Y Hasegawa

University of Tsukuba, Tsukuba, Ibaraki, Japan

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Publications (49)120.64 Total impact

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    ABSTRACT: In leukemogenesis, Notch signaling can be up- and down-regulated in a context-dependent manner. The transcription factor hairy and enhancer of split-1 (Hes1) is well characterized as a downstream target of Notch signaling. Hes1 encodes a basic helix-loop-helix-type protein, and represses target gene expression. Here we report that deletion of the Hes1 gene in mice promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and down-regulated the promoter activity. FLT3 was consequently up-regulated in MLL-AF9-expressing immortalized and leukemia cells with a Hes1- or RBPJ-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. We also accessed two independent databases containing mRNA expression profiles and found that the expression level of FLT3 mRNA was negatively correlated with those of HES1 in patient AML samples. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development, probably by down-regulating FLT3 expression.Leukemia accepted article preview online, 19 September 2014. doi:10.1038/leu.2014.281.
    Leukemia 09/2014; 29(3). DOI:10.1038/leu.2014.281 · 10.43 Impact Factor
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    K Maie · Y Okoshi · N Takaiwa · N Kurita · Y Hasegawa · M Homma · K Ishii · Y Kohda · S Chiba ·

    Annals of Oncology 11/2013; 25(1). DOI:10.1093/annonc/mdt477 · 7.04 Impact Factor
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    ABSTRACT: Oral mucositis (OM) is a frequent adverse effect of allogenic or autologous hematopoietic SCT. It results from direct toxic injury to the mucosal epithelial cells by the immunosuppressive regimen. Here, we compared the incidence and severity of OM between a group of 24 patients who received proper oral management during hematopoietic SCT and a group of 24 who did not. The oral management group received pre-hematopoietic SCT instruction on oral care and an oral examination in the clean room. Differences in the incidence and severity of OM between the two groups were examined statistically. OM was observed in 14 (58.3%) patients in the oral management group and 22 (91.6%) in the control group. The median of the OM score was 1 for the oral management group (range 0 to 3) and 2 for the control group (range 0 to 3). There was a significant difference in the OM score (P<0.05) and in the incidence of OM between the two groups (P<0.01). This study shows that oral management may decrease the occurrence of OM. Our results also suggest that it is important to include an oral management provider on the hematopoietic SCT team.
    Bone marrow transplantation 08/2011; 47(5):725-30. DOI:10.1038/bmt.2011.171 · 3.57 Impact Factor
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    S Sato · Y Kozuma · Y Hasegawa · H Kojima · S Chiba · H Ninomiya ·
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    ABSTRACT: Erythroid cells in the marrow express CD71, transferrin receptor, and reticulocytes released from the marrow lose their expression during maturation. The immature reticulocyte fraction, the proportion of reticulocytes with the highest content of RNA, has been determined by hematology analysis. In the present study, we examined CD71 expression on immature reticulocytes by flow cytometry (FCM) in paroxysmal nocturnal hemoglobinuria (PNH) patients with reticulocytosis. We modified 'reticulocyte-gated FCM' to multi-color FCM, i.e. RNA/CD71, RNA-CD59 or CD59/CD71/CD45. In PNH, in addition to the increased number of immature reticulocytes (%CD71-positive), a more immature phenotype in regard to both CD71 intensity and RNA content levels was demonstrated. In seven PNH patients studied, %CD71-positive reticulocytes were significantly increased at 32.2 +/- 11.9% (n = 10, normal 10.4 +/- 3.5%, P = 0.002). RNA content levels (assessed by mean fluorescence index, MFI) in CD71-positive reticulocytes were significantly increased at 812.0 +/- 215.2 MFI in PNH (n = 10, normal 508 +/- 86.1 MFI, P = 0.002). These data indicate that stimulated erythropoietic conditions induce the release of more immature reticulocytes to the peripheral blood than ordinary erythropoietic conditions. CD71 intensity on immature reticulocytes was well correlated with their RNA content levels, indicating the usefulness of CD71 as an immature reticulocyte marker.
    International journal of laboratory hematology 04/2009; 32(1 Pt 1):e137-43. DOI:10.1111/j.1751-553X.2009.01148.x · 1.82 Impact Factor
  • M Homma · Y Inoue · Y Hasegawa · H Kojima · Y Kohda ·
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    ABSTRACT: Blood ribavirin concentration was monitored after the administration of high-dose oral ribavirin in a case of adenovirus-induced haemorrhagic cystitis post-stem-cell transplantation. Combination use of intravenous gamma immunoglobulin (15 g/3 days) and high-dose ribavirin (RBV; 9000 mg/4 days) provided plasma ribavirin concentration of 24.3 microM and achieved virus eradication. High level of erythrocyte ribavirin (1085 microM; mostly as phosphorylated metabolites) with long half-life (15 days) caused severe anaemia, which required several blood transfusions for 2 weeks after the cessation of the ribavirin treatment. It was suggested that blood transfusion and intensive haemoglobin level monitoring is necessary for at least 4 weeks after the RBV, because of the high accumulation of phosphorylated ribavirin in erythrocytes even after stopping ribavirin administration.
    Journal of Clinical Pharmacy and Therapeutics 03/2008; 33(1):75-8. DOI:10.1111/j.1365-2710.2008.00874.x · 1.67 Impact Factor
  • H Ninomiya · S Sato · Y Hasegawa · T Nagasawa ·
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    ABSTRACT: Paroxysmal nocturnal haemoglobinuria (PNH) is a haemolytic disease characterized by complement-sensitive red blood cells (RBC). PNH-affected RBC (PNH-RBC) should have a shortened mean lifespan (MLS); however, direct measurement is difficult. We have recently developed a sensitive flow cytometric assay to analyse PNH-affected reticulocytes that may closely correspond to the PNH clone-derived erythropoiesis. Naturally, the CD59-negative populations in reticulocytes were larger than those in whole RBC in PNH. We estimated the MLS of PNH-RBC in six PNH patients from the differences in the ratios of CD59-negative populations between reticulocytes and whole RBC. The MLS of PNH-RBC was calculated using the following formula: W/100 = R x M/[(100 - R) x 120 + R x M], where W, percentage CD59-negative whole RBC; R, percentage CD59-negative reticulocytes; M, MLS (days) of CD59-negative RBC. The MLS of PNH-RBC, estimated as 16-45 days in the PNH patients, showed a weak positive and a weak negative relation with RBCs and percentage reticulocytes, respectively, among the patients. The MLS, in individual patients, altered irrespective of RBC and percentage reticulocytes. The MLS calculated from our methods may be a parameter that evaluates the haemolytic conditions in PNH.
    International Journal of Laboratory Hematology 03/2008; 30(1):41-5. DOI:10.1111/j.1365-2257.2007.00897.x · 1.82 Impact Factor

  • Bone Marrow Transplantation 05/2007; 39(8):513-4. · 3.57 Impact Factor
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    K Yamagata · K Onizawa · T Yanagawa · Y Hasegawa · H Kojima · T Nagasawa · H Yoshida ·
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    ABSTRACT: Pre-hematopoietic stem cell transplantation (HSCT) dental treatment is essential to prevent serious infections from oral sources during immunosuppression, in patients who undergo HSCT therapy. This study was planned to establish a dental management protocol for such patients. Forty-one patients scheduled for HSCT to treat hematological malignancies were consecutively enrolled in the prospective trial. The dental status of all patients was evaluated by clinical and radiographic examination at a median of 47 days before the commencement of HSCT therapy. Thirty-six patients had one or more dental diseases; the remaining five had none. Caries was found in 26 patients, apical periodontitis in 19, marginal periodontitis in 24 and a partially erupted third molar in 11. Our policy is to preserve patients' teeth whenever possible, and therefore minimal dental intervention was planned. Treatment was completed for all 36 patients with dental pathologies, before the conditioning regimen began. All patients received the scheduled HSCT therapy without alteration, interruption or delay, and did not show any signs or symptoms associated with odontogenic infection while they were immunosuppressed. This protocol, therefore, appears to be appropriate for the pre-HSCT dental treatment of patients with hematological diseases.
    Bone Marrow Transplantation 09/2006; 38(3):237-42. DOI:10.1038/sj.bmt.1705429 · 3.57 Impact Factor
  • A Kitamura · Y Yamashita · Y Hasegawa · H Kojima · T Nagasawa · N Mori ·
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    ABSTRACT: Most lymphomas arising in the nasal cavity are thought to be of natural killer (NK) cell origin. However, some reports indicate that T- and B-cell lymphomas may also primarily arise in the nasal cavity. We therefore studied lymphomas arising in the nasal cavity both histologically and immunohistochemically. Of the 32 cases investigated, 20 cases were also available as fresh frozen specimens. We diagnosed 31 cases as extranodal NK/T-cell lymphoma and one as plasmacytoma. The neoplastic cells were immunoreactive for CD3 (polyclonal) 31/31, LMP-1 12/31, CD20 (L26) 0/31, granzyme B 30/31, TIA-1 30/30, CD56 (123C3) 29/31, CD4 0/31 and CD8 3/31. In situ hybridization for Epstein-Barr virus-encoded small RNA-1 (EBER-1) was detected in 31/31. In frozen tissue sections, neoplastic cells mostly showed CD3 (Leu4)-, CD4 (Leu3a)-, CD5 (Leu1)-, CD8 (Leu2)-, CD16 (Leu11)-, CD56 (Leu19)+, betaF1-, TCRdelta1-, perforin+, CD94+ phenotypes. These immunohistochemical findings indicate their NK cell origin. In three cases, neoplastic cells were positive for CD8. In one of these cases, neoplastic cells were positive for CD8beta and Valpha24, suggesting their NKT-cell origin. Our present study indicates that primary lymphomas arising in the nasal cavity are mostly of NK cell derivation. Our present study also suggests that a small number of cases are derived from NKT-cells.
    Histopathology 12/2005; 47(5):523-32. DOI:10.1111/j.1365-2559.2005.02265.x · 3.45 Impact Factor
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    S Shimizu · H Kojima · C Yoshida · K Suzukawa · HY Mukai · Y Hasegawa · S Hitomi · T Nagasawa ·
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    ABSTRACT: A 26 year old pregnant woman with antithrombin III deficiency developed recurrent septicaemia with Serratia marcescens. In spite of the administration of antibiotics, high grade fever persisted. She subsequently manifested lower abdominal pain, and spontaneous abortion occurred. After the abortion, she became completely afebrile. The amnion was turbid, and microscopic examination of the placenta showed haemorrhage and massive infiltration of neutrophils, suggestive of infectious chorioamnionitis. Pulsed field gel electrophoresis showed that isolates from the blood, urine, and vaginal discharge were genetically identical. Intravenous pyelography revealed that she had a bilateral completed double ureter. It was thought that a urinary tract anomaly caused infection with S marcescens, and the pathogen spread to the chorioamnion via the bloodstream. This is the first report of chorioamnionitis caused by S marcescens in a non-immunocompromised host. In addition, these findings indicate that the chorioamnion can serve as a site for persistent infection in normal pregnancies.
    Journal of Clinical Pathology 12/2003; 56(11):871-2. DOI:10.1136/jcp.56.11.871 · 2.92 Impact Factor
  • H Kojima · N Takei · Y Mukai · Y Hasegawa · K Suzukawa · M Nagata · M Noguchi · N Mori · T Nagasawa ·
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    ABSTRACT: It is now well recognized that hemophagocytic syndrome (HPS) is occasionally associated with malignant lymphomas. However, its association with Hodgkin's disease has been only rarely reported. We present here a 72-year-old woman manifesting with HPS as the primary and solitary clinical symptom of Hodgkin's disease. She had been suffering from high-grade fever and anemia for more than a month. Based on the findings in bone marrow aspirates, she was diagnosed as having HPS. In spite of extensive surveys including various cultures, serological tests for collagen disease, abdominal and cardiac sonography, chest computed tomography (CT), and renal biopsy, the origin of the fever was not determined. She was treated with steroid pulse therapy and then referred. Radiological studies revealed only mild hepatosplenomegaly and small lymph node swellings around celiac and common hepatic arteries. Reevaluation of the bone marrow specimen revealed the infiltration of small numbers of CD30-, CD15-, and EBER-1-positive large-sized lymphocytes with bizarre nucleus. Under the diagnosis of Hodgkin's disease, she was treated with combination chemotherapy containing pirarubicin, cyclophosphamide, vincristine, and prednisolone. However, it was not effective and she died of rapidly progressive hepatic failure on the 5th day of the chemotherapy. Autopsy was performed, which showed proliferation of lymphoma cells in para-aortic lymph nodes. We believe that diagnostic survey to rule out the underlying lymphoma should be vigorously performed for patients with hemophagocytic syndrome of unknown origin.
    Annals of Hematology 02/2003; 82(1):53-6. DOI:10.1007/s00277-002-0572-2 · 2.63 Impact Factor
  • H Kojima · M Abei · N Takei · Y Mukai · Y Hasegawa · T Iijima · T Nagasawa ·
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    ABSTRACT: Hepatitis B virus (HBV) is a well known pathogen that sometimes causes fulminant hepatitis in patients undergoing cytotoxic chemotherapy. Fibrosing cholestatic hepatitis (FCH) is a recently recognized unique variant of viral hepatitis, which has been occasionally reported in HBV-infected recipients of liver, renal, or bone marrow transplantation. We present here a 48-yr-old male in whom HBV was reactivated during post-remission chemotherapy for acute myelogenous leukemia, which resulted in rapidly fatal outcome. He manifested with deterioration of liver function in association with enormous replication of HBV. Liver biopsy showed marked ballooning of hepatocytes, cholestasis, and periportal fibrosis with minimum infiltrates. Immunostaining revealed that hepatocytes were strongly positive for hepatitis B surface antigen. Under the diagnosis of FCH, he was treated with lamivudine and interferon beta, which was not effective. Autopsy showed severe atrophy of the liver and marked degeneration of hepatocytes. Hematologists should be aware that FCH is a fatal complication that can develop under post-chemotherapy immunosuppressed conditions. Although there is no convincing evidence, prophylactic administration of lamivudine seems to be a reasonable strategy.
    European Journal Of Haematology 09/2002; 69(2):101-4. DOI:10.1034/j.1600-0609.2002.02719.x · 2.07 Impact Factor
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    ABSTRACT: To better understand how humans adapt to hypoxia, the levels of hemoglobin (Hb), serum erythropoietin (Epo), and vascular endothelial growth factor (VEGF) were measured in 106 patients with severe obstructive sleep apnea-hypopnea syndrome. The results indicated that temporal hypoxic stimulation increases Hb. Furthermore, a minor increase in Epo and a substantial increase in VEGF were found. The induction in patients with severe sleep apnea was greater than that reported in other types of hypoxia. (Blood. 2001;98:1255-1257)
    Blood 09/2001; 98(4):1255-7. DOI:10.1182/blood.V98.4.1255 · 10.45 Impact Factor
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    ABSTRACT: We analyzed the clinicopathological features of 5 Japanese patients with CD56+ primary cutaneous lymphomas (3 men and 2 women aged 25 to 73 years). Except for 1 patient in whom bone marrow involvement was simultaneously observed, all patients presented with cutaneous lesions. Based on their Epstein-Barr virus (EBV) status, we categorized these patients into 2 groups, namely EBV-encoded small RNA-1 (EBER-1) (3 patients) and EBER-1- (2 patients). Generalized lymphadenopathy and bone marrow involvement were observed only in EBER-1 patients. Morphologically, angiocentric proliferation was more prominent in EBER-1+ patients and was accompanied by panniculitis-like changes. The lymphomas in EBER-1- patients featured monomorphic proliferation of lymphoblastic cells with no cytoplasmic granules. Phenotypically, CD3-, cytoplasmic CD3 epsilon+, and CD56+ were common findings in both types. The EBER-1- type showed an additional distinguishing feature, CD7+, CD4+, CD8-, HLA-DR+, and terminal deoxynucleotidyl transferase-positive (TdT+) phenotype. The lymphoma was primarily resistant in the EBER-1+ type, and the patients died within 6 months of admission. In contrast, the lymphoma in the EBER-1- patients was originally chemosensitive. Collectively, we consider there to be at least 2 types of CD56+ primary cutaneous lymphomas, corresponding to nasal-type natural killer (NK)/T-cell lymphomas (EBER-1+) and blastic NK-cell lymphomas (EBER-1-).
    International Journal of Hematology 01/2001; 72(4):477-83. · 1.92 Impact Factor
  • Y Yamashita · S Nakamura · Y Kagami · Y Hasegawa · H Kojima · T Nagasawa · N Mori ·
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    ABSTRACT: We studied 10 cases of Lennert's lymphoma (lymphoepithelioid lymphoma) to evaluate the cellular origin of the neoplastic cells. There were six men and four women, aged 38 to 75 years (median, 56 yrs; mean, 59 yrs). The lymphoma cells tended to remain confined to lymph nodes, and extranodal involvement was rare. The mean overall survival was 42.2 months, which is relatively good compared with other peripheral T-cell lymphomas. Morphologically, the lymph node was occupied by small to large clusters of epithelioid cells interspersed with medium to large atypical lymphoid cells. In seven cases, large atypical lymphoid cells resembling Hodgkin's or Reed-Sternberg cells were observed. The phenotypes of these neoplastic cells were CD3+ CD4- CD8+ in five cases, CD3+ CD4+ CD8- in four cases, and CD3+ CD4- CD8- in one case. TIA-1 was positive by immunohistochemical staining in seven cases, whereas four cases were positive for granzyme B. Clonal rearrangement of the T-cell receptor gene was confirmed in all cases by either Southern blot hybridization or a polymerase chain reaction-based denature gradient gel electrophoresis method. Epstein-Barr virus was negative by in situ hybridization in all but one case. Lennert's lymphoma was formerly known as a CD4+ helper T-cell neoplasm. Our results suggest that, at least in some cases, the neoplastic cells are of cytotoxic T-cell origin.
    American Journal of Surgical Pathology 01/2001; 24(12):1627-33. · 5.15 Impact Factor
  • N Mori · Y Yamashita · T Tsuzuki · A Nakayama · M Nakazawa · Y Hasegawa · H Kojima · T Nagasawa ·
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    ABSTRACT: Aggressive natural killer (NK) cell leukaemia will be categorized as a distinct entity in the new WHO classification of malignant lymphomas. However, its non-leukaemic features remain unclear. We therefore investigated the morphological and immunophenotypic features of this lymphoma. Four cases with aggressive NK cell lymphoma were morphologically and immunohistochemically studied. All cases followed an aggressive course with death occurring within about 3 months of initial presentation. In these cases, the neoplastic cells disseminated throughout systemic lymph nodes and invaded various tissues and organs. The lymphoma cells were large cells showing nuclear irregularity and a pattern of sinusoidal invasion in lymph nodes. Apoptosis and coagulation necrosis were both frequently observed. Haemophagocytosis was observed in all cases. Neoplastic cells in paraffin-embedded tissue specimens from these patients had CD3(CD3epsilon)+ CD56(123C3)+ granzyme+ TIA-1+ EBERT+ CD43(MT1)- CD45RO(UCHL-1)- CD57(Leu7)- CD20(L26)- phenotypes. In the two cases where tissue was available for immunohistochemical study in frozen sections, neoplastic cells showed CD56(Leu19)+ perforin+ Fas ligand(FasL)+ CD2(Leu5b)- CD3(Leu4)- CD4(Leu3)- CD5(Leu1)- CD7(Leu9)- CD8(Leu2)- betaF1- TCRdelta1- phenotypes. CD16(Leu11b) was positive in one case. : Natural killer cell lymphomas appear to represent a non-leukaemic counterpart of aggressive natural killer cell leukaemia, a relationship similar to that in adult T-cell leukaemia/lymphoma. Awareness and diagnosis of this aggressive lymphoma is important because of its fulminant course.
    Histopathology 11/2000; 37(4):363-71. DOI:10.1046/j.1365-2559.2000.00936.x · 3.45 Impact Factor
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    ABSTRACT: The neural cell adhesion molecule, CD56, is expressed on acute myelogenous leukemia (AML) cells in 17-20% of the patients. However, the clinical and biological significance of its expression in AML has not been well analyzed from the standpoint of CD56 expression and its association with differentiation to a natural killer (NK) cell lineage. Here we present a 78-year-old patient with chronic myelomonocytic leukemia (CMML) whose leukemic cells had features of both monocytes and NK cells. We demonstrated that the leukemic cells were positive for CD4, CD56 and interleukin-2 (IL-2) receptor beta chain (CD112) in addition to myelomonocytic markers such as CD33, CD11b and CD11c. These leukemic cells proliferated well in vitro in response to 10-100 U/ml of IL-2, and functionally showed significant cytotoxicity against K562 target cells in a 4-hour (51) Cr release assay. All the above data indicate that these cells possessed at least some of the biological features of NK cells. Accordingly, we speculate that the leukemic cells in this patient may have been derived from a possible common progenitor of monocytes and NK cells.
    Leukemia and Lymphoma 06/2000; 37(5-6):617-21. DOI:10.3109/10428190009058515 · 2.89 Impact Factor
  • K Watanabe · Y Yamashita · A Nakayama · Y Hasegawa · H Kojima · T Nagasawa · N Mori ·
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    ABSTRACT: Recent analyses have suggested that Hodgkin's or Reed-Sternberg (HRS) cells in most cases of classic Hodgkin's disease are derived from germinal centre B-cells. However, there is controversy over which B-cell antigens are expressed in HRS cells. We studied 51 cases of classic Hodgkin's disease to immunohistochemically characterize HRS cells for pan-B-cell markers and specific markers for plasma cells. HRS cells expressed CD20 (L26) in 18 cases (35%), CD19 (B4) in nine (18%) and CD79a (mb-1) in 13 (25%). Furthermore, HRS cells were positive for CD138 (B-B4) in 24 cases (45%) and for PCA-1 in 24 (45%). In 41 (80%) cases, HRS cells expressed more than one B-cell marker. We then subclassified cases into those positive for plasma cell markers (n = 27) (group 1) and those negative for them (n = 24) (group 2). The average age in group 1 (40 years) was younger than in group 2 (54 years) (P < 0.05). The percentage of nodular sclerosis (NS) subtype in group 1 (52%) was 1.5 times greater than in group 2 (33%) (P < 0.05). With regard to Epstein-Barr virus encoded small RNA (EBER) in-situ hybridization, 14 cases (64%) were positive in group 2, but only seven cases (31%) were positive in group 1 (P < 0.025). In most cases of classic Hodgkin's disease, HRS cells expressed later stage of B-cell development. We consider that two different clinicopathological groups may correlate with the two different expressions of B-cell markers.
    Histopathology 04/2000; 36(4):353-61. DOI:10.1046/j.1365-2559.2000.00830.x · 3.45 Impact Factor
  • Y Hasegawa · A Bai · H Kojima · T Komeno · H Ninomiya · T Nagasawa ·
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    ABSTRACT: Two elderly patients with chronic myelomonocytic leukemia were treated with cytosine arabinoside (Ara-C) and aclarubicin (ACR) under simultaneous administrations of macrophage colony-stimulating factor (M-CSF) (CAM), and both obtained good responses. Examination of apoptosis using flow cytometry revealed induction of apoptotic death of leukemia cells by CAM in Patient 2, while neither induction of apoptotic death of leukemia cells nor clinical response were seen with CAG (Ara-C, ACR, and granulocyte colony-stimulating factor) given prior to CAM in Patient 1. These findings suggested that chemotherapy combined with simultaneous administration of M-CSF could effectively reduce monocytic leukemia cells by inducing programmed cell death.
    Leukemia and Lymphoma 03/2000; 36(5-6):589-93. DOI:10.3109/10428190009148407 · 2.89 Impact Factor
  • Y Hasegawa · T Nagasawa ·