ABSTRACT
An Epstein-Barr virus (EBV)-seronegative 31-year-old male underwent cardiac transplantation in 1991 for congenital cardiomyopathy. He presented with a protracted course of waxing and waning lymphadenopathy beginning four years after transplantation with eventual progression to a fulminant EBV-positive large cell lymphoma eight years after transplantation. Risk factors for the development of post-transplant lymphoproliferative disease in this patient, the importance of a standardized approach to pathology in assessing therapeutic options, and the management strategies used are discussed.
Subject(s)
Epstein-Barr Virus Infections/complications , Heart Transplantation/adverse effects , Lymphoma, Large B-Cell, Diffuse/pathology , Plasma Cells/pathology , Adult , Humans , Hyperplasia , Male , RecurrenceSubject(s)
Adenosine/analogs & derivatives , Antineoplastic Agents/toxicity , Bone Marrow Cells/metabolism , Carrier Proteins/metabolism , Membrane Proteins/metabolism , Myelodysplastic Syndromes/metabolism , Antimetabolites, Antineoplastic/toxicity , Bone Marrow Cells/drug effects , Cell Survival/drug effects , Cytarabine/toxicity , Flow Cytometry , Fluorescent Dyes , Humans , Ligands , Methotrexate/toxicity , Myelodysplastic Syndromes/pathology , Nucleoside Transport Proteins , ThionucleosidesABSTRACT
The authors report an unusual case of peripheral T-cell lymphoma in a 16-year-old boy who presented initially with jaundice, splenomegaly, anemia, and thrombocytopenia. A lymphoma was found subsequently in the spleen, which was infiltrated extensively in the red pulp by medium-sized, blastic-appearing lymphoma cells. Immunologic characterization of these cells revealed positivity for CD3, CD5, CD45RO, CD56, and T-cell intracellular antigen (TIA), and negativity for CD2, CD3, CD4, CD8, CD57, CD34, and terminal deoxynucleotidyl transferase (TdT). Conventional cytogenetic studies revealed the presence of isochromosome 7q. On follow up, this patient deteriorated rapidly, with evidence of liver and bone marrow involvement. Although the overall clinical and pathologic features of this disease were characteristic of hepatosplenic gammadelta T-cell lymphoma, the T-cell receptor of this tumor showed an immunophenotype of alphabeta not gammadelta lineage. Using the Southern blot technique, the authors demonstrated monoclonal gene rearrangement of the T-cell receptor beta-chain. Thus, they confirmed the existence of hepatosplenic alphabeta T-cell lymphoma. In view of its overall similarity to hepatosplenic gammadelta T-cell lymphoma, this unusual entity probably represents a slight biologic variation of the same disease.
Subject(s)
Anemia, Hemolytic/etiology , Liver Neoplasms/complications , Lymphoma, T-Cell/complications , Splenic Neoplasms/complications , Thrombocytopenia/etiology , Adolescent , Humans , Liver Neoplasms/pathology , Lymphoma, T-Cell/pathology , Male , Splenic Neoplasms/pathologyABSTRACT
Some patients with thrombotic thrombocytopenic purpura (TTP) remain plasma-exchange-dependent for prolonged periods of time. This exposes patients to risk, uses substantial resources, and requires prolonged hospitalization. We have splenectomized 7 such patients following 25-42 plasma exchanges while patients were in partial remission only and were clinically stable. In 6 patients, including 1 with TTP secondary to mitomycin C, thrombocytopenia promptly resolved. Relapse has not occurred during 18 or more months of observation. The seventh patient did not respond. We conclude that splenectomy should be considered as an alternative to continued plasma-exchange therapy in such patients.
Subject(s)
Plasma Exchange , Purpura, Thrombotic Thrombocytopenic/therapy , Splenectomy , Adrenal Cortex Hormones/therapeutic use , Antineoplastic Agents/adverse effects , Aspirin/therapeutic use , Combined Modality Therapy , Erythrocyte Transfusion , Humans , Mitomycin/adverse effects , Platelet Aggregation Inhibitors/therapeutic use , Platelet Count , Purpura, Thrombotic Thrombocytopenic/drug therapy , Purpura, Thrombotic Thrombocytopenic/surgery , Remission Induction , Treatment OutcomeABSTRACT
We compared the expression of matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in bone marrow acute myelogenous leukaemia (AML) blasts and leukaemic cell lines (HEL, HL-60, K-562 and KG-1) with their expression in normal bone marrow cells. All AML samples and leukaemic cell lines tested expressed MMP-9 and/or MMP-2 mRNA and, accordingly, these gelatinases were secreted into media. Moreover, TIMP-1 and TIMP-2 mRNA and secreted proteins were demonstrated in all the AML samples. Although all the leukaemic cell lines expressed TIMP-1, the HL-60 cells also expressed TIMP-2. In contrast, normal steady-state bone marrow immature progenitor cells (CD34+ cells) did not express or secrete either MMP-2 or MMP-9, but more mature mononuclear cells from normal bone marrow expressed and secreted MMP-9. Also, normal bone marrow CD34+ cells and mononuclear cells expressed TIMP-1 and TIMP-2 mRNA, but these proteins were not detectable by reverse zymography. Furthermore, whereas bone marrow fibroblasts and endothelial cells secreted only latent MMP-2, the activated form of this enzyme was found in media conditioned by cells obtained from long-term cultures of normal and AML bone marrow adherent layers. Our finding of up-regulated production of gelatinases, TIMP-1 and TIMP-2 by leukaemic cells suggests that these proteins may be implicated in the invasive phenotype of AML.
Subject(s)
Bone Marrow Cells/metabolism , Collagenases/metabolism , Gelatinases/metabolism , Leukemia, Myeloid, Acute/metabolism , Metalloendopeptidases/metabolism , Tissue Inhibitor of Metalloproteinase-1/metabolism , Tissue Inhibitor of Metalloproteinase-2/metabolism , Adolescent , Adult , Aged , Female , Hematopoietic Stem Cells/metabolism , Humans , Male , Matrix Metalloproteinase 2 , Matrix Metalloproteinase 9 , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction/methods , Tumor Cells, CulturedABSTRACT
Nucleoside analogs are important components of treatment regimens for acute leukemia in adults. Plasma membrane permeation of the nucleoside analog molecules, the initial event in the cellular conversion of nucleosides to active agents, is mediated by nucleoside-specific membrane transporters. The widely-expressed es nucleoside transporter accepts as substrates diverse nucleoside analogs, including cytarabine (araC), 2-chlorodeoxyadenosine, and fludarabine. The cellular content of es transporter sites has been measured in blasts from patients with acute lymphoblastic leukemia and acute myelogenous leukemia, by a sensitive, quantitative flow cytometry assay that employs the tightly-bound es ligand, SAENTA fluorescein. Values for es transporter expression varied ten-fold among samples from patients with acute myelogenous leukemia. In this article, we review current findings that document, in confocal fluorescence microscopy images and in flow cytometry assays of SAENTA fluorescein-stained cells, the patient-to-patient variance of es transporter expression in leukemic blasts from patients. Our data show a correlation between the expression of es transporters and the in vitro sensitivity to nucleoside drugs of blasts from acute leukemia patients. These findings show that the flow cytometry assay of es expression provides a facile means of predicting resistance of leukemia cells to the cytotoxicity of araC and other nucleosides.
Subject(s)
Carrier Proteins/biosynthesis , Cytarabine/pharmacokinetics , Leukemia, Myeloid, Acute/metabolism , Membrane Proteins/biosynthesis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Acute Disease , Antimetabolites, Antineoplastic/pharmacokinetics , Carrier Proteins/antagonists & inhibitors , Drug Resistance, Neoplasm , Flow Cytometry , Fluoresceins/metabolism , Gene Expression , Humans , Leukemia, Myeloid, Acute/drug therapy , Lymphocytes/metabolism , Membrane Proteins/antagonists & inhibitors , Microscopy, Confocal , Nucleoside Transport Proteins , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Purine Nucleosides/metabolismABSTRACT
Cytarabine (araC) is converted to araC 5'-triphosphate after entering leukemia cells as a substrate for nucleoside transport processes. This study tested the relationship between araC cytotoxicity, measured in an in vitro tetrazolium dye reduction assay of cell viability, and the cellular abundance of es nucleoside transport elements, assayed by a flow cytometric method that used the es-specific stain, 5-(SAENTA-x8)-fluorescein (5-(Sx8)-F), in cultured leukemia cells and in myeloblasts and lymphoblasts (blasts) from leukemia patients. Cellular es site abundance (B(max) value for 5-(Sx8)-F binding) varied sixfold among nine leukemic myeloblast samples from patients. In cultured OCI/AML-2 myeloblasts and CCRF-CEM T-lymphoblasts, and in fresh leukemic blasts, es sites were fractionally blocked by treatment with graded concentrations of nitrobenzylthioinosine (NBMPR), an inhibitory es site ligand, to simulate the variation in es expression found in leukemic blasts from patients with acute myeloid leukemia. When the cytotoxicity of a single concentration of araC was determined in NBMPR-treated leukemia cells, cell kill correlated closely with the intensity of 5-(Sx8)-F fluorescence (r = .92 to .99), a measure of the cell surface abundance of functional es nucleoside transporter sites. Concentrations of NBMPR that achieved half-maximal reduction (4.3 to 12 nmol/L) of cellular 5-(Sx8)-F fluorescence (measured by flow cytometry) approximated IC50 values (1 to 10 nmol/L) previously found for inhibition by NBMPR of es-mediated nucleoside fluxes in several cell types, supporting the view that 5-(Sx8)-F interacted with the estransporter. The correlation of araC cytotoxicity and the B(max) for 5-(Sx8)-F binding to es sites in cultured leukemia cells and in leukemic blasts from acute leukemia patients (r = .95) suggests that the flow cytometry assay of es capacity may be useful in predicting clinical response to araC.
Subject(s)
Antimetabolites, Antineoplastic/toxicity , Carrier Proteins/metabolism , Cytarabine/toxicity , Leukemia/metabolism , Nucleosides/metabolism , Acute Disease , Adenosine/analogs & derivatives , Affinity Labels , Cell Death/drug effects , Flow Cytometry , Fluorescein , Fluoresceins , Humans , Leukemia/drug therapy , Leukemia/pathology , Thionucleosides , Tumor Cells, CulturedABSTRACT
PURPOSE: To evaluate a policy of immunosuppression with antithymocyte globulin (ATG) as primary therapy for adults with severe aplastic anemia (SAA) regardless of the availability of an HLA-identical bone marrow donor. PATIENTS AND METHODS: Thirty-one consecutive adults with SAA who satisfied the age criteria for allogeneic bone marrow transplantation (BMT) (age less than 51 years) were treated with ATG 20 mg/kg/day for 10 days along with high-dose corticosteroids. Patients with an HLA-identical donor received a transplant if they did not respond to ATG or if they developed life-threatening complications during or soon after ATG administration. Eight patients with no response to ATG were also treated with oral cyclosporine 12.5 mg/kg/day. RESULTS: Eleven patients had a complete and five a partial response to ATG; two patients improved with cyclosporine treatment, resulting in an overall response rate of 58% to immunosuppression. Nine of 14 patients with donors received a BMT: seven because they did not respond to ATG and two because of serious infections. Seven grafts were obtained from related and two from unrelated donors. There was no significant difference in survival between those with and without a related HLA-identical donor (log-rank p value = 0.969). At a median follow-up of 58 months, 26 of 31 are alive with an actuarial survival of 80% at 5 years. Two patients died of infection, two died from complications of BMT, and one remains transfusion-dependent. One patient died of refractory leukemia at 30 months; one patient relapsed with hypoplasia 95 months after initial therapy with ATG. He showed a complete response to treatment with cyclosporine. No other late hematologic events have occurred. CONCLUSIONS: This treatment approach resulted in the restoration of hematopoiesis and independence from transfusion in 80% of patients with SAA entered into the study. The efficacy of allogeneic BMT in salvaging cases in which ATG failed does not appear to be compromised. Follow-up for the development of clonal hematologic disorders remains an important part of this treatment policy.