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)

In order to determine whether combination chemotherapy offered any advantage over single-agent therapy in cases of metastatic non-small cell bronchogenic carcinoma, we performed a randomized study in 56 patients comparing combination chemotherapy (cyclophosphamide, doxorubicin, methotrexate, procarbazine, leucovorin--CAMP-L) with a regimen in which the same drugs were given sequentially (methotrexate/leucovorin followed by cyclophosphamide/doxorubicin at progression). Of the patients receiving the combination, 52% (14 of 27) had either a partial response or stable disease, compared to 17% (5 of 29) in the sequential group. Of the patients with adenocarcinoma, those in the combination group had a significantly longer survival than those treated in the sequential group (medians, 10.0 vs 2.8 months; P less than 0.01); such a difference could not be demonstrated for patients with squamous carcinoma. Patients who achieved a partial response had a median survival of 15.3 months; those with stable disease survived a median of 10.0 months; and those with no response survived a median of 2.5 months (P less than 0.0001). Four patients died from chemotherapy-related complications: three from methotrexate toxicity and resultant infection and one from pneumonia associated with neutropenia. We conclude that the short survival of non-responding patients and the survival benefit accompanying response or stabilization make early aggressive combination therapy useful for patients with metastatic non-small cell lung cancer.
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PMID:Metastatic non-small cell bronchogenic carcinoma: a randomized trial of sequential vs combination chemotherapy. 630 93

Chronic neutropenia comprises several different diseases that vary in degree of severity and management. We analysed the levels of the neutrophil-derived protein pro-LL-37 in plasma of patients with chronic neutropenia to assess whether it could be used to differentiate different categories of chronic neutropenia. All patients with severe congenital neutropenia were pro-LL-37 deficient. This was in contrast to patients with autoimmune or idiopathic neutropenia, who exhibited normal pro-LL-37 levels while patients with cyclic neutropenia displayed an oscillation of pro-LL-37 in plasma. Plasma levels of pro-LL-37 may thus prove useful for differential diagnosis of chronic neutropenia.
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PMID:Low plasma levels of the protein pro-LL-37 as an early indication of severe disease in patients with chronic neutropenia. 1739 97

A promising therapeutic strategy for the management of severe Pseudomonas infection in neutropenic patients may result from the coadministration of colony-stimulating factors (CSFs) that help maintain immune competence and antimicrobial peptides, a novel generation of adjunctive therapeutic agents with antimicrobial and anti-inflammatory properties. A promising peptide with these properties is LL-37, the only member of the cathelicidin family of antimicrobial peptides found in humans. BALB/c male mice were rendered neutropenic by intraperitoneal administration of cyclophosphamide on days -4 and -2 preinfection. Septic shock was induced at time 0 by intraperitoneal injection of 2x10 colony-forming units of P. aeruginosa American Type Culture Collection (ATCC) 27853. All animals were randomized to receive intravenously isotonic sodium chloride solution, 1 mg/kg of LL-37, 20 mg/kg of imipenem, 0.1 mg/kg of granulocyte CSF (G-CSF), 1 mg/kg of LL-37+0.1 mg/kg of G-CSF, or 20 mg/kg of imipenem+0.1 mg/kg of G-CSF. Lethality and bacterial growth in blood, peritoneum, spleen, liver, and kidney were evaluated. All regimens were significantly superior to controls at reducing the mouse lethality rate and bacterial burden in organs. Particularly, the combination between LL-37 and G-CSF was the most effective in protecting neutropenic mice from the onset of sepsis and in vitro significantly reduced the apoptosis of neutrophils. Combination therapy between LL-37 and G-CSF is a promising therapeutic strategy for the management of severe Pseudomonas infection complicated by neutropenia.
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PMID:Efficacy of LL-37 and granulocyte colony-stimulating factor in a neutropenic murine sepsis due to Pseudomonas aeruginosa. 1839 59

Neutropenia as a consequence of bone marrow failure, severe infections, or intensive chemotherapy is frequently associated with life-threatening sepsis. Ex vivo expansion of CD34(+) stem cells has been shown to generate apparently functional neutrophils, and the use of autologous ex vivo-expanded cells can reduce the duration of neutropenia. Nonetheless, the principal antimicrobial capabilities of such cells, and thus their true therapeutic potential, is unknown. Using established protocols, we derived mature neutrophils from normal human adult bone marrow (BM) CD34(+) cells and compared them with freshly isolated peripheral blood neutrophils (PBN). Despite functional similarities between ex vivo-differentiated neutrophils (EDN) and PBN in assays of respiratory burst and phagocytosis, EDN showed marked impairment in their ability to kill both Escherichia coli and Streptococcus pneumoniae compared with PBN. We found that EDN were able to detect (through Toll-like receptor 2 [TLR2], TLR4, and CD14 expression), phagocytose, and mount a respiratory burst to microorganisms. EDN, however, were unable to release neutrophil elastase in response to formyl-met-leu-phe and showed a significantly reduced expression of neutrophil elastase, cathepsin G myeloperoxidase, and LL-37/human cathelicidin protein 18 (hCAP18) as determined by Western blotting. Ultrastructural analysis was consistent with a failure of normal granule development in EDN. Neutrophils derived from BM CD34(+) cells may therefore provide apparently functional cells as assessed by common methodologies; however, important deficiencies may still limit their therapeutic potential. The results presented here suggest additional key tests that such cells may need to undergo prior to clinical use and highlight the potential challenges of using ex vivo modified stem cells in therapeutic settings. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Ex vivo-expanded bone marrow CD34+ derived neutrophils have limited bactericidal ability. 1866 8

The underlying cause of neutropenia may be difficult to determine due to similar clinical presentation in many neutropenic conditions. The neutrophil protein hCAP-18 (pro-LL-37) is a major component of neutrophil secondary granules and in this prospective study we assessed the use of hCAP-18 levels in blood plasma for differential diagnosis of neutropenic patients (n = 133) of various aetiologies. Plasma levels of hCAP-18 were determined using immunoblot and ELISA. Patients with severe congenital neutropenia (n = 23) presented with the lowest levels of plasma hCAP-18 and differential diagnostic accuracy revealed high sensitivity (100%) and specificity (98.8%) for hCAP-18 ELISA. The correlation coefficient of the hCAP-18 ELISA versus immunoblotting was (R = 0.831) and that of the peptide LL-37 ELISA versus immunoblotting was (R = 0.405) (P < 0.001). Plasma hCAP-18 levels thus displayed high diagnostic value in differential diagnosis of chronic neutropenia. Neutropenic patients with Shwachman-Diamond syndrome, Barth syndrome, Cohen syndrome, acute myeloid leukaemia and specific granule deficiency presented with reduced plasma hCAP-18 levels as well. The blood plasma level of hCAP-18 was thus low in conditions in which the neutrophil antibacterial propeptide hCAP-18 is deficient, i.e. severe congenital neutropenia and neutrophil-specific granule deficiency, and in conditions in which bone marrow myelopoiesis is negatively affected.
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PMID:The antimicrobial propeptide hCAP-18 plasma levels in neutropenia of various aetiologies: a prospective study. 2611 62

The human antimicrobial peptide LL-37 is produced by neutrophils and epithelial cells, and the peptide can be detected in plasma as well as saliva. LL-37 is active against both gram-positive and gram-negative bacteria including oral pathogens such as Porphyromonas gingivalis and Streptococcus mutans. Besides its antimicrobial properties, LL-37 modulates the innate immune system, and furthermore, it also affects host cell viability. Although, both structural and functional properties of LL-37 have been extensively investigated, its physiological/pathophysiological importance in-vivo is not completely understood. In this review, Kostmann disease (morbus Kostmann) is highlighted since it may represent a LL-37 knockdown model which can provide new important information and insights about the functional role of LL-37 in the human in-vivo setting. Patients with Kostmann disease suffer from neutropenia, and although they are treated with recombinant granulocyte colony-stimulating factor (G-CSF) to normalize their levels of neutrophils, they lack or have very low levels of LL-37 in plasma, saliva and neutrophils. Interestingly, these patients suffer from severe periodontal disease, linking LL-37-deficiency to oral infections. Thus, LL-37 seems to play an important pathophysiological role in the oral environment antagonizing oral pathogens and thereby prevents oral infections.
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PMID:What can we learn about functional importance of human antimicrobial peptide LL-37 in the oral environment from severe congenital neutropenia (Kostmann disease)? 3227 9