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David C Dale

Publications and source records attributed to David C Dale.

At least 19 recordsLinked to original sources
PubMed2006

Effect of patient socioeconomic status and body mass index on the quality of breast cancer adjuvant chemotherapy.

PURPOSE: The purpose of this study was to investigate the relationship between socioeconomic status (SES) and the use of intentionally reduced doses of chemotherapy in the adjuvant treatment of breast cancer. PATIENTS AND METHODS: Patients with breast cancer treated with a standard chemotherapy regimen (n = 764) were enrolled in a prospective registry after signing informed consent. Detailed information was collected on patient, disease, and treatment, including chemotherapy doses. Zip code level data on median household income, proportion of people living below the poverty level, and educational attainment were obtained from the US Census. Doses for the first cycle of chemotherapy lower than 85% of standard were considered to be reduced. Univariate analyses and multivariate logistic regression were performed to identify factors associated with the use of reduced first cycle doses. RESULTS: In univariate analysis, individual education attainment, zip code SES measures, body mass index, and geographic region were all significantly associated with receipt of intentionally reduced doses of chemotherapy. In multivariate analysis, controlling for geography, factors independently associated with reduced doses were obesity (odds ratio [OR], 2.47; 95% CI, 1.36 to 4.51), severe obesity (OR, 4.04; 95% CI, 1.46 to 11.19), and education less than high school (OR, 3.07; 95% CI, 1.57 to 5.99). CONCLUSION: Social disparities in breast cancer outcomes may be in part the result of lower quality chemotherapy doses in the adjuvant treatment of breast cancer. Efforts to address such prescribing patterns may help reduce SES disparities in breast cancer survival.

Adult↗
PubMed2006

Epoetin alfa increases hemoglobin levels and improves quality of life in anemic geriatric cancer patients receiving chemotherapy.

GOAL: To evaluate epoetin alfa (EPO) treatment of anemia in geriatric cancer patients receiving chemotherapy, a retrospective subgroup analysis was conducted of anemic cancer patients > or =65 years of age from three 16-week community-based studies of thrice-weekly (TIW) or once-weekly (QW) EPO for chemotherapy-related anemia (CRA). PATIENTS AND METHODS: Analyses were conducted on the overall geriatric population (> or =65 years) and by age subgroup (65-74, 75-84, and > or =85 years), and compared with younger patients (<65 years) for each individual study and for pooled data. MAIN RESULTS: Some 3,634 geriatric patients were compared with 3,467 younger patients. From baseline to final measurement, EPO therapy significantly increased Hb by 2.0 g/dl in patients > or =65 years and 1.9 g/dl in patients <65 years (P<0.0001) and reduced transfusion utilization in both groups (P<0.006). Both age groups also had significant improvements in quality of life (QOL), measured by the 100-mm Linear Analog Assessment Scale (LASA). In younger patients, mean LASA changes were significantly greater than those in geriatric patients (P<0.05); however, QOL improvements in both age groups were clinically meaningful. There were no significant differences across geriatric age subgroups or between TIW and QW regimens for Hb change or QOL improvement. Overall hematopoietic response rate to EPO was 65.4% for patients > or =65 years and 64.7% for patients <65 years. Predictors of greater hematopoietic response (based on a pooled analysis) included lower body weight, baseline Hb, and baseline serum erythropoietin levels; better tumor response; and history of EPO dose reduction and longer time on study. CONCLUSIONS: Anemic geriatric patients receiving EPO for CRA responded comparably to younger patients <65 years and should be treated similarly.

Aged↗
PubMed2006

Predictors of reduced dose intensity in patients with early-stage breast cancer receiving adjuvant chemotherapy.

BACKGROUND: This retrospective study was undertaken to define risk factors for reductions in dose intensity of adjuvant chemotherapy in women with early stage breast cancer (ESBC). METHODS: A nationwide survey of 190 community oncology practices was conducted between 1998 and 2002 with data collected retrospectively on 3,707 patients treated with adjuvant chemotherapy for ESBC. End points included reductions in dose intensity, delivered relative dose intensity (RDI) <85%, and the incidence of chemotherapy dose delays >/=7 days and dose reduction >/=15%. Demographic and clinical characteristics, incidence of febrile neutropenia (FN), and patterns of use of granulocyte colony-stimulating factor (G-CSF) were also assessed. RESULTS: Average RDI for all regimens was 88%, with 30% of patients receiving <85% of standard for their regimen. Seventeen percent of the reduction in average RDI was planned from the start of therapy, and 13% was unplanned. In univariate analysis, significant predictors of reduced RDI were: age >/=65 years (41%, P < 0.001), body surface area (BSA) >2 m(2) (37%, P < 0.001), negative lymph nodes (33%, P < 0.001), FN (36%, P = 0.013), and comorbidities (40%, P = 0.013), particularly renal disease (86%, P = 0.004). Dose reduction was less with prophylactic G-CSF (24%, P < 0.001). In multivariate analysis, significant independent predictors of reduced RDI included: advanced age, greater BSA, comorbidities, anthracycline-based regimens, a 28-day schedule and FN, while primary G-CSF prophylaxis was associated with a significant reduction in risk. CONCLUSION: A significant proportion of patients with potentially curable ESBC continue to experience planned and unplanned reductions in RDI.

Age Factors↗
PubMed2006

Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients.

BACKGROUND: Hospitalization for febrile neutropenia (FN) in cancer patients is associated with considerable morbidity, mortality, and cost. The study was undertaken to better define mortality, length of stay (LOS), cost, and risk factors associated with mortality and prolonged hospitalization in cancer patients with FN. METHODS: The longitudinal discharge database derived from 115 US medical centers was used to study all adult cancer patients hospitalized with FN between 1995 and 2000, comprising a total of 41,779 patients. Primary outcomes included mortality, LOS, and cost per episode. RESULTS: Overall, in-hospital mortality was 9.5%. Patients without any major comorbidities had a 2.6% risk of mortality, whereas 1 major comorbidity was associated with a 10.3% and more than 1 major comorbidity with a > or = 21.4% risk of mortality, respectively. Mean (median) length of stay was 11.5 (6) days, and the mean (median) cost was $19,110 ($8,376) per episode of FN. Patients hospitalized for > or = 10 days (35% of all patients) accounted for 78% of overall cost. Independent major risk factors for inpatient mortality included invasive fungal infections, Gram-negative sepsis, pneumonia and other lung disease, cerebrovascular, renal, and liver disease. Main predictors for LOS > or = 10 days included leukemia, invasive fungal infections, other types of infection, and several comorbid conditions. CONCLUSION: Factors associated with increased mortality, LOS, and cost in hospitalized adult cancer patients with FN include patient characteristics, type of malignancy, comorbidities, and infectious complications. These factors may be useful in identifying patients at increased risk of serious medical complications and mortality for more aggressive supportive care measures.

Adult↗
PubMed2006

The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.

In patients with severe congenital neutropenia (SCN), sepsis mortality is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported. We studied 374 patients with SCN and 29 patients with Shwachman-Diamond syndrome (SDS) on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry. In SCN, sepsis mortality was stable at 0.9% per year. The hazard of MDS/AML increased significantly over time, from 2.9% per year after 6 years to 8.0% per year after 12 years on G-CSF. After 10 years, the cumulative incidence was 8% for sepsis mortality and 21% for MDS/AML. A subgroup of SCN patients (29%) received more than the median dose of G-CSF (> or = 8 microg/kg/d), but achieved less than the median absolute neutrophil count (ANC) response (ANC < 2.188 x 10(9)/L [2188/microL] at 6-18 months). In these less-responsive patients, the cumulative incidence of adverse events was highest: after 10 years, 40% developed MDS/AML and 14% died of sepsis, compared with 11% and 4%, respectively, of more responsive patients whose ANC was above the median on doses of G-CSF below the median. Risk of MDS/AML may be similar in SDS and SCN. In less-responsive SCN patients, early hematopoietic stem cell transplantation may be a rational option.

Female↗
PubMed2006

Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations.

OBJECTIVE: To investigate cases of severe congenital neutropenia (SCN) to ascertain SCN inheritance after determining that the same sperm donor was used by 4 different families to impregnate mothers. STUDY DESIGN: Because the donor sperm was not available, alternative methods were used to determine whether the sperm donor transmitted SCN. DNA isolated from leukocytes was used to sequence the ELA2 gene in the affected children and their mothers. ELA2 was amplified by polymerase chain reaction (PCR), and the product was sequenced. PCR was also performed with genomic DNA from the mothers and affected children using a set of 22 microsatellite PCR primers on chromosomes 14 and 19 to establish linkage to the paternal allele. RESULTS: None of the mothers had a mutation in ELA2, but all 5 affected children had the same mutation affecting the fourth exon at site S97L. Linkage mapping analysis confirmed that all affected children had the same paternal allele on chromosome 19, which contains ELA2. CONCLUSIONS: Our findings indicate that the father provided consistent haplotypes leading to the expression of SCN in all affected children, supporting an autosomal dominant inheritance in which ELA2 mutations occur.

Child↗
PubMed2006

Severe congenital neutropenia.

Severe congenital neutropenia (CN) includes a variety of hematologic disorders characterized by severe neutropenia, with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L, and associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann syndrome, is an autosomal recessive disorder, characterized histopathologically by early-stage maturation arrest of myeloid differentiation. CN with similar clinical features occurs as an autosomal dominant disorder and many sporadic cases also have been reported. This genetic heterogeneity suggests that several pathophysiological mechanisms may lead to this common clinical phenotype. Recent studies on the genetic bases of CN have detected inherited or spontaneous point mutations in the neutrophil elastase gene (ELA 2) in about 60% to 80% of patients and, less commonly, mutations in other genes. Acquisition of additional genetic defects during the course of the disease, for example, granulocyte colony-stimulating factor (G-CSF) receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability as a common feature for all congenital neutropenia subtypes. Data on more than 600 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) demonstrate that, regardless of the particular CN subtype, more than 95% of these patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained above 1.0 x 10(9)/L. Adverse events include mild splenomegaly, osteoporosis, and malignant transformation into myelodysplasia (MDS)/leukemia. If and how G-CSF treatment impacts on these adverse events is not fully understood. In recent analyses the influence of the G-CSF dose required to achieve neutrophil response (ANC >1,000/microL) in the risk of developing acute myeloid leukemia (AML) has been reported. Hematopoietic stem cell transplantation (HSCT) is still the only treatment available for patients who are refractory to G-CSF treatment.

Granulocyte Colony-Stimulating Factor↗
PubMed2006

An adult dog with cyclic neutropenia treated by lentivirus- mediated delivery of granulocyte colony-stimulating factor.

Cyclic neutropenia occurs in humans and gray collie dogs, is characterized by recurrent neutropenia, and is treated by daily injections of recombinant granulocyte colony-stimulating factor (G-CSF). After showing that canine recombinant G-CSF increased neutrophil counts in an affected dog, we administered intramuscularly 2 x 10(9) infectious units (IU) of a lentiviral vector encoding canine G-CSF cDNA. Elevated, therapeutic neutrophil production was obtained for nearly 18 months. Lentiviral vector treatment provided a mean neutrophil count of 29,230 +/- 12,930 cells/microl, which was significantly increased over both the pretreatment value (5,240 +/- 4,800 cells/microl; p < 0.0001) and the neutrophil count during G-CSF administration (17,820 +/- 11,100 cells/microl; p < 0.0001). By systemic infusion of recombinant G-CSF to normal dogs we estimated that 2 x 10(9) IU of lentivirus delivered 3.5 microg of G-CSF per kilogram per day. After lentiviral vector treatment the gray collie gained weight, showed no clinical signs of infection and fever, and no longer needed housing in a pathogen-free environment. Genomic DNA harvested from muscle at the injection sites was positive for provirus, whereas gonad, lung, spleen, heart, liver, kidney, and noninjected muscle samples were negative. These studies show that an adult animal is responsive long-term to lentivirus-mediated G-CSF delivery, suggesting this approach may be applied for treatment of adult patients with cyclic and other neutropenias.

Animals↗
PubMed2006

Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden.

BACKGROUND AND OBJECTIVES: Severe congenital neutropenia (SCN) or Kostmann syndrome was originally reported to be an autosomal recessive disease of neutrophil production causing recurrent, life-threatening infections. Mutations in the neutrophil elastase gene (ELA-2) have previously been identified in patients with sporadic or autosomal dominant SCN. DESIGN AND METHODS: We studied 14 individuals (four patients with SCN and ten close relatives) belonging to the original Kostmann family in northern Sweden for mutations in the ELA-2 and the granulocyte colony-stimulating factor (G-CSF) receptor genes. RESULTS: One patient belonging to the original Kostmann family harbored a novel heterozygous ELA-2 mutation (g.2310T-->A;Leu92His) that was not inherited from her parents. The mutation was identified in DNA isolated from both whole blood and skin fibroblasts, suggesting a sporadic de novo mutation. As a young adult this patient sequentially acquired two mutations in the gene for the G-CSF receptor (G-CSFR) and therefore recently received a hematopoietic stem cell transplant, due to the risk of evolution to leukemia. Moreover, another patient developed acute leukemia and was treated with transplantation. No pathogenic ELA-2 or G-CSFR gene mutations were found in this patient or the other two patients, nor in any healthy relative. INTERPRETATION AND CONCLUSIONS: Our data are the first to document leukemia evolution and G-CSFR gene mutations in the original Kostmann kindred. In addition, our findings indicate that ELA-2 mutations are not the primary cause of SCN in the Swedish Kostmann family.

Adult↗
PubMed2005

Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist.

Improving approaches for hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is clinically important because increased numbers of these cells are needed for enhanced transplantation. Chemokine stromal cell derived factor-1 (also known as CXCL12) is believed to be involved in retention of HSCs and HPCs in bone marrow. AMD3100, a selective antagonist of CXCL12 that binds to its receptor, CXCR4, was evaluated in murine and human systems for mobilizing capacity, alone and in combination with granulocyte colony-stimulating factor (G-CSF). AMD3100 induced rapid mobilization of mouse and human HPCs and synergistically augmented G-CSF-induced mobilization of HPCs. AMD3100 also mobilized murine long-term repopulating (LTR) cells that engrafted primary and secondary lethally-irradiated mice, and human CD34(+) cells that can repopulate nonobese diabetic-severe combined immunodeficiency (SCID) mice. AMD3100 synergized with G-CSF to mobilize murine LTR cells and human SCID repopulating cells (SRCs). Human CD34(+) cells isolated after treatment with G-CSF plus AMD3100 expressed a phenotype that was characteristic of highly engrafting mouse HSCs. Synergy of AMD3100 and G-CSF in mobilization was due to enhanced numbers and perhaps other characteristics of the mobilized cells. These results support the hypothesis that the CXCL12-CXCR4 axis is involved in marrow retention of HSCs and HPCs, and demonstrate the clinical potential of AMD3100 for HSC mobilization.

Animals↗
PubMed2005

Effective storage of granulocytes collected by centrifugation leukapheresis from donors stimulated with granulocyte-colony-stimulating factor.

BACKGROUND: Donor stimulation with granulocyte-colony-stimulating factor (G-CSF) has increased the number of neutrophils (PMNs) that can be collected for granulocyte transfusion therapy. Clinical utility, however, has been limited by the inability to store functional PMNs ex vivo. This study was conducted to determine whether granulocyte products from G-CSF-stimulated donors could be effectively stored at reduced temperature (22 degrees C vs. 10 degrees C) with maintenance of functional properties in vitro and in vivo. STUDY DESIGN AND METHODS: Nine normal subjects received G-CSF (600 microg subcutaneously) 12 hours before centrifugation leukapheresis. Granulocyte products were divided and stored for 24 and 48 hours under four conditions: 1) 22 degrees C; 2) 22 degrees C, with supplemental G-CSF (100 ng/mL); 3) 10 degrees C; and 4) 10 degrees C, with supplemental G-CSF. Functional PMN activity during ex vivo storage was assessed in vitro and in vivo by the skin-window technique for granulocytes stored at 10 degrees C for 24 hours. RESULTS: Surface expression of CD11b/CD18, CD14, CD16, CD32, and CD64 was maintained during 48-hour storage at reduced temperature. Inducible respiratory burst activity, bactericidal activity, and fungicidal activity were preserved during storage for 48-hour storage at 10 degrees C. Proinflammatory cytokine production was decreased in product stored at 10 degrees C. Supplemental G-CSF ex vivo did not substantially improve functional activity during storage. After storage at 10 degrees C for 24 hours, in vitro chemotactic potential was maintained, and transfused granulocytes retained capacity to circulate and migrate appropriately in vivo. CONCLUSIONS: Granulocyte product collected by centrifugation leukapheresis from G-CSF-stimulated donors can be effectively stored at subphysiologic temperature for 24 hours with preservation of functional activity. Storage at 10 degrees C appears to be slightly superior to storage at 22 degrees C.

Adult↗
PubMed2005

Augmented mobilization and collection of CD34+ hematopoietic cells from normal human volunteers stimulated with granulocyte-colony-stimulating factor by single-dose administration of AMD3100, a CXCR4 antagonist.

BACKGROUND: AMD3100, a selective antagonist of CXCR4, rapidly mobilizes CD34+ hematopoietic progenitor cells (HPCs) from marrow to peripheral blood with minimal side effects. STUDY DESIGN AND METHODS: To further investigate potential clinical utility of AMD3100 for CD34+ cell mobilization and collection, a Phase I study in normal volunteers was performed examining single-dose administration of AMD3100 alone and in combination with a standard 5-day granulocyte-colony-stimulating factor (G-CSF) regimen. RESULTS: AMD3100 (160 microg/kg x 1 on Day 5) significantly increased both G-CSF-stimulated (10 microg/kg/day) mobilization of CD34+ cells (3.8-fold) and leukapheresis yield of CD34+ cells. Moreover, collection of CD34+ cells was comparable between individuals mobilized by a single-dose regimen of AMD3100 (240 microg/kg) and individuals mobilized with a 5-day regimen of G-CSF. AMD3100-mobilized leukapheresis products contained significantly greater numbers of T and B cells compared to G-CSF-stimulated leukapheresis products. CONCLUSION: These findings indicate that AMD3100 can be used alone or as an adjunct to G-CSF to mobilize cells for HPC transplantation.

Anti-HIV Agents↗
PubMed2004

Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin's lymphoma: a nationwide study.

PURPOSE: To assess the incidence of and risk factors for reduced relative dose-intensity (RDI) in patients treated with chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). METHODS: A nationwide survey was conducted of 567 oncology practices with data extracted from the records of 4,522 patients with aggressive NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); CHOP-rituximab (CHOP-R); or cyclophosphamide, mitoxantrone, vincristine, and prednisone (CNOP). The primary outcome was the average RDI for each regimen based on both planned and reference standards. Other assessments included the incidence of febrile neutropenia and patterns of colony-stimulating factor (CSF) use, as well as the average RDI in high-risk subgroups. RESULTS: Dose reductions > or = 15% occurred in 40% of patients and treatment delays > or = 7 days occurred in 24% of patients, resulting in 53% and 48% of patients receiving an RDI less than 85% of the minimum six-cycle and National Comprehensive Cancer Network guideline standards, respectively. Reduced RDI was more prevalent in older patients, with 60% of patients older than 60 years receiving RDI less than 85%. Multivariate analysis identified several independent predictors for reduced RDI, including age older than 60 years, advanced disease stage, poor performance status, and no prophylactic CSF use. Age was no longer a significant risk factor in patients who received prophylactic CSF. CONCLUSION: Patients with aggressive and potentially curable NHL treated with CHOP, CHOP-R, or CNOP frequently receive reduced RDI. Predictive models based on the risk factors identified for reduced RDI should enable the targeted use of appropriate supportive care, facilitating the delivery of full chemotherapy doses on schedule.

Aged↗
PubMed2004

Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells.

Kostmann syndrome, or severe congenital neutropenia (SCN), is an autosomal recessive disorder of neutrophil production. To investigate the potential role of apoptosis in SCN, bone marrow aspirates and biopsies were obtained from 4 patients belonging to the kindred originally described by Kostmann and 1 patient with SCN of unknown inheritance. An elevated degree of apoptosis was observed in the bone marrow of these patients, and a selective decrease in B-cell lymphoma-2 (Bcl-2) expression was seen in myeloid progenitor cells. Furthermore, in vitro apoptosis of bone marrow-derived Kostmann progenitor cells was increased, and mitochondrial release of cytochrome c was detected in CD34(+) and CD33(+) progenitors from patients, but not in controls. Administration of granulocyte colony-stimulating factor (G-CSF) restored Bcl-2 expression and improved survival of myeloid progenitor cells. In addition, cytochrome c release was partially reversed upon incubation of progenitor cells with G-CSF. In sum, these studies establish a role for mitochondria-dependent apoptosis in the pathogenesis of Kostmann syndrome and yield a tentative explanation for the beneficial effect of growth factor administration in these patients.

Apoptosis↗