Monoclonal and oligoclonal gammopathy after bone marrow transplantation

Serial serum protein electrophoreses were performed on 60 patients undergoing allogeneic and syngeneic bone marrow transplantation (BMT). More than 50% of patients (31 of 60) developed transient oligoclonal and monoclonal gammopathies that appeared an average of 84 days posttransplantation (range 27 to 336 days) and persisted an average of 175 days (range 14 to 652 days). Immunofixation analysis revealed 82% of the M components to be of the immunoglobulin G (IgG) type and 18% to be IgM; 56% were kappa and 44% were lambda. A strong correlation between development of graft versus host disease (GVHD) and appearance of M components was observed (73% incidence in GVHD patients v 27% in non-GVHD patients, P = .0003). Two of the three syngeneic graft recipients also developed monoclonal gammopathies. Evidence of oligoclonal circulating B-cell populations was found in 68% of patients posttransplantation by flow cytometric B-cell clonal excess assay. No correlation of recovery of particular B- or T-lymphocyte subsets and development of M components was seen. The development of transient oligoclonal and monoclonal gammopathies after transplantation may be a ubiquitous finding reflecting recapitulation of early B-cell ontogeny.     

Use of recombinant human erythropoietin in allogeneic bone marrow transplant donor/recipient pairs

In an attempt to reduce or eliminate homologous red blood cell transfusion requirements during allogeneic bone marrow transplantation (BMT), we instituted a novel program whereby recombinant human erythropoietin was administered to pairs of BMT donors and recipients. Eleven recipients and their HLA-matched donors were enrolled. Donors treated with recombinant human erythropoietin (rHuEPO) were phlebotomized a median of 6 U (range, 4 to 11 U) of blood over a 5-week period. This donor-derived blood was available to the BMT donor or recipient as needed. Transplant recipients were also treated with rHuEPO post-BMT to hasten erythropoiesis. Five of 11 BMT recipients underwent transplant receiving only donor-derived red blood cell transfusion, compared with 0 of 11 concomitant control recipients (P = .04). In addition, the time to absolute reticulocyte count > or = 10(4)/microL was statistically shorter in the rHuEPO-treated recipient group. This study serves as a paradigm for hematopoietic growth factor use in allogeneic BMT to decrease or eliminate homologous transfusion exposures and to possibly hasten hematopoietic engraftment.     

Mutations in N-ras predominate in acute myeloid leukemia

Using synthetic oligomers we investigated fresh samples of acute myeloid leukemia (AML) for the presence of mutated ras oncogenes. Our original results showed that five of eight samples contained a mutation in codon 13 of the N-ras gene. In a subsequent study involving 37 samples, we found only one N-ras-13 mutation, and, in addition, mutations in codon 61 of the N-ras gene in four cases and a mutation in codon 12 of the Ki-ras gene in two cases. Amplification of ras genes was not observed. We conclude that in approximately 20% to 25% of AML cases, a mutated ras oncogene is present, predominantly the N-ras gene. The occurrence of mutations does not correlate with the cytological features of the leukemia.     

Antiinflammatory effects of estrogen on microglial activation

In the present study the effects of 17beta-estradiol on microglial activation are described. Estrogen replacement therapy has been associated with decreased severity of age-related neurodegenerative diseases such as Alzheimer's disease, and estrogens have potent immunosuppressive properties outside of the brain. To determine the role that microglial cells might play in estrogen-mediated neuroprotection, primary rat microglia and N9 microglial cell lines were treated with increasing doses of 17beta-estradiol before or during immunostimulation by lipopolysaccharide, phorbol ester, or interferon-gamma. Pretreatment with 17beta-estradiol, but not 17alpha-estradiol or progesterone, dose dependently attenuated microglial superoxide release and phagocytic activity. Additionally, 17beta-estradiol attenuated increases in inducible nitric oxide synthase protein expression, but did not alter nuclear factor-KB activation. The antiinflammatory effects of 17beta-estradiol were blocked by the antiestrogen ICI 182,780. Additionally, 17beta-estradiol induced rapid phosphorylation of the p42/p44 mitogen-activated protein kinase (MAP kinase), and the MAP kinase inhibitor PD 98059 blocked the antiinflammatory effects of 17beta-estradiol. Overall, these results suggest that estrogen receptor-dependent activation of MAP kinase is involved in estrogen-mediated antiinflammatory pathways in microglial cells. These results describe a novel mechanism by which estrogen may attenuate the progression of neurodegenerative disease and suggest new pathways for therapeutic intervention in clinical settings.     

Methylthioadenosine phosphorylase deficiency in acute leukemia: pathologic, cytogenetic, and clinical features

Blast cells from 100 cases of acute leukemia were evaluated for the presence of methylthioadenosine phosphorylase (MTAase), an enzyme important in polyamine metabolism. Ten cases (10%) had undetectable levels of MTAase activity. Of the 10, 5 had acute lymphoblastic leukemia (ALL), 3 had acute myeloblastic leukemia (AML) and 2 expressed mixed lineage markers as determined by immunophenotyping. A relatively high frequency (38%) of MTAase deficiency was seen in ALL of T-cell origin. Nonmalignant hematopoietic cells from three patients with MTAase-deficient leukemias had readily detectable enzyme activity. Chromosomal abnormalities were detected in four of the seven MTAase- deficient cases in which karyotypic analysis was performed. No consistent karyotypic defect was apparent, and only one case displayed changes in chromosome 9, the putative location of the MTAase structural gene. The clinical findings among the enzyme-deficient cases were unremarkable except that all patients were male (P less than .01). Only one patient had "lymphomatous" features. We conclude that MTAase deficiency occurs in a wide variety of acute leukemias, that the lack of enzyme activity is specific to the malignant cells, and that an increased incidence occurs in ALL of T-cell origin. Furthermore, no specific gross chromosomal abnormality is associated with the enzyme deficiency. The marked male predominance in patients with MTAase- deficient acute leukemias suggests involvement of the X chromosome in the loss of enzyme activity. The absence of MTAase in some leukemias may be therapeutically exploitable.     

Trisomy 21 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study (8602)

Of 1,036 children with newly diagnosed non-T, non-B acute lymphoblastic leukemia (ALL) and a demonstrated cytogenetic abnormality treated on the frontline Pediatric Oncology Group (POG) therapeutic trial 8602, there were 33 patients with trisomy 21 as the sole abnormality. Of these 33, 14 had Down syndrome (DS). Although the non-DS (NDS) trisomy 21 cases tended to be older than the DS cases, there were no other significant differences in clinicobiologic features nor in treatment outcomes between the DS and NDS groups, nor between the entire trisomy 21 group and the other chromosome abnormality group. Among NDS patients with +21 and one additional abnormality, +X, +16, -20, and structural abnormalities involving 6q or 12p were common findings. Kaplan-Meier event-free survival (EFS) curves showed a 4-year EFS of 80% (SE, 12%) in NDS trisomy 21 cases, 71% (SE, 22%) in DS cases with trisomy 21 as the sole abnormality, and 69% (SE, 2%) in cases with other chromosome abnormalities. Trisomy 21 as a sole acquired abnormality in NDS patients suggests a good prognosis.     

In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells

Background  

Based on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed (multitargeted antifolate, MTA) and gemcitabine (2',2'-difluorodeoxycytidine, dFdC) with irradiation (RT) seems promising. This in vitro study, for the first time, presents the triple combination of MTA, dFdC and irradiation using various treatment schedules.