, p = 0.87, DFS: 46% vs. 42%, respectively, p = 0.94). These findings suggest that concurrent imatinib administration with chemotherapy improved the outcomes of Ph+MPAL patients to the level seen in Ph+BCP-ALL patients and should, therefore, be considered as the standard therapy for these patients.This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 04/2014; 93(4). DOI:10.1111/ejh.12343 · 2.07 Impact Factor
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    ABSTRACT: Although studies have demonstrated a high prevalence of extramedullary (EM) relapse after allogeneic stem cell transplantation (allo-SCT) in patients with acute myeloid leukemia (AML), the prevalence of EM relapse has not been compared with that after chemotherapy. This study investigated the prevalence of EM relapse among 498 adult AML patients (median age, 57 years; range, 15-82 years) who underwent intensive chemotherapy. A total of 281 relapses occurred in 210 patients (36 after allo-SCT; 245 after chemotherapy), and 33 relapses (11.7%) were accompanied by EM disease. Among these relapses, EM disease was more frequently observed at relapse after allo-SCT than after chemotherapy (25% vs. 9%, respectively; p=0.008). Eight of 33 relapses after the first allo-SCT had EM disease, and only presence of extensive chronic graft-versus-host disease (GVHD) was identified as a predisposing factor for EM relapse. Additionally, the 1-year overall survival rate after relapse was not significantly different when comparing those with EM relapse and those with BM relapse (38% vs. 16%, respectively; p=0.279). These data suggest that AML patients undergoing allo-SCT should be closely followed for signs of EM relapse, especially those with extensive chronic GVHD.
    Leukemia research 09/2013; 37(11). DOI:10.1016/j.leukres.2013.08.017 · 2.35 Impact Factor
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    ABSTRACT: The presence of pre-transplant anti-HLA antibodies in recipients of cord blood transplantation (CBT) is associated with failed engraftment. However, only a small number of studies have reported that recipient-derived anti-HLA antibodies persist after CBT and have potential impact on the outcome. Of 61 patients who underwent HLA-mismatched CBT at Saiseikai Maebashi Hospital, three patients were identified as having anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB. All patients achieved successful engraftment. However, the three patients with the pre-transplant anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB continued to produce these antibodies even after engraftment; the persistence of these antibodies served as a sensitive minimal residual disease (MRD) marker. In contrast, donor HLA-specific and newly produced third party antibodies were not detectable even after relapse. The persistence of anti-HLA antibodies even after engraftment may be a potential marker for MRD, but is not a significant factor in secondary humoral engraftment failure.
    International journal of hematology 03/2013; 97(4). DOI:10.1007/s12185-013-1304-1 · 1.92 Impact Factor
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    ABSTRACT: Objectives: The categorization of T-cell acute lymphoblastic leukemia (T-ALL) into four subgroups according to the degree of thymic differentiation was proposed in 1995, and this categorization scheme has been described in the World Health Organization classification 4th edition with minor changes. The aim of this study is to explore the clinical significance of leukemia cell differentiation stages in patients with T-ALL. Methods: We analyzed 36 adult T-ALL patients, including six patients (17%) in pro-T stage, 16 (44%) in pre-T stage, three (8%) in cortical-T stage, and 11 (31%) in medullary-T stage. Pro-T and pre-T stages were arbitrarily clustered as the immature group, and cortical-T and medullary-T stages as the mature group. Results: Patients in the immature group had unique presentations, including lower lactate dehydrogenase levels, lower frequency of mediastinal tumor, and higher expression of myeloid antigens than the mature group. There was no difference in the treatment strategies between both groups. Although patients in the immature group had a lower complete remission (CR) rate when compared with the mature group (45% vs. 79%, respectively; P = 0.04), the 3-yr overall survival (OS) for both groups was comparable (27% vs. 38%, respectively; P = 0.66). Such discrepancy between the CR rates and the OS could be partially explained by survival benefit of allogeneic transplantation observed in the immature group but not in the mature group. Conclusions: These findings indicate that T-ALL patients can be categorized into two biologically distinctive subgroups according to the differentiation stages, and this stratification might enable prospective identification of patients with poor chemotherapy response.
    European Journal Of Haematology 02/2013; 90(4). DOI:10.1111/ejh.12088 · 2.07 Impact Factor
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    ABSTRACT: To investigate the clinical significance of granulocytic sarcoma (GS) in adults with acute myeloid leukemia (AML), 434 consecutive patients with AML were analyzed retrospectively. Forty-five patients (10.4%) with GS at diagnosis were younger (P < 0.001), presented with higher white blood cell counts (P = 0.03) and were more likely to conform to French-American-British M4 (P = 0.001) and M5 (P = 0.045) classifications than those without GS. In contrast, no significant difference in frequency of cytogenetic abnormalities was found between the GS and non-GS groups. Treatment outcomes in 260 patients (40 with GS) who underwent intensive chemotherapy, excluding patients with acute promyelocytic leukemia, were investigated. Complete remission rates did not differ significantly between the GS and non-GS groups (75.0% vs 79.1%; P = 0.192, respectively) or the 5-year overall survival (OS) rates (39.9% vs 38.7%; P = 0.749, respectively). However, the GS group had a significantly higher relapse rate than the non-GS group (74.2% vs 55.3%; P = 0.048) and a significantly lower 5-year disease-free survival rate (8.2% vs 25.7%, respectively; P = 0.005). When considered together with the results of multivariate analysis, which identified the presence of GS as an independent predictor for disease-free survival time, these findings indicate that GS might identify a high-risk subset of patients with AML.
    Cancer Science 05/2012; 103(8):1513-7. DOI:10.1111/j.1349-7006.2012.02324.x · 3.52 Impact Factor
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    ABSTRACT: Post-transplant lymphoproliferative disorder (PTLD) is a fatal complication of allogeneic hematopoietic stem cell transplantation (HSCT) that is caused by reactivation of Epstein-Barr virus (EBV). A successful approach, monitoring EBV-DNA load in peripheral blood (PB) accompanied by preemptive rituximab therapy, has recently been reported. Here, we describe a 29-year-old woman who developed isolated central nervous system (CNS) PTLD. She received HSCT against acute myelogenous leukemia from a related human leukocyte antigen-haploidentical donor, following a conditioning regimen that included antithymocyte globulin. Tacrolimus and methylprednisolone were given as prophylaxis for graft-versus-host disease. On day +172, the patient's consciousness deteriorated. Magnetic resonance imaging showed six ring-enhanced lesions in the cerebral hemispheres. These tumors were diagnosed, via a craniotomy and tumorectomy, as PTLD. EBV-DNA load was elevated in the cerebrospinal fluid (CSF) but not detected in PB. She was treated with whole-brain irradiation and rituximab, and achieved partial remission of the tumors. This case serves as a reminder that vigilance is required regarding the development of isolated CNS PTLD; it is worth examining EBV-DNA replication in CSF for diagnosis even when the EBV-DNA load is negative in PB.
    International journal of hematology 11/2011; 94(5):495-8. DOI:10.1007/s12185-011-0951-3 · 1.92 Impact Factor

  • European Journal Of Haematology 09/2011; 88(2):181-2. DOI:10.1111/j.1600-0609.2011.01713.x · 2.07 Impact Factor
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    ABSTRACT: Antibody (Ab)-mediated pure red cell aplasia (PRCA) is a rare but important side effect in patients with chronic kidney disease who receive recombinant human erythropoietin (rhEPO). Ab-mediated PRCA was first reported in the 1990s, and the incidence subsequently increased and reached a peak in 2001. After improvements in rhEPO products and the administration route, the incidence was reduced by 90%, and now Ab-mediated PRCA only develops in a limited number of patients who receive rhEPO subcutaneously for a long period. We describe here the clinical course of one such rare patient with Ab-mediated PRCA. The patient was a 70-year-old man with chronic renal failure secondary to diabetic nephropathy. He had not received rhEPO therapy before the initiation of hemodialysis. He started hemodialysis and began to receive rhEPO therapy intravenously. Three months later, his hemoglobin level started declining and he became transfusion dependent. A diagnosis of Ab-mediated PRCA was made by bone marrow examination and detection of anti-EPO Abs. He was successfully treated with cyclosporine and became independent of blood transfusions. This case is a reminder that vigilance is required regarding the development of Ab-mediated PRCA upon rhEPO therapy, regardless of the administration route.
    Acta Haematologica 06/2011; 126(2):114-8. DOI:10.1159/000328041 · 1.12 Impact Factor

  • Annals of Hematology 10/2007; 86(9):697-8. DOI:10.1007/s00277-007-0292-8 · 2.63 Impact Factor
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    ABSTRACT: We present a case of a 74-year-old male, who had a relapse of minimal change nephrotic syndrome (MCNS) as the initial presentation of acquired hemophilia A. MCNS had been maintained in remission with prednisolone 10 mg for 15 years. In early December 2005, the patient developed edema of the right leg, was admitted to a local general hospital, and was diagnosed as having a relapse of MCNS based on massive proteinuria (urine protein 6.1 g/day). One week later, severe anemia (hemoglobin 4.4 g/dl) and acute renal failure (creatinine 2.0 mg/dl) developed, and a CT scan of the abdomen revealed a hematoma in the left iliopsoas muscle. He was referred to our hospital with bleeding tendency. Laboratory examination revealed prolonged APTT 80.5 seconds), reduced factor VIII activity (<1%) and thepresence of factor VIII inhibitor at a titer of 19 Bethesda units/ml, based on which he was diagnosed as having acquired hemophilia A. With recombinant activated FVII, hemostasis was obtained and prednisolone administration 60 mg/day (1 mg/kg) was started. Both the acquired hemophilia A and MCNS responded well to the treatment with prednisolone. Six weeks after initiation of the treatment, factor VIII inhibitor and urine protein disappeared. This patient is considered to be a rare case; to the best of our knowledge, this is the third report of acquired hemophilia A with nephrotic syndrome.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 07/2007; 48(6):514-7.