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ABSTRACT: In order to test for improved survival following autologous transplantation (ASCT), we conducted a prospective clinical trial of post-ASCT thalidomide therapy in Japanese patients with multiple myeloma (MM). Twenty-five newly diagnosed patients received double or single ASCT with high-dose melphalan (200 mg/m(2)). Two months after stem cell infusion, if the patients failed to achieve a near-complete response, thalidomide was administered at 200 mg/day until disease progression or occurrence of intolerable adverse events. Seventeen patients were in partial response or minimal response after ASCT and received thalidomide alone. Their median progression-free survival (PFS) from ASCT was 17.4 months, and the median overall survival (OS) was 42.9 months. Some patients with normal karyotype experienced durable disease stabilization for over 5 years. Five patients who exhibited high-risk chromosomal changes such as t(4;14) or deletion of chromosome 13 or 17 showed very short PFS and OS compared with those who did not. Observed grade 3 or 4 toxicities included infection in three patients, hematological toxicities in three, and gastrointestinal toxicities in two, but there was no grade 3 or higher peripheral neuropathy, probably due to appropriate dose modifications. This long-term prospective study is the first to demonstrate the feasibility of post-ASCT thalidomide therapy in Japanese patients with MM.
International journal of hematology 09/2012; 96(4):477-84. · 1.17 Impact Factor
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ABSTRACT: A 62-year-old man with diffuse large B-cell lymphoma received five courses of R-CHOP chemotherapy. The patient developed cellulitis in the bilateral lower extremities without fever, and blood culture yielded Helicobacter cinaedi after five-day culture. Although the response to tazobactam/piperacillin (TAZ/PIPC) was prompt, cellulitis recurred immediately after discontinuation of the drug. Even after two months of treatment with PIPC plus amikacin followed by amoxicillin, it recurred again soon after stopping the antibiotics. H. cinaedi reportedly causes bacteremia and cellulitis in immunocompromised patients mostly in patients with acquired immunodeficiency syndrome. Only sporadic cases have been reported in association with hematological malignancies. Physicians should be aware of H. cinaedi as one of the causative pathogens of bacteremia and cellulitis in patients with hematological malignancies. Longer incubation period of blood culture is needed to detect the microbe and long-term use of antimicrobials is required to prevent recurrent cellulitis.
[Rinshō ketsueki] The Japanese journal of clinical hematology 06/2012; 53(6):623-7.
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ABSTRACT: We report two patients who achieved a marked improvement of hematopoiesis with the use of deferasirox (DSX) for transfusional iron overload. Case 1 is an 81-year-old male who was diagnosed with primary myelofibrosis in July, 2007. He required regular red blood cell (RBC) transfusion of 4 units/month when he was started on DSX treatment in June, 2009. Four months after the treatment, he became transfusion independent, and has maintained hemoglobin levels of around 13 g/dl until today. Case 2 is a 70-year-old female with acute myeloid leukemia with myelodysplasia-related changes. She had been on RBC transfusion of 4 units/month when she was started on DSX treatment in January, 2010. Two months after the treatment, she became transfusion-independent, and 5 months after treatment, blast cells completely disappeared in the peripheral blood, together with normalization of white blood cell and neutrophil counts. Achieving durable transfusion-independency and normalization of white blood cell count and differential with a single use of DSX is a very rare event. Prospective accumulation of more patients and research to understand the mechanism underlying these effects are clearly warranted.
[Rinshō ketsueki] The Japanese journal of clinical hematology 01/2012; 53(1):78-82.
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ABSTRACT: Thrombopoietin stimulates megakaryopoiesis and platelet production by binding to its receptor, Mpl, on hematopoietic progenitor cells. Previously, a murine VB22B minibody for Mpl was shown to stimulate megakaryocyte colony formation in vitro and increase the platelet count in cynomolgus monkeys. In this study, we directly compared the effects of a humanized VB22B minibody (huVB22B) with those of thrombopoietin and eltrombopag under the hypothesis that Mpl agonists might have different biological effects on megakaryopoiesis, platelet production, intracellular signal transduction, and platelet function.
Human bone marrow-derived CD34(+) cells were used for colony formation assays and proplatelet formation assays in vitro. The DNA ploidy in megakaryocytes was analyzed by flow cytometry. Phosphorylation of signal transducers and activators of transcription and mitogen-activated protein kinase was detected by Western blotting using specific antibodies. The effects of the Mpl agonists on platelet aggregation were analyzed by aggregometry using human platelets.
HuVB22B was as potent as thrombopoietin and eltrombopag in its ability to form mature megakaryocytes using human CD34(+) cells in vitro. It did not affect granulocyte-macrophage or erythroid colony formation. HuVB22B increased the number of proplatelet-forming megakaryocytes more efficiently than thrombopoietin or eltrombopag. Despite stronger phosphorylation of signal transducers and activators of transcription and mitogen-activated protein kinase compared with thrombopoietin in human platelets, huVB22B did not enhance adenosine diphosphate- or collagen-induced platelet aggregation. Eltrombopag did not enhance agonist-induced platelet aggregation.
We found that huVB22B, eltrombopag, and thrombopoietin have different effects on megakaryopoiesis, platelet function, and intracellular signaling. The precise mechanisms for these different biological effects regarding stimulation through the same receptor, Mpl, remain to be elucidated.
Experimental hematology 05/2011; 39(8):829-36. · 3.11 Impact Factor
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ABSTRACT: To establish cell lines from the patient with plasmablastic lymphoma, who was immunologically competent including negative human immunodeficiency virus (HIV) serology, and analyze the unique chromosomal translocations seen in the cell lines in order to unveil the pathogenesis of this tumor, which had no evidence of Epstein-Barr virus involvement.
Establishment of the cell lines was attempted by inoculating the patient's lymph node biopsy specimen subcutaneously to immunodeficient mice. Comparative genomic hybridization (CGH) array and FISH analysis were performed to identify breakpoints of the two chromosomal translocations. Of the 4 candidate genes identified by FISH analysis to be involved in the translocations, reverse transcription-PCR, Western blot, flow cytometry, and proliferation assay were performed to identify the exact genes involved.
Analysis of the cell lines identified loss of p16 at the protein level by chromosomal translocation of t(9;13) and upregulation of MDR-1 by t(4;7). The cell lines expressing MDR-1 acquired resistance to chemotherapeutic agents such as cisplatin and doxorubicin, but not bortezomib. Expression of B lymphoid lineage marker genes of these cell lines was negative for paired box 5 (Pax5) or PR domain containing 1, with ZNF domain (PRDM1), but was positive for X-box binding protein 1 (Xbp1).
We established three novel cell lines of plasmablastic lymphoma. Characterization of the unique chromosomal translocation identified loss of p16 and upregulation of MDR-1 at protein level. Expression of Xbp1(s), which is involved in the maturation of plasma cells, corresponded to the plasmablastic appearance of the tumor. These cell lines may be a useful tool to understand the pathophysiology of the disease and to develop novel treatment strategies.
Clinical Cancer Research 02/2011; 17(8):2101-9. · 7.74 Impact Factor
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ABSTRACT: Hereditary factor XII (FXII) deficiency is a clinically asymptomatic, autosomal recessive disorder. We have experienced a rare case of FXII deficiency in a patient previously diagnosed with hereditary spastic paraplegia (HSP). The patient had no major bleeding episodes and presented with a prolonged activated partial thromboplastin time (APTT) at hospital administration. Sequencing of the FXII gene revealed a novel missense mutation at exon 4 that substitutes arginine 84 to proline (R84P). To elucidate the molecular mechanism of FXII deficiency, wild-type and R84P mutant FXII cDNA were transiently expressed in CHO cells. We found that secretion but not synthesis of R84P mutant protein was markedly reduced compared to wild type. These results indicated that R84P mutation might impair the intracellular transport or secretion of FXII protein of the cells and could be a useful tool for the analysis of structure-function relationship and intracellular protein transport of FXII protein in the future.
Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 02/2011; 22(3):227-30. · 1.25 Impact Factor
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ABSTRACT: Adult onset Langerhans cell histiocytosis (LCH) is a rare disorder. Its clinical features have been well described in children, however remain poorly defined in adults. Optimal treatment strategy is still under debate. We have encountered two cases of adult onset LCH, which obtained a durable disease control by combination chemotherapy using prednisone, vinblastine and 6-mercaptopurine. Herein, we report their clinical features together with a review of the current literature.
Internal Medicine 01/2011; 50(8):909-14. · 0.94 Impact Factor
