Patient selection in high-dose trials of breast cancer.
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Antineoplastic Agents↗
Biomedical subjects
J F DiPersio
Publications and source records attributed to J F DiPersio.
Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation.
Graft-versus-host disease (GvHD) is the major limiting toxicity of allogeneic bone marrow transplantation. T cells are important mediators of GvHD, but the molecular mechanisms that they use to induce GvHD are controversial. Three effector pathways have been described for cytotoxic T lymphocytes: one requires perforin and granzymes, the second Fas (APO-1; CD95) and its ligand. Thirdly, secreted molecules (e.g., TNF-alpha, gamma-IFN) can also mediate cytotoxicity. Together, these mechanisms appear to account for virtually all cytotoxicity induced by activated CTL in standard in vitro lytic assays. Using transplants across histocompatibility barriers, we were able to analyze the contributions of these effector molecules to cell-mediated cytotoxicity in vivo in a GvHD model. We found that Fas ligand is an important independent mediator of class II-restricted acute murine GvHD, while perforin/granzyme-dependent mechanisms have only a minor role in that compartment. In contrast, perforin/ granzyme-dependent mechanisms are required for class I-restricted acute murine GvHD, while Fas ligand is not. The perforin/granzyme pathway may therefore represent a novel target for anti-GvHD drug design. In support of this approach, we provide additional data suggesting that specific perforin/granzyme inhibitors should not adversely affect hematopoietic recovery after transplantation.
Animals↗
Autotransplantation for relapsed or refractory non-Hodgkin's lymphoma (NHL): long-term follow-up and analysis of prognostic factors.
One hundred and thirty-six patients autografted for relapsed or refractory non-Hodgkin's lymphoma (NHL) were evaluated to assess long-term event-free survival and to identify important prognostic factors. High-dose therapy consisted primarily of carmustine (BCNU), etoposide, cytarabine, and cyclophosphamide (BEAC) followed by unpurged autologous stem cell rescue. The 5-year Kaplan-Meier event-free survival (EFS) for the entire cohort was 34% (95% confidence interval: 24-44%) with a median follow-up of approximately 3 years (range 0-7.5 years). For patients entering with minimal disease (defined as all areas < or = 2 cm), the 5-year EFS was 40 vs 26% for those entering with bulky disease (P = 0.0004). In the multivariate analysis, minimal disease on entry and administration of involved-field XRT post-transplant were significantly associated with improved EFS; the latter association was observed mainly in the cohort of patients with bulky disease. The overall 100-day treatment-related mortality rate was 4.4% (3% for the last 71 patients). New strategies are needed to reduce the high rate of relapse (50-60%) following auto-transplantation for relapsed or refractory NHL.
Adolescent↗
Granulocyte-macrophage colony-stimulating factor with induction treatment of acute myelogenous leukemia.
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Antineoplastic Combined Chemotherapy Protocols↗
Human blood-mobilized hematopoietic precursors differentiate into osteoclasts in the absence of stromal cells.
Osteoclastogenesis is a complex process that is facilitated by bone marrow stromal cells (SCs). To determine if SCs are an absolute requirement for the differentiation of human hematopoietic precursors into fully mature, osteoclasts (OCs), CD34+ cells were mobilized into the peripheral circulation with granulocyte colony-stimulating factor, harvested by leukapheresis, and purified by magnetic-activated cell sorting. This procedure yields a population of CD34+ cells that does not contain SC precursors, as assessed by the lack of expression of the SC antigen Stro-1, and that differentiates only into hematopoietic cells. We found that CD34+, Stro-1- cells cultured with a combination of granulocyte/macrophage colony-stimulating factor, interleukin 1, and interleukin 3 generated cells that fulfill current criteria for the characterization of OCs, including multinucleation, presence of tartrate-resistant acid phosphatase, and expression of the calcitonin and vitronectin receptors and of pp60c-src tyrosine kinase. These OCs also expressed mRNA for the noninserted isoform of the calcitonin receptor and excavated characteristic resorption pits in devitalized bone slices. These data demonstrate that accessory SCs are not essential for human osteoclastogenesis and that granulocyte colony-stimulating factor treatment mobilizes OC precursors into the peripheral circulation.
Acid Phosphatase↗
Mutational analysis of the alpha subunit of the human interleukin-3 receptor.
The alpha subunit of the human interleukin-3 receptor (IL-3R alpha) is a 70-kD glycoprotein member of the hematopoietin receptor superfamily. This protein associates with a beta subunit common to the receptors for IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) to form a high-affinity receptor for IL-3. To identify regions of IL-3R alpha critical for ligand binding and receptor function, cDNAs encoding mutant receptors were generated and expressed in COS cells along with the beta subunit. Mutant receptors lacking almost the entire cytoplasmic domain of IL-3R alpha [IL-3R alpha(CD)] or carrying a substitution of trp for leu in the membrane proximal leu-ser-x-trp-ser (LSXWS) box bound 125I-IL-3 with nearly the same affinity as wild-type IL-3R alpha. In contrast, a mutant lacking the entire "LSXWS" motif failed to bind 125I-IL-3 with high affinity despite showing surface expression. In addition, hybrid receptors composed of the first 104 amino acids (aa) of IL-3R alpha joined to aa 118 through 400 of the alpha subunit of the GM-CSF receptor (GM-R alpha) [IL-3R alpha/GM-R alpha] or the first 118 aa of GM-R alpha joined to aa 104 through 378 of IL-3R alpha [GM-R alpha/IL-3R alpha] failed to bind 125I-IL-3 in the presence of the beta subunit. A third hybrid receptor composed of the first 281 residues of IL-3R alpha fused to residues 306 through 379 of GM-R alpha [IL-3R alpha/GM-R alpha-DS] also failed to bind 125I-IL-3 in the presence of the beta subunit but, in contrast to the IL-3R alpha/GM-R alpha hybrid, demonstrated weak surface expression. Mutant receptors lacking the N-terminal 30 aa and the N-terminal 9 aa also did not bind 125I-IL-3 with high affinity, although both were expressed on the cell surface. These data suggest that although the cytoplasmic domain and the leucine residue of the "LSXWS" box are not critical for ligand binding or beta-subunit association, the "LSXWS" motif and amino-terminal sequences are important for these functions.
Amino Acid Sequence↗
Leukodepleted-ABO-identical blood components in the treatment of hematologic malignancies: a cost analysis.
To assess the effect of ABO-identical, filtration leukodepleted transfusions on resource consumption and costs of care we performed a cohort study in consecutive adult patients admitted for induction therapy of acute myeloid or lymphoid leukemia during 1985-92 (n = 120) and consecutive adult patients admitted for autologous bone marrow transplantation for Hodgkin's or non-Hodgkin's lymphoma during 1989-1991 in our university hospital. Patients with acute leukemia received either ABO unmatched, unfiltered transfusions (1985-89), ABO identical, unfiltered transfusions (1987-90), or ABO identical, filtered transfusions (1990-92). Patients with lymphoma received either ABO unmatched, unfiltered transfusions (1989-90) or ABO identical, filtered transfusions (1990-91). Mean platelet transfusion requirements per patient decreased with ABO identical platelets and filtered transfusions: from 143 to 71 units in the transplant setting; from 146 to 83 in acute leukemia (P < 0.05). Mean hospital ancillary service charges in 1992 dollars decreased with ABO identical platelets and filtered transfusions approximately $14,000 per patient for acute leukemia and $26,000 for for lymphoma. Per patient actual costs for filters ($643 in transplantation for lymphoma and $875 in leukemia) were offset by savings in actual blood component purchase costs alone ($4,127 in lymphoma and $3,283 in leukemia). In our setting, introduction of ABO identical platelets and filtration leukodepletion were implemented with substantial decreases in costs.
ABO Blood-Group System↗
Roquinimex-induced graft-versus-host reaction after autologous bone marrow transplantation.
BACKGROUND: Roquinimex is being used for posttransplantation immunotherapy of autologous bone marrow transplantation for acute and chronic myelogenous leukemia. This immunotherapeutic agent is a cytokine inducer and may induce an autologous graft-versus-host (GVH) and graft-versus-tumor reactions. OBJECTIVE: Our purpose was to examine patients undergoing this immunotherapy for clinical signs and symptoms of acute GVH reactions and to correlate these symptoms with their clinical outcome. METHODS: We studied eight patients receiving requinimex therapy. RESULTS: We found autologous GVH reactions in three of eight patients (38%) treated with this immunotherapy. Their disease was manifested by localized or widespread violaceous papules that on histologic evaluation were compatible with a grade II GVH reaction. The acute cutaneous GVH reaction was associated with eccrine sweat gland necrosis, a dermatologic toxicity usually associated with chemotherapy. CONCLUSION: Long-term studies of larger numbers of patients treated with this immunotherapy will determine whether these GVH reactions confer significant, sustained, antitumor effects.
Acute Disease↗
Patients > or = age 40 years undergoing autologous or allogeneic BMT have regimen-related mortality rates and event-free survivals comparable to patients < age 40 years.
To evaluate the safety and efficacy of marrow transplantation for older adults, the regimen-related mortality and event-free survival for patients > or = 40 years were compared with those for patients < 40 years. Of 148 consecutive patients receiving autotransplants for lymphoma or Hodgkin's disease, 70 were < 40 years and 78 were > or = 40 years at the time of transplant, including 40 who were > or = 50 years and 12 who were > or = 60 years. Eleven patients (16%) in the younger age group died from transplant-related complications compared with 4 (5%) in the older age group. The 4-year actuarial event-free survivals (EFS) for the younger and older age groups were 43% and 48%, respectively. After adjustment for covariates with prognostic significance, older age was marginally associated with improved event-free survival (P = 0.08). Of 92 consecutive patients undergoing allogeneic BMT during the same period, 62 patients were < 40 years and 30 patients were > or = 40 years, including 8 patients > or = 50 years, and 1 patient > 60 years. Non-relapse mortality (including deaths from GVHD) occurred in 28 of the younger patients (45%) and 9 of the older patients (30%). The 3-year actuarial EFS for the younger patients was 26% vs. 56% for the patients > or = 40 years (P = 0.057). However, this difference was mainly due to the higher proportion of patients with CML and early-stage leukemia in the older age group.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Hepatitis B reactivation following allogeneic bone marrow transplantation: case report and review of the literature.
A case of hepatitis B reactivation following allogeneic bone marrow transplantation for acute myelogenous leukemia is reported. The presence of hepatitis B surface antibody prior to transplantation indicated previous infection with hepatitis B. The presence of hepatitis B surface antigen was first detected 21 months after transplantation. Testing for hepatitis B reactivation was prompted by the development of acute hepatitis B in the patient's spouse. Screening for hepatitis B infection may be helpful when abnormal liver function tests develop after bone marrow transplantation.
Acute Disease↗
Three conserved motifs in the extracellular domain of the human granulocyte-macrophage colony-stimulating factor receptor subunit are essential for ligand binding and surface expression.
The receptor for the human granulocyte-macrophage colony-stimulating factor (GM-CSF) (GM-R) is a heterodimeric complex consisting of two subunits, GM-R alpha and GM-R beta. Structural analyses have shown a number of highly conserved amino acid motifs present in both GM-R alpha and GM-R beta. These motifs include QYFLY, CXW, XW, and WSXWS motifs in the extracellular domain; a conserved cysteine in the transmembrane domain; and the entire cytoplasmic domain, including the LXVLX box in the carboxy terminal region of the cytoplasmic domain. We have investigated the role of these motifs in GM-R alpha by examining the effects of specific motif mutations on ligand binding and surface expression. Transient expression of these mutant GM-R alpha subunits in COS cells shows that these extracellular motis are essential for ligand binding. Alterations of the cytoplasmic region of GM-R alpha do not alter GM-CSF binding or the reconstitution of high-affinity receptors when coexpressed with GM-R beta. Permeabilization and immunostaining of cells transfected with mutant GM-R alpha subunits yields data suggesting that each of the mutant subunits is present in the cytoplasm. Immunostaining of both intact and permeabilized COS cells transiently transfected with wild-type or mutant GM-R alpha s showed that extracellular domain mutants accumulated in the cytoplasm and were not efficiently transported to the cell surface.
3T3 Cells↗
Effects of GM-CSF on Ki67 expression and cell cycle traverse in acute myelogenous leukemia specimens and cell lines.
A new strategy in the treatment of acute myelogenous leukemia is to attempt to increase the growth fraction of clonal leukemic cells prior to administration of chemotherapeutic agents by the administration of hematopoietic growth factors. We have studied the effect of GM-CSF on the cell cycle status and Ki67 nuclear antigen expression of AML blasts in vitro. The effect of growth factors and stromal cell co-culture on Ki67 expression in leukemic cell lines was also examined. Neither stromal cell co-culture nor exposure of factor-dependent and factor-independent cell lines to GM-CSF, IL-3, SCF, or combinations thereof significantly changed the percentage of cells expressing Ki67. In the AML population analyzed as a whole, exposure of blasts to GM-CSF for up to 96 h did not significantly change the percentage of cells in S phase or expressing Ki67.
Antigens, Neoplasm↗
Characterization of the adherence of normal and leukemic CD34+ cells to endothelial monolayers.
The capacity of normal CD34+ marrow cells and CD34+ leukemic cell lines to adhere to human umbilical vein endothelial cells has been examined. Such interactions have importance since the processes of homing and egress within the marrow microenvironment involve the traverse of sinusoidal endothelium. Umbilical vein endothelial monolayers expressed CD44 and CD54 constitutively, and expression of both E-selectin (ELAM) and vascular cell adhesion molecule-1 (VCAM-1) were inducible with interleukin-1 (IL-1) alpha and beta and tumor necrosis factor (TNF). CD34+ marrow cells bound to unstimulated endothelial layers (33 vs. 16% to plastic), and their adhesion was significantly increased in the presence of IL-1 or TNF. This increased adhesion was not inhibited by functionally blocking antibodies to E-selectin or to CD54 but was partially inhibited by antibodies to VCAM. CD34+ KG1a cells also bound to endothelial monolayers (33 vs. 8% to plastic), and such adhesion was also upregulated by pretreatment of the endothelial cells with IL-1 or TNF. In contrast to normal CD34+ cells, this increased adhesion was inhibited by antibodies to E-selectin but not to VCAM. These findings indicate that adhesion of both normal CD34+ cells and leukemic blasts to endothelial cells can be upregulated by inflammatory mediators such as TNF and IL-1.
Antigens, CD↗
Leukocyte-reduced transfusions of ABO-identical platelets and clinical outcome in autologous bone marrow transplantation for lymphoma.
In observational studies, use of ABO-identical platelets and leukocyte-reduced blood components have been associated with prolonged survival and reduced morbidity in acute leukemia. We present an analysis of the clinical results of instituting a policy of ABO-identical, leukoreduced transfusions in adult patients with lymphoma undergoing autologous bone marrow transplantation. Consecutive patients with Hodgkin's disease or non-Hodgkin's lymphoma were treated with a BEAC conditioning regimen. The use of ABO-identical platelets and leukoreduction of blood components was associated with reductions in mean number of days with fever > or = 38.5 degrees C (17 vs 10), number of days of antibiotics (34 vs 22) and numbers of days until recovery of neutrophil count > or = 500 x 10(6)/l (26 vs 18). Use of leukoreduced transfusions was the only statistically significant treatment factor predicting more rapid neutrophil engraftment. No significant difference in event-free or overall survival was observed. The differences in morbidity were not explained by variations in supportive care such as use of hematopoietic growth factors, use of peripheral blood stem cells or by any measures of pretransplant disease extent or severity. While conclusions based on cohort studies must be viewed conservatively, these data are consonant with observations from previous animal models and clinical studies. ABO-identical platelet transfusions and leuko-reduction are associated with reduced morbidity in patients undergoing autologous bone marrow transplantation for lymphoma.
ABO Blood-Group System↗
Sequence analysis and functional studies of interleukin-3 receptor alpha subunit-encoding cDNAs amplified from KG-1 leukemic cells and normal human marrow.
Two partial cDNAs encoding the human interleukin-3 receptor alpha subunit (IL-3R alpha) were cloned from KG-1 leukemic cells using the polymerase chain reaction. Sequence analysis of these cDNAs predicted two single-amino-acid (aa) changes as compared with the published TF-1 leukemic cell IL-3R alpha sequence [Kitamura et al., Cell 66 (1991) 1165-1174]. These changes were confirmed by sequence analysis of a second set of independently derived cDNAs. Identical aa changes were found in the IL-3R alpha encoded by cDNAs cloned from normal CD34+ human marrow cells. Ligation of the partial cDNAs derived from KG-1 cells resulted in a full-length functional IL-3R alpha cDNA clone. Deletion of the extracellular 'LSXWS' consensus sequence resulted in complete loss of detectable [125I]IL-3 binding when this mutant receptor was co-expressed in COS-7 cells with the beta subunit of the IL-3 receptor.
Base Sequence↗
Treatment of relapsed or refractory Hodgkin disease and non-Hodgkin lymphoma with high-dose chemoradiotherapy followed by unstimulated autologous peripheral stem cell rescue.
Nine patients with relapsed or refractory Hodgkin disease or non-Hodgkin lymphoma underwent peripheral stem cell autografting because of a history of marrow involvement with visible lymphoma. Peripheral stem cells were collected during a process of unstimulated leukapheresis. Recovery to a neutrophil count of 0.1 x 10(9)/L was seen at a median of 14 days compared with a median of 18 days for a concurrent series of marrow recipients (P = .12). Recoveries to a neutrophil count of 0.5 x 10(9)/L and a platelet count of 50 x 10(9)/L occurred at medians of 25 days and 28 days, respectively. These figures are not significantly different from those obtained in the marrow recipients. Of the original nine patients, six are surviving free of disease progression or relapse at a median of 240 days posttransplant. Two patients died of transplant-related complications and one relapsed 250 days post-transplant. All surviving patients remain independent of transfusions and six have attained almost complete hematological reconstitution. Although administration of cytotoxic therapy and granulocyte-macrophage colony-stimulating factor (GM-CSF) may enhance the yield of early progenitor cells during leukapheresis, unstimulated leukapheresis results in a stem cell product capable of rapidly restoring and sustaining marrow function even after multiple courses of intensive "salvage" therapy. Additional follow-up will be needed to determine whether preliminary survival figures continue to compare favorably with those of patients with similar extramedullary disease states undergoing marrow transplants.
Adult↗
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF): receptor biology, signal transduction, and neutrophil activation.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are two of the growing number of recognized cytokines involved in the regulation of hematopoiesis. The purification of these factors and the subsequent cloning of the cDNAs which encode these proteins have led to their widespread clinical use in the setting of therapy or disease-induced myelosuppression. Although originally purified on the basis of their colony-stimulating properties, GM-CSF and G-CSF may also play important roles in the regulation of effector cell function. The mechanisms underlying progenitor cell proliferation and effector cell stimulation remain poorly understood. However, the characterization of the GM-CSF and G-CSF receptors and recent work in signal transduction are helping to elucidate these mechanisms. This paper will review the biology of the GM-CSF and G-CSF receptors, the mechanisms of post-receptor signal transduction, and the resultant effects on neutrophil function. In addition, the current and potential clinical uses of these factors will be examined in light of their ability to activate and perhaps enhance the function of neutrophils.
Animals↗
Activation of neutrophils by granulocyte-macrophage colony-stimulating factor.
A hypothetical pathway of GM-CSF-induced signaling in human neutrophils is presented in Figure 4. The earliest postreceptor events leading to activation of cellular kinases and phosphorylation of c-raf on tyrosine and serine remain a mystery. It is conceivable that downstream events such as the production of LTB4 and PAF as well as other autocrine or paracrine activators of neutrophil-activation function may be involved in neutrophil activation and priming, or they may be downstream events irrelevant in the signaling cascade. The association of GM-CSF signaling and G-proteins, PLD, c-raf, tyrosine kinases, and the Na+/H+ antiport remain poorly understood.
Actins↗