Familial polycythemia vera in father and daughter.
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Adult↗
Biomedical subjects
C Shimazaki
Publications and source records attributed to C Shimazaki.
t(7;11) and trilineage myelodysplasia in acute myelomonocytic leukemia.
A 48-year-old Japanese man was admitted to our hospital because of general fatigue, nasal bleeding, and petechiae on his extremities. He was diagnosed with acute myelomonocytic leukemia with trilineage myelodysplasia (T-MDS). Chromosomal analysis of bone marrow cells revealed t(7;11)(p15;p15), which has been rarely reported but known to be characteristic of Japanese patients. Although t(7;11)(p15;p15) has been reported mainly in acute myelogenous leukemia (AML), it can be occasionally found in so-called stem cell diseases such as chronic myelogenous leukemia or chronic myeloproliferative disorders. Therefore, t(7;11)(p15;p15) might affect trilineage progenitors or stem cells as well as myeloid lineage cells, subsequently resulting in AML with T-MDS, as in our case reported here.
Antineoplastic Combined Chemotherapy Protocols↗
Expression of adhesion molecules on myeloma cells.
We investigated the expression of adhesion molecules including LFA-1 alpha (CD11a), Mac-1 (CD11b), LFA-1 beta (CD18), VLA-beta 1 (CD29), H-CAM (CD44), VLA-4 (CD49d), VLA-5 (CD49e), ICAM-1 (CD54), N-CAM (CD56), LFA-3 (CD58), VNR-beta (CD61), and LECAM-1 (CD62L) on fresh myeloma cells and human myeloma cell lines. By two-color flow cytometric analysis with anti-CD38 antibody, we demonstrated that myeloma cells were located in the strongly CD38-positive (CD38++) fractions. Fresh myeloma cells were obtained from 28 patients with multiple myeloma (MM) and 3 patients with plasma cell leukemia (PCL). All myeloma cells expressed VLA-4 on their surface. Most of the myeloma cells also expressed VLA-5, ICAM-1, and LFA-3, H-CAM was strongly expressed in 3 cases of PCL and 2 cases of aggressive myeloma, and moderately expressed in other MMs. N-CAM was expressed in 68% of MMs, but none of the 3 PCLs. LFA-1 was expressed in two cases of aggressive myeloma, but not expressed in other non-aggressive myelomas. Most of the myeloma cells did not express Mac-1, VNR-beta, or LECAM-1. These results suggest that VLA-4, VLA-5, ICAM-1, LFA-3, and H-CAM are involved in cellular interaction and migration in MM, and that the expression of N-CAM and LFA-1 varies with disease activity in MM.
ADP-ribosyl Cyclase↗
[Mobilization and collection of peripheral blood stem cells].
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Antineoplastic Agents↗
[Natural killer cell lymphoma having a nodular shadow in the lung as an initial finding, developed to leukemia complicated with hemophagocytic syndrome at the time of relapse].
A 57-year-old female was admitted to Uji hospital for the further evaluation of nodular shadow on her right lung. During the period of admission, she developed cervical lymph node swelling. She was diagnosed as having malignant lymphoma (diffuse, small cleaved cell) by lymph node biopsy. She received combined chemotherapy and obtained partial remission for seven months until she developed fever and pancytopenia. Laboratory data showed increased number of large granular lymphocytes (LGLs) in blood. Bone marrow revealed increased number of LGLs with hemophagocytosis by macrophage. Surface marker analysis revealed LGLs were positive for CD2 CD16, and CD56 and negative for CD3, CD4, CD8, and CD20. T-cell receptor genes beta and gamma were in germ line configuration. Analysis of Epstein-Barr virus genome using termini probe indicated a monoclonal proliferation of LGLs. Reexamination of the biopsy specimen of lymph node revealed LGLs which was negative for CD3 and CD20. The patient was diagnosed as a leukemic phase of natural killer (NK) cell lymphoma complicated with hemophagocytic syndrome (HPS). Serum levels of interferon-gamma, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and interleukin-6 increased, which might be related to HPS.
Antigens, CD↗
[Three cases of secondary acute myeloid leukemia after long-term treatment with oral etoposide].
Three cases of secondary acute myeloid leukemia (AML) that developed after long term treatment with oral etoposide were reported. Case 1 was a 72-year-old male in whom small cell lung cancer was diagnosed in January 1987. He developed AML (M4) in February 1993 after long-term treatment with oral etoposide (total dose 14,650 mg) t(9; 11) (p21; q23) with rearrangement of MLL genes was recognized. Case 2 was a 68-year-old female non-Hodgkin's lymphoma (NHL) was diagnosed in February 1989. AML (M4Eo) with inv(16) (p13q22) developed in March 1994 after long-term treatment with oral etoposide (total dose 5,100 mg). Case 3 was a 39-year-old male in whom NHL was diagnosed in January 1991. He developed AML(M2) with t(11; 19) (q23; p13) in May 1994 after long-term treatment with oral etoposide (total dose 20,450 mg). These three cases suggest that long-term treatment with oral etoposide may be associated with a risk of developing a secondary AML in patient with malignancies.
Administration, Oral↗
Translocations and amplification of the BCL2 gene are detected in interphase nuclei of non-Hodgkin's lymphoma by in situ hybridization with yeast artificial chromosome clones.
Translocation of the BCL2 gene in B-cell malignancies carrying t(14;18) and amplification of the BCL2 gene in a cell line (HBL-2) derived from a non-Hodgkin's lymphoma (NHL) were detected specifically in both metaphase spreads and interphase nuclei by fluorescence in situ hybridization (FISH) using yeast artificial chromosomes (YACs). A YAC clone containing the BCL2 gene yA153A6, a 360-kb clone spanning from approximately 60 kb upstream of BCL2 exon 1 to approximately 60 kb 3' of the minor breakpoint cluster region, was used for single-color FISH analysis. Seven patients with NHL and one patient with acute lymphoblastic leukemia were analyzed for BCL2 translocations. Interphase nuclei of NHL patients showed three signals when hybridized with the yA153A6 probe. This was expected because the YAC clone spans the BCL2 breakpoint regions on 18q21.3. In a patient with acute lymphoblastic leukemia, a positive signal for BCL2 was detected on der(14) at band 14q32.33 by single-color FISH with the yA153A6 probe, whereas no signals were detected on der(18). The amplification of BCL2 in the HBL-2 cell line was observed on a characteristic abnormal chromosome 18, add(18)(q23); the periodic pattern of the fluorescent signal of this region was suggestive of an amplicon. Using double-color FISH with YAC clones containing the more centromeric 18q21.3 gene gastrin-releasing peptide (y302F10) and the 14q32.33 gene (IgH; Y6), we detected t(14;18) by showing the juxtaposition of the 18q21.3 and 14q32.33 bands on the derivative chromosome 18. Interphase FISH with these YAC clones provided a rapid procedure for the diagnosis of B-cell malignancies carrying t(14;18). In addition, we showed that translocations and amplification of the BCL2 gene can be detected at the single-cell level.
Adult↗
Loss of the cyclin-dependent kinase 4-inhibitor (p16; MTS1) gene is frequent in and highly specific to lymphoid tumors in primary human hematopoietic malignancies.
The cyclin-dependent kinase 4-inhibitor (CDK41; p16; or MTS1) gene has been proposed as a candidate for a tumor-suppressor gene located in chromosome 9p21, a frequently deleted region in a wide spectrum of human cancers, including leukemias. Recent studies disclosed that it was frequently deleted or mutated in a variety of primary human cancers, including acute lymphoblastic leukemia. The purpose of this study is to figure out the precise manners and frequencies of p16 gene inactivation in diverse hematopoietic tumor types and thus to clarify its significance in development of human hematopoietic malignancies. A total of 410 tumor specimens from patients with primary hematopoietic malignancies were examined for deletions of the p16 gene as well as the neighboring p15 gene and the nearby interferon alpha gene by Southern blot analysis. Tumor-specific mutations or small deletions of the p16 gene were also studied in 74 patients using single-strand conformation polymorphism analysis and direct sequencing. Loss of the p16 gene was most frequently observed among the three genes examined and was found in 59 of the 410 patients: 2 of 134 with acute myelocytic leukemia, 41 of 105 with acute lymphocytic leukemia, 2 of 15 with chronic lymphocytic leukemia, 5 of 14 with adult T-cell leukemia, 4 of 33 with non-Hodgkin's lymphoma, 3 of 8 with mixed-lineage leukemia, and 2 of 61 with chronic myelocytic leukemia. In 16 of the 59 patients, the p16 deletions occurred due to rearrangements within the small region between the p15 exon 2 and the p16 exon 2. Tumor-specific mutations or small deletions of the p16 gene were not detected in the 74 patients examined, including 12 of 14 patients with hemizygous deletions of the gene. Loss of the p16 gene is frequent in and highly specific to lymphoid malignancies (54 of 183 [30%] in lymphoid tumor v2 of 219 [1%] in myeloid tumors; P < .0001). The deletion analyses strongly suggest that the p16 gene is a tumor-suppressor gene located in chromosome 9p21 that is involved in development of human lymphoid tumors. Gene deletions but not minute mutations should be the predominant mechanism of p16 gene inactivation in these types of tumors.
Adolescent↗
[Various immunoproliferative disorders].
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Cryoglobulinemia↗
Mobilization of peripheral blood progenitor cells by high-dose Ara C, VP-16 and recombinant human granulocyte colony-stimulating factor: factors affecting progenitor cell yields.
Forty seven patients with hematological malignancies were treated with high doses of cytosine arabinoside (Ara C; 12 g/m2) and etoposide (VP-16), followed by recombinant human granulocyte colony-stimulating factor (rhG-CSF; 50 micrograms/m2). Peripheral blood progenitor cells (PBPC) were collected during rapid leukocyte recovery using a CS-3000 blood cell separator. A blood volume of 9 liters was processed in each apheresis, with 162 apheresis procedures performed. The mean numbers of mononuclear cells (MNC) and colony-forming unit granulocyte-macrophage (CFU-GM) harvested per apheresis were 4.4 x 10(8)/kg and 142.5 x 10(4)/kg, respectively. A sufficient number of CFU-GM for engraftment (> 30 x 10(4)/kg) could be harvested by a single apheresis in 35 of 47 patients (74%). Various factors that influence the collection of progenitor cells were analyzed by univariate and multivariate analyses. The number and duration of previous chemotherapy cycles were the most significant factors affecting CFU-GM yield. In patients with malignant lymphoma, age also had an influence in addition to these two factors. MNC harvested had an impact on CFU-GM yields by univariate analysis. These observations suggest that high-dose Ara C plus VP-16 followed by G-CSF is an effective regimen for harvesting PBPC. PBPC should be collected in the early stage of first-line chemotherapy.
Adolescent↗
Isoforms of PML-retinoic acid receptor alpha fused transcripts affect neither clinical features of acute promyelocytic leukemia nor prognosis after treatment with all-trans retinoic acid. The Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho).
All-trans retinoic acid (ATRA) has been used as a potent differentiation drug for acute promyelocytic leukemia (APL). Although the mechanism of its effectiveness upon APL remains unclear, the PML-retinoic acid receptor alpha (RARA) chimeric protein produced by t(15;17) is assumed to underlie the sensitivity of APL cells to ATRA. There are two major isoforms of PML-RARA transcripts; short (S) and long (L), according to the breakpoints in the PML gene. We therefore compared the clinical variables, the response to ATRA and the prognosis between 28 patients with type S and 68 patients with type L. Patients were treated in multi-institutional trials with ATRA, and chemotherapy was combined when peripheral blasts and leukocyte counts increased during the therapy. The clinical features at diagnosis were similar between the two molecular subtypes, and there was no significant difference in remission induction rates; 86% for the type S group and 90% for the type L group. There was no statistical difference in overall survival and CR duration as well as disease-free survival (DFS). In newly diagnosed patients, predicted 2-year DFS was 66% for the type S group and 67% for the type L group. In refractory or relapsed patients, it was 19 and 23%, respectively. These data indicated that isoforms of PML-RARA fused transcripts affect neither the clinical features of APL nor the prognosis after treatment with ATRA.
Adolescent↗
Establishment of a novel myeloma cell line KPMM2 carrying t(3;14)(q21;q32), which proliferates specifically in response to interleukin-6 through an autocrine mechanism.
We established a new human myeloma cell line, KPMM2, which proliferates specifically in response to IL-6 via an autocrine mechanism. The proliferative response of KPMM2 cells to exogenous IL-6 was significantly stimulated in a dose-dependent manner. The growth was markedly inhibited by an anti-IL-6 mAb and an anti-IL-6 receptor (IL-6R) mAb in a dose-dependent manner. KPMM2 cells expressed IL-6 and IL-6R mRNA by RT-PCR. Flow cytometric analysis showed cell surface expression of IL-6R. IL-6 protein was detected in the culture supernatant by ELISA. IL-11, oncostatin M and leukemia inhibitory factor had no effect on the proliferation of KPMM2 cells although interferon-alpha and interferon-gamma inhibited the growth. Furthermore, KPMM2 cells bore a t(3;14)(q21;q32) translocation and this finding is of potential interest for future studies in the light of the nuclear protein BM28 (CDCL1, for cdc-like 1) mapped on 3q21, which plays an important role in the cell cycle. In this report, we demonstrated completely an IL-6-dependent autocrine growth mechanism in KPMM2 cell line. This cell line may be useful to investigate the pathogenesis of multiple myeloma and to evaluate the therapeutic potential of IL-6 blocking agents in vitro and in vivo.
Aged↗
Serum levels of endogenous and exogenous granulocyte colony-stimulating factor after autologous blood stem cell transplantation.
Although the administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) enhances myeloid engraftment and reduces infectious morbidity after autologous and allogeneic bone marrow transplantations, the effect of rhG-CSF on neutrophil recovery in autologous blood stem cell transplantation (ABSCT) is controversial. We previously demonstrated that a low dose, delivered subcutaneously, of rhG-CSF (50 micrograms/m2) accelerates neutrophil recovery in ABSCT, but the optimal dosage of rhG-CSF is not known. To elucidate the effect of rhG-CSF on neutrophil recovery, we determined serum levels of endogenous and exogenously administered G-CSF in 24 patients receiving ABSCT. Of these, five received bolus subcutaneous injection of 50 micrograms/m2 rhG-CSF, 10 received 150 micrograms/m2, and nine received no rhG-CSF. Endogenous G-CSF levels rose immediately after ABSCT, and an inverse correlation was found between the serum level of G-CSF and the absolute neutrophil count (r = -0.73, p < 0.01). The pre-dose level in patients receiving rhG-CSF rose gradually, reaching a maximum between days 3 and 6. The level gradually decreased as the neutrophil count began to rise, even through administration of the same dose of rhG-CSF continued. Pharmacokinetic data showed that the half-life of elimination of G-CSF (t1/2) exceeded 15 hours during severe neutropenia but decreased during the recovery of neutrophils. These observations suggest that neutrophils provide a negative feedback mechanism for clearing G-CSF from the circulation. Pre-dose levels of G-CSF in patients receiving 50 micrograms/m2 rhG-CSF reached 10 ng/mL, equivalent to the concentrations used in clonogenic assay in vitro to stimulate myeloid progenitor cells.
Adolescent↗
Nonrandom chromosomal rearrangements of 14q32.3 and 19p13.3 and preferential deletion of 1p in 21 patients with multiple myeloma and plasma cell leukemia.
Structural chromosomal abnormalities and their break-points were characterized in 17 patients with multiple myeloma (MM) and 4 with plasma cell leukemia by banding. Chromosome 14q32 translocations with a variety of partners were detected in 13 patients, and a variant translocation t(8;22)(q24.1;q11) was detected in 1. Three recurrent 14q32 translocations have been identified: t(6;14)(p21.1;q32.3) occurring in 3 cases, and t(11;14)(q13;q32.3) and t(14;18) (q32.3;q21.3) each occurring in 2 cases. Translocations t(1;14)(q21;q32.3), t(3;14)(p11;q32),t(7;14)(q11.2;q32.3), and t(11;14)(q23;q32.3) were found in each patient, whereas in the remaining 2 patients, partner chromosomes could not be determined. The band 19p13.3 was newly delineated as a recurrent breakpoint involved in translocations in MM. Chromosomes 1 and 6 were also commonly involved in structural abnormalities (14 and 10 patients, respectively), although no particular bands were noted. However, the short arm of chromosome 1 was preferentially involved in deletion, suggesting a certain antioncogene on 1p associated with the development of myeloma. In addition; fluorescence in situ hybridization was successfully applied to determine the nature of the structural abnormalities in a patient with t(8;22) translocation. The present findings suggest that there may be subsets of 14q32 translocations specific to MM.
Adult↗
IgE plasma cell leukemia successfully treated with combination VAD (vincristine, doxorubicin, dexamethasone) and MP (melphalan, prednisolone) followed by interferon-alpha.
A 69-year-old woman with IgE/kappa plasma cell leukemia (PCL) was treated with a sequential combination of VAD (vincristine, doxorubicin, dexamethasone) and MP (melphalan, prednisolone) followed by interferon-alpha (IFN alpha). A complete remission was achieved for 14 months. Maintenance therapy with IFN alpha has continued for an additional 10 months. IgE PCL is extremely rare. The biological characteristics of the myeloma cells, including surface marker, adhesion molecule, karyotype, DNA analysis, and the response to various cytokines, are presented.
Aged↗
Trichosporon cutaneum fungemia in patients with acute myeloblastic leukemia and measurement of serum D-arabinitol, Candida antigen (CAND-TEC), and beta-D-glucan.
Two patients with acute myeloblastic leukemia are described who developed fungemia due to Trichosporon cutaneum. Fungemia occurred at the leukocyte nadir following the administration of anti-cancer chemotherapy. One patient was cured but the other died. Both patients received prednisolone continuously and had central venous catheters in place for parenteral hyperalimentation. T. cutaneum isolates were resistant to 5-fluorocytosine and moderately susceptible to fluconazole. One case was complicated by endophthalmitis due to T. cutaneum; this is the second report of such a complication in the world. We investigated the serum levels of beta-D-glucan, D-arabinitol, and Candida antigen (CAND-TEC); beta-D-glucan was elevated in both cases, which suggests that simultaneous measurements of these laboratory values are useful for the diagnosis and possibly for the evaluation of therapy for this fungal infection.
Antigens, Fungal↗
Mouse anti-human interleukin-6 receptor monoclonal antibody inhibits proliferation of fresh human myeloma cells in vitro.
Interleukin-6 (IL-6) is a major growth factor in multiple myeloma. We investigated the effect of mouse anti-human IL-6 receptor monoclonal antibody (anti-IL-6R mAb) on the in vitro proliferation of freshly isolated myeloma cells from 21 patients to evaluate the therapeutic potential. The addition of anti-IL-6R mAb inhibited more than 30% of the spontaneous proliferation of myeloma cells in 9 of 21 cases in a dose- (0.1 to 20 micrograms/ml) and time-dependent manner. The inhibitory effects of anti-IL-6R mAb did not differ significantly from that of anti-IL-6 mAb, and were correlated with the extent of the response of myeloma cells to IL-6. Flow cytometric analysis showed that all myeloma cells expressed IL-6R, whose intensity was not correlated with either the extent of response of myeloma cells to IL-6 or the inhibitory effects of anti-IL-6R mAb on proliferation of myeloma cells. Although our study showed heterogeneity in the proliferative responses of myeloma cells to IL-6 and anti-IL-6R mAb, these observations suggest the possibility of using anti-IL-6R mAbs for treating some patients with multiple myeloma whose growth depends on IL-6.
Animals↗
Prognostic significance of loss of a chromosome 17p and p53 gene mutations in blast crisis of chronic myelogenous leukaemia.
In 31 cases of chronic myelogenous leukaemia (CML) we examined the prognostic significance of chromosomal loss of a 17p and p53 mutations at the onset of blast crisis (BC). p53 mutations were closely related to a shortened survival in CML-BC (P < 0.005 by the logrank test), whereas loss of a 17p by itself was not a poor prognostic indicator. The prognostic significance of loss of a 17p, however, emerged when combined with its predominance in the metaphases analysed. This predominance might easily and rapidly be screened by polymerase chain reaction-based analysis in about half of the cases.
Adolescent↗