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D T Scadden

Publications and source records attributed to D T Scadden.

87 records · Page 5Linked to original sources
PubMed1991

GM-CSF as an alternative to dose modification of the combination zidovudine and interferon-alpha in the treatment of AIDS-associated Kaposi's sarcoma.

Combined zidovudine (ZDV) and interferon-alpha (IFN) is an appealing therapy for AIDS-associated Kaposi's sarcoma because of the antiretroviral as well as antitumor potential of this combination. Overlapping myelotoxicity of these agents, however, frequently complicates their clinical use. This phase I/II study was undertaken to test the safety and efficacy of granulocyte-macrophage colony stimulating factor (GM-CSF) in those patients who became neutropenic while receiving ZDV (1,200 mg/day) and IFN (9 MU/day). Despite a "high-risk" population of patients, the tumor response rate among evaluable patients was 50% (33% overall). Sixty-four percent of patients required GM-CSF and all patients receiving GM-CSF had a prompt improvement in their absolute neutrophil count (ANC). The use of GM-CSF was associated with an improved end of study ANC (p less than 0.05), but was not associated with tumor response, CD4 count improvement, or improved change in hemoglobin concentration. GM-CSF/ZDV/IFN was not associated with increased toxicity over ZDV/IFN; however, two unusual events occurred in the GM-CSF/ZDV/IFN group: erythema multiforme and glucose intolerance. Dose-limiting thrombocytopenia and anemia were seen in two patients and anemia in one patient on GM-CSF/ZDV/IFN. No consistent alterations in serum HIV p24 antigenemia were noted in either group. The use of GM-CSF mitigated the neutropenia of combined ZDV and IFN. Further study evaluating the utility of this hematopoietic growth factor in combination therapies for AIDS patients is warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Granulocyte-macrophage colony-stimulating factor mitigates the neutropenia of combined interferon alfa and zidovudine treatment of acquired immune deficiency syndrome-associated Kaposi's sarcoma.

The combined use of zidovudine (ZDV) and interferon (IFN) alfa-2a has been shown to have antiretroviral and antitumor potential benefit in the treatment of acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). However, the clinical use of this combination is frequently complicated by the overlapping myelotoxicity of these agents. We report here the results of a phase I/II study in which granulocyte-macrophage colony-stimulating factor (GM-CSF) was used for those KS patients who became neutropenic while receiving ZDV (1,200 mg/d) and IFN (9 x 10(6) U/d). Nineteen of 29 patients (66%) developed an absolute neutrophil count (ANC) of less than 1,000 cells per cubic millimeter and were begun on GM-CSF. All experienced a prompt increase in the ANC. Those patients receiving GM-CSF/ZDV/IFN alfa-2a had an improved end of study ANC when compared with the ZDV/IFN alfa-2a group, but did not have an increased rate of tumor response, end of study CD4 cell count, or improvement in any other hematologic variable. The use of GM-CSF was not associated with increased toxicity and, in particular, was not associated with a change in serum human immunodeficiency virus (HIV) p24 antigen. Tumor response was noted in 50% of the assessable patients (33% overall) despite "high-risk" characteristics in 80%. Of the responding patients, seven were on GM-CSF and might have otherwise required an alteration in ZDV/IFN alfa-2a dose level. Further study of GM-CSF as an alternate to dose modification of this (ZDV/IFN alfa-2a) and other combination therapies for AIDS patients is warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Lack of evidence for infection of or effect on growth of hematopoietic progenitor cells after in vivo or in vitro exposure to human immunodeficiency virus.

The pathogenesis of the hematologic abnormalities commonly observed in patients with acquired immunodeficiency syndrome (AIDS) is incompletely understood. We report here that in vitro growth of myeloid (CFU-GM) and erythroid (BFU-E) progenitor cells from six patients with AIDS was not significantly different from that of normal human immunodeficiency virus (HIV) seronegative donors: 25.3 +/- 5 CFU-GM per 5 x 10(4) low density marrow cells and 33.5 +/- 5 BFU-E were observed in AIDS patients versus 32.7 +/- 5 CFU-GM and 42.1 +/- 5 BFU-E in controls. Furthermore, no HIV-DNA in individual colonies (CFU-GM and BFU-E) could be detected using the polymerase chain reaction (PCR) technique, although HIV-1 DNA was detected in peripheral blood mononuclear cells from the same patients. Similarly, normal bone marrow cells exposed in vitro to different isolates of HIV or recombinant purified HIV-1 envelope glycoprotein (gp) 120 did not exhibit any difference in growth of CFU-GM or BFU-E as compared with mock exposed bone marrow cells. HIV-1 DNA could not be detected by the PCR technique in individual colonies derived from HIV exposed marrow. This study suggests that committed myeloid and erythroid progenitors from AIDS patients are responsive to hematopoietic growth factors in vitro and do not appear to contain HIV-1 DNA. Also, HIV or its envelope gp did not alter the growth of hematopoietic progenitor cells in vitro. No evidence of HIV infection of progenitor cells could be demonstrated. Impaired hematopoiesis in patients with AIDS may not be related to direct effects of HIV on committed progenitor cells.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Human immunodeficiency virus infection of human bone marrow stromal fibroblasts.

The human immunodeficiency virus (HIV) preferentially infects CD4 positive T cells and monocytes. Other human cell types have been reported to be infectable with HIV, including cells of mesenchymal origin. In this report, we show that both primary human bone marrow stromal fibroblasts and an immortalized human stromal fibroblast line are susceptible to HIV infection. These cells are capable of passing HIV to cells of lymphoid or myeloid lineage, and may thereby act as a reservoir of virus. This in vitro system may be a useful model for assessing the pathophysiology of hematopoietic dysfunction in AIDS patients.

Actins↗
PubMed1990

Human cells infected with retrovirus vectors acquire an endogenous murine provirus.

A 5.2-kilobase mouse RNA is expressed in human cells following infection with recombinant retroviruses propagated in mouse NIH 3T3 cells as psi-2 pseudotypes. This RNA is transcribed from a defective mink cell focus-forming provirus and copackaged into virions and integrated into human target cell DNA at a frequency comparable to that of the recombinant retrovirus genome.

Animals↗
PubMed1990

Human immunodeficiency virus does not induce interleukin-1, interleukin-6, or tumor necrosis factor in mononuclear cells.

The production of interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) by fresh peripheral blood mononuclear cells was evaluated after exposure to human immunodeficiency virus (HIV) or purified recombinant HIV-1 envelope glycoprotein (rgp120). To exclude the role of contaminating endotoxin in this study, all media were subjected to ultrafiltration and reagents contained less than 25 pg of endotoxin per ml by Limulus assay. Under endotoxin-free conditions, no increases in IL-1 beta, IL-6, or TNF-alpha mRNA or protein were detectable in cell cultures exposed to HIV-1, HIV-2, or rgp120 (0.1 to 10 micrograms/ml), as compared with cytokine levels in mock-exposed cultures. However, concentrations of endotoxin (lipopolysaccharide) as low as 0.5 ng/ml induced significant production of mRNA and protein for these three cytokines. Preincubation of mononuclear cells with "shake" HIV-1 preparations and also mock-infected shake preparations prior to lipopolysaccharide stimulation resulted in a two- to threefold increase in IL-1 beta and TNF-alpha production. This priming effect was not observed with rgp120 (0.1 to 10 micrograms/ml) or standard HIV-1 or mock-infected supernatants, suggesting the presence of biologically active material independent of virus in the shake preparations. Our studies indicate that, in the absence of endotoxin, HIV-1, HIV-2, and HIV gp120 do not induce production of IL-1 beta, IL-6, or TNF-alpha by peripheral blood mononuclear cells.

Cells, Cultured↗
PubMed1990

Granulocyte macrophage colony stimulating factor (GM-CSF) in AIDS.

Overall GM-CSF is a well tolerated intervention in patients with HIV associated disease. As in a number of other clinical settings, it is able to improve myelopoiesis and abrogate the myelotoxicity of chemotherapeutic agents. At present, clinical data is insufficient to indicate an ultimate clinical benefit from the use of GM-CSF in terms of opportunistic infection, mortality or quality of life for HIV infected patients. As phase I and phase II trials are completed however comparative clinical trials addressing these issues are anticipated. Hematopoietic growth factors may permit the use of optimal doses of therapeutics and thereby play an adjunctive role in the combination therapies anticipated for the treatment of HIV related disease.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Hematopoietic growth factors. Biology and clinical applications.

The hematopoietic growth factors are potent regulators of blood-cell proliferation and development. The first phase of clinical trials suggests that they may augment hematopoiesis in a number of different conditions of primary and secondary bone marrow dysfunction. Future clinical use is likely to include combinations of these growth factors, in order to stimulate early marrow progenitors and obtain multilineage effects. An improved understanding of the biologic and clinical effects of hematopoietic growth factors promises future clinical applications for conditions of impaired function and reduced numbers of blood cells.

Colony-Stimulating Factors↗
PubMed1989

Production of tumor necrosis factor alpha and interleukin 1 beta by monocytic cells infected with human immunodeficiency virus.

The production of tumor necrosis factor alpha (TNF alpha) and IL-1 beta by the monocytic cell line THP-1, productively infected with HIV-1, was investigated using specific RIA and Northern blot analysis. HIV-infected cells, like uninfected cells, did not constitutively produce any detectable amounts of protein or mRNA for TNF alpha or IL-1 beta. After stimulation with LPS or a combination of LPS plus IFN-gamma, TNF alpha and IL-1 beta were detected in tissue culture supernatants and cell lysates and transcripts for both cytokines were seen on Northern blots. No significant difference in production of these two cytokines was observed between uninfected and chronically infected cells. Acutely HIV-infected cells, however, showed phenotypic changes compatible with maturation and an increase in TNF alpha and IL-1 beta mRNA production, and released significantly higher levels of TNF alpha and IL-1 beta compared with chronically infected or uninfected cells. Furthermore, LPS stimulation of HIV-infected cells increased virus production. These results suggest that HIV-infected monocytic cells may produce increased amounts of TNF alpha and IL-1 beta in response to stimuli that could be present in vivo.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Extravasation of liposomal daunorubicin in patients with AIDS-associated Kaposi's sarcoma: a report of four cases.

PURPOSE/OBJECTIVES: To report on four patients with AIDS-related Kaposi's sarcoma who were treated with liposomal daunorubicin (DaunoXome, NeXstar Pharmaceuticals, Inc., San Dimas, CA) as part of phase I/II and phase III clinical trials and who experienced extravasation during IV infusion. DATA SYNTHESIS: All patients were treated with ice as an immediate intervention. In addition, two patients received treatment with multiple subcutaneous injections of steroids. Two patients experienced erythema, swelling, and pain after the extravasation. Two patients who were treated aggressively reported erythema and swelling without pain. Three patients observed changes in the texture of their skin that was accompanied by decreased sensation, which developed after 8-16 weeks. These changes completely resolved in all patients receiving intervention after six months. None of the patients suffered tissue necrosis. CONCLUSIONS: Extravasation with liposomal daunorubicin is notable for the absence of tissue necrosis that typically is observed with anthracyclines. Long-term effects were limited to skin discoloration and decreased sensation, both of which resolved in all patients. IMPLICATIONS FOR NURSING PRACTICE: The lack of observed skin necrosis with daunorubicin suggests a treatment advantage with a reduction in the required aggressive extravasation procedures for free anthracyclines as well as increased safety for the patient. Additional data is needed to confirm these observations.

Acquired Immunodeficiency Syndrome↗