Publications (68)198.78 Total impact
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Article: Acute Myelogenous Leukemia With PIG-A Gene Mutation Evolved from Aplastic Anemia—Paroxysmal Nocturnal Hemoglobinuria Syndrome
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ABSTRACT: We report a patient with aplastic anemia (AA)—paroxysmal nocturnal hemoglobinuria (PNH) syndrome who developed acute myelogenous leukemia (AML). Flow cytometric analysis showed that the leukemic cells in the bone marrow lacked CD59 antigen on their surface and were positive for P-glycoprotein. Heteroduplex and single-strand conformation polymorphism analysis followed by sequencing of the leukemic cells in the bone marrow disclosed 1 frameshift-type mutation in exon 2 of the phosphatidylinositol glycan-class A (PIG-A) gene, which deductively produces truncated PIG-A protein. These findings provide direct evidence that the leukemic cells evolved from the affected PNH clone. Cytogenetic analysis in the bone marrow in each stage of AA-PNH, AML, and at relapse of AML showed normal, −7, and −7 plus −20, respectively, showing evidence of a clonal evolution. Because complete remission of AML was not achieved by intensive chemotherapies, allogeneic peripheral blood stem cell transplantation (PBSCT) from the patient’s HLA-matched sister was performed successfully with recovery of CD59 antigen on bone marrow hematopoietic cells; however, leukemia relapsed 4 months after PBSCT. Leukemia derived from PNH may be resistant to intensive chemotherapy, and a highly myeloablative regimen may be required for stem cell transplantation to eradicate the PNH-derived leukemia clone.International Journal of Hematology 04/2012; 73(2):206-212. · 1.27 Impact Factor -
Article: A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia.
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ABSTRACT: Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has shown efficacy and safety in chronic immune thrombocytopenia (ITP). However, ethnic differences in eltrombopag exposure have been reported: area under the curve exposure to eltrombopag was 87% greater among ITP patients of East Asian descent than among ITP patients of non-East Asian ITP descent. To evaluate the efficacy and safety of eltrombopag by using, in Japanese ITP patients, lower starting (12.5 mg) and maximum (50 mg) doses of eltrombopag than the standard starting (50 mg) and maximum (75 mg) doses approved in the USA and Europe. We examined 23 Japanese patients with previously treated chronic ITP with a platelet count of < 30,000 μL(-1) in a multicenter study comprising a randomized, double-blind, placebo-controlled phase for 6-week evaluation (15 eltrombopag, and eight placebo) and an open-label phase for 6-month evaluation (23 eltrombopag). The response rate (platelet count of ≥ 50,000 μL(-1) ) at week 6 of the 6-week double-blind phase was 60% in eltrombopag-treated patients and 0% in placebo-treated patients. Ten of 23 patients (43.5%) responded for ≥ 75% of predefined assessment visits during the 6-month open-label phase. Notably, 22% (5/23) of patients responded to 12.5 mg of eltrombopag, which was administered within the first 3 weeks of eltrombopag treatment. Bleeding decreased with eltrombopag treatment as compared with baseline. Eltrombopag was generally well tolerated; one patient experienced a transient ischemic attack on day 9. Eltrombopag (12.5-50 mg) is effective for the management of Japanese patients with chronic ITP (NCT00540423).Journal of Thrombosis and Haemostasis 03/2012; 10(5):799-806. · 5.73 Impact Factor -
Article: Expansion of CD8+/perforin+ T-cells predicts response to ciclosporin A therapy in patients with erythroid hypoplasia/aplasia.
British Journal of Haematology 02/2012; 157(5):641-5. · 4.94 Impact Factor -
Article: [Successful treatment with bortezomib for a patient with plasma cell leukemia accompanied by severe hyperbilirubinemia].
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ABSTRACT: A 59-year-old woman was admitted to our hospital with jaundice, renal dysfunction, anemia and hypercalcemia. Primary plasma cell leukemia (PCL) was diagnosed based on findings of IgA-λ type M-protein, 22% plasma cells in the bone marrow and 23.1% plasma cells of WBC in the peripheral blood. Because the total bilirubin (T.Bil) level increased even after the administration of prednisolone (PSL), dexamethasone and methylprednisolone, the patient was started on bortezomib (0.7 mg/m(2) on days 1, 4, 8 and 11 for 3 weeks) combined with PSL (40 mg/day). The level of T.Bil decreased and the patient's condition remarkably improved. We then increased the dose of bortezomib to 1.0 mg/m(2) in the second course, but discontinued treatment just after starting the third course because NCI-CTCAE Grade 3 peripheral neuropathy developed. According to the criteria of the International Myeloma Working Group, the response category was VGPR (=very good partial response) at 1 month after pausing treatment. We recommend these novel agents for PCL, which is an aggressive form of extramedullary plasma cell cancer.[Rinshō ketsueki] The Japanese journal of clinical hematology 01/2012; 53(1):92-6. -
Article: Overexpression of BMI-1 correlates with drug resistance in B-cell lymphoma cells through the stabilization of survivin expression.
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ABSTRACT: The expression of BMI-1 is correlated with disease progression in cancer patients. We showed that ectopic expression of BMI-1 in B-cell lymphoma cell lines, HT and RL, conferred resistance to etoposide and oxaliplatin, known to enhance sensitivity by targeting the survivin gene, but not to irinotecan, which is not relevant to the downregulation of survivin expression. The expression of survivin was not only augmented in cells transduced with BMI-1, but persisted in the presence of etoposide in cells overexpressing BMI-1. By contrast, the mock-transduced cells succumbed in the medium with anticancer drugs, with an accompanying decrease in BMI-1 and survivin expression. BMI-1 overexpression stabilized survivin post-translationally without an accompanying rise in the mRNA, suggesting survivin as a potential target for BMI-1. Knockdown of either BMI-1 or survivin restored sensitivity to etoposide in the BMI-1-overexpressing lymphoma cells. An analysis of six patients with B-cell lymphoma showed that in the drug-resistant patients, levels of BMI-1 and survivin were maintained even after drug administration. However, downregulation of both BMI-1 and survivin expression was observed in the drug-sensitive patients. Therefore, BMI-1 might facilitate drug resistance in B-cell lymphoma cells through the regulation of survivin. BMI-1 could be an important prognostic marker as well as a future therapeutic target in the treatment of drug-resistant lymphomas.Cancer Science 01/2012; 103(1):34-41. · 3.33 Impact Factor -
Article: Morphologic analysis in myelodysplastic syndromes with del(5q) treated with lenalidomide. A Japanese multiinstitutional study.
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ABSTRACT: Lenalidomide is known to be effective in myelodysplastic syndromes (MDS) with del(5q) in improving anemia and suppressing del(5q) cells. MDS with del(5q) shows increase of nonlobulated megakaryocytes. However, histopathology of MDS with del(5q) treated with lenalidomide has not been fully studied. We investigated the morphologic changes in lenalidomide treated low- or intermediate-1-risk MDS with del(5q). All of evaluable patients showed high proportion of nonlobulated megakaryocytes. The nonlobulated megakaryocytes were markedly decreased in 6 patients during therapy in parallel with suppression of del(5q) cells. Our analysis suggests that single allele deletion of common deleted region inhibits nuclear lobulation of megakaryocytes.Leukemia research 12/2011; 36(5):575-80. · 2.36 Impact Factor -
Article: Successful treatment of IgM-monoclonal gammopathy of undetermined significance associated with cryoglobulinemia and cold agglutinin disease with immunochemotherapy with rituximab, fludarabine, and cyclophosphamide.
Annals of Hematology 09/2011; 91(5):797-9. · 2.62 Impact Factor -
Article: [Successful treatment with low-dose dasatinib in a patient with chronic eosinophilic leukemia intolerant to imatinib].
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ABSTRACT: A 77-year-old man with cough and dyspnea was admitted to hospital. Chest X-ray demonstrated reticulated shadows in the bilateral inferior lung fields and marked eosinophilia was detected in peripheral blood. Although he received steroid pulse therapy, eosinophilia became more serious and he was referred to our hospital. Bone marrow examination demonstrated a hypercellular marrow that consisted predominantly of dysplastic eosinophils with differentiation. FISH analysis of bone marrow cells demonstrated 4q12 deletion and RT-PCR analysis detected FIP1L1-PDGFRA fusion gene, leading to the diagnosis of chronic eosinophilic leukemia (CEL). Treatment with low-dose imatinib was immediately initiated; however, drug-induced systemic edema was progressive and became intolerable. Therefore, we changed imatinib to low-dose dasatinib (20 mg/day), resulting in complete molecular response of CEL after 3 months without any severe adverse effects. This is the first report on the efficacy of low-dose dasatinib for the treatment of CEL. The peak level (Cmax) of dasatinib in this patient was 55.3 nM, which exceeded the concentration of dasatinib required to inhibit cells with FIP1L1-PDGFRA by 50%. Thus, low-dose dasatinib with therapeutic drug monitoring can be a useful therapy for imatinib-intolerant CEL even in elderly patients.[Rinshō ketsueki] The Japanese journal of clinical hematology 07/2011; 52(7):546-50. -
Article: Good's syndrome-associated pure red cell aplasia with myelodysplastic syndrome.
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ABSTRACT: We report a case of Good's syndrome-associated pure red cell aplasia (PRCA) with myelodysplastic syndrome (MDS). In this case, effector memory T (T(EM)) cells were expanded in the bone marrow. It remains uncertain whether the development of MDS was caused by the basic marrow defects or radiation therapy. However, since CD8(+) perforin(+) T(EM) cells expanded in the bone marrow, as was previously described for 3 of our patients with thymoma-associated PRCA, it is highly possible that the pathogenic mechanism of PRCA that is accompanied by thymoma is related to the expanded CD8(+) perforin(+) T(EM) cells in this MDS-complicated case.Internal Medicine 01/2011; 50(18):2011-4. · 0.94 Impact Factor -
Article: Mantle cell lymphoma superimposed on multicentric Castleman's disease.
Journal of Clinical and Experimental Hematopathology 01/2011; 51(2):147-50. -
Article: Clinical and genetic features of therapy-related myeloid neoplasms after chemotherapy for acute promyelocytic leukemia.
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ABSTRACT: Acute promyelocytic leukemia (APL) is a highly curable disease with excellent complete remission and long-term survival rates. However, the development of therapy-related myeloid neoplasms (t-MN) is being reported with increasing frequency in patients successfully treated for APL. We attempted to clarify the different clinical features and hematologic findings between t-MN and relapse cases, and to identify gene alterations involved in t-MN. We compared 10 relapse and 11 t-MN cases that developed in 108 patients during their first complete remission from APL. At APL diagnosis, t-MN patients had lower white blood cell counts than did relapse patients (P = .048). Overall survival starting from chemotherapy was significantly worse in t-MN patients than in relapse patients (P = .022). The t-MN cases were characterized as CD34(+)/HLA-DR(+) and PML-RARA(-), and 4 RUNX1/AML1 mutations were detected. T-MN is easily distinguished from APL relapse by evaluating these hematologic features, and it may originate from primitive myeloid cells by chemotherapy-induced RUNX1 mutations.Blood 12/2010; 116(26):6018-22. · 9.90 Impact Factor -
Article: Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin lymphoma.
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ABSTRACT: Using artificial receptors, it is possible to redirect the specificity of immune cells to tumour-associated antigens, which is expected to provide a useful strategy for cancer immunotherapy. Given that B-cell non-Hodgkin lymphoma (B-NHL) cells invariably express CD19 and CD38, these antigens may be suitable molecular candidates for such immunotherapy. We transduced human peripheral T cells or a T-cell line with either anti-CD19-chimeric receptor (CAR) or anti-CD38-CAR, which contained an anti-CD19 or anti-CD38 antibody-derived single-chain variable domain respectively. Retroviral transduction led to anti-CD19-CAR or anti-CD38-CAR expression in T cells with high efficiency (>60%). The T cell line, Hut78, when transduced with anti-CD19-CAR or anti-CD38-CAR, exerted strong cytotoxicity against the B-NHL cell lines, HT and RL, and lymphoma cells isolated from patients. Interestingly, use of both CARs had an additive cytotoxic effect on HT cells in vitro. In conjunction with rituximab, human peripheral T cells expressing either anti-CD19-CAR or anti-CD38-CAR enhanced cytotoxicity against HT-luciferase cells in xenografted mice. Moreover, the synergistic tumour-suppressing activity was persistent in vivo for over 2 months. These results provide a powerful rationale for clinical testing of the combination of rituximab with autologous T cells carrying either CAR on aggressive or relapsed B-NHLs.British Journal of Haematology 10/2010; 151(1):37-46. · 4.94 Impact Factor -
Article: Roles of Src-like adaptor protein 2 (SLAP-2) in GPVI-mediated platelet activation SLAP-2 and GPVI signaling.
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ABSTRACT: Glycoprotein VI (GPVI) /Fc receptor gamma (FcRγ)-chain complex is one of the collagen receptors in platelets and responsible for the majority of the intracellular signaling events through a similar pathway to immune receptors. Src-like adaptor protein 2 (SLAP-2) is a recently characterized adaptor protein predominantly expressed in hematopoietic cells. In T cells, SLAP-2 was reported to associate with several tyrosine phosphorylated proteins, and function as a negative regulator of signaling downstream of T cell antigen receptor by virtue of its interaction with the ubiquitin ligase c-Cbl. But the data regarding the presence and role of SLAP-2 proteins in platelets is limited. We describe the characterization of SLAP-2 in human platelets. Human platelets were analyzed by Western blot analysis, immunoprecipitation, and pull down assay, etc. Immunoprecipitation revealed the presence of two forms of SLAP-2 with approximately 28 kD and 25 kD, and following stimulation of GPVI, the additional form with approximately 32 kD apppeared. We have found that upon GPVI activation, SLAP-2 translocated from the Triton X-100-soluble fraction to the Triton X-100-insoluble cytoskeleton fraction, with concomitant association with Syk, c-Cbl, and LAT. SLAP-2 appears to play a role in regulating signaling pathways by bringing important signaling molecules such as c-Cbl and Syk into proximity of cytoskeletal substrates. In platelets, SLAP-2 may have function as a negative regulator of GPVI-mediated signaling by interacting with c-Cbl, being similar to that reported in T cells.Thrombosis Research 10/2010; 126(4):e276-85. · 2.44 Impact Factor -
Article: Giant granulocytic sarcoma of the vagina concurrent with acute myeloid leukemia with t(8;21)(q22;q22) translocation.
International journal of hematology 10/2010; 92(3):553-5. · 1.17 Impact Factor -
Article: Establishment of an HS23 stromal cell-dependent myeloma cell line: fibronectin and IL-6 are critical.
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ABSTRACT: A multiple myeloma (MM) cell line, MSG1, which depends on HS23 stromal cells for its survival, was established from the pleural effusion of a patient with MM who expressed the M-protein of IgA-λ in his serum. During the first 2 months of culture, the myeloma cells survived on adhesive cells from the pleural effusion and, subsequently, they continued to proliferate on HS23 stromal cells. The phenotype of the established MSG1 cell line was: CD138(+), CD38(++), CD19⁻, CD56⁻, VLA-4(+), VEGFR1(+) and VEGFR2(+). Immunohistochemical staining also demonstrated expression of the IgA and λ chain in MSG1 cytoplasm. Karyotype analysis indicated complex chromosomal abnormalities; hypertriploidy, including the deletion of chromosomes 13 and 17, and c-myc translocation. MSG1 cells continued to proliferate, not only when co-cultured with HS23 cells, but also when cultured only on fibronectin-coated plates with the supernatant of HS23 cells or with control medium containing IL-6. Tocilizumab, an anti-IL-6 receptor antibody, inhibited MSG1 survival under these conditions. Therefore, MSG1 may be a unique myeloma cell line that is useful for the study of cell adhesion-mediated drug resistance induced by adhesion molecules and IL-6 stimulation of myeloma cells.International journal of hematology 10/2010; 92(4):598-608. · 1.17 Impact Factor -
Article: Expansion of CD8+ /perforin+ effector memory T cells in the bone marrow of patients with thymoma-associated pure red cell aplasia.
British Journal of Haematology 09/2010; 150(6):712-5. · 4.94 Impact Factor -
Article: Synergistic and persistent effect of T‐cell immunotherapy with anti‐CD19 or anti‐CD38 chimeric receptor in conjunction with rituximab on B‐cell non‐Hodgkin lymphoma
[show abstract] [hide abstract]
ABSTRACT: Using artificial receptors, it is possible to redirect the specificity of immune cells to tumour-associated antigens, which is expected to provide a useful strategy for cancer immunotherapy. Given that B-cell non-Hodgkin lymphoma (B-NHL) cells invariably express CD19 and CD38, these antigens may be suitable molecular candidates for such immunotherapy. We transduced human peripheral T cells or a T-cell line with either anti-CD19-chimeric receptor (CAR) or anti-CD38-CAR, which contained an anti-CD19 or anti-CD38 antibody-derived single-chain variable domain respectively. Retroviral transduction led to anti-CD19-CAR or anti-CD38-CAR expression in T cells with high efficiency (>60%). The T cell line, Hut78, when transduced with anti-CD19-CAR or anti-CD38-CAR, exerted strong cytotoxicity against the B-NHL cell lines, HT and RL, and lymphoma cells isolated from patients. Interestingly, use of both CARs had an additive cytotoxic effect on HT cells in vitro. In conjunction with rituximab, human peripheral T cells expressing either anti-CD19-CAR or anti-CD38-CAR enhanced cytotoxicity against HT-luciferase cells in xenografted mice. Moreover, the synergistic tumour-suppressing activity was persistent in vivo for over 2 months. These results provide a powerful rationale for clinical testing of the combination of rituximab with autologous T cells carrying either CAR on aggressive or relapsed B-NHLs.British Journal of Haematology 07/2010; 151(1):37 - 46. · 4.94 Impact Factor -
Article: Cerebral sinus thrombosis and heparin-induced thrombocytopenia in a patient with paroxysmal nocturnal hemoglobinuria.
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ABSTRACT: Paroxysmal nocturnal hemoglobinuria is a rare acquired disorder of clonal hematopoietic stem cells and it is characterized as a hypercoagulable disorder. We report a 36-year-old woman with the rare triad of paroxysmal nocturnal hemoglobinuria, cerebral sinus thrombosis triggered by infection, and rapid-onset heparin-induced thrombocytopenia after resensitization of heparin. This case raises caution for heparin-induced thrombocytopenia in paroxysmal nocturnal hemoglobinuria.Internal Medicine 01/2010; 49(10):941-3. · 0.94 Impact Factor -
Article: Pure red cell aplasia associated with imatinib-treated FIP1L1-PDGFRA positive chronic eosinophilic leukemia.
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ABSTRACT: A 28-year-old man with marked eosinophilia is described. FIP1L1/PDGFRA mRNA showed multiple alternatively-spliced fusion transcripts. Sequencing analysis showed that the deduced DNA breakpoints were intron 10 in the FIP1L1 gene and exon 12 in the PDGFRA gene. Then, a diagnosis of chronic eosinophilic leukemia (CEL) was made. Whereas the response to the treatments with prednisolone and hydroxyurea were unsatisfactory, treatment with imatinib showed a rapid decrease of eosinophils. The hemoglobin level also dropped and bone marrow examination showed pure red cell aplasia. Continued administration of very low dose imatinib (100 mg every 5 days) led to and maintained complete molecular remission, with good tolerability.Internal Medicine 01/2010; 49(12):1195-200. · 0.94 Impact Factor -
Article: AML1/RUNX1 point mutation possibly promotes leukemic transformation in myeloproliferative neoplasms.
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ABSTRACT: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid cell lineages. Some patients exhibit leukemic transformation (LT) by unknown mechanisms, and chemotherapy may increase the risk of LT. To clarify the molecular mechanisms of LT, gene alterations involved in LT from patients in the chronic phase (CP) of MPNs were identified. Among 18 patients who progressed to leukemia, AML1/RUNX1 mutations were detected in 5 patients at the LT but in none at the CP. To investigate the leukemogenic effect of AML1/RUNX1 mutants, the AML1D171N mutant was transduced into CD34(+) cells from patients in the CP of MPNs. The D171N transduction resulted in proliferation of immature myeloid cells, enhanced self-renewal capacity, and proliferation of primitive progenitors. Taken together, these results indicate that AML1/RUNX1 point mutations may have a leukemogenic potential in MPN stem cells, and they may promote leukemic transformation in MPN.Blood 10/2009; 114(25):5201-5. · 9.90 Impact Factor
Top co-authors
Top Journals
Institutions
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1998–2012
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Hiroshima University
- Department of Hematology and Oncology
Hiroshima-shi, Hiroshima-ken, Japan
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2011
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Saitama Medical University
- Division of Hematology/Oncology
Saitama, Saitama-ken, Japan
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2010
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Hiroshima City Hospital
Hiroshima-shi, Hiroshima-ken, Japan
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2009
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Akita University Hospital
Akita, Akita-ken, Japan
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