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K Oshimi

Publications and source records attributed to K Oshimi.

At least 73 records · Page 4Linked to original sources
PubMed1997

The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis.

The lymphoproliferative disease of granular lymphocytes (LDGL), also referred to as LGL leukemia, is a heterogeneous disorder, but is clinically, morphologically, and immunologically distinct. Although LDGL has recently been included in the revised classification of lymphomas as an independent clinical entity, no consensus exists on the criteria to establish the diagnosis. The aim of this report was to refine the parameters needed to make the diagnosis of LDGL. We studied 11 patients with chronic granular lymphocytosis selected from among 195 cases observed by our institutions from three different geographic areas (North America, Europe, and Asia). These cases did not meet the current criteria for inclusion in LDGL, since all patients had less than 2,000 GL/microL. However, in each of these patients, we found evidence for expansion of a discrete GL population. Clonal rearrangement of the T-cell receptor (TCR) beta gene was found in peripheral blood mononuclear cells (PBMC) of all nine patients with CD3+ LDGL. Using recently generated monoclonal antibodies (MoAbs) against the TCR V beta gene regions, we identified a unique TCR V beta on GL from each of three patients studied. In two patients with CD3- LDGL, we also identified a restricted pattern of reactivity, by staining with MoAbs against p58 antigen found on normal natural killer (NK) cells. The clinical features of these 11 patients with relatively low absolute number of GL were similar to those reported previously for patients with greater than 2,000 GL/microL. These data demonstrate that newer techniques such as MoAbs against V beta gene regions and p58 molecules and molecular analyses are useful to identify expansions of discrete GL proliferations. Demonstration of an expansion of a restricted GL subset is evidence for the diagnosis of LDGL, even in patients with a relatively low GL count. Our results also contribute to distinguish between the end of normality and the beginning of pathology in the broad spectrum of GL lymphocytoses.

Aged↗
PubMed1997

Decreased or altered expression of the FHIT gene in human leukemias.

The FHIT (fragile histidine triad) gene on chromosome 3p14 is a candidate tumor suppressor gene, and its transcripts are shown to be abnormal in several human cancers. We examined 40 leukemia samples for the alterations of FHIT transcripts by reverse transcriptase-polymerase chain reaction (RT-PCR) and direct sequencing. Intact FHIT mRNA was not detected in two patients with acute myeloid leukemia (AML) and in one patient with chronic lymphocytic leukemia (CLL). The three cases expressed only an aberrant FHIT mRNA lacking exons 3 to 6 (FHIT delta 3-6 mRNA), which could encode a polypeptide of 13 amino acids. Southern blot analysis on two samples from these cases showed no rearrangements of the FHIT gene. Although intact FHIT mRNA was detected as the main band in the remaining 37 samples, 33 of them (14 of 14 AML, 11 of 13 chronic myeloid leukemia, five of five acute lymphocytic leukemia, and three of five CLL) expressed aberrant FHIT delta 3-6 mRNA. We barely detected the FHIT delta 3-6 mRNA in only one of 25 normal control samples. Our results suggest that loss of the normal FHIT function may be involved in the genesis of at least some human leukemias and that expression of aberrant FHIT transcripts is rather specific and frequent in leukemia samples.

Acid Anhydride Hydrolases↗
PubMed1997

Expression of the MDR1 and MDR3 gene products in acute and chronic leukemias.

We performed immunocytochemistry to detect mdr1 and mdr3 P-glycoproteins (P-gps) in 81 patients with acute and chronic leukemia, using the mdr1 P-gp-specific monoclonal antibody (MoAb) MRK16, and the mdr3 P-gp-specific MDR3M. Immunoreactivity for the mdr1 gene product was positive in 27 out of 81 (33%) patients. Immunoreactivity with the anti-mdr3 P-gp MoAb was positive in 20 out of 81 (25%) patients. Of 54 patients with acute leukemia, 17 (31%) were positive for mdr1 P-gp and 8 (15%) for mdr3 P-gp. A high proportion (60%) of patients with chronic lymphocytic leukemia (CLL) were mdr3 P-gp positive. Of the patients with granular-lymphocyte proliferative disorder (GLPD), a chronic T-cell or natural killer cell leukemia, 8/17 (47%) were positive for mdr1 P-gp and 6/17 (35%) for mdr3 P-gp. Of 23 patients with chronic leukemia (CLL and GLPD), 10 (37%) were positive for mdr1 P-gp and 12 (44%) for mdr3 P-gp. To clarify the function of the mdr3 P-gp, we examined the intracellular rhodamine123 (Rh123) levels of mdr1 P-gp-negative and mdr3 P-gp-positive leukemic cells from patients with acute lymphocytic leukaemia, on the addition of 10 microM cyclosporin A (CyA). The addition of CyA led to significant increases in intracellular Rh123 levels in mdr1 P-gp-negative and mdr3 P-gp-positive leukemic cells. Results of the assay for dye efflux suggested that the mdr3 P-gp has a role in drug resistance, and functional drug-efflux capacity. In 31 acute leukemia patients at initial diagnosis, mdr1 or mdr3 P-gp expression correlated significantly to an outcome of complete remission (CR). In 54 acute leukemia patients, exposure to precytotoxic agents correlated significantly to expression, with a significant higher number of patients mdr1 or mdr3 P-gp positive than negative. In the 54 patients with acute leukemia, mdr1 P-gp expression correlated to mdr3 P-gp expression significantly (p=0.0007). In the 27 patients with chronic leukemia (CLL and GLPD), mdr1 and mdr3 P-gp expression did not correlate to exposure to precytotoxic agents, nor did mdr1 P-gp expression correlate to mdr3 P-gp expression. It may be speculated that precytotoxic agents induced mdr1 and mdr3 P-gp expression in acute leukemia; however, in chronic leukemia, both P-gps were expressed independently of exposure to precytotoxic agents.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1997

Cyclophosphamide therapy for pure red cell aplasia associated with granular lymphocyte-proliferative disorders.

Granular lymphocytes have been characterized as cells with azurophilic granules in the cytoplasm. Patients with increased numbers of granular lymphocytes are designated as granular lymphocyte-proliferative disorders (GLPDs). A variety of haematological abnormalities are associated with T-cell-lineage GLPD. Among these, pure red cell aplasia is frequent, and adequate therapy is required. Seven patients with pure red cell aplasia, or a related condition complicating T-cell-lineage GLPD, were entered into this study. Cyclophosphamide was initiated at a daily oral dose of 100 mg. After 2 weeks the dose was reduced to 50 mg/d, and maintained at that dose. Cyclophosphamide was administered until the lymphocyte count was <1 x 10(9)/l and T-cell receptor-beta gene analysis was used to monitor the response to treatment. All the patients were successfully treated, irrespective of their former treatment. Clinical remission was associated with the disappearance of the abnormal granular lymphocyte clone, as detected by Southern blot hybridization analysis. Therapeutic responses began after 8 weeks, and clinical complete remissions were obtained after 6 months. Oral cyclophosphamide monotherapy can successfully treat the pure red cell aplasia associated with T-cell-lineage GLPD.

Adult↗
PubMed1997

T-cell lymphoma of CD3+CD4+CD56+granular lymphocytes with hemophagocytic syndrome.

A case of T-cell lymphoma of granular lymphocyte (GL) morphology and CD3+CD4+CD56+ phenotype is reported. The lymphoma originated in the subcutaneous tisse of the right thigh and subsequently infiltrated into various organs including the lymph nodes, peripheral blood, bone marrow, skin, lungs, liver, spleen, and peritoneal cavity, and the patient finally developed a hemophagocytic syndrome. The lymphoma cells were positive for CD2, CD3, CD4, and CD56, and negative for CD8, CD16, CD20, and CD57. An identical clonal rearrangement of the T-cell receptor beta chain genes was detected in cells from a lymph node, peripheral blood, and ascites fluid, indicating the monoclonal proliferation of T cells in such organs. This is a T-cell GL lymphoma, expressing the unusual phenotype of CD3+CD4+CD8-CD16-CD56+, which has not been previously reported. The development of hemophagocytic syndrome has also to our knowledge not previously been reported in T-cell GL lymphoma.

Aged↗
PubMed1997

Detection of proliferating cell nuclear antigen (PCNA) in peripheral blood mononuclear cells and sera of patients with malignant lymphoma.

Proliferating cell nuclear antigen (PCNA) was detected in the peripheral blood mononuclear cells (PBMC) of patients with malignant lymphoma (ML). Twenty-one of 27 patients with ML had PCNA expressing PBMC (5.25+/-4.75% cells), which tended to increase in the advanced clinical stage of ML. PCNA in PBMC extracts was detected in 11 of 16 patients (54.5+/-41.9 ng/ml). The percentage of PCNA-positive cells correlated significantly with the concentration of PCNA in PBMC extracts (P < 0.005). Serum PCNA was detected in 6 of 16 patients (160.1+/-141.1 ng/ml), but did not correlate with the number of PCNA-positive cells. In some cases, the concentration of serum PCNA increased after chemotherapy while the percent PCNA-positive cells decreased. Our finding indicate that detection of PCNA in PBMC appears to help monitoring the extent of disease in ML and the serum PCNA level may be used in therapeutic studies of lymphoma patients.

Biomarkers, Tumor↗
PubMed1996

Necrosis and apoptosis associated with distinct Ca2+ response patterns in target cells attacked by human natural killer cells.

1. During the process of cell death, rises in cytosolic Ca2+ concentration ([Ca2+]i) together with structural changes were investigated in target cells attacked by purified CD3-,CD16+ human natural killer (NK) cells. 2. In the target cell line K562, a rapid [Ca2+]i rise to 1-2 microM occurred a few minutes after NK cell-target cell contact, immediately followed by leakage of the Ca2+ indicator dye fura-2 from the cell. Cells were permeabilized, but their chromatin was not fragmented. The changes were basically consistent with those seen in necrosis induced by activated complement. 3. In the target cell line MOLT-4, which expressed the apoptosis-inducing surface antigen Fas much more strongly than K562, the majority of attacked cells displayed a [Ca2+]i rise to 0.7-1 microM followed by a slow decline, often associated with diminishing [Ca2+]i oscillations. As a whole, [Ca2+]i remained higher than 150 nM for at least 1.5-3 h (approximately 100 nM in control cells). 4. MOLT-4 cells attacked by NK cells became bubble shaped within 20 min of the main [Ca2+]i rise reaching its peak, and then both the cell and chromatin were fragmented into small pieces. These findings were basically consistent with those in apoptosis induced by a monoclonal antibody against the surface antigen Fas. 5. NK cells induced both necrosis and apoptosis in cell lines insensitive to NK cells in the presence of an antibody against the major histocompatibility complex class I (antibody-dependent cell-mediated cytotoxicity, ADCC). The distinct Ca2+ responses patterns described above corresponded to necrosis or apoptosis in different cells stimulated by the common ADCC pathway. 6. Human NK cells were found to be capable of inducing necrosis (membrane damage) or apoptosis (nuclear damage) depending on the target cell types. The characteristic Ca2+ response profile was a good indicator for distinguishing between the modes of cell death induced by the cytotoxicity of the killer cells.

Antibodies, Monoclonal↗
PubMed1996

Lymphoproliferative disorders of natural killer cells.

Natural killer (NK) cells are a distinct non-T, non-B lineage of lymphocytes that mediate major histocompatibility complex-unrestricted cytotoxicity. Morphologically they are large granular lymphocytes, and phenotypically they commonly express CD16 and CD56 antigens, without expressing cell surface CD3. Although the developmental pathway of NK cells is not fully understood, they arise from CD34+ hematopoietic stem cells and, at least in part, differentiate in the bone marrow. They gain byctoplasmic CD3 gamma delta epsilon zeta antigens during maturation, and lose cytoplasmic CD3 gamma delta epsilon thereafter until the terminal maturation. Lymphoproliferative disorders of NK cells include NK cell-lineage granular lymphocyte-proliferative disorders (NK-GLPD), NK-cell lymphoma, and acute leukemia of NK-cell lineage. NK-GLPD are relatively rare. Most patients exhibit a chronic indolent clinical course, and do not require specific treatment. However, some patients exhibit an aggressive clinical course, and die of the disease despite extensive chemotherapy. This aggressive type NK-GLPD is caused by Epstein-Barr virus (EBV). Patients with NK-cell lymphoma are rare, and often exhibit necrotic lesion and angiocentric morphology. This tumor is mainly found in the nasal tract, but the true incidence of NK-cell lymphoma in nasal lymphomas is not known. Probably many lymphomas arising from the nasal cavity, but not from paranasal sinuses, are of NK-cell lineage. NK-cell lymphoma is also caused by EBV, and is resistant to combination chemotherapy. Acute leukemia of NK-cell lineage is very rare. Several cases of acute lymphoblastic leukemia and a single case of blast crisis of chronic myelogenous leukemia have been documented to have leukemic blasts characteristic of NK cells. However, the precise lineage and differentiation stage of the leukemic blasts have not been delineated.

Acute Disease↗
PubMed1995

Mutations of the p53 gene in myelodysplastic syndrome and overt leukemia.

We analysed p53 mutations in 24 patients with myelodysplastic syndrome (MDS) and overt acute myeloid leukaemia after a period of MDS, using polymerase chain reaction-single strand conformation polymorphism analysis. In exons 5 to 8, mobility shifts were detected in five of the 24 patients. Sequence analysis was subsequently performed, and four missense mutations (16.7%) and one silent nucleotide substitution were identified. Patients harbouring mutations were characterized as having advanced disease. Loss of the wild type allele was observed in three of the four patients with missense mutations. No mobility shifts of the N-ras or FMS gene were detected in these four patients. We next analysed the correlation of the p53 mutations with the progression of MDS in three patients. The mutation was accompanied by the progression in two of the three patients. These findings suggest that mutations of the p53 gene are associated with progression in some cases of MDS, while being compatible with stable disease or clonal evolution in others.

Base Sequence↗
PubMed1995

Nasal natural killer (NK) cell lymphoma: report of a case with activated NK cells containing Epstein-Barr virus and expressing CD21 antigen, and comparative studies of their phenotype and cytotoxicity with normal NK cells.

Malignant lymphomas arising from the nasal cavity have been considered to be derived from T cells, but recent surface marker studies suggest that more than half of the lymphomas are derived from natural killer (NK) cells. Here we describe a case of nasal lymphoma whose lymphoma cells were identified as NK cells by morphological, phenotypic, immunogenotypic, and functional studies. We believe this is the first study with functional evidence of NK activity. When compared with normal freshly isolated NK cells or activated NK cells, the surface phenotypes and NK activity of the patient tumour cells were those of the activated, but not resting, NK cells. Also, Epstein-Barr virus (EBV) was detected in the tumour cells and the lymphoma cells were found to be monoclonally expanded. The patient's lymphoma cells also expressed EBV receptor CD21 (CR2) and CD30 (Ki-1) that have not been described on normal NK cells. We therefore examined highly enriched NK cells of normal donors, and found that some resting and/or activated NK cells express these antigens.

Antigens, CD↗
PubMed1995

Telomeric DNA in normal and leukemic blood cells.

We studied telomeric DNA in leukemic cells as well as in normal T cells, B cells, monocytes, polymorphonuclear leukocytes, and bone marrow hematopoietic progenitor cells. No marked differences were observed in the sizes of the telomeric repeats in the various populations of normal blood cells obtained from donors in their twenties to sixties, and the telomere length ranged between 8.5 and 9.0 kb. The leukemic cells of 12 patients with acute leukemia (seven with myeloid and five with lymphoid leukemia) showed a variable reduction in the length of telomeric DNA, ranging from 2.7 to 6.4 kb. The average telomere length was 4.8 and 4.7 kb in myeloid and lymphoid leukemia, respectively, while the telomere length in peripheral blood mononuclear cells obtained from the same patients during complete remission was 8.5 and 7.9 kb, respectively. When the same Southern blots were hybridized with Alu or alphoid sequences, no marked changes in the sizes of the repetitive DNA sequences were observed, indicating that the DNA abnormality in the leukemic cells was specific to the telomere region. Investigation of telomeric DNA changes may be helpful in determining the biological properties of leukemic cells.

Adult↗
PubMed1995

[Clinical course of a HIV-seropositive patient with thrombocytopenia and hypergammaglobulinemia who was initially screened by annual complete physical examination].

A 57-year-old man was admitted because of hypergammaglobulinemia which was initially pointed out by annual complete physical examination. No significant abnormal findings were observed except polyclonal hypergammaglobulinemia at that time (IgG; 2,662 mg/dl, IgA; 422 mg/dl). Seven months later, he has progressed to show thrombocytopenia. The laboratory data showing the reduction of peripheral CD 4-positive T cells (CD 4; 0.2 x 10(9)/l, CD 4/8 ratio; 0.19) and positive serum HIV antibody revealed that his hypergammaglobulinemia and thrombocytopenia were resulted from HIV infection. The peripheral platelet count decreased to 28 x 10(9)/l at minimal point, however, it recovered to 160 x 10(9)/l within 7 months without treatment. His good performance status has been still maintained over 4 years. His whole clinical course suggests that there is no significant correlation between peripheral platelet counts, serum gammaglobulin levels or the amounts of PAIgG in this case. This case proposes that we should also consider a possibility of HIV infection for the patients showing hypergammaglobulinemia.

HIV Seropositivity↗
PubMed1995

Abolition of suppressive effect of acute myeloid leukemia cells on normal granulocyte-macrophage colony formation induced by interleukin-5 associated with eosinophilic cell induction.

The effects of recombinant interleukin-5 (rIL-5) on leukemic blasts obtained from 22 acute myeloid leukemia (AML) patients were investigated. Recombinant IL-5 stimulated leukemic colony formation in the leukemic blasts of 50% of the patients (11/22), and in 7 of these 11 cell cultures leukemic eosinophilic colonies were induced. Eosinophilic cell induction was associated with cellular proliferation, that is, colony or cluster formation. Leukemic blasts cultured with rIL-5 and forming eosinophilic colonies no longer suppressed normal granulocyte-macrophage colony formation, suggesting that functional differentiation of these leukemic blasts took place. Induction of this type of functional differentiation of leukemic blasts may be of clinical value in promoting normal hematopoiesis.

Acute Disease↗
PubMed1995

[Characterization of peripheral blood natural killer (NK) cells in two patients with CD16+ CD56- NK cell-lineage granular lymphocyte-proliferative disorder].

In normal peripheral blood natural killer (NK) cells, the subset of CD16+ CD56+ cells is predominant, and that of CD16+ CD56- cells is rarely present. Because we have found the expansion of CD16+ CD56- NK cells in the peripheral blood of two patients with NK cell-lineage granular lymphocyte-proliferative disorders (NK-GLPD), the clinical findings and cellular characteristics of these patients were compared with those of CD16+ CD56+ NK-GLPD patients. Although CD16+ CD56- and CD16+ CD56+ NK-GLPD cells were morphologically different, clinical findings and courses, and NK activity did not differ significantly. Because strong NK activity was demonstrated in CD16+ CD56- NK-GLPD cells, the CD56 antigen, one of the adhesion molecules, did not seem to play a major role in NK cell-mediated cytotoxicity. The CD56 antigen is known to be more strongly expressed by immature NK cells than by mature NK cells. However, because interleukin 2-activated CD16+ CD56- NK-GLPD cells rapidly expressed the CD56 antigen, the degree of CD56 antigen expression did not always correlate with the maturity of NK cells.

Aged↗
PubMed1994

Expression of multidrug resistance P-glycoprotein on peripheral blood mononuclear cells of patients with granular lymphocyte-proliferative disorders.

The immunological findings and clinical course of 33 patients with granular lymphocyte-proliferative disorders (GLPD) are presented. Based on the surface phenotypes of peripheral blood granular lymphocytes (GL), the GLPD were divided into two groups, namely CD3+ T cell-lineage GLPD (T-GLPD) and CD3- CD16+ NK cell-lineage GLPD (NK-GLPD). Twenty-one patients had T-GLPD, and 12 had NK-GLPD. One patient with T-GLPD and two patients with NK-GLPD had progressive clinical courses and died of the disease despite receiving combination chemotherapy. Among eleven patients analysed for the expression of multidrug resistance P-glycoprotein, six of eight patients with T-GLPD and all three patients with NK-GLPD clearly expressed P-glycoprotein. Since patients with immature NK-GLPD appear to undergo a progressive clinical course, we suggest that therapeutic trials using P-glycoprotein blockers in addition to chemotherapy might be beneficial for such patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Cytotoxicity of cytokine-induced killer cells coated with bispecific antibody against acute myeloid leukemia cells.

Various types of cytokines have been used in in vitro experiments to generate cytokine-induced killer (CIK) cells that are reactive to patient acute myeloid leukemia (AML) cells. Of these CIK cells, interleukin-2 (IL-2)-activated peripheral blood mononuclear cells, i.e., lymphokine-activated killer (LAK) cells, with the initial addition of the anti-CD3 monoclonal antibody (T3 LAK cells), are the most potent cytotoxic lymphocytes, and have marked proliferative capacity. The cytotoxicity of such T3 LAK cells against CD13+ AML cells is further enhanced by the addition of anti-CD3 x anti-CD13 bispecific antibody (BsAb) during the cytotoxicity assay. The combined use of T3 LAK cells and the BsAb can be used for ex vivo purging of CD13+ AML cells in autologous bone marrow transplantation. Other cytokines, such as IL-7 or IL-7 in combination with IL-2, or newly identified cytokines, will also be tested in attempts to obtain more specific and more potent effector cells. Studies of methods to increase the susceptibility of AML cells to CIK are also required.

Acute Disease↗