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Biomedical subjects

E D Thomas

Publications and source records attributed to E D Thomas.

At least 55 records · Page 3Linked to original sources
PubMed1993

Allogeneic marrow transplantation: the Seattle experience.

Allogeneic marrow transplantation from a normal donor provides potential life-saving therapy for a variety of inherited and acquired diseases of the hematopoietic and immune systems including malignancies. However, even with an HLA-identical sibling donor the success of allografts can be compromised by GvHD and associated complications such as opportunistic infection. Non-HLA minor histocompatibility determinants still represent significant barriers to safe and successful transplants in some cases. In the absence of an HLA-identical sibling, alternate donors, including HLA-matched unrelated volunteers and HLA partially matched relatives can provide opportunity for effective therapy, though with increased risk of graft rejection and GvHD. HLA matching appears to be a critical factor, with the incidence and severity of GvHD exceeding acceptable limits as the number of incompatible HLA antigens increases. Although the United States NMDP and the marrow donor registries in other countries that currently have more than 1.2 million HLA-typed donors have profoundly improved the likelihood of finding an HLA-matched unrelated donor for the majority of White patients, many Whites and most patients of other racial origin cannot at this time find a match. Effective and safe treatment for these patients will require improved methods for managing HLA-mismatched transplants.

Academic Medical Centers↗
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

Chimeric BCR-abl messenger RNA as a marker for minimal residual disease in patients transplanted for Philadelphia chromosome-positive acute lymphoblastic leukemia.

We correlated polymerase chain reaction (PCR)-detectable BCR-abl fusion transcripts with cytogenetic status in 24 patients with acute lymphocytic leukemia (ALL). Of 10 Philadelphia chromosome negative (Ph-) patients, only one was found to exhibit a BCR-abl fusion transcript. Fourteen patients with Ph+ ALL, including eight in clinical remission, exhibited PCR-detectable BCR-abl rearrangements. A detectable Ph chromosome was present in only five of the eight patients in clinical remission. Of the three cytogenetically negative, BCR-abl-positive patients, two eventually succumbed to post-bone marrow transplantation (BMT) relapse. The third died of early transplant complications. Serial PCR analyses were performed on four Ph+ ALL patients in clinical remission who underwent allogeneic BMT. One patient who was PCR negative on post-BMT days 21 and 75 became PCR-positive on day 116 and died in relapse on day 154. One patient was weakly positive for BCR-abl on day 23, negative on day 56, but died of transplant complications on day 124. Two patients exhibited no post-BMT BCR-abl rearrangements and remain well on days 279 and 371. Our findings suggest that PCR analysis may be useful in the early identification of relapse in patients transplanted for Ph+ ALL.

Adult↗
PubMed1991

Abnormal methylation of the calcitonin gene marks progression of chronic myelogenous leukemia.

The clinical aspects of disease progression in chronic myelogenous leukemia (CML) are well established, but the nature of the molecular events responsible is not known. We have previously reported a consistent pattern of novel sites of methylation in the 5' region of the calcitonin (CT) gene and other chromosome 11p loci in acute myelogenous and and lymphoid leukemias. In the present study, CT gene methylation patterns were investigated in peripheral blood from 51 patients with CML. Abnormal patterns were found in only 2 of 31 patients in chronic phase, but in 5 of 8 patients in accelerated phase, and in 11 of 12 patients in blast crisis (P less than .005). For one patient studied in blast crisis, abnormal CT gene methylation was found in the peripheral blast cells but not in the granulocytes. In two of three patients studied with CML and having normal peripheral cell patterns, abnormal patterns were found in marrow blast cells. In one patient, only partial normalization of the CT gene methylation pattern was seen after chemotherapy induction of a second chronic phase and the patient relapsed 5 months later. Our findings indicate that abnormal methylation of the 5' region of the CT gene is regularly a marker of disease progression in CML which may prove clinically useful. This abnormal methylation site is part of an imbalance in DNA methylation that may play a role in the progressive genetic instability which characterizes the advancing stages of CML.

Biomarkers, Tumor↗
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

Use of a probe to repeat sequence of the Y chromosome for detection of host cells in peripheral blood of bone marrow transplant recipients.

In situ hybridization for the Y chromosome (Y-ISH) was used to identify residual host cells in the peripheral blood of 51 recipients of sex-mismatched allogeneic marrow not depleted of T cells following conditioning with high-dose cyclophosphamide and total body irradiation (TBI). One patient who rejected the graft showed rapid reappearance of host cells after transient donor marrow engraftment. Host cells were detected at low levels in 49 of the remaining 50 patients. Host peripheral blood mononuclear cells (PBMC) decreased with time and reached a plateau at 1.0 +/- 0.2% within four weeks after transplantation, while the percentage of host granulocytes (GRAN) reached a plateau at background level. The mean absolute numbers of host PBMC or GRAN were less than 0.015 x 10(9)/L and did not vary significantly over the period studied. Neither the percentages nor the absolute numbers of host PBMC or GRAN were significantly affected by HLA-matching, TBI dose-intensity, pretransplant remission status, subsequent development of acute or chronic graft-versus-host disease or relapse after transplantation. The authors conclude that it is common to find a few residual host cells in the peripheral blood of allogeneic marrow transplant recipients, and the presence of these cells has no clinical significance.

Adolescent↗
PubMed1991

Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies.

Less than 40% of the patients who could benefit from marrow transplantation have an HLA-matched relative who can serve as a donor. For this reason, several centers have explored marrow transplantation from other categories of donors. This retrospective study analyzes the results of marrow transplantation for 52 patients receiving grafts from HLA-A,B,DR,Dw-phenotypically matched, MLC-compatible, unrelated volunteer donors compared to a disease, disease-stage, and age-matched cohort of 104 patients transplanted from HLA-genotypically identical sibling donors. The patients transplanted from unrelated donors had an increased incidence of grade II-IV acute graft-versus-host disease compared to patients transplanted from related donors (79% vs. 36%, P much less than 0.001). However, the probability of relapse-free survival appears similar in the two groups (P = 0.39 over all, with estimates of 41% vs. 46% at 1 year). We conclude from this preliminary data that marrow transplantation from HLA-matched unrelated donors should be considered in most, if not all, circumstances where transplantation from an HLA-matched sibling would be indicated if such a donor were available.

Acute Disease↗
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↗