Biomedical subjects
Publications and source records attributed to K Hirashima.
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In the treatment of severe infections complicated to blood dyscrasia, the efficacy and usefulness of fosfomycin (FOM) in combination with sulbactam (SBT)/cefoperazone (CPZ) were compared between patients receiving FOM in the first followed by SBT/CPZ (Group A) and those receiving both drugs simultaneously (Group B). The following results were obtained. 1. The efficacy rate was 56.3% for Group A and 47.9% for Group B, with no significant difference. 2. The efficacy for patients suspected of the presence of septicemia, the efficacy rate was 57.9% for Group A and 54.3% for Group B, with no significant difference. 3. As for underlying disease, patients with acute myelogenous leukemia were most prevailing. In these patients, the efficacy rate was 57.1% for Group A and 27.3% for Group B, with no statistically significant difference. However, the efficacy rate tended to be higher in Group A. 4. The administration of antibiotics was effective to restore the neutrophil count to 501/microliters or higher in 77.8% and 45.5% of the cases for Groups A and B, respectively, with significantly higher efficacy for Group A. 5. In the safety evaluation a total of 115 cases were included. Side effects and laboratory abnormalities were seen in 3 cases each, but none of them were serious in degree. From these results, it was confirmed that the combination therapy consisting of administration of FOM followed by SBT/CPZ with some interval is effective for severe infections complicated to blood dyscrasia.
Microcytic hypochromic red blood cells (RBC) were discovered in a 31 year-old Bangladeshi man. Additional laboratory data revealed only slight elevations of LDH and transaminase activities. The patient was clinically asymptomatic and showed no signs of anemia. On this basis, along with biochemical genetic analysis of hemoglobin, a diagnosis of hemoglobinopathy (HbE) was made. HbE is common in southeast Asia with over 30% of the population affected. Most people are asymptomatic. In northern Asia, including Japan, HbE is found in only 0.001% of the population. With ther recent influx of southeast Asians to Japan, care must be taken not to overlook the diagnosis of hemoglobinopathies.
A 56-year-old man was admitted to our hospital in September, 1996. Chromosomal translocation (15; 17) and a PT-PCR study for PML-RAR alpha mRNA were positive in bone marrow aspirates, and acute promyelocytic leukemia was diagnosed. After CR was obtained with all-trans retinoic acid (ATRA) followed up with chemotherapy, the RT-PCR became negative. When he was readmitted in April, 1997, skin eruption on his chest and extremities were observed. Specimens taken for biopsy revealed leukemia cutis, and RT-PCR became positive in the same specimen. Bone marrow PT-PCR was also positive without abnormal promyelocytes. Although he was treated with oral ATRA 80 mg/day again, no significant improvement in leukemia cutis was noted. After combined therapy with Ara-C and acularubicin, skin eruption disappeared and bone marrow RT-PCR became negative. A second CR was then obtained. Although it is unknown whether the administration of ATRA is related to extramedullary relapse or not, we recommend combined chemotherapy for such cases.
Cefpirome (CPR) and amikacin (AMK) were used concomitantly to treat infections complicated by hematological diseases. A total of 100 subjects were evaluated, and the allover efficacy rate was 72.0%. Acute leukemia was found in the largest number of patient, 55, followed by 12 cases of malignant lymphoma and 6 cases of chronic myelogenous leukemia. By type of infection, patients having suspected sepsis were the largest in number, being 50, and the efficacy rate was 68.0%. The efficacy rates for sepsis and pneumonia were 57.1% (7 cases) and 61.1% (18 cases), respectively. The efficacy rates by neutrophil counts before administration of CPR and AMK and at 7 days after administration were both 71.9% in the group of less than 500/microliter, both 60.0% in the group of less than 100/microliter. The efficacy rate was 75.0% in the group of granulocyte colony stimulating factor (G-CSF) concomitant usage, and 70.0% in the non-concomitant usage group. Concomitant treatment with CPR and AMK exhibited a high level of safety and efficacy rates in infections complicated by hematological diseases and high.
A 77-year-old woman with complaints of fever and systemic lymphadenopathy was admitted to our hospital on February 16, 1995. Serum IgM was elevated to 2,097 mg/dl. Lymph node biopsy showed diffuse infiltration with lymphoplasmacytoid cells. Thus, she was diagnosed as having Waldenström's macroglobulinemia. Considering her age and congestive heart failure, she was treated with oral administration of low-dose etoposide (25 mg/day). Splenomegaly and superficial lymphadenopathy disappeared after one course of therapy. Until her death due to pneumonia, complete remission continued for one year without any symptoms and adverse effects except for mild diarrhea. Low-dose etoposide therapy was considered to be well tolerated and useful for elderly patients with Waldenström's macroglobulinemia.
Bone marrow magnetic resonance imaging (MRI) was obtained in 48 patients with myelodysplastic syndrome (MDS) (35 cases) or aplastic anaemia (AA) (13 cases). The lower thoracic and lumbar spine were evaluated on sagittal plane using a 1.5 Tesla superconducting MR unit with a surface coil. Pulse sequence of STIRs (TR 2000 msec, TI 160 msec, TE 20 msec) were applied. Four distinct patterns of signal intensity (SI) on the STIR images were classified as follows: pattern 1, homogeneously low SI; 2, marginally high SI; 3, heterogeneously high SI; 4, homogeneously high SI. In all 13 patients with AA, STIR images initially revealed pattern 1. In 25 of 35 cases with MDS patients, the STIR images were initially classified as pattern 3. The STIR images of 6 AA and 5 MDS patients with a clinical response to treatment showed pattern 2 similar to that of normal marrow distribution. The STIR images of MDS patients showed an abnormal distribution of SI. Significant signal changes in the STIR images can be observed in successive examinations of the patients, thus facilitating follow-up of the disease and treatment. MRI of the bone marrow provides a noninvasive means of grossly examining a large fraction and is a useful technique in patients with aplastic anaemia or myelodysplastic syndrome.
A multicenter randomized controlled study was undertaken in order to determine whether epoetin beta (EPO) ameliorates the anemia in aplastic anemia (AA) patients treated with granulocyte colony-stimulating factor (G-CSF). Enrolled patients were randomized into 3 groups: group C receiving G-CSF alone as the control; group L receiving G-CSF and 200 IU/kg of EPO; group H receiving G-CSF and 400 IU/kg of EPO. Throughout the study, the dose and the administration interval of G-CSF were adjusted to maintain neutrophil counts between 1000 and 5000 microliters EPO was administered subcutaneously for 12 wk as the first step in treatment and when favorable effects were observed over this period, treatment was continued for another 12 wk as the second step in treatment. Significant erythroid responses were defined as increases in untransfused hemoglobin values > 1.0 g/dl or > 50% decreases in RBC transfusion requirements over the treatment period. Of 131 patients enrolled, 88 patients allocated to groups L and H were evaluated for toxicity to EPO and 110 were evaluated for erythroid responses. Four of the 31 patients (12.9%) in group C, 6 of the 41 patients (14.6%) of group L, and 14 of the 38 patients (36.8%) of group H showed erythroid responses in the first step in treatment. The erythroid responses of group H were significantly higher than those of the other 2 groups (p < 0.05). The significant effects of EPO were due to erythroid responses in non-severe AA. Responding patients were significantly different from non-responders with regard to disease severity, hemoglobin concentration, reticulocyte count, serum endogenous erythropoietin levels and serum transferrin receptors; non-severe AA patients were more likely to respond to EPO, and responding patients had lower serum EPO and higher hemoglobin concentration, reticulocyte count and serum transferrin receptors than non-responders. The response rate increased in the second step in treatment, suggesting that long-term treatment improved the efficacy of EPO. No serious side-effects were observed. From these results, we conclude that EPO given in combination with G-CSF is a safe and effective alternative for the treatment of anemia of a subset of AA patients.
We reported a 59-year-old woman who received a diagnosis of psoriasis vulgaris at the age of 35 and had been under medical treatment. She was admitted to our department on August 16, 1993 because of lymphadenopathy, arthralgia and neuralgia. We observed cervical and axillar lymphadenopathy 1-3 cm in diameter, anemia and leukothrombocytosis. Elevated levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and immunoglobulin G (IgG), but not M-protein were observed by immunological analysis of the serum. Bone marrow aspiration biopsy revealed hypercellularity with myeloid hyperplasia and slight increase in plasma cells. Elevated levels of serum interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF) were detected; IL-6 was 62.1 pg/ml and G-CSF was 66 pg/ml, but IL-1 alpha, IL-1 beta and TNF-alpha were within the normal range. Idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hyperimmunoglobulinemia was diagnosed by lymph-node biopsy and the patient received following treatment with prednisolone and hydroxyurea. Leukocytes, platelets and skin eruptions increased again when the steroid dose was tapered, so we changed treatments to MP (melphalan, prednisolone) therapy. In addition, various neurological abnormalities such as convulsions, loss of consciousness and peripheral polyneuritis were observed. Despite treatment her condition deteriorated and she finally died. Very few reports show these neurological abnormalities in IPL or Castleman's disease therefore we think this is a very rare case.
Cytokines regulate proliferation and differentiation of hematopoietic progenitor cells. Recently it has been clarified that physiological cell death, apoptosis plays important role of hematopoiesis. So we evaluated the effects of granulocyte-colony stimulating factor (G-CSF) on leukemic cells, especially focused on apoptosis. Intravenous inoculation of radiation-induced murine leukemia cell line, C2M-A5 into the parent C3H mice resulted in the development of myeloid leukemia. However, the leukemic death of the mice was completely suppressed by the daily subcutaneous injection of recombinant human (rh)G-CSF from the next day (Bessho M. et al., Leuk Res 1989:13:1001-1007). In the in vitro study using C2M-A5 cells, we found that apoptosis appears on the cells at 48 hours after addition of G-CSF in culture. The cells in this stage lost the leukemogenicity to C3H mice (Bessho M. et al., Leukemia 8:1185-1190:1994). To clarify the mechanism of the induction of apoptosis by G-CSF we studied cell cycle and molecular changes in C2M-A5 cells cultured in medium with or without rhG-CSF by means of using the flowcytometry and Northern and Western blot analyses. After addition of rh G-CSF to culture, C2M-A5 cells removed to S phase, next arrested at G0/G1 phase on and after 24 hours, and 48 hours later, apoptosis was observed. Overexpression of mRNAs for c-myc (3-24 hours later) and for p53 (6-24 hours later), were observed in the cell cultured in rhG-CSF administered medium with a concomitant down-expression of bcl-2 mRNA (from 6 hours later). Tyrosine-phosphorylated protein (17 kd) appeared at 48 hours after administration of rhG-CSF to cell culture. This protein was suggested for specific apoptosis induction by rhG-CSF. These results are summarized as follows. (1) rhG-CSF induced apoptosis to C2M-A5 and deprived its leukemogenicity to mice. (2) Induction of apoptosis was associated with cell cycle and correlated to the changes of the expression rates of c-myc,p53, and bcl-2. (3) Tyrosine kinase may play an important role in apoptosis induction to C2M-A5 by rhG-CSF.
A 51-year-old man was admitted to our hospital in December 1993, because of fatigue. Peripheral blood tests showed a WBC of 49,400/microliter with 36% plasma cells and 35% monocytes, Hb 14.5 g/dl, and Plt 137,000/microliter. Bone marrow aspirate revealed hypercellularity with 48.7% plasma cells and 22.4% monocytes. Plasma cells in blood were positive for CD38 and PCA-1. Serum calcium, IgA and M-CSF levels were elevated to 14.1 mg/dl, 2,337 mg/dl and 2.7 ng/ml, respectively. Immunoelectrophoresis of serum and urine revealed IgA lambda type M protein and lambda type Bence Jones protein, respectively. Rearrangements of immunoglobulin heavy chain and light chain were demonstrated by Southern blotting analysis. Plasma cell leukemia (IgA lambda type) was diagnosed. He was treated with combination chemotherapy and IFN-alpha and achieved complete remission. However, he suffered a meningeal relapse in February 1995, and died in April 1996. It seems likely that the enhanced production of M-CSF by myeloma cells and/ or activated B cells stimulated monocyte production.
We evaluated the effects of various hematopoietic growth factors (HGFs) on the prevention of apoptosis in blasts from 19 patients with acute myeloblastic leukemia (AML) by assessing DNA ladder formation. After incubation without HGF, apoptosis was noted in all but two patients. HGFs prevented, did not affect, or enhanced apoptosis in 39 (60%), 14 (22%), or 12 (18%) of 65 suspension cultures, respectively. HGFs that prevented apoptosis also stimulated and/or synergized blast colony formation in 35 of 39 corresponding methylcellulose cultures. HGFs that alone stimulated colony formation also prevented apoptosis in all but two of 28 corresponding suspension cultures. In contrast, HGFs that did not prevent apoptosis also failed to stimulate growth in 17 of 26 corresponding methylcellulose cultures. HGFs that enhanced apoptosis alone never stimulated colony formation. After incubation, we noted enhanced c-fos and cjun genes as well as induction of p21 protein. An appropriate dose of HGF elevated c-fos, reduced c-jun and p21, induced G1/S transition, and inhibited apoptosis. In two patients, apoptosis was not induced after incubation. Cells not treated with HGF expressed no c-fos, c-jun, or c-myc, and remained in G0/G1. Taken together, our results support the conclusion that not only c-fos, cjun, and c-myc, but also p53 and p21 are required for blast apoptosis. HGF differentially prevents apoptosis and induces mitosis, and both events seem to be integral to the self-renewal of AML clonogenic cells.
Deoxyspergualin (DSG) is an immunosuppresive agent of proven effectiveness in the prevention and treatment of transplant rejection; its most frequent side effect is reversible bone marrow suppression. To clarify the mechanisms of bone marrow suppression induced by DSG, we monitored the numbers of peripheral blood and marrow stem cells in C3H/HeN mice receiving 14 days of DSG injections at a highly immunosuppressive dose of 10 mg/kg/day. In the peripheral blood cells, DSG induced severe anemia and mild leukopenia because of a decrease in granulocyte counts, although these phenomena were reversible. During DSG administration, nucleated cell counts in the femur also markedly decreased, whereas the absolute numbers of various stem cells and progenitor cells, except for erythroid colony-forming units (CFU-E), remained normal or increased; CD34- or c-kit-positive and lineage-negative cell levels markedly increased on the day DSG administration ceased. These findings indicate that DSG-induced anemia and leukopenia are not initiated by a generalized killing of these stem cells, but rather by a transient suppression of their ability to mature. Significantly, the severe anemia induced by DSG resembles pure red cell aplasia in humans, because there were marked decreases in peripheral reticulocytes, marrow CFU-E, and erythroblasts, with no decrease in renal erythropoietin mRNA expression. Furthermore, DSG-induced anemia was completely ameliorated by treatment with human recombinant erythropoietin.
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The stage-specific embryonic Ag-1 (SSEA-1) is a carbohydrate Ag and regarded as an onco-developmental Ag. Sialyl SSEA-1 Ag, the sialylated form of SSEA-1, is frequently expressed in human cancer cells as well as in murine cancer cells. A mAb, FH-6, was shown to specifically recognize the Ag. We have generated five anti-Id Abs directed to the paratope-related idiotopes of the FH-6 Ab. One of these anti-Id Abs, Id-F2, increased the survival of host mice that were inoculated with Meth-A cells expressing the sialyl SSEA-1 Ag. To clarify the exact mechanism underlying the antitumor effect of the anti-Id Ab, we established a T cell line that recognized Id-F2 in association with MHC class II molecules. The T cell line was CD4+V beta 8+, and produced IL-2, exhibiting helper activity for B cells. The VH CDR2 region of the Id-F2 amino acid sequences turned out to be strongly immunogenic to T cells. When the immune complexes, consisting of the sialyl SSEA-1 Ag, FH-6, and Id-F2, were formed at the Meth-A cell-surface, the T cell line showed a strong proliferative response. The possible roles played by such T cell subsets in the anti-tumor effect are discussed.
We demonstrated that tumor necrosis factor-alpha (TNF-alpha) rapidly and markedly enhances p21 gene and protein expression prior to monocytic differentiation and apoptosis in p53-null HL-60 cells. TNF-alpha induced early small and delayed large peaks of apoptosis at 6 and 48 h of incubation, respectively. At 24 h of incubation, apparent monocytic differentiation of the cells was noted. Down-regulation of c-myc and c-myb and G0/G1 arrest were observed at 6-12 and 36 h, respectively. Actinomycin D markedly inhibited TNF-alpha-induced p21 mRNA expression, suggesting that the p21 gene is induced at the transcriptional level. We confirmed that TNF-alpha induces p53-independent apoptosis in HL-60 cells, which accompanies monocytic differentiation.
The present multicenter study was performed to evaluate the effect of recombinant human granulocyte-colony stimulating factor (rhG-CSF) on combination therapy using aztreonam (AZT) and clindamycin (CLDM) to treat severe infection in neutropenic patients with hematologic diseases. Forty-three neutropenic patients with infections (rhG-CSF group) were treated with AZT (2 g) and CLDM (600 mg) 2-3 times daily as well as rhG-CSF (Lenograstim or Filgrastim: 2-5 mu/kg/day). The clinical efficacy of this regimen was compared to that obtained in 44 febrile neutropenic patients, with hematologic diseases, who received only AZT and CLDM in a previous study (historical control group). The overall efficacy rate was 69.8% (30/43) in the rhG-CSF group and 65.9% (29/44) in the historical control group. Although the neutrophil count was significantly increased and C-reactive protein tended to be lower in the rhG-CSF group, the daily maximum body temperature profiles of the 2 groups were nearly the same. These results suggest that rhG-CSF is of little benefit in the treatment of single infectious episodes in neutropenic patients, and that appropriate antibiotic therapy is more important.
We demonstrated bundle formation of microtubules both in the cytoplasmic processes and in the cytoplasm near the nucleus of cultured megakaryocytes by means of electron and immunofluorescent microscopy. To determine whether this bundle formation was related to megakaryocyte maturation, we studied the effects of recombinant human interleukin-6 (rhIL-6) in vitro and in vivo on this event. About 75% of the megakaryocytes in the bone marrow had no fibrous microtubule structures in the cytoplasm (type I), and about 25% had bundles of microtubules (type II). The formation of these bundles was promoted by rhIL-6 both in vitro and in vivo. Considerably more megakaryocytes cultured with recombinant murine (rm) IL-3 and rhIL-6 became type II than those cultured with rmIL-3 alone. Megakaryocytes from mice given rhIL-6 (10 microg/animal/d) subcutaneously also began to form bundles in proportion to an increase in platelet counts. After the administration of rhIL-6, about half of the megakaryocytes contained microtubule bundles in their cytoplasm. These results indicate that microtubule-bundle formation is one maturational event in megakaryocyte development and that rhIL-6 could accelerate this event.