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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proliferation and differentiation of hematopoietic progenitor cells are regulated by a network of stimulatory and inhibitory cytokines. An understanding of the molecular mechanisms of growth control may provide a physiologic basis for the innovative therapy of bone marrow disorders. Among various accessory cells, bone marrow T lymphocytes are capable of stimulating, as well as inhibiting, hematopoietic progenitor cells. We have now elucidated molecular mechanisms regulating the differential expression of T cell genes encoding for the stimulatory and inhibitory hematopoietic programs. Stimulation of hematopoiesis requires granulocyte-macrophage colony stimulating factor (GM-CSF), whereas inhibition requires interferon-gamma (IF gamma). Both cytokines can be induced by interleukin-2 (IL2). The T cell IL2 receptor consists of a 75 kD chain (p75) mainly expressed on a subset of resting T cells and a 55 kD chain (p55) which is strongly expressed upon T cell activation. P55 and p75 associate on activated T cells to form a dimeric receptor molecule exhibiting high affinity for IL2. The p75 monomer has an intermediate affinity for IL2. Expression of p55 in the context of the high affinity IL2 receptor constitutes a requirement for T cell IFg release. In contrast, p75 alone is capable of mediating the production of GM-CSF. Thus, T cells may be capable of selective production of cytokines with specific effects in hematopoietic growth control. Utilizing a human peripheral blood leukocyte genomic library, we identified various clones containing the entire GM-CSF gene, including coding and regulatory regions. Cloning of the GM-CSF gene allowed clinical studies utilizing recombinant DNA-derived GM-CSF. Chemotherapy-induced neutropenia contributes to both complications of cytotoxic therapy as well as increased relapse incidence of underlying disease. In a prospective randomized study, we have demonstrated that GM-CSF abrogates neutropenia following aplasiogenic chemotherapy in children and adolescents with solid tumors, and that GM-CSF may reduce the duration of infectious episodes after cytotoxic therapy. Next, we escalated the cumulative doses of cytotoxic therapy in an ablative regimen followed by hematopoietic stem cell transplantation to treat patients with poor prognosis pediatric tumors. Morbidity of this highly toxic ablative regimen depends on the duration of myeloid aplasia. Median duration of aplasia following hyper-VAMP was 13 days with CM-CSF and 29 days without GM-CSF. In addition, we have employed p55 blocking monoclonal antibody for prevention of graft vs. host disease in bone marrow transplantation. The understanding of specific molecular mechanisms of hematopoietic immuno-regulation can thus be utilized to provide novel approaches to the treatment of bone marrow failure and cancer.
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PMID:Molecular regulation of hematopoietic cytokines: implications and indications for clinical use in pediatric oncology. 130 80

Chemotherapy-induced neutropenia is a major dose-limiting factor in the management of cancer patients. Most chemotherapeutic agents are active against proliferating cells, interfering with DNA replication and/or mitosis. A number of chemokines, notably macrophage inflammatory protein-1 alpha [MIP-1alpha], have been reported to induce cell-cycle arrest in immature hematopoietic progenitors, raising the possibility that chemokines, such as MIP-1alpha, could be used to reduce or even eliminate the hematologic toxicity of cycle-active chemotherapy. We tested the effectiveness of BB-10010 [a genetically engineered analog of human MIP-1alpha] in vivo against three different cytotoxic drugs [cyclophosphamide (Cy), 5-fluorouracil (5-FU) and cytosine arabinoside (Ara-C)] commonly used in cancer therapy. BB-10010 treatment reduced the toxicity of all three agents, though the precise mode of protection varied with the cytotoxic drug used. BB-10010 reduced the neutropenic interval in Cy-treated mice without affecting the neutropenic nadir, whereas the absolute neutrophil counts [ANC] of both 5-FU and Ara-C treated mice were significantly higher throughout the neutropenic interval for mice receiving BB-10010 prior to chemotherapy. These findings indicate that the ability to manipulate the cell cycle of hematopoietic progenitors with chemokines, such as BB-10010/MIP-1alpha and other negative regulators, may be exploited to reduce chemotherapy-induced neutropenia; furthermore, the fact that BB-10010 is effective against several different cytotoxic agents is cause for guarded optimism that this approach may be generally applicable, and, once optimized for patient use, may prove to be of significant clinical benefit.
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PMID:Protective effects of BB-10010 treatment on chemotherapy-induced neutropenia in mice. 1002 56

Myelosuppression and neutropenia represent the major dose-limiting toxicity of cancer chemotherapy. Chemotherapy-induced neutropenia may be accompanied by fever, presumably due to life-threatening infection, which generally requires hospitalization for evaluation and treatment with empiric broad-spectrum antibiotics. The resulting febrile neutropenia is a major cause of the morbidity, mortality, and costs associated with the treatment of patients with cancer. Furthermore, the threat of febrile neutropenia often results in chemotherapy dose reductions and delays, which can compromise long-term clinical outcomes. Prophylactic colony-stimulating factor (CSF) has been shown to reduce the incidence, severity, and duration of neutropenia and its complications. Guidelines from the American Society of Clinical Oncology recommend the use of CSF on the basis of the myelosuppressive potential of the chemotherapy regimen. The challenge in ensuring the appropriate and cost-effective use of prophylactic CSF is to determine which patients would be most likely to benefit from it. A number of patient-, disease-, and treatment-related factors are associated with an increased risk of neutropenia and its complications. A number of clinical predictive models have been developed from retrospective datasets to identify patients at greater risk for neutropenia and its complications. Early studies have demonstrated the potential of such models to guide the targeted use of CSF to those patients who are most likely to benefit from the early use of these supportive agents. Additional prospective research is needed to develop more accurate and valid risk models and to evaluate the efficacy and cost-effectiveness of model-targeted use of CSF in high-risk patients.
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PMID:Risk assessment in oncology clinical practice. From risk factors to risk models. 1468 13

Chemotherapy-induced neutropenia is a frequent complication in cancer patients receiving myelosuppressive chemotherapy. Chemotherapy-induced neutropenia can result in febrile neutropenia and potentially life-threatening infections requiring hospitalization and intravenous anti-infectives. Chemotherapy dose may be reduced or delayed as a result of chemotherapy-induced neutropenia, which can negatively impact treatment outcomes. Granulocyte colony-stimulating factors, such as filgrastim, stimulate neutrophil production and can therefore reduce the incidence and severity of chemotherapy-induced neutropenia. Filgrastim undergoes rapid renal clearance and needs to be administered daily. The development of pegfilgrastim represents a significant advance in the management of chemotherapy-induced neutropenia as the longer serum half-life allows once-per-chemotherapy administration, and evidence supports increased prophylactic effectiveness in reducing the incidence of febrile neutropenia. This paper reviews the development of pegfilgrastim and summarizes recent clinical data on the use of this simple, effective and well-tolerated option for the management of chemotherapy-induced neutropenia in patients with cancer.
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PMID:Pegfilgrastim: a recent advance in the prophylaxis of chemotherapy-induced neutropenia. 1530 6

Chemotherapy-induced neutropenia is managed in different ways in clinical practice. Chemotherapy dose reductions and delays are used more often than proactive, first-cycle use of colony-stimulating factors, but such dose modifications can result in suboptimal treatment outcomes. This article reviews how 3 oncology practices have used practice pattern studies to assess and improve their quality of care, particularly in the management of neutropenia. These practices analyzed their records for the occurrence of neutropenia and for delays or reductions in chemotherapy doses. Once baseline measurements of quality of care were established, the practices developed guidelines to optimize their management of neutropenia. The practice patterns were assessed again after the guidelines had been implemented, to determine the effect of these guidelines on clinical outcomes. All 3 practices had fewer delays and reductions of chemotherapy doses after the guidelines were used. These differences were both clinically and statistically significant. Clinical experience shows that nurses are well positioned to assess which patients may be at the greatest risk for neutropenia and its complications and therefore should be treated with colony-stimulating factors. Practice guidelines for the use of colony-stimulating factors are being developed, but broader acceptance of these guidelines is needed to support nurses' recommendations.
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PMID:Protocols for managing chemotherapy-induced neutropenia in clinical oncology practices. 1568 84

Chemotherapy-induced neutropenia increases the risk of infection. There appears to be a wide variability in the severity and length of infective episodes. Susceptibility to infections is determined by the underlying malignant disease and its treatment, environmental factors (e.g. nutritional state of the patient and hygiene) and genetically determined variations of the immune system. The majority of primary immunodeficiencies are rare (c. frequency one in 10 000), whereas some genetic polymorphisms in the innate immune system, such as profound mannose-binding lectin deficiency, are much more common (c. frequency one in 10). Here, we review the potential role of the innate immune system in determining susceptibility to infections in patients with neutropenia.
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PMID:Susceptibility to infection in patients with neutropenia: the role of the innate immune system. 1595 96

Chemotherapy-induced neutropenia is a major dose-limiting side effect of intensive chemotherapy in cancer patients. Recently, pegfilgrastim (a product with a long half-life, resulting in once-per-cycle dosage) was introduced to prevent neutropenia in adults. The authors report 32 episodes of pegfilgrastim use in seven pediatric cancer patients to diminish chemotherapy-induced neutropenia. Feasibility was assessed by adherence to treatment protocol and safety was assessed by adverse effects. There were only two treatment delays (6%) due to neutropenia. No short-term adverse effects were recorded. The use of pegfilgrastim is feasible in pediatric cancer patients, without short-term adverse effects or major treatment delay due to neutropenia.
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PMID:Pegfilgrastim in pediatric cancer patients. 1628 99

Chemotherapy-induced neutropenia (CIN) and its complications exact a substantial toll on patients with cancer. Febrile neutropenia (FN), a sign of life-threatening infections, is associated with lengthy hospitalizations, early mortality, and high medical costs. In addition, neutropenia is the primary cause of dose reductions and dose delays, limiting the delivery of the chemotherapy at full dose and on schedule and thus compromising long-term survival in patients with potentially curable malignancies. Many recent studies in several major tumor types have documented that the greatest risk of neutropenia and its complications is in the first cycle of chemotherapy, with more than 50% of the first episodes of neutropenia and FN occurring in the first cycle. In addition to their other negative effects, these first-cycle events are also associated with early termination of the chemotherapy. The disproportionately high risk of neutropenia in the first cycle has important implications for managing CIN, as well as for the development and use of guidelines for supportive care. It highlights the importance of determining which patients are at high risk for neutropenia and its complications before the chemotherapy is initiated and implementing interventions, such as prophylactic growth factor support in the first and subsequent cycles, to reduce that risk.
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PMID:The timing of chemotherapy-induced neutropenia and its clinical and economic impact. 1673 83

Chemotherapy-induced neutropenia is not only a major risk factor for infection-related morbidity and mortality, but is also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact on the success of treatment, particularly when treatment intent is either curative or to prolong survival. The incidence of severe or FN can be reduced by prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim, lenograstim or pegfilgrastim. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. While several academic groups have produced evidence-based clinical practice guidelines in an effort to standardise and optimise the management of FN, there remains a need for generally applicable, European-focused guidelines. To this end, we undertook a systematic literature review and formulated recommendations for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. We recommend that patient-related adverse risk factors such as elderly age (>or=65 years), be evaluated in the overall assessment of FN risk prior to administering each cycle of chemotherapy. In addition, when using a chemotherapy regimen associated with FN in >20% patients, prophylactic G-CSF is recommended. When using a chemotherapy regimen associated with FN in 10-20% patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Finally, studies have shown that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications, where indicated.
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PMID:EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. 1675 Mar 58

Chemotherapy-induced neutropenia is a major dose-limiting toxicity of systemic cancer chemotherapy that can lead to fever and infection, requiring prompt analysis and in-patient treatment with broad-spectrum antibiotics. Complicated neutropenia may lead to reduction and/or delay of systemic anti-cancer treatment, which may compromise outcome. Haematopoietic growth factors have the ability to augment haematopoietic cell cycling and are used to facilitate more dose-intense treatments and to decrease treatment-related complications. This review focuses on randomised trials that investigated the use of colony-stimulating factors (CSF) to prevent treatment-related febrile complications in haematological malignancies in (younger) adult patients. In general, these studies demonstrated that CSF reduced the duration of severe neutropenia but not always its febrile complications; therefore inconsistent results regarding clinically relevant reduction of hospitalisation, duration of therapeutic antibiotics, infection-related or disease-related mortality and economic effects were reported. Current developments in treatment of haematological malignancies will pose new challenges as a shift in infectious pathogens can be expected.
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PMID:Review of the value of colony stimulating factors for prophylaxis of febrile neutropenic episodes in adult patients treated for haematological malignancies. 1759 21


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