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Biomedical subjects

E D Thomas

Publications and source records attributed to E D Thomas.

At least 19 recordsLinked to original sources
PubMed1992

Methylation of the DXS255 hypervariable locus 5' CCGG site may be affected by factors other than X-chromosome activation status.

Differences in the methylation status of certain cytosine residues between active and inactive X chromosomes can be used to determine X-inactivation in females heterozygous for X-linked restriction fragment length polymorphisms. We have studied methylation patterns in 105 females heterozygous at the DXS255 locus by Southern blotting of PstI and MspI or HpaII double digests and hybridization with the probe M27B. Unequivocal patterns of unilateral or bilateral X-inactivation were obtained in 15/64 and 49/64 cases, respectively. In the remaining 41 cases the results were unclear due to the absence of HpaII digestion of one or both PstI fragments. In 7 samples an unequivocal digestion pattern was demonstrated on repeat analysis, suggesting that the initial ambiguous pattern was due to incomplete HpaII digestion. In certain individuals, methylation at the 5' CCGG DXS255 locus may be affected by factors other than X-inactivation, making analysis of clonality with the M27B probe impossible. These individuals should be clearly identified in studies of clonality.

Blotting, Southern↗
PubMed1992

The use of radiolabeled anti-CD33 antibody to augment marrow irradiation prior to marrow transplantation for acute myelogenous leukemia.

Disease recurrence remains a major limitation to the use of marrow transplantation to treat leukemia. Previous transplant studies have demonstrated that higher doses of total-body irradiation result in less disease recurrence, but more toxicity. In this study, the possibility of delivering radiotherapy specifically to marrow using a radiolabeled anti-CD33 antibody (p67) was explored. Biodistribution studies were performed in nine patients using .05-.5 mg/kg p67 trace-labeled with 131I. In most patients initial specific uptake of 131I-p67 in the marrow was seen, but the half-life of the radiolabel in the marrow space was relatively brief, ranging from 9-41 hr, presumably due to modulation of the 131I-p67-CD33 complex with subsequent digestion and release of 131I from the marrow space. In four of nine patients these biodistribution studies demonstrated that with 131I-p67 marrow and spleen would receive more radiation than any normal nonhematopoietic organ, and therefore these four patients were treated with 110-330 mCi 131I conjugated to p67 followed by a standard transplant regimen of cyclophosphamide plus 12 Gy TBI. All four patients tolerated the procedure well and three of the four are alive in remission 195-477 days posttransplant. This study demonstrates the feasibility of using a radiolabeled antimyeloid antibody as part of a marrow transplant preparative regimen and also highlights a major limitation of using conventionally labeled anti-CD33--namely, the short residence time in marrow. Strategies to overcome this limitation include the use of alternative labeling techniques or the selection of cell surface stable antigens as targets.

Adolescent↗
PubMed1992

Donor alloreactivity may predict acute graft-versus-host disease in HLA-matched bone marrow transplantation for leukemia in early remission.

The pretransplant alloantigen-dependent responding and stimulating capacity of donors and of recipients was studied retrospectively, in a study of prediction of acute graft-versus-host disease. Donor responding capacity (DRC) and host stimulating capacity (HSC) were defined by mixed lymphocyte culture (MLC) and normalized by help of the pool response. High and low DRC and strong and weak HSC was defined by distribution plots. Kaplan-Meier estimates of the risk of developing Grade II or higher aGvHD showed that first remission patients (N = 125) had a significantly different risk if transplanted with marrow from a donor with high (N = 54) or low (N = 71) DRC (chi 2 = 9.49; d.f. = 1; p less than 0.002). This was not the case for patients transplanted in later remissions. Host SC status had no significant influence on the aGvHD status (chi 2 = 1.75 and 2.40; d.f. = 1; p = 0.19 and 0.12, defined by normal controls A and B respectively). In conclusion, the results indicate that pretransplant donor alloreactivity may predict aGvHD, confirming the results from a Scandinavian study. The results need to be confirmed in prospective studies of alloreactivity as risk factor for aGvHD.

Acute Disease↗
PubMed1992

Is there a better way to deliver total body irradiation?

The available data suggest that the antileukemic, immunosuppressive and toxic effects of TBI are highly dose dependent and if TBI is given as single daily fractions at 5-10 cGy/minute, an optimal dose for the treatment of most leukemias is somewhere between 12 and 16 Gy. Giving radiation as a single dose rather than fractionating it increases both its immunosuppressive as well as its toxic effects. The relative anti-leukemic effects of single vs. fractionated irradiation are less clear, but available data support the view that fractionation does not substantially reduce the effects of TBI on myeloid tissue. Increasing the dose rate increases toxicities and, although data are not yet complete, likely increases both immunosuppressive and anti-tumor effects. The impact of total dose, dose fractionation and dose rate are highly interdependent and how best to manipulate these 3 factors to lead to an optimal combination is as yet unknown. Directing radiotherapy to sites of leukemia using monoclonal antibodies or other carriers such as growth factors is feasible and, although there are many aspects of this approach which have yet to be worked out, targeted radiotherapy may prove to be the best way to achieve the therapeutic goals of increased tumor ablation and immunosuppression without increased toxicities.

Bone Marrow Transplantation↗
PubMed1992

Mixed leukocyte culture reactivity and graft-versus-host disease in HLA-identical marrow transplantation for leukemia.

The results of pretransplant mixed leukocyte culture (MLC) assays were compared to subsequent risk of graft-versus-host disease (GVHD) in 783 patients receiving marrow transplants from HLA genotypically identical sibling donors. The mean MLC response observed between 1303 normal HLA identical sibling pairs was 0.0 +/- 4.2% RR. The donor anti-recipient MLC reaction, an in vitro response that presumably might be relevant to GVHD, was significantly increased (greater than mean + 2 sd) in 83 (10.6%) of the cases, most often in patients in relapse at the time of testing. No association was found, however, between this increased donor anti-recipient MLC reactivity pretransplant and the incidence or severity of subsequent acute or chronic GVHD. These data suggest that the increased MLC responses sometimes observed between leukemia patients and their HLA identical sibling donors prior to marrow transplantation do not represent genetic differences capable of causing GVHD.

Bone Marrow Transplantation↗
PubMed1991

Expression of Epstein-Barr virus-encoded growth-transformation-associated proteins in lymphoproliferations of bone-marrow transplant recipients.

The expression of Epstein-Barr virus (EBV)-encoded, growth-transformation-associated proteins was studied in lymphoproliferations of 9 allogeneic bone-marrow transplant (BMT) recipients. Immunoblots of cell lysates were probed with polyspecific and monospecific antisera directed against EBNA 1, 2, 3 and 6, and the membrane protein LMP. All tumors expressed EBNA 1 and LMP. EBNA 2 was detected in the tumors of 8 patients, and EBNA 3 and 6 in the tumors of 5 patients. The LMP regulatory sequences, 5' of the LMP gene, were totally unmethylated in all 7 cases, while the coding sequences of LMP and EBNA 2 were more methylated in CpG dinucleotides. EBV-transformed lymphoblastoid cell lines (LCL) express EBNA 1 to 6 and LMP; in contrast, Burkitt lymphomas express only EBNA 1. In vitro experiments have shown that EBNA 2, 3 and LMP can generate targets for cytotoxic T cells (CTL). These combined observations are consistent with the hypothesis that the EBV-associated lymphoproliferative disease of the BMT recipients escapes CTL-mediated rejection due to the failure of host immunosurveillance rather than to the down-regulation of immunogenic EBV-encoded antigens.

Adolescent↗
PubMed1991

Frontiers in bone marrow transplantation.

The early murine experiments and human studies that indicated the potential of marrow transplantation are reviewed. The results of marrow grafting for a variety of human diseases are summarized. Current directions of research are indicated.

Anemia, Aplastic↗
PubMed1990

Stem cell selection--clinical experience.

The ability to isolate large numbers of hematopoietic progenitors will facilitate an understanding of the growth and differentiation of bone marrow. Furthermore, isolating hematopoietic progenitors will have widespread clinical applications to autologous marrow transplantation, allogeneic marrow transplantation, gene therapy, and in vitro marrow expansion. With the development of avidin-biotin immunoadsorption, it is now feasible to isolate large numbers of these progenitor cells for clinical purposes. Successful hematopoietic reconstitution has been demonstrated in lethally irradiated baboons transplanted with CD34+ cells isolated by immunoadsorption with the anti-CD34 antibody 12-8. Recent studies have shown that CD34+ cells enriched from the marrow of patients with metastatic breast cancer can be used for autologous marrow transplantation.

Animals↗
PubMed1979

Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts.

To determine whether allogeneic bone-marrow transplantation is associated with a graft-versus-leukemia effect, we examined the relation between relapse of leukemia and graft-versus-host disease in 46 recipients of identical-twin (syngeneic) marrow, 117 recipients of HLA-identical-sibling (allogeneic) marrow with no or minimal graft-versus-host disease, and 79 recipients of allogeneic marrow with moderate to severe or chronic disease. The relative relapse rate was 2.5 times less in allogeneic-marrow recipients with graft-versus-host disease than in recipients without it (P less than 0.01). This apparent antileukemic effect was more marked in patients with lymphoblastic than nonlymphoblastic leukemia, and in those who received transplants during relapse rather than during remission, and was most evident during the first 130 days after transplantation. Survival of all patients was comparable since the lesser probability of recurrent leukemia in patients with graft-versus-host disease was offset by a greater probability of other causes of death.

Acute Disease↗
PubMed1979

Disappearance of Ph1-positive cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin.

Four patients (21, 41, 13 and 38 years of age) with a history of chronic granulocytic leukemia for 12, 10, 11, and 106 months, respectively, were treated with dimethyl busulfan, cyclophosphamide, 920 rads of total-body irradiation and intravenous marrow infusion from normal, genetically identical twins. Serial chromosome analyses were performed on marrow aspirates cultured without mitotic stimulants. No Ph1-positive cells were detected in the marrows from the normal twins, whereas just before therapy, all 100 metaphases examined from each patient were Ph1-positive. Chromosome analyses were performed three to five times per patient after transplantation, and not a single Ph1-positive cell was detected. The patients remain hematologically normal 22, 23, 26 and 31 months after transplantation. The results show that the Ph1-positive clone can be eradicated by vigorous therapy and that the marrow in chronic granulocytic leukemia can be repopulated by stem cells from normal twins.

Adult↗