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Biomedical subjects

Hideaki Mizoguchi

Publications and source records attributed to Hideaki Mizoguchi.

At least 19 recordsLinked to original sources
PubMed2007

Roles of DRB1 *1501 and DRB1 *1502 in the pathogenesis of aplastic anemia.

OBJECTIVE: Although a number of reports have documented a significantly increased incidence of HLA-DR15 in aplastic anemia (AA), the exact role of HLA-DR15 in the immune mechanisms of AA remains unclear. We herein clarify the difference between DRB1( *)1501 and DRB1( *)1502, the two DRB1 alleles that determine the presentation of HLA-DR15, in the pathophysiology of AA. MATERIALS AND METHODS: We investigated the relationships of the patients( *) HLA-DRB1 allele with both the presence of a small population of CD55(-)CD59(-) (PNH-type) blood cells and the response to antithymocyte globulin (ATG) plus cyclosporin (CsA) therapy in 140 Japanese AA patients. RESULTS: Of the 30 different DRB1 alleles, only DRB1( *)1501 (33.6% vs 12.8%, p(c) < 0.01) and DRB1( *)1502 (43.6% vs 24.4%, p(c) < 0.01) displayed significantly higher frequencies among the AA patients than among a control. AA patients possessing HLA-DR15 tended to be old, and especially, the frequency of DRB1( *)1502 in patients 40 years of age and older (52.4%) was markedly higher than that in those younger than 40 years old (16.2%, p(c) < 0.01). Only DRB1( *)1501 was significantly associated with the presence of a small population of PNH-type cells and it also showed a good response to ATG plus CsA therapy in a univariate analysis. A multivariate analysis showed only the presence of a small population of PNH-type cells to be a significant factor associated with a good response to the immunosuppressive therapy (p < 0.01). CONCLUSIONS: Although both DRB1( *)1501 and DRB1( *)1502 contribute to the development of AA, the methods of contribution differ between the two alleles.

Adolescent↗
PubMed2005

Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia.

We investigated the clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria (PNH)-type blood cells in patients with acquired aplastic anemia (AA). We quantified CD55-CD59- granulocytes and red blood cells (RBCs) in peripheral blood from 122 patients with recently diagnosed AA and correlated numbers of PNH-type cells and responses to immunosuppressive therapy (IST). Flow cytometry detected 0.005% to 23.1% of GPI-AP- cells in 68% of patients with AA. Sixty-eight of 83 (91%) patients with an increased proportion of PNH-type cells (PNH+) responded to antithymocyte globulin (ATG) + cyclosporin (CsA) therapy, whereas 18 of 39 (48%) without such an increase (PNH-) responded. Failure-free survival rates were significantly higher (64%) among patients with PNH+ than patients with PNH- (12%) at 5 years, although overall survival rates were comparable between the groups. Numbers of PNH-type and normal-type cells increased in parallel among most patients with PNH+ who responded to IST, suggesting that these cells are equally sensitive to immune attack. These results indicate that a minor population of PNH-type cells represents a reliable marker of a positive IST response and a favorable prognosis among patients with AA. Furthermore, immune attack against hematopoietic stem cells that allows PNH clonal expansion might occur only at the onset of AA.

Adolescent↗
PubMed2005

A novel NF-kappaB inhibitor DHMEQ selectively targets constitutive NF-kappaB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo.

Multiple myeloma (MM) is a fatal lymphoid malignancy that is incurable with conventional modalities of chemotherapy. Strong and constitutive activation of nuclear factor kappa B (NF-kappaB) is a common characteristic of MM cells. In our study we successfully target NF-kappaB with a novel NF-kappaB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ). DHMEQ completely abrogates constitutive NF-kappaB activity and induces apoptosis of MM cells, whereas control peripheral blood mononuclear cells (PBMC) are resistant to NF-kappaB inhibition and apoptosis by DHMEQ treatment. DHMEQ inhibition of NF-kappaB triggers activation of caspases 8 and 9, as well as G0/G1 cell cycle arrest accompanied by downregulation of antiapoptotic genes Bcl-XL and c-FLIP and cell cycle progression gene cyclins D1 and D2. DHMEQ-mediated inhibition of vascular endothelial growth factor (VEGF) production in MM cells raises the possibility that DHMEQ abrogates the autocrine VEGF loop and enhances its antitumor effects by inhibiting neovascularization in the bone marrow. Using an in vivo NOD/SCID/gammac(null) (NOG) mice model, we show that DHMEQ has a potent inhibitory effect on the growth of MM cells. Compared to other compounds having the potential to inhibit NF-kappaB, DHMEQ is a unique compound that blocks the translocation of NF-kappaB p65 into the nucleus and selectively targets NF-kappaB activated in tumor cells. Therefore, our study presents a new molecular target therapy in MM.

Animals↗
PubMed2005

Clonal T cells of pure red-cell aplasia.

This study detected clonal T cells in patients with acquired pure red-cell aplasia (PRCA) by Southern blotting and polymerase chain reaction (PCR). Twenty-nine adult patients with acquired PRCA were enrolled in this study. Seventeen patients had primary acquired PRCA, while 12 patients had the secondary form. Twenty-two of 29 (76%) patients demonstrated TCR rearrangement by at least one method. We divided the patients into three groups depending on T-cell clonality. The CD4/8 ratio of patients who were positive on Southern blotting was significantly lower than that of other groups. Except for the CD4/8 ratio, other laboratory findings did not significantly differ among the three groups. The CD4/8 ratio should be a useful surrogate marker to detect T-cell clonality.

Adult↗
PubMed2005

Characterization of genotype H hepatitis B virus strain identified for the first time from a Japanese blood donor by nucleic acid amplification test.

The Japanese Red Cross has been conducting a nucleic acid amplification test (NAT) screening for hepatitis B virus (HBV), hepatitis C virus and human immunodeficiency virus 1 among blood donors since July 1 1999. The first case of HBV genotype H was found and reported in Japan. Serological markers of HBV were not detected in this NAT-positive donation. It may be that the positive donation was in the serological window period at the early stage of infection. The complete genome of 3215 nt was sequenced, and the sequence had 99.3 % homology with the strain from Los Angeles, USA (LSA2523). Here, a leucine zipper motif was found in the region of the HBV surface antigen conserved through genotypes A-H.

Blood Donors↗
PubMed2005

Evaluation of cytomegalovirus-specific T-cell reconstitution in patients after various allogeneic haematopoietic stem cell transplantation using interferon-gamma-enzyme-linked immunospot and human leucocyte antigen tetramer assays with an immunodominant T-cell epitope.

Cytomegalovirus (CMV) infection is a major complication for patients who received allogeneic haematopoietic stem cell transplantation (HSCT). Accurate monitoring of CMV-specific T-cell reconstitution is required for appropriate decision on treatment, such as anti-viral drugs, which have adverse effects. Although human leucocyte antigen (HLA) tetramer and interferon-gamma-enzyme-linked immunospot (IFN-gamma-ELISPOT) assays have been used to measure CMV-specific T cells, detailed comparison of these assays and kinetics of anti-CMV T-cell reconstitution between reduced-intensity transplantation (RIST) and conventional HSCT has not yet been performed. In this study, we performed prospective comparative monitoring of CMV-specific T cells using HLA tetramer and IFN-gamma-ELISPOT assays with a single immunodominant CMV(495) peptide in 28 HLA-A*0201 and 9 HLA-A*0206 patients after various allogeneic HSCTs. The IFN-gamma-ELISPOT assay was more sensitive for evaluation of functional T cells than the HLA tetramer assay, and CMV-specific T cells were reconstituted earlier in patients who received RIST without anti-thymocyte globulin (ATG) than those receiving RIST with ATG or conventional HSCT. The threshold level for protection from CMV reactivation was estimated as over 1 x 10(6) cells/l peripheral blood with the IFN-gamma-ELISPOT assay. These results demonstrate that the IFN-gamma-ELISPOT assay with CMV(495) provides more accurate evaluation on CMV immunity in HLA-A*0201 and -A*0206 patients, and may be useful for determining timing of various treatments.

Adolescent↗
PubMed2005

Long-term results of a multicenter randomized, comparative trial of modified CHOP versus THP-COP versus THP-COPE regimens in elderly patients with non-Hodgkin's lymphoma.

In treating elderly non-Hodgkin's lymphoma (NHL) patients, it is particularly important to use drugs that have a low incidence of adverse events and high efficacy. In this multicenter study, THP (pirarubicin)-COP (cyclophosphamide, vincristine, and prednisolone) was compared to two thirds dosage of full CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen with regard to both adverse events and efficacy. For a third group, etoposide (E) was added to the THP-COP regimen (THP-COPE) in order to achieve high dose-intensity. Subjects were 486 previously untreated patients, aged 65 or older (range, 65-92 years; median, 74 years), with NHL. Subjects were randomly assigned to receive THP-COP, two thirds CHOP, or THP-COPE. Four hundred and forty-three patients were assessed for response and followed for 8 years after the last subject registered. The complete remission rates for the THP-COP, CHOP, and THP-COPE groups were 42.5%, 41.4%, and 48.0%, respectively. There was no difference in overall survival or progression-free survival among these 3 groups. In aggressive lymphoma, there was also no difference in complete response (CR) rate (45.3% in THP-COP, 44.9% in CHOP, 48.0% in THP-COPE), overall survival, and progression-free survival among these groups. The 5- and 8-year survival rates for all patients were 29.4% and 18.7%, respectively. The 5- and 8-year survival rates for patients with aggressive lymphoma were 27.4% and 17.4%, respectively. Although long-term survival for patients with aggressive lymphoma on our regimens was not worse compared to previous reports, the CR rate was lower. Because severe adverse events were not observed, higher dose chemotherapy may be directed to achieve better CR rates. In patients with T-cell-type lymphoma, the CR rate was greater after treatment with THP-COP (51.4%) or THP-COPE (57.7%) compared to treatment with CHOP (19.4%). Pirarubicin may be more useful for T-cell lymphoma than doxorubicin. Because adverse cardiac events were reported only in CHOP, adverse cardiac events might be low in the THP group.

Aged↗
PubMed2005

Assessment of the international prognostic scoring system for determining chemotherapeutic indications in myelodysplastic syndrome: Japanese retrospective multicenter study.

To standardize a rational therapeutic strategy of chemotherapy using the International Prognostic Scoring System (IPSS), we retrospectively analyzed 292 high-risk myelodysplastic syndrome (MDS) patients in 20 hospitals in Japan. Results of multivariate analysis of the data on patients who received all types of chemotherapy indicated that poor cytogenetics as shown by the IPSS was the only significant risk factor (P = .047). We then focused on the IPSS composition of each patient. The intermediate 2 (Int-2) category consisted of a heterogeneous group. We attempted to subdivide the category into Int-2A and Int-2B. Patients with good or intermediate cytogenetics had > or = 5% bone marrow (BM) blasts (Int-2A), and most of the other patients had poor cytogenetics and < or = 10% BM blasts (Int-2B). In the Int-2B category, overall survival for patients who received chemotherapy was significantly worse than for those who did not receive chemotherapy (P = .005). Most patients in the High category who had the diagnosis of MDS according to the World Health Organization classification had poor overall survival with or without chemotherapy. We propose the Int-2B and High categories may be considered possible high risk, whereas all patients in the Int-2A category and patients with more than 5% BM blasts in the Int-1 category may be categorized as being at possible intermediate risk. Our proposition may be useful for developing a chemotherapeutic strategy for patients with MDS in Japan.

Adult↗
PubMed2005

Aplastic anemia.

Explore the source record for details and available documents.

Anemia, Aplastic↗
PubMed2005

[Clinical course of the disease and the level of WT1 mRNA in 191 patients with acute myeloid leukemia (AML): joint research by 23 institutions in Japan].

We evaluated the clinical course of acute myeloid leukemia (AML) and the levels of WT1 mRNA in 191 AML patients. Of 114 previously untreated patients with AML, 107 cases were positive for WT1 mRNA (93.9% : 107/114). WT1 mRNA expression-levels declined to below 50 copies/microg RNA ("negative") after remission was achieved in all 66 patients who achieved remission and 84.8% (47/54) cases were "negative" at the end of the follow-up periods. On the other hand, WT1 mRNA was expressed in 87.0% of non-remission cases (47/54), maintaining 50 copies/microg of RNA or higher ("positive"). In all 29 cases who relapsed during the follow-up observation period after achieving remission, WT1 mRNA levels declined transiently approximately around the time of achieving remission and then rose again when the disease relapsed. Moreover, we determined the time of elevation of WT1 mRNA in 29 relapsed cases. In 79.3% of relapsed cases (23/29), WT1 mRNA levels rose above 200 copies/microg RNA, 43 days (median) before the diagnosis of "relapse". Given the percent of the correct diagnosis, WT1 mRNA at 200 copies/microg RNA appeared to be a reasonable cut-off level for early detection of AML-relapse. The WT1 mRNA level reflected the clinical condition. Taken together, these findings indicate that WT1 mRNA levels allow us to detect the presence of so-called "minimal residual disease" (leukemic cells) that cannot be detected by morphological examination. Besides these promising data, this kit is suitable for routine monitoring of AML because this kit utilizes peripheral blood as a test specimen, reducing the patient's burden at the time of collection of clinical samples as compared with bone marrow aspirate.

Adult↗
PubMed2004

Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan.

: To determine and directly compare the clinical course of white and Asian patients with paroxysmal nocturnal hemoglobinuria (PNH), data were collected for epidemiologic analysis on 176 patients from Duke University and 209 patients from Japan. White patients were younger with significantly more classical symptoms of PNH including thrombosis, hemoglobinuria, and infection, while Asian patients were older with more marrow aplasia. The mean fraction of CD59-negative polymorphonuclear cells (PMN) at initial analysis was higher among Duke patients than Japanese patients. In both cohorts, however, a larger PNH clone was associated with classical PNH symptoms, while a smaller PNH clone was associated with marrow aplasia. Thrombosis was significantly more prevalent in white patients than Asian patients, and was associated with a significantly higher proportion of CD59-negative PMN. For individual patients, CD59-negative populations varied considerably over time, but a decreasing PNH clone portended hematopoietic failure. Survival analysis revealed a similar death rate in each group, although causes of death were different and significantly more Duke patients died from thrombosis. Japanese patients had a longer mean survival time (32.1 yr vs. 19.4 yr), although Kaplan-Meier survival curves were not significantly different. Poor survival in both groups was associated with age over 50 years, severe leukopenia/neutropenia at diagnosis, and severe infection as a complication; additionally, thrombosis at diagnosis or follow-up for Duke patients and renal failure for Japanese patients were poor prognostic factors. These data identify important differences between white and Asian patients with PNH. Identification of prognostic factors will help the design of prospective clinical trials for PNH.

Adolescent↗
PubMed2004

Pharmacokinetics of pegylated recombinant human megakaryocyte growth and development factor in healthy volunteers and patients with hematological disorders.

OBJECTIVES: The purpose of this study is to examine the pharmacokinetics of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in healthy volunteers with normal hematopoiesis and patients with idiopathic thrombocytopenic purpura (ITP), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and aplastic anemia (AA). METHODS: PEG-rHuMGDF was intravenously administered to healthy volunteers and patients with ITP, AML, MDS, and AA. The serum concentration of PEG-rHuMGDF was measured and the pharmacokinetics was investigated using non-linear mixed-effects modeling technique. RESULTS: The systemic clearance (CL) and volume of distribution at steady-state (Vss) consistently decreased in the healthy subjects, when the dose increased. In AML patients, CL and Vss decreased when the dose increased, but the change of CL was not statistically significant. In contrast, no significant dose dependency of these parameter estimates was observed in MDS patients. In AA patients there was no significant change in Vss but the CL of the higher dose groups was slightly smaller than that of the lower dose groups. Relatively smaller CL and Vss in ITP patients than those of healthy volunteers at the same dose were observed. CONCLUSIONS: This saturable pathway of CL may involve the receptor-mediated endocytosis and degradation by megakaryocyte lineage cells and platelets. The saturable distribution space can be also explained by the receptors on hematopoietic cells. The non-saturable distribution space corresponds to the value of plasma and interstitial fluid volume.

Case-Control Studies↗
PubMed2004

Efficacy and safety of imatinib mesylate for patients in the first chronic phase of chronic myeloid leukemia: results of a Japanese phase II clinical study.

Imatinib mesylate is a relatively new drug that targets the BCR-ABL chimeric protein, the molecular basis of chronic myeloid leukemia (CML). A phase II clinical trial in 39 Japanese patients in the first chronic phase of CML was conducted with imatinib mesylate at a dose of 400 mg/day. Hematologic complete response was obtained in 92.3% of the patients, complete cytogenetic response (CR) was obtained in 43.6%, and major partial CR was obtained in 20.5% of the patients. Although 29 of 39 patients required an adjustment of dosing because of grade 3 or 4 adverse events, most of the events were reversible, and 25 of the 29 patients were able to resume therapy. Between day 15 and day 35, grade 3 or 4 neutropenia and/or leukocytopenia occurred in 13 patients, and grade 3 thrombocytopenia occurred in 5 patients. Overall, nonhematologic grade 3 adverse events occurred in 28.2% of the patients. These data support the use of imatinib mesylate as the treatment of choice for chronic-phase CML patients.

Adult↗