Myeloid Colony-stimulating Factors Research Articles

Unraveling a Novel Mechanism of RUNX1 Activity in Familial Platelet Disorder with Associated Myeloid Malignancy

Acute myeloid leukemia (AML) has a higher incidence and death rate than all other types of adult-onset acute leukemia in the USA, thus requiring a better understanding of the molecular mechanisms behind its progression. Since familial platelet disorder with associated myeloid malignancy (FPDMM) is closely related to AML and is caused by mutations in the RUNX1 gene, elucidation of RUNX1 in the development of FPDMM serves as a model for understanding the genesis of AML.FPDMM is a rare autosomal dominant disorder. FPDMM patients are characterized with defective megakaryopoiesis, abnormal platelet count and function, and bleeding disorders. Importantly, ~60% of patients develop hematological malignancies later on in their lives. FPDMM patients carry heterozygous, germline mutations in the RUNX1 gene. RUNX1 is a transcription factor that plays a critical role during early stages of definitive hematopoiesis, and megakaryopoiesis. Significantly, RUNX1 mutations have been reported in many cases of AML and myelodysplastic syndrome. RUNX1's C-terminal contains a VWRPY motif, which is a conserved binding site for transducin like enhancer of split1 (TLE1). TLE1 is a transcriptional corepressor that inhibits several transcription factors. Previous studies showed that RUNX1 missing the VWRPY motif could not bind TLE1, resulting in overexpression of RUNX1's target genes. However, the significance of RUNX1-TLE1 interaction was never investigated in regard to megakaryopoiesis, FPDMM pathogenesis, or leukemogenesis. Hence, there is a need to better understand the role of RUNX1-TLE1 interaction and their significance in megakaryopoiesis in general.A new FPDMM family has been identified carrying a GC insertion at the end of RUNX1's C-terminus. Genomic DNA sequencing of two patients from the family confirmed the mutation, which resulted in a frame shift mutation (L472fsX). As a result, the VWRPY motif is absent. Instead, the mutant protein contains additional, unrelated 123 amino acids, whose expression has been confirmed by western blot. Our hypothesis states that because the RUNX1 mutant lacks the TLE1 binding motif (VWRPY), its repression is defective which in turn affects normal megakaryopoiesis. Thereby, we are presenting a novel RUNX1 mutation in FPDMM and a possible novel mechanism that has never been studied before in FPDMM patients.To evaluate the effect of the mutation on RUNX1-TLE1 interaction, fluorescence resonance energy transfer (FRET) was performed in HEK293 cells. CFP-RUNX1 wild type (wt) and mutant co-transfected with YFP-CBFβ gave a FRET efficiency of 14% ± 2.5% and 16% ± 2.7%, respectively; suggesting that the mutation did not disrupt the physical binding between RUNX1 and its co-factor CBFβ. CFP-RUNX1 wt co- transfected with YFP-TLE1 gave an average of 10% ± 3.3% FRET efficiency, while CFP-RUNX1 mutant co-transfected with YFP-TLE1 gave an average of 0.65% ± 1.8% FRET efficiency, indicating no binding between the RUNX1 mutant and TLE1. These findings demonstrate that the existence of RUNX1’s C-terminus mutation abolished RUNX1’s interaction with TLE1.Furthermore, to assess the effect of the disrupted interaction between RUNX1 and TLE1 on RUNX1's activity, we performed a dual luciferase assay, which measures the promoter activity of a RUNX1's target, myeloid colony stimulating factor receptor (MCSFR). Results show that TLE1 was able to partially repress RUNX1 wt activity when co-transfected with CBFβ, consistent with previous data. On the contrary, TLE1 did not repress RUNX1 mutant activity, which resulted in increased RUNX1's target expression. Therefore, these preliminary results are consistent with the proposed regulatory role for RUNX1 and TLE1 during hematopoiesis.To corroborate these results, we have generated human induced pluripotent stem cells (iPSCs) from the FPDMM patient's blood cells containing the RUNX1 L472fsX mutation to model the defects in megakaryopoiesis. We are currently analyzing the hematopoietic differentiation of the mutated iPSCs and studying the mechanism through expression and pathway analysis of RNA-Seq data. Moreover, we have generated a mouse model closely representing the mutation using CRISPR-Cas9 system. Bothmodels will be used to provide a better understanding of megakaryopoiesis in general, and FPDMM pathogenesis and their progression to leukemia in particular. DisclosuresNo relevant conflicts of interest to declare.

Arterial Thickness and Immunometabolism: The Mediating role of Chronic Exercise

Metabolic alterations and cardiovascular diseases, such as atherosclerosis, are associated with lifestyle modifications, particularly the increase of physical inactivity and poor eating habits, which contribute to one of the main causes of death in modern times. Cardiovascular diseases are positively correlated with several illnesses, such as obesity, hypertension and dyslipidemia, and these disorders are known to contribute to changes in immune cells, cytokines and metabolism. Atherosclerosis is a chronic inflammatory disease characterized by the formation of lipid plaques and fibrous tissue (atheroma) in the artery walls and this process is related to the oxidation of LDL-c (low density lipoprotein) and the formation of a particle, termed LDLox, which can generate toxic injury to the vessel wall. In this atherogenic process there is an inflammatory response generated by the injury in the vascular endothelium, which in itself is able to express and secrete a variety of molecules, such as myeloid colony-stimulating factors (M-CSF), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor alpha (TNF-α), that act as activators of the immune system. Therefore, the main purpose of this review is to highlight the immuno-metabolic alterations involving the thickening and stiffness of arteries observed in atherosclerosis, and how chronic exercise can act as an anti-inflammatory and anti-atherogenic approach.

Myeloid colony-stimulating factors as regulators of macrophage polarization.

The scope of functional heterogeneity in macrophages has been defined by two polarized end states known as M1 and M2, which exhibit the proinflammatory activities necessary for host defense and the tissue repair activities required for restoration of homeostasis, respectively. Macrophage populations in different tissue locations exist in distinct phenotypic states across this M1/M2 spectrum and the development and abundance of individual subsets result from the local and systemic action of myeloid colony-stimulating factors (CSFs) including M-CSF and GM-CSF. These factors have relatively non-overlapping roles in the differentiation and maintenance of specific macrophage subsets. Furthermore, there is now evidence that CSFs may also regulate macrophage phenotype during challenge. Cell culture studies from multiple laboratories demonstrate that macrophages developed in the presence of GM-CSF exhibit amplified response to M1 polarizing stimuli while M-CSF potentiates responses to M2 stimuli. As a consequence, these factors can be important determinants of the magnitude and duration of both acute and chronic inflammatory pathology and may, therefore, be potential targets for therapeutic manipulation in specific human disease settings.

First use of myeloid colony-stimulating factors in humans

It is widely believed that the first use of myeloid colony-stimulating factors in humans was sargramostim (GM-CSF) in victims of the Goiania, Brazil radiation accident in 1987.1 GM-CSF was later approved by US FDA in 1991, as was filgrastim (G-CSF). However, with the recent release of previously classified documents from the ex-Soviet Union, we are now able to correct the historical record.

Re: Personalized Medicine and Cancer Supportive Care: Appropriate Use of Colony-Stimulating Factor Support of Chemotherapy

Re: Personalized Medicine and Cancer Supportive Care: Appropriate Use of Colony-Stimulating Factor Support of Chemotherapy

In situ proliferation and differentiation of macrophages in dental pulp.

The presence of macrophages in dental pulp is well known. However, whether these macrophages proliferate and differentiate in the dental pulp in situ, or whether they constantly migrate from the blood stream into the dental pulp remains unknown. We have examined and compared the development of dental pulp macrophages in an organ culture system with in vivo tooth organs to clarify the developmental mechanism of these macrophages. The first mandibular molar tooth organs from ICR mice aged between 16 days of gestation (E16) to 5 days postnatally were used for in vivo experiments. Those from E16 were cultured for up to 14 days with or without 10% fetal bovine serum. Dental pulp tissues were analyzed with immunohistochemistry to detect the macrophages and with reverse transcription and the polymerase chain reaction (RT-PCR) for the detection of factors related to macrophage development. The growth curves for the in vivo and in vitro cultured cells revealed similar numbers of F4/80-positive macrophages in the dental pulp. RT-PCR analysis indicated the constant expression of myeloid colony-stimulating factor (M-CSF) in both in-vivo- and in-vitro-cultured dental pulp tissues. Anti-M-CSF antibodies significantly inhibited the increase in the number of macrophages in the dental pulp. These results suggest that (1) most of the dental pulp macrophages proliferate and differentiate in the dental pulp without a supply of precursor cells from the blood stream, (2) M-CSF might be a candidate molecule for dental pulp macrophage development, and (3) serum factors might not directly affect the development of macrophages.

Use of Colony-Stimulating Factors With Chemotherapy: Opportunities for Cost Savings and Improved Outcomes

Myeloid colony-stimulating factors (CSFs) decrease the risk of febrile neutropenia (FN) from high-risk chemotherapy regimens administered to patients at 20% or greater risk of FN, but little is known about their use in clinical practice. We evaluated CSF use in a multiregional population-based cohort of lung and colorectal cancer patients (N = 1849). Only 17% (95% confidence interval [CI] = 8% to 26%) patients treated with high-risk chemotherapy regimens received CSFs, compared with 18% (95% CI = 16% to 20%) and 10% (95% CI = 8% to 12%) of patients treated with intermediate- (10%-20% risk of FN) and low-risk (<10% risk of FN) chemotherapy regimens, respectively. Using a generalized estimating equation model, we found that enrollment in a health maintenance organization (HMO) was strongly associated with a lower adjusted odds of discretionary CSF use, compared with non-HMO patients (odds ratio = 0.44, 95% CI = 0.32 to 0.60, P < .001). All statistical tests were two-sided. Overall, 96% (95% CI = 93% to 98%) of CSFs were administered in scenarios where CSF therapy is not recommended by evidence-based guidelines. This finding suggests that policies to decrease CSF use in patients at lower or intermediate risk of FN may yield substantial cost savings without compromising patient outcomes.

Myeloid Colony-Stimulating Factors Do Not Increase the Risk of Mortality or Disease Activity Measures in Patients with Acute Myeloid Leukemia: Systematic Review and Meta-Analysis.

Abstract 2045Poster Board II-22Myeloid colony-stimulating factors (M-CSFs) are recommended as primary prophylaxis for the prevention of febrile neutropenia (FN) in patients who are at high risk for developing it. Since acute myeloid leukemia (AML) cells express functional growth factor receptors on their surface, concerns have been raised regarding the effect of M-CSFs on these cells. We assessed the safety of M-CSFs in AML patients. Systematic review and meta-analysis of all randomized controlled trials that compared the addition of M-CSFs during and following chemotherapy to chemotherapy alone in patients with AML was conducted. Trials evaluating the role of M-CSFs administered for the purpose of stem cell collection and/or priming e.g., before and/ or only for the duration of chemotherapy, were excluded. Both patients with and without neutropenia and/ or fever on admission were included. Two reviewers appraised the quality of trials and extracted data independently. The primary outcome was all-cause mortality at defined points in time. Secondary outcomes included complete remission (CR), disease free survival (DFS), relapse and infection rates. Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. The search yielded 17 trials including 4800 patients (range 53-803 per trial). 14 trials included patients undergoing induction chemotherapy, two trials included patients undergoing consolidation and one trial included patients undergoing salvage chemotherapy. The addition of M-CSFs to chemotherapy yielded no difference in all-cause mortality at 30 days, 1 year and at the end of follow-up [RR 1.00 (95% CI.0.82-1.22), RR 1.07 (95% CI 0.97-1.19) and RR 1.02 (95% CI 0.98-1.05), respectively] (Fig.1). There was no difference with regard to CR [RR 1.03 (95% CI 0.98-1.07)], relapse [RR 0.99 (95% CI 0.91-1.08)] and DFS [HR 1.00 (95% CI 0.90-1.13)]. M-CSFs did not decrease the occurrence of bacteremias, RR 0.96 (95% CI 0.82-1.12) or invasive fungal infections, RR 1.40 (95% CI 0.90-2.19). The addition of M-CSFs to chemotherapy does not affect all-cause mortality and leukemia associated clinical end points, e.g. CR, relapse rate and DFS. Hence, the use of M-CSFs for prevention of FN in patients with AML is safe. However, since prevention of neutropenia does not result in improved survival, they should not be used on a routine basis. Their use in the individual patient can be considered according to the clinical situation. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Preliminary safety results from a multicenter phase II trial of nanoparticle albumin-bound paclitaxel/cyclophosphamide in early stage breast cancer plus trastuzumab in HER-2+ patients (pts)

e11509 Background: Docetaxel/cyclophosphamide has demonstrated superior disease free and overall survival compared to doxorubicin/cyclophosphamide in the treatment of early stage breast cancer with an acceptable safety profile, with grade (G) 3/4 neutropenia of 61% and no cardiotoxicity. Nanoparticle albumin-bound (nabtm)-paclitaxel (nab-P) is a novel formulation with demonstrated superior efficacy to conventional paclitaxel (P) in treatment of metastatic breast cancer with a comparable safety profile. We therefore conducted a multicenter phase II pilot trial of weekly nab-P/cyclophosphamide to assess the safety and tolerability of this combination in early stage breast cancer. Methods: Eligibility: T1–4pN0–3M0, ECOG PS 0–2, normal organ function, normal LVEF for pts receiving trastuzumab (T). Treatment consisted of nab-P 100 mg/m2 day (D) 1, 8, 15 with cyclophosphamide (C) 600 mg/m2 D1 q 21 days x 4 cycles. T was given in IHC 3+ or FISH HER2+ pts with an 8 mg/kg loading dose followed by 6mg/kg q21D x 52 weeks. Results: 63 pts enrolled from April 2008 through September 2008; 33 pts are evaluable for safety with a median of 2 cycles. Baseline characteristics: median age 57 years (range 33–76); ECOG PS 0–94%, T1-T2 tumors - 100%, node negative 61%, hormone receptor negative 33%, HER 2+ 15%, triple negative 27%, ductal histology 73%, premenopausal 37 %. nab-P dose modifications occurred in 10 of 33 pts with nab-P reductions in 2 pts: 1 each due to G3 neutropenia- cycle 2 and G3 neuropathy- cycle 4. All 8 nab-P treatment delays were due to G3 neutropenia at D15. G3/4 neutropenia was present in 30% with only 1 G4 episode. 1 pt utilized myeloid colony stimulating factors. There were no G3/4 non-heme toxicities present in &gt; 5 % of pts and no LVEF declines in pts receiving T. 17 pts remain on study with 3 pts receiving T. Conclusions: The combination of weekly nab-P with cyclophosphamide is feasible and well tolerated with an acceptable safety profile as adjuvant therapy for early stage breast cancer. The addition of T to this combination did not create any safety concerns. Full safety data for the 63 pts will be updated at the time of the meeting. [Table: see text]

The role of myeloid colony-stimulating factors in the treatment of acute lymphoblastic leukemia - more questions than answers?

The role of myeloid colony-stimulating factors in the treatment of acute lymphoblastic leukemia - more questions than answers?

A Phase III, Randomized, Double-Blind, Placebo-Controlled Comparative Trial of Pegfilgrastim Versus Filgrastim after Autologous Peripheral Blood Stem Cell Transplantation (PBSCT).

Introduction: Myeloid colony stimulating factors accelerate engraftment and shorten hospital stay following PBSCT. Pegfilgrastim (Peg-G), a pegylated granulocyte colony-stimulating factor is equivalent to filgrastim (G) when used to hasten neutrophil recovery after conventional chemotherapy. While small non-randomized trials suggest that Peg-G could be used in lieu of G to speed hematopoietic reconstitution after PBSCT, no large Phase III trial data exist. This phase III, randomized, double-blind, placebo controlled comparative trial of Peg-G vs G After autologous PBSCT compared the efficacy, costs and safety of the two treatments.Methods: Consented adult patients undergoing an autologous PBSCT at our institution were eligible if they had collected > 2 × 106 CD34/kg for transplant. Patients were randomized to either fixed-dose Peg-G at 6 mg SQ x1 dose plus daily G-placebo or daily G at 5 mg/kg/day plus Peg-G placebo × 1, all starting on day +1 posttransplant. G or G-placebo continued until sustained engraftment, defined as neutrophils > 5000/ml × 3 days, or 10,000/ml × 1 day, or through day +25 posttransplant. They were stratified based on prep regimen (TBI vs other) and CD34 cell dose/kg (< 5 vs ≥ 5 × 106/kg). The primary endpoint was time to neutrophil engraftment of >500/ml × 3 days. Patients not engrafting to this level by day +19 were permitted to receive open label G. Analysis of infectious complications and cytokine costs as defined by the number of days of G vs the cost of Peg-G plus any rescue doses of G was determined.Results: We enrolled 78 patients who underwent myeloablative autologous PBSCT for myeloma, lymphoma, testicular, or ovarian carcinoma between 11/03 and 5/07 of whom 39 were randomized to each group. The mean CD34 doses were 4.1 and 4.7 × 106/kg (p = .68) for the Peg-G and G groups respectively. The groups were matched for age, sex, weight, and underlying disease. The median time to neutrophil engraftment was 9 and 10 days respectively for the Peg-G and G groups (p = 0.15). No patient required rescue G to achieve engraftment. The median time to an ANC of 1500/ml × 3 or 5000/ml × 1 was the same in both groups (12 days), but only 45% vs 97% of patients reached a WBC of 5000/ml × 3 or 10,000/ml × 1 (p < .0001) in the Peg-G vs G groups. For the Peg-G vs G groups there were no differences in: platelet engraftment (11 vs. 13 days, p = 0.29), the number of platelet transfusions (5 vs. 4, p = 0.3), incidence of positive cultures for bacterial pathogens (23 vs. 15%, p = 0.39), days of fever (1 vs 2, p = 0.2) or duration of hospital stay (19 vs 19 days). There was 1 death in each group prior to engraftment each due to sepsis. The number of days of G given to that arm to reach an ANC of 1500/ml × 3 or 5000/ml × 1 was 12. Considering the Average Wholesale Price for the actual doses used in this trial for the two groups there was a per-patient savings of $961 for the Peg-G group compared to the G-group using this engraftment endpoint (p < .001).Conclusions: This Phase III study demonstrated equivalency between Peg-G and G in the ability to achieve prompt neutrophil recovery post PBSCT. There was no difference in infectious complications and the use of Peg-G did achieve a significant cost savings over G.

Mice Lacking Three Myeloid Colony-Stimulating Factors (G-CSF, GM-CSF, and M-CSF) Still Produce Macrophages and Granulocytes and Mount an Inflammatory Response in a Sterile Model of Peritonitis

To assess the combined role of G-CSF, GM-CSF, and M-CSF in myeloid cell production, mice deficient in all three myeloid CSFs were generated (G-/-GM-/-M-/- mice). G-/-GM-/-M-/- mice share characteristics found in mice lacking individual cytokines: they are toothless and osteopetrotic and furthermore acquire alveolar proteinosis that is more severe than that found in either GM-/- or G-/-GM-/- mice. G-/-GM-/-M-/- mice have a significantly reduced lifespan, which is prolonged by antibiotic administration, suggesting compromised ability to control bacterial infection. G-/-GM-/-M-/- mice have circulating neutrophils and monocytes, albeit at significantly reduced numbers compared with wild-type mice, but surprisingly, have more circulating monocytes than M-/- mice and more circulating neutrophils than G-/-GM-/- mice. Due to severe osteopetrosis, G-/-GM-/-M-/- mice show diminished numbers of myeloid cells, myeloid progenitors, and B lymphocytes in the bone marrow, but have significantly enhanced compensatory splenic hemopoiesis. Although G-/-GM-/-M-/- mice have a profound deficiency of myeloid cells in the resting peritoneal cavity, the animals mount a moderate cellular response in a model of sterile peritonitis. These data establish that in the absence of G-CSF, GM-CSF, and M-CSF, additional growth factor(s) can stimulate myelopoiesis and acute inflammatory responses.

Pegfilgrastim: Current and Future Perspectives In the Treatment of Chemotherapy-Induced Neutropenia

Myeloid colony-stimulating factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor) are commonly used in clinical practice for the prevention of anticancer chemotherapy-induced neutropenia and its potentially life-threatening complications. Pegfilgrastim is a novel recombinant human G-CSF pharmaceutically developed by covalent binding of a polyethylene glycol molecule to the N-terminal sequence of filgrastim. Due to its unique neutrophil-mediated clearance, pegfilgrastim can be administered once per chemotherapy cycle. Clinical trials have demonstrated that a single, fixed, subcutaneous dose of pegfilgrastim is comparable in safety and efficacy to daily injections of filgrastim for decreasing the incidence of infection following myelosuppressive chemotherapy in patients with cancer. Recent trials have been conducted to evaluate the use of pegfilgrastim in different clinical settings, including support of dose-dense regimens, mobilization and transplantation of hematopoietic stem cells.

Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: Association with tumor-derived growth factors

A leukemoid reaction with granulocytosis and splenomegaly has been observed in animals and humans with a variety of tumors. We have employed four color flow cytometry to characterize the leukemoid reaction induced by the transplantable mouse mammary carcinoma 4T1 in female BALB/c mice. Gr-1 + myeloid cells with the morphology of granulocytes increased in peripheral blood from < 15% pre-transplant to nearly 80% of total CD45 + leukocytes at four weeks post-transplant. Though the granulocyte:lymphocyte ratio increased markedly, the absolute numbers of CD19 + B lymphocytes, CD4 + and CD8 + T lymphocytes, and the CD4/CD8 ratio in peripheral blood did not change significantly. Femurs from tumor-bearing mice showed myeloid hyperplasia of the fatty marrow. There was a notable increase in cells with a Gr-1 dim/CD11b bright immature granulocyte phenotype, and these cells were also found in peripheral blood and spleen. Spleen weights had increased 8.5-fold by four weeks post-tumor transplant, mainly due to granulocytic hyperplasia. Cultured 4T1 tumor cells constitutively expressed mRNA for the myeloid colony-stimulating factors G-CSF and GM-CSF, and IFN-γ-inducible M-CSF transcripts were also detected. Tumors excised from mice had transcripts for G-CSF and GM-CSF, but only G-CSF protein was found in high levels in serum of tumor-bearing mice. These data demonstrate that 4T1 tumor-bearing mice exhibit a leukemoid reaction that apparently is caused by the production of colony-stimulating factors produced by the tumor. The 4T1 tumor may serve as an excellent model for the study of this reaction.

Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome

T-cell large granular lymphocyte leukemia (TLGL) is an atypical chronic lymphoproliferative disorder derived from cytotoxic T-cells (CTL). Unlike most forms of leukemia, the pattern of bone marrow infiltration in TLGL may be subtle and the cytopenias are often lineage specific, with neutropenia dominating. Both granulocytic survival and proliferation defects are observed and are mediated by humoral and cell-mediated mechanisms respectively. Splenic production of immune complexes induces a neutrophil survival defect, where as Fas expression by leukemic CTL results in a marrow based proliferation defect. These humoral and cell-mediated pathways induce granulocytic apoptosis through independent intracellular mechanisms which are not mutually exclusive and may be observed concurrently in individual patients with either TLGL or FS. A variety of therapeutic interventions have been utilized in the management of TLGL and Felty syndrome, including methotrexate, cyclosporine A, cyclophosphamide, glucocorticoids, myeloid colony stimulating factors and splenectomy. Their efficacy and mechanisms of action are reviewed.

Racial Comparison of Outcomes and Costs for Inpatient Neutropenic Patients: A Multicenter Evaluation

Purpose Racial disparities have been reported in the care and outcome of cancer patients. We evaluated whether race would influence the cost and outcomes of inpatient neutropenic cancer patients in a multicenter study from a large health care system in the southern United States. Methods Data was collected on all cancer inpatients with a diagnosis code for neutropenia in a 16-hospital system between October 1, 2002, and September 30, 2003. Demographics, treatment outcomes, and costs were compared between white and minority patients. A P value less than .05 was considered statistically significant. Results Two hundred seventy-nine cancer patients (0.29% of all admits) had a diagnosis of neutropenia. Demographics were similar between white and minority patients. However, minorities were more likely to be younger than whites (P = .002). With regards to outcomes, length of stay (LOS), LOS in the intensive care unit, and discharge status were not statistically different. Total hospital, medication, laboratory, radiation, surgery, and respiratory costs were also similar (P > .05), although minorities were less likely to receive myeloid colony-stimulating factors (P = .032) and more likely to have higher nursing care costs (P = .048). Conclusion In light of the escalating reports of racial disparities in cancer care, these minimal differences are encouraging.

Racial Comparison of Outcomes and Costs for Inpatient Neutropenic Patients: A Multicenter Evaluation

Racial disparities have been reported in the care and outcome of cancer patients. We evaluated whether race would influence the cost and outcomes of inpatient neutropenic cancer patients in a multicenter study from a large health care system in the southern United States. Data was collected on all cancer inpatients with a diagnosis code for neutropenia in a 16-hospital system between October 1, 2002, and September 30, 2003. Demographics, treatment outcomes, and costs were compared between white and minority patients. A P value less than .05 was considered statistically significant. Two hundred seventy-nine cancer patients (0.29% of all admits) had a diagnosis of neutropenia. Demographics were similar between white and minority patients. However, minorities were more likely to be younger than whites (P = .002). With regards to outcomes, length of stay (LOS), LOS in the intensive care unit, and discharge status were not statistically different. Total hospital, medication, laboratory, radiation, surgery, and respiratory costs were also similar (P > .05), although minorities were less likely to receive myeloid colony-stimulating factors (P = .032) and more likely to have higher nursing care costs (P = .048). In light of the escalating reports of racial disparities in cancer care, these minimal differences are encouraging.

Human peripheral CD2−/lo T cells: an extrathymic population of early differentiated, developing T cells

We previously reported that a subset of human peripheral blood CD3+ T cells expresses low-to-null CD2 levels (CD2-/lo), produces type 2 cytokines and is inducible to differentiate to functionally mature IFN-gamma+ cells. Multiple-color immunofluorescence analysis indicated that this population, representing <0.1% of the T cells in fresh lymphocytes, contains subsets that are phenotypically immature, including CD4-CD8- and CD3+TCR- cells. Ex vivo, the CD2-/lo cells can proliferate (carboxyfluorescein diacetate succinimidyl ester analysis) independently from exogenous stimulation, respond to CD3-mediated stimulation with significantly greater proliferation than the autologous mature cells and their subsets are inducible to undergo in vitro a developmental sequence similar to that reported for the phenotypically similar thymic populations. This is especially evident for the CD4+CD8+ subset. CD2-/lo T-cell populations exhibit a TCR repertoire (Vbeta chain distribution) that is complete but different (complementarity determining region R3 analysis) from that of the autologous CD2+ T cells. These characteristics distinguish peripheral CD2-/lo T cells as possible early differentiated T cells that may undergo extrathymic maturation, and potentially contribute to maintain the peripheral naive T-cell pool. These findings define the existence of phenotypically immature T cells in the periphery. Also, given the high numbers of CD2-/lo T cells generated, upon ex vivo culture, from peripheral lymphocytes of all adult and neonatal individuals tested, they have relevance to clinical applications for immune reconstitution of T cells, as well as myeloid cells, via myeloid colony-stimulating factors and type 2 cytokines.

Immunological peculiarities of extremely preterm infants: a challenge for the prevention of nosocomial sepsis

To review the main aspects of fetal immune development focusing on the host defenses of extremely preterm infants against bacterial pathogens, and describing the possibilities of immunotherapeutic intervention for the prevention of neonatal nosocomial sepsis. Electronic search of MEDLINE database for articles published in the last 15 years. Those with relevant information regarding the target issue were selected. Immunity of extremely preterm infants is deficient due to skin fragility, insufficient complement system components, decreased bone marrow neutrophil storage pool, and lower chemotaxis, adherence, deformability, and neutrophil enzyme activities. Further limitations are found at NK cell-mediated cytotoxicity, T cell proliferation and cytokine production, B and T cell cooperation, and antibody synthesis by B lymphocytes. No definitive benefits of interventions for enhancing the immune function, such as the use of intravenous immunoglobulin or myeloid colony-stimulating factors, have been demonstrated. As a consequence of the immaturity of several immune components, extremely preterm infants are highly susceptible to nosocomial infections. The very limited possibilities for intervention in this system require the control of extrinsic factors for the prevention of nosocomial sepsis in these infants.

Granulocyte Macrophage Colony-Stimulating Factor: Current Practice and Novel Approaches

Endogenous myeloid colony-stimulating factors (CSFs) have demonstrated the ability to enhance the clinical management of immunosuppressed patients with cancer. These agents are associated with significant decreases in chemotherapy-associated infections, antibiotic use, length of hospital stays, and mortality. Two major endogenous recombinant myeloid CSFs currently are being manufactured. Granulocyte macrophage CSF (GM-CSF) (sargramostim, Leukine, Immunex Corporation, Seattle, WA) has broad activity in the proliferation and differentiation of myeloid lineage progenitor cells, whereas granulocyte CSF (filgrastim, Neupogen, Amgen, Inc., Thousand Oaks, CA) acts selectively on cells of the granulocyte lineage. Clinical trials suggest that GM-CSF has clinical benefits beyond enhancing neutrophil recovery, including shortening the duration of mucositis and diarrhea, stimulating dendritic cells, preventing infection, acting as an adjuvant vaccine agent, and facilitating antitumor activity.