Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment-related morbidity, and in some cases, mortality, associated with autologous and allogeneic bone marrow transplantation has decreased in the past decade largely due to the use of blood stem cells combined with hematopoietic growth factors. However, these procedures remain morbid, with several series documenting regimen-related injury to the oral mucous membranes, the worst form of toxicity from a patient perspective. The pathophysiology of transplant-related mucositis is related to two major events: direct mucosal basal cell injury leading to atrophy and ulcerations, and local infections that can become systemic, the latter of which are exacerbated by the severe neutropenia accompanying high-dose chemotherapy. Recent investigational agents designed to interfere with these two aspects of mucositis have been developed and are showing promise in early clinical trials. In particular, keratinocyte growth factor (KGF) and interleukin-11 appear active. They increase basal cell proliferation, prevent apoptosis due to the preparative regimen, and appear to ameliorate the mucositis seen with high-dose chemotherapy regimens. Oral, nonabsorbable anti-infective agents are also being tested in an attempt to prevent both local and systemic infections. Devoid of significant side-effects, KGF is now in large phase 2 trials that, if positive, will be a significant advance in promoting less morbid transplants by reducing pain and the risk of secondary infections and thus may reduce supportive care costs.
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PMID:Mucositis associated with stem cell transplantation: current status and innovative approaches to management. 1143 15

Oral and intestinal mucositis are among the most significant dose-limiting toxic effects of intensive cancer treatment and are associated with adverse clinical and economic outcomes. Palifermin (Kepivancetrade mark), an N-truncated recombinant human keratinocyte growth factor-1, is the first agent to be approved for prevention of oral mucositis. Keratinocyte growth factor, a potent epithelial mitogen, appears to play a major role in the healing process. Palifermin has multiple biological activities that appear to protect the mucosal epithelium and promote its early regeneration after irradiation- and chemotherapy-induced injury. These include inhibition of epithelial cell apoptosis and DNA damage, up-regulation of detoxifying enzymes and down-regulation of pro-inflammatory cytokines, as well as enhanced migration, proliferation and differentiation of epithelial cells. Palifermin reduces the incidence, severity and duration of oral mucositis in patients with haematological malignancies undergoing myelotoxic conditioning therapy and haematopoietic stem-cell transplantation. Clinical sequelae, including febrile neutropenia and resource use (opioid analgesia and parenteral feeding), are concomitantly reduced. Other potential applications being explored include use in the solid tumour setting, reduction of intestinal mucositis and reduction of GVHD in allogenic transplantation. Thus, the development of palifermin and other potential new agents for preventing chemotherapy- and radiotherapy-induced mucositis represents an important breakthrough in oncological supportive care.
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PMID:Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic growth factor with multiple biological activities in preventing chemotherapy- and radiotherapy-induced mucositis. 1703 May 44

A double-blind, randomized trial showed that, compared with placebo, palifermin (recombinant human keratinocyte growth factor) reduced the frequency and duration of oral mucositis in patients with hematologic malignancies undergoing high-dose chemotherapy and total-body irradiation with autologous stem-cell support. This previously published study also showed a significant reduction in the incidence of adverse subsequent outcomes. The objective of this study was to estimate the impact of palifermin prophylaxis on hospital costs of transplantation in the trial. This was a retrospective, economic analysis of estimated costs for a previously published clinical trial. Costs were not collected during the trial. Therefore, we estimated the direct medical costs of hospitalization using hospital charges from similar patients' hospitalization charges selected from the National Inpatient Sample, a population-based, nationally representative sample of hospital claims. Costs were estimated from charges using Medicare's state-specific cost-to-charge ratios. These cost estimates were applied to the outcome data (incidence of febrile neutropenia, bacteremia/fungemia, or pneumonia, and use of total parenteral nutrition) from the clinical trial. Patients were those with hematologic malignancies who received high-dose chemotherapy and total-body irradiation with autologous stem cell transplant. We compared the estimated total hospital costs (in 2005 United States dollars) incurred by patients who received palifermin in the clinical trial with those incurred by patients who received placebo. Costs were analyzed from the provider's perspective. The mean cost of a hospital day in this population varied between $2,834, when no adverse outcomes occurred, and $4,663, when all 4 outcomes occurred. Reductions in adverse outcomes and their associated hospital stay offset the acquisition price of palifermin. A nonsignificant mean savings of $3,595 per patient (95% confidence interval: $2,090-$5,103) was observed. In sensitivity analyses, this observation was robust to all plausible values of per diem hospital costs and hypothetic per diem outpatient costs. In addition to its previously demonstrated clinical benefit, palifermin prophylaxis offers a favorable economic profile among patients with hematologic malignancies who receive total body irradiation and autologous stem cell support.
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PMID:Economic impact of palifermin on the costs of hospitalization for autologous hematopoietic stem-cell transplant: analysis of phase 3 trial results. 1758 Feb 58

Oral mucositis, the breakdown of the mucosal lining of the oropharynx, occurs as a result of a toxic insult to the normal epithelium of the oral mucosa. Typically this is seen after exposure to a toxic agent such as radiation or chemotherapy; therefore, it is a frequent problem for patients undergoing treatment for cancer. In clinical trials, mucositis has been reported in up to 98% of patients receiving high-dose chemotherapy followed by hematological stem cell transplant. When mucositis develops it causes severe patient symptoms such as pain, but it is also associated with inferior clinical outcomes including increased infection, narcotic use and even mortality. In clinical trials, palifermin, a recombinant humanized keratinocyte growth factor (rHuKGF), has demonstrated an ability to decrease the incidence and duration of mucositis. In the registrational phase III trial in patients undergoing stem cell transplant for hematological malignancies, only 63% of patients who received palifermin developed World Health Organization grade 3 or 4 mucositis compared to 98% of patients on the placebo arm (1). The patients on the palifermin arm also had a shorter duration of mucositis with significantly decreased pain, use of narcotics, need for total parenteral nutrition and febrile neutropenia. Based on these results, palifermin became the first drug that has been approved by the U.S. Food and Drug Administration (FDA) to decrease the incidence and duration of severe oral mucositis in patients with hematological malignancies receiving high-dose chemotherapy requiring hematopoietic stem cell support. The development of mucositis is also a problem for patients receiving treatment for nonhematological tumors. In clinical trials, mucositis has been reported in over 75% of patients receiving combined chemo-/radiotherapy for head and neck cancer or fluorouracil for metastatic colon cancer. Initial phase I and II clinical trials of palifermin have demonstrated a benefit in patients receiving chemotherapy with or without radiation therapy for solid tumors; however, large phase III trials need to be completed before palifermin can gain FDA approval for this indication.
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PMID:Recombinant human keratinocyte growth factor palifermin reduces oral mucositis and improves patient outcomes after stem cell transplant. 1772 47

Infectious diseases continue to be major causes of morbidity and mortality in pediatric patients with cancer. Yet not all pediatric patients with cancer with fever and neutropenia are at equal risk for substantial morbidity or mortality from infection. Patients at highest risk for developing infectious complications are those with severe and prolonged neutropenia, substantial medical comorbidity, and hematologic malignancy, or recipients of stem-cell transplantation. These "high-risk" patients also have concomitant host immune deficits as well: severe mucositis, lymphopenia, hypogammaglobulinemia, and gut microbial dysbiosis. Because bacterial and fungal infections are the most common infectious complications, continuation of empirical antibacterial antibiotics that were initiated at the onset of febrile neutropenia and prompt initiation of empirical antifungal therapy in the setting of prolonged fever and neutropenia continue to be the standard of care. In high-risk patients, antibiotic therapy should be maintained until neutrophil counts have recovered. Adjunctive therapies have been shown to be ineffective (e.g., colony-stimulating factors) or necessitate further study (e.g., granulocyte infusions or keratinocyte growth factor treatment to heal mucositis). Prophylactic use of antibacterial and antifungal antibiotics in high-risk patients has shown promise but the fear of inducing antimicrobial-resistant strains remains a deterrent. Finally, the novel concepts of manipulating the host gut microbiota and/or augmenting GI mucosal immunity to prevent invasive bacterial and fungal infections in pediatric patients with cancer offers great promise, but more definitive studies need to be performed.
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PMID:Prolonged febrile neutropenia in the pediatric patient with cancer. 2445 97