PubMed Health⌕ Search

Biomedical subjects

S E Krown

Publications and source records attributed to S E Krown.

At least 19 recordsLinked to original sources
PubMed1992

Histologic predictors of survival in acquired immunodeficiency syndrome-associated Kaposi's sarcoma.

The relationship between 22 histologic variables and survival was investigated in 93 patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). All the patients were homosexual men in whom KS was the initial manifestation of AIDS. All patients were followed for at least 12 months or until death. Histologic specimens of the initial KS biopsy were reviewed in a blind manner by two of the authors and were evaluated for the presence of a number of histologic features. In a univariate analysis nodular lesions of KS (upsilon patch or plaque lesions), the absence of hemosiderin, the absence of irregular vascular spaces, and the presence of spindle cell nodules were all significantly associated with increased length of survival. Two variables previously shown to be related to survival (CD4:CD8 cell ratio, initial lesion on lower extremities) were included in a multivariate analysis (Cox model) in addition to the histologic variables. Complete data were available from 85 patients. In the multivariate analysis a higher helper to suppressor T-cell ratio, initial lesion on lower extremities, presence of spindle cell nodules, and nodular histology (upsilon patch or plaque histology) were all significantly associated with increased length of survival. These data suggest that in AIDS-associated KS, as in reticuloendothelial neoplasms, histologic features may be useful in identifying prognostically different subgroups of patients.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Interferon-alpha, zidovudine, and granulocyte-macrophage colony-stimulating factor: a phase I AIDS Clinical Trials Group study in patients with Kaposi's sarcoma associated with AIDS.

PURPOSE: To increase the hematologic tolerance of interferon-alpha (IFN alpha) and zidovudine combination therapy by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF), and to evaluate the safety, tolerance, and potential efficacy of the combination in patients with Kaposi's sarcoma and AIDS. PATIENTS AND METHODS: Seventeen patients with Kaposi's sarcoma associated with AIDS received zidovudine 200 mg orally every 4 hours and GM-CSF 5 micrograms/kg/d subcutaneously. Successive cohorts received IFN-alpha 2b at a daily subcutaneous dose of 5, 10, or 20 million units. The dose of GM-CSF was titrated to maintain the neutrophil count between 1 and 5 x 10(9) cells/L. Doses of all three drugs were reduced, as required, for nonhematologic toxicities. RESULTS: GM-CSF induced leukocytosis in all patients. On average, a dose of 1.25 micrograms/kg/d was sufficient to maintain the neutrophil count within the desired range. The combination of 20 million units of IFN-alpha with zidovudine and GM-CSF induced dose-limiting toxicity in four of six patients. The major side effects were constitutional symptoms, which included malaise, anorexia, fatigue, fever, and were dose-limiting in three patients. Severe anemia and/or thrombocytopenia developed in three patients. Seven patients (41%; 95% confidence interval [CI], 18% to 64%) showed objective tumor regression that persisted for a median of 51 weeks. A rapid decrease in free-serum p24 antigen levels was observed in seven patients who had measurable levels at baseline; the mean time required to isolate human immunodeficiency virus (HIV-1) from peripheral-blood cells was increased by 7 days. The number and percentage of CD4-positive lymphocytes showed no significant change. CONCLUSIONS: GM-CSF prevents neutropenia induced by the IFN-alpha and zidovudine combination and induced no adverse effects on immune function or HIV activity. However, nonhematologic toxicity precluded a major increase in the maximum-tolerated doses of IFN-alpha and zidovudine.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Medical management of AIDS patients. Kaposi's sarcoma.

Kaposi's sarcoma (KS) presents with variable severity in the context of HIV infection. Various therapeutic approaches can be taken, and these are determined by the extent and location of KS lesions and the severity of tumor-related symptoms. New insights into the pathogenesis of KS lesions may provide innovative treatment strategies and a more rational basis for the control of this neoplasm.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Interferon-alpha therapy in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome.

High dose IFN-alpha is an effective treatment for a subset of patients with Kaposi's Sarcoma, that is, those who lack systemic symptoms (e.g. fever, weight loss), and co-existing HIV-associated conditions (e.g. opportunistic infections), and whose cell-mediated immunity system is only mildly or moderately impaired. There is little evidence that the addition of chemotherapeutic agents to IFN-alpha improves treatment outcome. Response rates in excess of 40% have been reported with the addition of AZT to IFN-alpha, and may prove active in patients with more severely impaired T-cell immunity. There is evidence that in responding patients, IFN-alpha also suppresses HIV replication, and in vitro studies indicate synergistic suppression of HIV by the IFN-alpha-AZT combination; evidence for in vitro synergy is being sought.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Interferon-alpha 2a in the treatment of acquired immunodeficiency syndrome-related Kaposi's sarcoma.

In a series of studies, recombinant interferon-alpha 2a (rIFN alpha 2a, Roferon-A) was administered alone (273 men) or combined with vinblastine (91 men) to patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Patients were treated with daily doses of rIFN alpha 2a ranging from 3 to 54 million international units (I.U.) administered intramuscularly. A dose of 36 million I.U. daily for approximately 10 weeks followed by a three times weekly maintenance schedule with the same dose resulted in the best overall therapeutic benefit. An escalating-dose regimen of 3, 9, and 18 million I.U. daily, each for 3 days, followed by 36 million I.U. daily, produced equivalent therapeutic benefit with amelioration of acute toxicity in some patients. Response was more likely in patients without a history of opportunistic infection or B symptoms (fever, night sweats, or weight loss). Response rate increased with increasing baseline CD4 lymphocyte count and was 45.5% in patients with a CD4 count of greater than 400/mm3. Responding patients with a CD4 count of greater than 200/mm3 had a distinct survival advantage over patients who had similar CD4 counts but whose tumors did not regress with therapy. The addition of vinblastine increased toxicity and did not improve the response rate or prolong survival. Side effects included fatigue, fever, chills, myalgias, headaches, anorexia, nausea, diarrhea, and dizziness. Mild abnormalities in hematologic and liver function tests occurred in some patients. Most adverse effects diminished or resolved with continued therapy. We conclude that rIFN alpha 2a offers important therapeutic benefit in a select group of patients with AIDS-related KS.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Interferon and other biologic agents for the treatment of Kaposi's sarcoma.

Interferon-alpha is an effective treatment for a subset of patients with AIDS-associated Kaposi's sarcoma. When given at high doses to patients who lack systemic signs, symptoms, and opportunistic infections associated with advanced HIV infection and who maintain some degree of cell-mediated immune function, tumor regression may be observed in a high proportion of patients. Although the addition of chemotherapy to IFN-alpha appears to confer no added benefits, the combination of IFN-alpha with zidovudine has induced high tumor response rates in preliminary studies, including responses in some patients considered unlikely to respond to IFN-alpha alone. IFN-alpha-induced tumor regression has also been associated with suppression of HIV, as measured by serum p24 antigen concentrations and peripheral blood virus cultures. Other biologic agents, including interferons beta and gamma, tumor necrosis factor, and IL-2, have also been tested, to a lesser extent, in patients with Kaposi's sarcoma. Although systemically administered IFN-beta and intralesional TNF injections have led to tumor regression in some cases, the role of these biologics has been incompletely defined. Additional studies of these agents in combination with nucleoside reverse transcriptase inhibitors such as zidovudine will be required to fully assess their role in the treatment of Kaposi's sarcoma and HIV infection. It can also be anticipated that newer biologic agents, which specifically inhibit the production or action of angiogenic factors believed to be involved in the genesis of Kaposi's sarcoma, will be studied in the near future.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Relationship and prognostic value of endogenous interferon-alpha, beta 2-microglobulin, and neopterin serum levels in patients with Kaposi sarcoma and AIDS.

We investigated whether elevated serum levels of beta 2-microglobulin and neopterin were related to the abnormal in vivo production of interferon described in patients with human immunodeficiency virus (HIV) infection, and whether these factors might add to measurements of CD4+ T cells in predicting survival and tumor regression in patients with Kaposi sarcoma associated with AIDS. beta 2-Microglobulin and neopterin levels were strongly correlated (r = 0.82), and were each significantly higher in patients with detectable serum interferon-alpha activity. Inverse correlations were observed between prognosis and levels of these serum products. Prediction by CD4+ T-cell count of tumor regression after treatment with interferon-alpha and zidovudine was improved by each of two factors: (a) the presence or absence of endogenous interferon-alpha activity, and (b) a combined variable reflecting relative levels of the interferon-inducible products, beta 2-microglobulin and neopterin. The level of beta 2-microglobulin was the single best predictor of survival. When beta 2-microglobulin was not considered, the endogenous interferon-alpha variable was the best predictor of survival, and the prediction was enhanced by addition of the combined variable, or the neopterin value alone. We conclude that serologic markers, which directly or indirectly reflect activation of the endogenous interferon system, may be valuable adjuncts to CD4+ T-cell counts in assessing prognosis and selecting and evaluating treatments for patients with Kaposi sarcoma and AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Interferon-alpha with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS)

OBJECTIVE: To evaluate safety, tolerance, and potential efficacy of interferon-alpha and zidovudine combination therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS). DESIGN: Open, phase-I study with randomization between two preparations of interferon-alpha. SETTING: Outpatient clinic of a cancer research center. PATIENTS: Forty-three patients with Kaposi sarcoma associated with AIDS. INTERVENTIONS: Patients were treated with interferon-alpha, 4.5, 9, or 18 million U/d, and zidovudine, 100 or 200 mg orally every 4 hours. MEASUREMENTS AND MAIN RESULTS: Neutropenia was the major dose-limiting toxicity. Fatigue, liver enzyme elevation, anemia, and thrombocytopenia were dose-limiting in some patients. Maximum tolerated dosages for interferon-alpha 2a with zidovudine, respectively, were 4.5 million U/d with 200 mg every 4 hours or 18 million U/d with 100 mg every 4 hours. An interferon-alpha n1 [corrected] dosage of 9 million U/d with zidovudine dosages of either 100 or 200 mg every 4 hours induced dose-limiting toxicity in most patients. Of 37 evaluable patients, 17 (46%; 95% CI, 30% to 62%) showed complete or partial tumor regression. Antitumor effects occurred more frequently in patients with baseline CD4 counts above 200 x 10(6) cells/L (65%) than in patients with lower baseline counts (30%, P = 0.05). Effects on CD4 cells were related to both initial CD4 count and interferon dose. Increased skin test reactivity and decreased serum human immunodeficiency virus (HIV) p24 antigen and virus recovery from blood cells were seen. CONCLUSIONS: Combined therapy with interferon-alpha and zidovudine can be safely administered to patients with AIDS and Kaposi sarcoma. The observed effects on tumor growth, HIV replication, and immune function support further studies of the combination in patients at various stages of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Treatment of AIDS-associated malignancy.

Neoplasms associated with acquired immunodeficiency syndrome (AIDS) present unique therapeutic challenges. High-grade systemic lymphomas, although often responsive to standard chemotherapy, will require the addition of CSFs, infection prophylaxis, and antiretroviral drugs to overcome poor marrow reserves, short response durations, and opportunistic infections. Treatment of primary central nervous system (CNS) lymphomas is complicated by their frequent occurrence as a late complication in debilitated patients. AIDS-associated Kaposi's sarcoma (KS) is a unique neoplasm whose pathogenesis is only beginning to be understood. Although responsive to standard therapy (RT, chemotherapy), considerable attention has been focused on the therapeutic potential of BRMs. Interferon alpha (IFN-alpha), which combines antiviral, antiproliferative, and immunoregulatory activities, has significant anti-KS activity, particularly in symptom-free patients with mild immunosuppression. Preliminary data links IFN-induced regression of KS to its anti-HIV activity and supports a role for endogenous IFN-alpha in the induction of refractoriness to IFN treatment. Recent data suggest synergistic anti-HIV and anti-KS activity for the combination of IFN-alpha and AZT. Additional study is needed to evaluate IFN effects on autocrine growth factors regulating the growth of KS.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Approaches to interferon combination therapy in the treatment of AIDS.

High-dose interferon alfa (IFN alfa) therapy induces an overall response rate of 25% to 30% in unselected patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma. Up to 50% of patients with relatively preserved immune reactivity respond to treatment. However, when dosages of 20 x 10(6) units or more per day are used to induce responses, constitutional and hematologic side effects may be significant. Therefore, efforts are being made to lower the effective dose of IFN alfa. One effort involves combining IFN alfa with zidovudine (AZT; Retrovir; Burroughs Wellcome, Research Triangle Park, NC). These agents act synergistically to block the multiplication of human immunodeficiency virus (HIV) in vitro. The drugs act at different points in the HIV multiplication cycle, which may explain their synergistic interaction. In addition, AZT enhances certain immune functions that have been correlated with a positive IFN alfa response. Preliminary clinical trials indicate that antitumor responses in Kaposi's sarcoma are seen with dosages of IFN alfa as low as 4.5 x 10(6) units per day when combined with AZT. However, the combination of IFN alfa and AZT may also produce dose-limiting hematologic side effects; these effects may limit the usefulness of the drug combination. Strategies for ameliorating these toxicities through the use of additional agents are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee.

The availability of uniform and precise criteria for disease evaluation, response to treatment, and clinical staging of Kaposi's sarcoma (KS) in individuals with the acquired immune deficiency syndrome (AIDS) would facilitate therapeutic trials in patients with this neoplasm. Recently, a group of oncologists conducting clinical trials in patients with AIDS-associated KS as part of a cooperative group established by the National Institute of Allergy and Infectious Diseases (NIAID) drafted such criteria. The criteria take into account the unique problems associated with the evaluation of patients with a disseminated cutaneous neoplasm in the setting of a systemic virus infection associated with immune deficiency. The recommendations include a standardized format for documenting the extent of KS on initial and subsequent evaluations, response definitions that include assessments of lesion nodularity and tumor-associated edema in addition to more traditional methods for evaluating tumor response, and a new staging system that includes extent of tumor, immune status, and other AIDS-related disease manifestations, akin to the tumor-node-metastasis (TNM) system used to stage other tumors. The adoption of standardized criteria for the evaluation of KS should prove useful for group trials and for other investigators involved in the treatment of this disease.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells.

Azidothymidine (AZT) and interferon alpha (IFN-alpha) are among the drugs showing strong in vitro activity against the human immunodeficiency virus type-1 (HIV-1). Each drug, however, has significant toxicity against normal marrow progenitor cells that frequently proves dose-limiting in patients. In this study, AZT and recombinant IFN-alpha 2a (rIFN-alpha 2a) were tested as single agents and in combination against normal myeloid (CFU-GM) and erythroid (BFU-E) colony forming cells in a standard methylcellulose culture assay. The data were analyzed using a quantitative computerized analysis based on the median-effect principle and the isobologram equation as described by Chou and Talalay (Adv Enz Regul 22:27, 1984). The ED90 for BFU-E and CFU-GM inhibition was then compared with previously measured in vivo plasma levels of each drug and the ED90 for the anti-HIV-1 effect in vitro. We demonstrate that (a) the drugs are strongly synergistic in inhibiting marrow progenitor cell growth and that this synergism occurs at drug levels that are within the range of measured plasma levels in phase I clinical trials, (b) BFU-E are more sensitive than CFU-GM to the inhibiting effects of AZT, rIFN-alpha 2a or both drugs in combination, (c) the drug concentrations in combination that synergistically inhibit bone marrow progenitors are much higher than those required to inhibit HIV-1 replication in vitro, and (d) the anti-HIV-1 effect for the combination of AZT and rIFN-alpha 2a was clearly superior to the effect of AZT or rIFN-alpha 2a alone as indicated by the combination index and the dose-reduction index. These data suggest that substantially lower doses of AZT and rIFN-alpha than those currently being tested in clinical trials might not only maintain a strong synergistic anti-HIV-1 effect but might also avoid significant hematologic toxicity.

Bone Marrow↗
PubMed1988

Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome.

A case of disseminated pneumocystosis occurring in a patient with the acquired immunodeficiency syndrome is described. Postmortem examination of this patient, who had three episodes of Pneumocystis carinii pneumonia during his 3-year clinical course, revealed clinically unsuspected infiltration of lymph nodes, spleen, adrenal glands, and bone marrow, in addition to persistent pulmonary infection by the organism.

Acquired Immunodeficiency Syndrome↗
PubMed1988

AIDS-associated Kaposi's sarcoma: variables associated with survival.

The records of 187 consecutive patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma were analyzed retrospectively for a number of prognostic variables. In a multivariate analysis, the initial site of disease was found to be related to survival. Initial lesions on the skin of the lower extremities or in the lymph nodes were associated with longer survival (p = 0.005 and p = 0.01, respectively). Higher helper/suppressor T cell ratios were strongly associated with longer survival (p less than 0.0001). Age and serum IgG antibody levels to cytomegalovirus did not appear to correlate. These results suggest that there are different subgroups of patients with AIDS-associated Kaposi's sarcoma, and that the initial site of disease, as well as immunologic parameters, may be useful in prognosis.

Acquired Immunodeficiency Syndrome↗