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Biomedical subjects

R Parkman

Publications and source records attributed to R Parkman.

At least 55 records · Page 3Linked to original sources
PubMed1991

Graft-versus-host disease.

Graft-versus-host disease, both acute and chronic, continues to be the major complication of human bone marrow transplantation. Improved posttransplant chemoprophylaxis has reduced the incidence of acute graft-versus-host disease, but the incidence of the chronic form of the disease remains unchanged. The use of donors that are not genotypically identical at the major histocompatibility complex increases the incidence of acute and chronic graft-versus-host disease. The clinical consequences of acute and chronic graft-versus-host disease are discussed.

Bone Marrow Transplantation↗
PubMed1991

Hepatic veno-occlusive disease post-bone marrow transplantation in children conditioned with busulfan and cyclophosphamide: incidence, risk factors, and clinical outcome.

We performed a retrospective analysis of the incidence, risk factors, and clinical outcome of hepatic veno-occlusive disease (VOD) in 50 children prepared for bone marrow transplantation with busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). The overall incidence of VOD was 28% (14/50). The incidence of VOD among patients transplanted for leukemia was 36% (14/39). In contrast, no patient transplanted for a genetic disease developed VOD. Neither patient age, sex, remission status, type of graft (i.e. allogeneic or autologous), past history of liver disease nor pretransplant liver function tests were associated with an increased risk of VOD. In addition, 23 of 50 patients had pretransplant samples available for antihepatitis C virus (HCV) testing; 3/23 were reactive (two of nine patients with VOD and one of 14 patients without VOD were positive for anti-HCV). We found a high incidence of pleural effusion in patients with VOD (7/14), an association that has previously not been described. VOD was manageable and resolved in all patients.

Adolescent↗
PubMed1991

Human graft-versus-host disease.

The principal clinical problem encountered following allogeneic bone marrow transplantation is acute and chronic graft-versus-host disease. The presence of acute graft-versus-host disease is the strongest predictor for the development of chronic graft-versus-host disease. The introduction of new prophylactic regimens has reduced the incidence of acute graft-versus-host disease. The clinical presentation and pathophysiology of acute and chronic graft-versus-host disease are discussed. New therapies for chronic graft-versus-host disease may result in improved treatment for human autoimmune diseases.

Bone Marrow Transplantation↗
PubMed1990

In vitro purging of human rhabdomyosarcoma cells using 4-hydroperoxycyclophosphamide.

The outcome of patients with advanced stage rhabdomyosarcoma is extremely poor, with a disease-free survival of less than 20% at 3 years. Autologous bone marrow transplantation for patients with Clinical Group IV rhabdomyosarcoma may be an effective therapy. The bone marrow involvement diagnosed by light microscopy is 29% for patients with advanced disease. The present study was performed to test the ability of 4-hydroperoxycyclophosphamide (4-HC) to eliminate clonogenic rhabdomyosarcoma cells. Four different human rhabdomyosarcoma cell lines were treated in vitro with 4-HC at a concentration of 100 micrograms/ml. Limiting dilution analysis was performed to detect surviving clonogenic tumor cells. Treatment with 4-HC resulted in 1.7-5.7 log of elimination of clonogenic tumor cells in all four cell lines. Exactly the same log tumor cell kill was obtained after mixing normal human bone marrow mononuclear cells with rhabdomyosarcoma cells. Treatment with 4-HC may be an effective method of eliminating clonogenic rhabdomyosarcoma cells ex vivo.

Bone Marrow↗
PubMed1990

Mycobacterium avium-intracellulare infections after allogeneic bone marrow transplantation in children.

Serious infections caused by the Mycobacterium avium-intracellulare (MAI) complex have been increasingly recognized in patients with acquired immunodeficiency syndrome (AIDS). Allogeneic bone marrow transplant recipients are prone to infections caused by a wide spectrum of organisms. However, infection with MAI has been reported only once in an allogeneic bone marrow transplant setting. We describe two allogeneic bone marrow transplant recipients with severe combined immunodeficiency syndrome (SCID) in whom MAI infections occurred. Thus, MAI must be added to the list of infectious pathogens that can infect allogeneic bone marrow transplantation (BMT) recipients. Aggressive multidrug antituberculosis therapy may be of benefit in such patients.

Bone Marrow Transplantation↗
PubMed1990

Bone marrow transplantation for the treatment of immune deficiency states.

The first successful allogeneic bone marrow transplants were performed in children with severe combined immune deficiency (SCID). Bone marrow transplants for patients with SCID have been in the forefront of clinical bone marrow transplantation including the first successful use of T lymphocyte-depleted haploidentical bone marrow and matched unrelated donors. Successful bone marrow transplantation for most forms of SCID requires only the engraftment of donor lymphoid stem cells; donor hematopoietic stem cell engraftment is usually not required. The Wiskott-Aldrich syndrome was the first genetic disease involving the hematopoietic stem cell to be completely corrected by allogeneic bone marrow transplantation. The successful transplantation of Wiskott-Aldrich syndrome patients demonstrated that agents with adequate anti-lymphoid and hematopoietic stem cell activity were necessary in order to achieve complete donor lymphoid and hematopoietic stem cell engraftment. Initially, total body irradiation and now busulfan are used to ablate recipient hematopoietic stem cells, while cyclophosphamide is used to ablate recipient lymphoid stem cells. No single agent/drug is capable of eliminating both stem cell populations. Histocompatible bone marrow transplantation has a role in the treatment of patients with immune deficiency due to primary defects of the hematopoietic stem cell. The recent introduction of cytokines (gamma-interferon and granulocyte colony stimulating factor) may reduce the need for bone marrow transplantation for myeloid immune deficiency states. Initial attempts to treat patients with the acquired immune deficiency syndrome by bone marrow transplantation were limited by the lack of effective concomitant anti-viral therapy. Bone marrow transplantation for immune deficiency states continues to be in the forefront of human bone marrow transplantation.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purged marrows for children with acute non-lymphoblastic leukemia in second remission.

Although autologous bone marrow transplantation (ABMT) following purging with 4-hydroperoxycyclophosphamide (4HC) has been effective for some adults with acute non-lymphoblastic leukemia (ANLL), there are few data on ABMT for children. We have performed ABMT for 13 patients (median age, 5 years) with ANLL in second remission. Bone marrow was treated ex vivo with 4HC to kill residual leukemic cells. In order to enhance the anti-leukemic effect of 4HC, exogenous red blood cells were eliminated from the marrow/4HC mixture. All patients were conditioned for transplantation with busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg), followed by infusion of the 4HC treated marrow. Eleven of 13 patients had complete hematologic reconstitution; there were no transplant-related deaths. Five patients relapsed at 2, 4, 5, 6 and 6 months post-BMT. Eight patients are disease-free survivors; the median time for survival is 24 months, with a projected disease-free survival of 61%. ABMT is a safe and efficacious treatment modality for children with ANLL in second remission. Our results suggest that the disease-free survival for pediatric patients may be superior to that seen in adults.

Actuarial Analysis↗
PubMed1990

Bone marrow transplantation for genetic diseases.

Bone marrow transplantation is the treatment of choice for a number of genetic diseases. Recently, bone marrow transplantation has been increasingly used for erythroid disorders, such as thalassemia and sickle cell anemia. A number of inherited metabolic disorders (i.e., storage diseases, leukodystrophies, and the like) may be corrected with a marrow transplant. Successful correction of genetic diseases with allogeneic bone marrow transplantation lays the groundwork for the use of specific gene therapy.

Bone Marrow Transplantation↗
PubMed1989

Pharmacology studies of 1-beta-D-arabinofuranosylcytosine in pediatric patients with leukemia and lymphoma after a biochemically optimal regimen of loading bolus plus continuous infusion of the drug.

In an attempt to maximize the therapeutic index and to overcome the large variations in 1-beta-D-arabinofuranosylcytosine (ara-C) plasma levels and host toxicities that have been documented with standard HDara-C regimens (3 g/m2 over 3 h every 12 h x 8 or x12 doses), pediatric patients with acute lymphocytic leukemia or lymphoma in relapse were treated with a regimen of loading bolus followed immediately by continuous infusion of ara-C. In addition, patients received a single dose of etoposide (VP-16, 1 g/m2) prior to the ara-C administration. In four patients, total body irradiation was administered as part of a bone marrow transplantation preparative regimen after the ara-C administration. The regimen was designed to attain and maintain plasma steady-state concentrations (Css) of ara-C three to four times the Km2 value of ara-C, which was determined with purified deoxycytidine kinase from the patients' tumor cells prior to treatment. Eight patients age 0.75 to 16 years with relapsed acute lymphocytic leukemia (three patients) or lymphoma (five patients, one with bone marrow involvement), received a test dose of 3 g/m2 ara-C injected over 1 h, and the plasma kinetics were determined. The peak plasma ara-C concentration of ara-C ranged from 57 to 199 microM with an average concentration of 103 +/- 49 microM; the half-lives of distribution (t1/2, alpha) and elimination (t1/2, beta) averaged 17 +/- 7 min and 4.04 +/- 3.1 h, respectively. The mean area under the plasma concentration time curve from 0 to 12 h (AUC0----12 h) of ara-C averaged 386.8 +/- 328.0 microMh (mean, +/- SD, n = 8). The peak concentration of uracil arabinoside averaged 501 +/- 123 microM, and it was eliminated with a t1/2, el of 2.3 +/- 0.6 h. The patients then received an individualized loading bolus (mean = 0.5 g/m2) followed by a continuous infusion regimen of ara-C (mean = 130 mg/m2/h), to achieve a Css in the range of 20 to 35 microM. The obtained plasma Css were similar to the desired ones, averaging in variation 10.7% +/- 8.2%. The percentage of variation of correlation of the AUC following the loading bolus plus the continuous infusion from 12 to 72 h was only 12.4% (mean = 2158 microMh, n = 8), whereas the percentage of variation of correlation of the AUC after the test dose of ara-C in the same patients was 84.8%.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1989

Graft-versus-host disease: an alternative hypothesis.

Medawar and Billingham in their classic experiments described three prerequisites for the development of graft-versus-host disease (GVHD): first, the presence of immunocompetent cells in the donor inoculum; second, the inability of the recipient to reject the donor cells; and third, a histocompatibility difference between the donor and recipient. These experiments are the basis for all later hypotheses related to the pathogenesis of GVHD. Recently, de Gast and colleagues reviewed the role of environmental antigens in the pathogenesis of GVHD and suggested that immunological responses to environmental antigens by the transplanted donor cells might contribute to an increased donor anti-recipient response. An area not addressed in that review was the potential role of autoreactivity in GVHD. In this short article, Robertson Parkman highlights the role of autoreactivity and autoantigens in the pathogenesis of both acute and chronic GVHD in histocompatible bone marrow transplantation.

Animals↗
PubMed1989

Lymphocyte phenotype does not predict immune function in pediatric patients infected with human immunodeficiency virus type 1.

To determine whether assays of lymphocyte phenotype were predictive of antigen-specific immunologic function in children infected with human immunodeficiency virus type 1 (HIV-1), we compared the antigen-specific cellular and humoral functions (tetanus toxoid-induced T lymphocyte blastogenesis and anti-tetanus toxoid antibody) with the patients' T lymphocyte phenotype, determined at the same time. Although both HIV-1-infected patient populations studied (pediatric hemophilia patients and other pediatric patients) had decreases in the values determined by their functional and phenotypic assays, no association between the functional and phenotypic assays was demonstrated. Thus some HIV-1-infected patients with a normal phenotype had no antigen-specific function, whereas other patients with a markedly abnormal T lymphocyte phenotype had normal antigen specific T lymphocyte function. These results indicate that the assessment of HIV-1-infected patients should include assays of antigen-specific immune function in addition to assays of T lymphocyte phenotype.

Acquired Immunodeficiency Syndrome↗
PubMed1988

A method for the preparation of mononuclear cells devoid of platelet contamination and its application to the evaluation of putative alpha-receptors in normal and asthmatic subjects.

Receptor studies of human mononuclear leukocytes (MNLs) are complicated by the presence of contaminating platelets which have common receptors. A method was devised to produce MNLs free of platelets (less than 1%) and consists of sequential Ficoll-Hypaque gradients, a BSA gradient and a washing step. Lack of platelet contamination was confirmed by the following criteria: (a) microscopic evaluation using fluorescent dyes showed less than 1% platelets; (b) PGE1 stimulation of the leukocyte membrane adenylate cyclase required addition of exogenous GTP while the platelet cyclase did not; (c) immunoblots of the cells and membranes using antibodies strongly reactive against platelet membranes showed no reactivity against MNL membranes; (d) [3H]yohimbine showed no binding in MNL membranes under conditions where substantial binding to platelets was detected. MNLs were viable as judged by dye exclusion. PHA stimulation of lymphocytes was unimpaired. Plasma membranes of MNLs were prepared by brief sonication and fractionation on a sucrose step gradient. Binding studies using 3H-DHE, an alpha-receptor ligand, revealed no binding in MNLs from normal subjects (n = 6). By contrast, studies on cells from subjects with mild asthma with medication appropriately withheld (n = 8) showed low levels of binding (60-300 fmol/10(6) cells). The subtype and functionality of the putative alpha-receptors are being further evaluated.

Adenylyl Cyclases↗