Therapy-related myelodysplastic syndrome with monosomy 5 after successful treatment of acute myeloid leukemia (M2)

We describe a patient who developed myelodysplastic syndrome over 2 years after achieving complete remission of acute myeloid leukemia (AML). The patient was treated in July 1998 with anthracycline, etoposide, and behenoyl cytarabine chemotherapy for AML (French-American-British classification, M2; World Health Organization classification, AML with maturation) and achieved complete remission. At presentation, no chromosomal abnormalities were detected. In December 2000, the patient's peripheral blood revealed pancytopenia, and his bone marrow was hypocellular with trilineage myelodysplasia and no blasts. Chromosomal analysis revealed complex karyotypic abnormalities, including monosomy 5. The patient was diagnosed with high-grade myelodysplastic syndrome (MDS)/refractory anemia with excess blasts (RAEB) subtype. The pancytopenia progressed rapidly, and he died 2 months after the diagnosis of MDS. Therapy-related MDS and AML (t-MDS/t-AML) developing after treatment for acute leukemia is unusual; the primary leukemia associated with most cases of t-MDS/t-AML is acute promyelocytic leukemia (APL). This unusual case suggests that AML excluding APL should be considered a primary hematologic malignancy for t-MDS/t-AML.     

The immunoregulation of rheumatoid factor by the CD8 T lymphocyte subset in rheumatoid arthritis.

Flow cytometric analysis on 81 peripheral blood samples from patients with rheumatoid arthritis (RA) showed that levels of serum IgM rheumatoid factor (RF) were associated with the CD8+ cell level. A significant elevation of natural killer (CD56) cell levels was also observed in RA peripheral blood. Using in vitro antibody production techniques, CD8+ cells from patients with RA appeared to act as suppressors of RF production. Paired blood and synovial fluid samples from 9 patients with RA indicated a significant increase in SF CD8+ cells and DR+ T cells over the corresponding peripheral blood levels. The data suggest that CD8+ cells in RA may respond to immunological abnormalities occurring during the course of the disease.     

Protein 4.1 deficiency and deletion of chromosome 20q are associated with acquired elliptocytosis in myelodysplastic syndrome

We report a case of myelodysplastic syndrome (MDS), associated with prominent elliptocytosis. A 66-year-old male presented with peripheral pancytopenia, and was diagnosed with MDS [refractory anaemia (RA)]. Apart from marked elliptocytosis, dyshaematopoietic features were not evident in his peripheral blood or hypercellular bone marrow. After 18 months, he had progressed to RA with excess blasts in transformation. Analysis of red blood cell membrane proteins by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) showed a reduced quantity of protein 4.1 (30% of control). Deletion of chromosome 20q was identified by conventional cytogenetic analysis and fluorescence in situ hybridization. Marked elliptocytosis, persistent for more than 17 months, decreased strikingly after chemotherapy with idarubicin and Ara-C. These findings suggest that acquired elliptocytosis occurred as an unusual morphological feature of MDS, associated with abnormalities of protein 4.1 and chromosome 20q.     

Disseminated mycobacterium avium-intracellulare infection in a patient with myelodysplastic syndrome (refractory anemia)

A 31-year-old woman presented with fever and arthralgla. Despite treatment with antimicrobials and cortlcosteroids, her symptoms persisted. A diagnosis of myelodysplastic syndrome (MDS)-refractory anemia (RA) was made by pancytopenia, dysplasia, and trisomy 8. Cultures of bone marrow, blood, and gastric juice showed Mycobacterium aviumintraceliuiare (MAI). She was treated with antimycobacterial drugs and recombinant human G-CSF/M-CSF and showed an initial response, but spike fever recurred and pancytopenia progressed. Hepatospienomegaly and marked retroperitoneal lymphade-nopathy were revealed, indicating further dissemination of MAI. Treatment with recombinant human GM-CSF and very-low-dose cytosine arabinoside, was started but was not effective. This case showed significant reduction in peripheral blood 1-lymphocytes, especially the CD4⁺ population, and low immunoglobulin levels. immunodeficiency state associated with long-term steroid therapy and MDS seemed to contribute to the development of the disseminated infection with MAI. © 1994 Wiley-Liss, Inc.     

Phenotypic abnormalities in CD8+ T lymphocyte subsets in patients with rheumatoid arthritis.

We analyzed the cell surface phenotype of CD8+ cells in both peripheral blood and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Utilizing the monoclonal antibodies anti-CD45RA, anti-CD29 and anti-S6F1-, one can define both suppressor effector (CD45RA+CD29-S6F1-) and killer effector (CD45RA-CD29+S6F1+) cells within the CD8 population. In patients with OA, normal proportions of CD8+CD45RA+, CD8+CD29+ and CD8+S6F1+ cells were found in both peripheral blood and SF. The peripheral blood of patients with RA, in contrast, showed a decreased percentage of CD8+CD45RA+ cells (13.4 +/- 2.6) (p less than 0.05), but a normal percentage of CD8+CD29+ and CD8+S6F1+ cells. In the SF of patients with RA, we observed a more dramatic decrease in CD8+CD45RA+ suppressor effector cells (6.4 +/- 5.0) (p less than 0.001), a significant increase in killer effector cells as measured by both CD8 + CD29+ (35.5 +/- 9.9) (p less than 0.001) and CD8 + S6F1+ cells (28.2 +/- 11.4) (p less than 0.01). These changes may contribute to the immunologic abnormalities previously noted in this disease and may provide some insight into the pathophysiologic mechanisms of RA.     

Myelodysplastic syndrome with complex chromosome abnormalities and peculiar fibril formation in granulocytes

We report a case of myelodysplastic syndrome with peculiar fibril formation in granulocytes shown through electron microscope and complex karyotypic abnormalities including ring chromosomes. The patient, a 76-year-old male, was consulted for mild pancytopenia in February 1987. After 5 month, his hematological findings showed severe pancytopenia getting worse rapidly and presence of blasts in the peripheral blood. He had slightly hypercellular marrow with marked trilineage dysplasia and increased number of blasts (12.6%). Chromosome analysis from the bone marrow cells revealed its various structural abnormalities, especially in No. 3, 4, 5, 7, 11 with translocation on 11q11, and large ring chromosomes derived from unknown one. By electron microscopic study, we observed bizarre structures, which was peculiar fibril formation as bundles of filament resembling actin paracrystals, throughout cytoplasm as well as within nucleus in granulocytes.     

Establishment and characterization of a new human eosinophilic leukemia cell line

A human eosinophilic leukemia cell line, designated as EoL, was established from the peripheral blood of a patient with Philadelphia chromosome-negative eosinophilic leukemia (EL). The EoL cell line grows in single cell suspension with a doubling time of 48 hours for about one year. The reactivity of these cells was tested with a panel of monoclonal antibodies; they were found to express surface IA antigen, myeloid antigen (IF10, MY9) and membrane receptors for interleukin 2 (IL-2, Tac antigen). Under standard culture conditions, a small percentage of cells having more typical eosinophilic characteristics was present. These cells had cytoplasmic granules and were positive for Luxol-fast-blue and eosinophil peroxidase. Under culture conditions to induce the maturation of myeloid cells, such as alkaline medium or addition of dimethyl sulfoxide (DMSO), the frequency of cells with typical eosinophilic features increased to about 40%. In addition, cytogenetic studies showed that cultured cells and original leukemic blasts presented similar chromosome abnormalities. EoL seems to be a unique leukemic line committed to the eosinophilic lineage and can provide a useful in vitro model for the study of malignant eosinophilic properties.     

Evidence of a local intestinal immunomodulatory effect of sulfasalazine in rheumatoid arthritis

Objective. To analyze whether the intestinal mucosa in rheumatoid arthritis (RA) is immnunologically abnormal and whether sulfasalazine (SSZ) possesses any local intestinal immunoregulatory effect. Methods. Lymphocyte subpopulations and HLA—DR expression were evaluated in biopsy specimens from the duodenal—jejunal mucosa and in peripheral blood samples obtained from 17 patients with RA, both before and after 16 weeks of SSZ treatment. The same mucosal assays were also performed in 7 controls. Results. The mucosa of the small intestine in RA patients showed no differences in morphology, HLA—DR expression, or the amounts and distribution of CD3+, CD4+, CD8+, and γ/δ+ lymphocytes compared with the control group. However, there was a reduction in mucosal CD3+ and γ/δ+ lymphocyte numbers after SSZ therapy, which did not correspond to a change in peripheral blood CD3+ lymphocyte number. SSZ treatment also tended to diminish the peripheral blood CD4+:CD8+ cell ratio (P = 0.05). Conclusion. No signs of inflammation or immunologic abnormalities were seen in RA duodenal-jejunal mucosa. In this part of the intestine, however, SSZ exerted immunoregulatory effects that were not encountered in the peripheral blood.     

Complex karyotypic abnormality in an aged patient with acute myeloid leukemia (M 2)

A 74-year-old man was admitted on November 1986 because of general fatigue. His peripheral blood showed pancytopenia without immature cells since December 1985. Hematological data showed RBC 150 X 10(4)/microliter, PLT 7,000/microliter, WBC 12,000/microliter with 93.6% leukemic cells. The bone marrow smear revealed NCC 14.5 x 10(4)/microliter with 76% leukemic cells. The leukemic cells were characterized by faint staining with peroxidase stain and strong positivity for CD 13 antigen determined with immunoperoxidase method and flow cytometric analysis. The chromosomal analysis of tumor cells represented as follows: 44, XY, -3, -4, -9, -20, 2q+, 6p-, 7q-, 12q+, +2 mar. Although remarkable reduction of leukemic cells in peripheral blood was obtained one month after initiation of 19-days intravenous continuous infusion of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), he suffered from severe systemic candida infection with severe leukopenia and died. Not only advanced age but also complex karyotypic abnormality would contribute to failure of treatment in this case. The significance of complex karyotypic abnormality in acute non-lymphocytic leukemia in discussed based on the current literature.     

Myelodysplasitic syndrome in two young brothers

Summary. We report the youngest cases of myelodysplastic syndrome (MDS) in two brothers aged 7 and 2 years. The maternal grandfather and maternal grandmother had been exposed to radioactive fallout after the atomic bomb attack on Hiroshima in 1945. The elder brother demonstrated pancytopenia with <1% blast cells in his peripheral blood and <5% in his bone marrow at diagnosis. The younger brother was thrombocytopenic without increased blasts. The karyotype of bone marrow cells from the elder brother was 46, XY, ?7, +der (7), t(1:7) (lqter-lq11:: 7q11–7pter), but the younger brother's karyotype was normal. Immature myeloid cells in the bone marrow from both brothers were morphologically abnormal. A diagnosis of refractory anaemia (RA) was made in both brothers. Atavism due to radioactive poisoning was suspected in the development of MDS in these two cases.     

CD7- T cells in rheumatoid arthritis.

OBJECTIVE. Rheumatoid arthritis (RA) is characterized by decreased expression of CD7 in the peripheral blood and in the synovium. The present study was designed to identify the basis for and functional consequences of this decreased expression. METHODS. Peripheral blood lymphocytes from normal controls and from patients with RA or systemic lupus erythematosus (SLE), and T cell lines derived from rheumatoid synovium, were evaluated using 3-color fluorescence-activated cell sorter analysis. RESULTS. Normal subjects and most SLE patients expressed homogeneous, bright CD7 on CD4+, CD45RA+ cells, whereas RA patients demonstrated a significantly increased proportion of CD7- cells. T cell lines derived from rheumatoid synovium demonstrated a striking deficiency of CD7 on CD4+, CD45RA- cells. CD4+, CD45RA+ cells from RA patients changed phenotype after in vitro activation to CD45RA negativity, with up-regulation of CD7. CD7-, CD4+, CD45RA- cells were assessed for their ability to induce pokeweed mitogen-driven IgM and IgM-rheumatoid factor synthesis, and they were found to be potent helper/inducer cells. An increased population of CD7-, CD4+ cells in peripheral blood was found to predict a low response to recall antigens. CONCLUSION. The low expression of CD7 in RA may explain some of the immune abnormalities which may contribute to the pathogenesis of this disease.     

CD7– T cells in rheumatoid arthritis

Objective. Rheumatoid arthritis (RA) is characterized by decreased expression of CD7 in the peripheral blood and in the synovium. The present study was designed to identify the basis for and functional consequences of this decreased expression. Methods. Peripheral blood lymphocytes from normal controls and from patients with RA or systemic lupus erythematosus (SLE), and T cell lines derived from rheumatoid synovium, were evaluated using 3-color fluorescence-activated cell sorter analysis. Results. Normal subjects and most SLE patients expressed homogeneous, bright CD7 on CD4+, CD45RA+ cells, whereas RA patients demonstrated a significantly increased proportion of CD7– cells. T cell lines derived from rheumatoid synovium demonstrated a striking deficiency of CD7 on CD4+, CD45RA– cells. CD4+, CD45RA+ cells from RA patients changed phenotype after in vitro activation to CD45RA negativity, with up-regulation of CD7. CD7–, CD4+, CD45RA– cells were assessed for their ability to induce pokeweed mitogen-driven IgM and IgM-rheumatoid factor synthesis, and they were found to be potent helper/inducer cells. An increased population of CD7-, CD4+ cells in peripheral blood was found to predict a low response to recall antigens. Conclusion. The low expression of CD7 in RA may explain some of the immune abnormalities which may contribute to the pathogenesis of this disease.     

Polycythemia vera terminating in myelodysplastic syndrome

A 77-year-old male, who had been treated with carboquone and busulfan for polycythemia vera (PV), developed myelodysplastic syndrome (MDS) 8 years later. On admission the peripheral blood revealed pancytopenia, but blastoid cells were not noted. The bone marrow showed hypercellularity, and functional and morphological abnormalities in trilineages of hemocytes. Cytogenetic study showed complex abnormalities involving chromosomes 5 and 7. We diagnosed this case as secondary MDS to alkylating agents. He was treated with 1, 25 (OH)2 vitamin D3. However, it was not effective and the percentage of myeloblasts increased to 14.4%. In spite of supportive therapy, he died of sepsis due to urinary tract infection.     

Characteristics of immunocompetent cells in synovial membranes from multiple sites in patients with rheumatoid arthritis.

The phenotypic characterization of enzymatically dissociated mononuclear cells in synovial membrane samples from multiple sites in two patients with rheumatoid arthritis (RA) were examined by fluorescence activated flow cytometry. In synovial membrane samples from each patient there was a consistent increase in the proportion of CD8+ cells (suppressor/cytotoxic), CD14+ cells (monocytes/macrophages), and HLA-DR+ cells compared with paired peripheral blood mononuclear cells. The proportion of CD4+ cells (helper/inducer) in synovial membrane was variable. Studies of in vitro production of IgM and IgM rheumatoid factor in one patient showed strikingly similar values for synovial membrane rheumatoid factor production at the two sites, which was enhanced compared with production in peripheral blood. These results suggest that in individual patients with RA the intra-articular immune response is comparable at multiple anatomical sites and that it is distinct from that in peripheral blood.     

Analysis of lymphocyte subsets of bone marrow in patients with rheumatoid arthritis by two colour immunofluorescence and flow cytometry.

Lymphocyte subsets defined by monoclonal antibodies were investigated in bone marrow and peripheral blood of 17 patients with rheumatoid arthritis (RA); 13 patients with osteoarthritis or aseptic necrosis served as controls. Patients with RA were found to have a raised OKT 4/8 ratio both in bone marrow and peripheral blood in comparison with the controls. Furthermore, bone marrow of RA showed a lower percentage of OKT 8+ T cells than that of controls. The percentage of HLA-DR+ T cells was higher in bone marrow than in peripheral blood of RA, though a slightly lower percentage was detected in bone marrow than in peripheral blood of controls. Thus T cell subsets in bone marrow of RA differ significantly from those of controls. Patients with RA had a higher OKT 4/8 ratio and a higher percentage of HLA-DR+ T cells in bone marrow than controls, suggesting that T cell subsets in bone marrow of RA are in an immunologically activated state and that T cell subsets are affected by rheumatoid inflammation in bone marrow of RA.     

Nontuberculous atypical mycobacterial infection with progressive pancytopenia in a patient with myelodysplastic syndrome

We describe a patient with myelodysplastic syndrome (MDS) who developed disseminated infection due to nontuberculous mycobacteria (NTM). A 64-year-old man was admitted because of persistent fever that had been unresponsive to antibiotics. Bone marrow aspiration specimens showed myelodysplasia (RA), but the origin of the fever was unclear. Cytopenia worsened to a level that required transfusion of red blood cells and platelets. Repeated bone marrow examination revealed hypoplasia with hemophagocytosis. Several weeks later, photochromogenic NTM was isolated from bone marrow specimens, sputum and broncho-alveolar lavage (BAL) fluid which had been obtained on admission. Antituberculosis treatment with clarithromycin markedly improved the patient's general condition and hematological abnormalities. Three months after resolution of the NTM infection, the peripheral blood monocyte count increased, the fever recurred, and the patient suddenly died of myocardial infarction. Disseminated infection with NTM has gained attention as a frequent complication of AIDS, and NTM can also be one of the pathogens causing disseminated infection in patients with MDS. In the present case, infection with mycobacteria that normally would have been digested by macrophages and would not have caused disseminated infection in a healthy individual, was probably related to the clinical features including high fever, severe pancytopenia and hemophagocytosis.     

Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis

Cytofluorometric analysis was performed to characterize the surface phenotype and activation status of freshly isolated synovial tissue lymphocytes (STL) and peripheral blood lymphocytes (PBL) from 7 patients with rheumatoid arthritis (RA). Proliferative synovium was enzymatically digested to obtain tissue-derived lymphocytes. Indirect immunofluorescent staining of patient PBL and STL with a variety of monoclonal antibodies failed to reveal a consistent alteration in the number of CD4+ (helper/inducer) PBL or STL. However, there was a significant decrease in the number of CD8+ (suppressor/cytotoxic) cells in rheumatoid STL (P less than 0.05). A significant reduction in the density of the T cell differentiation antigens CD3 and CD4 was observed in RA PBL and STL, compared with control PBL. These differences in antigen density were not seen when normal PBL were subjected to the same enzymatic digestion. Both RA PBL and STL manifested increased expression of HLA-DR antigens, without augmentation of interleukin-2 receptor expression. Alterations in the expression of the T cell differentiation antigens and activation antigens by patient PBL closely paralleled the abnormalities observed in STL. In contrast, STL of patients with RA exhibited an increase in the expression of the adhesion-related glycoproteins (leukocyte function-associated 1 [LFA-1] and very late activation 1 [VLA-1] antigens), not observed with autologous PBL. These studies demonstrate that lymphocytes isolated from the synovial tissues of RA patients bear an activated phenotype, exemplified by the modulation of CD3 and CD4 and the expression of HLA-DR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Markedly disturbed glutathione redox status in CD45RA+CD4+ lymphocytes in human immunodeficiency virus type 1 infection is associated with selective depletion of this lymphocyte subset

We investigated the percentage of CD45RA+ and CD45RO+ T cells in peripheral blood and the intracellular glutathione redox balance in these lymphocyte subsets in patients with human immunodeficiency virus type 1 (HIV-1) infection and healthy controls. In HIV-1-infected patients there was a preferential depletion of CD45RA+CD4+ cells, which was most pronounced in symptomatic patients. In CD4+ lymphocytes from HIV-1-infected patients the glutathione abnormalities were clearly most pronounced in the CD45RA+ subset with a marked increase in level of oxidized glutathione and decreased ratio of reduced to total glutathione as the major characteristics. These abnormalities were shown in CD45RA+ CD4+ lymphocytes from both symptomatic and asymptomatic patients, whereas similar abnormalities in CD45RO+CD4+ cells were found only in symptomatic patients. The glutathione abnormalities in CD45RA+CD4+ lymphocytes were significantly correlated with low numbers of total CD4+ lymphocytes, decreased proportion of CD45RA+CD4+ lymphocytes, and raised serum levels of tumor necrosis factor-alpha. In the CD8+ lymphocytes a decrease in both proportion and absolute numbers of CD45RA+ cells was found, with markedly increased level of oxidized glutathione and decreased ratio of reduced to total glutathione in this subset. These findings suggest that glutathione redox disturbances in CD45RA+ T cells may be of pathogenic importance for the preferential depletion of this subset considered to represent naive T cells, during HIV-1 infection.     

Karyotypic polymorphism in acute myelofibrosis

Acute myelofibrosis (AMF) was diagnosed in a 59-yr-old black male in September 1978, on the basis of pancytopenia, lack of hepatosplenomegaly, fibrosis of the marrow, and paucity of teardrop red blood cells in the peripheral blood. Since then the patient has demonstrated an unusually long survival of 36 mo with a changing cytogenetic course. His initial 46, XY normal karyotype changed in 20 mo to trisomy 8, followed 1 yr later by 1:4 translocation in peripheral blood. Simultaneously with these changes, the fibrosis in the bone marrow progressively decreased, ultimately terminating in chronic granulocytic leukemia-like presentation with reversal to 46, XY karyotype. Fibroblast culture failed to show any evidence of cytogenetic abnormalities. The disappearance of fibrosis confirmed by trichrome and reticulin stains and lack of cytogenetic abnormalities in fibroblasts confirms the secondary role of fibrosis.     

Donor-Type Myelodysplastic Syndrome with t(2;3) and Monosomy 7 after Allogeneic Peripheral Blood Stem Cell Transplantation and Liver Transplantation in a Patient with Severe-Type Aplastic Anemia

Secondary clonal hemaloiogical disease in donor cells has rarely been reported as a complication of allogeneic stem cell transplantation in hematological disease. We report a case of myelodysplastic syndrome that showed cytogenetic abnormalities of t(2;3) and monosomy 7, which developed 2 years after peripheral blood stem cell transplantation for aplastic anemia and 1 year after liver transplantation for drug-induced hepatic failure. This secondary malignancy of donor origin is most frequently seen in patients with leukemia. We suspect that the chromosomal abnormalities are related to hepatitis-associated aplastic anemia, administration of granulocyte colony-stimulating factor and erythropoietin for posttransplantion pancytopenia, and repeated infections after liver transplantation.