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)

We report here the case of a 55-year-old patient with chronic granular lymphocyte disorder associated with moderate neutropenia. The majority of peripheral blood lymphocytes displayed a CD3-, CD8-, CD16+, CD56(NKH1)- phenotype. The patient's cells showed high spontaneous cytotoxic activity against K562 targets and developed the ability to kill the natural killer (NK)-resistant target Daudi following activation with interleukin 2 (IL-2). Simultaneously, IL-2 induced proliferation of these cells, albeit to a low level. The effects of IL-2 are likely to be mediated through the IL-2R beta chain (p70) which is expressed on these cells in the absence of the IL-2R alpha chain (p55, Tac). IL-4 was demonstrated to be inhibitory of both the cytotoxic and proliferative effects of IL-2. Thus, despite an unusual CD56- phenotype, the expanded lymphocyte population in this patient display functional and phenotypic properties of normal, non-activated NK cells. These cells probably represent the counterpart of a minor NK cell subpopulation, present in normal individuals at a low frequency, and which has never been fully characterized functionally. In addition, we show that the cytolytic activity of this NK cell population can be blocked in vitro in the presence of a cAMP analog or of theophylline, possibly providing new means of investigating the role of NK cell cytotoxicity on the pathogenesis of associated symptoms in such patients.
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PMID:In vitro responsiveness to interleukins and theophylline of CD16+, CD56- natural killer cells in a patient with chronic granular lymphocyte disorder. 137

Because recombinant interleukin 2 (rIL-2) and recombinant alpha-interferon (rIFN-alpha) exhibit synergistic antitumor activity in C3HMT1820 T-cell lymphoma and B16 melanoma tumor systems, we have performed a Phase I study of this combination in 55 patients with advanced malignancies for whom no standard therapy exists. Successive groups of greater than or equal to 4 patients have been entered into 12 dose levels (1A-3D), with dose levels 1-3 referring to doses of rIL-2 of 0.1, 0.5, and 2.0 x 10(6) units/m2, respectively, and dose levels A-D referring to doses of recombinant human alpha 2a-interferon (rHuIFN-alpha 2a) of 0, 0.1, 1.0, and 10.0 x 10(6) units/m2. Both agents were given on Mondays, Wednesdays, and Fridays, with rIL-2 being given as i.v. bolus injections and rHuIFN-alpha 2a being given intramuscularly. Myelosuppression was dose-limiting and was related primarily to the dose of rHuIFN-alpha 2a. The maximum-tolerated dose level was reached at a dose of rIL-2 of 2.0 x 10(6) units/m2 and of rHuIFN-alpha 2a of 10.0 x 10(6) units/m2 (dose level 3D). At this dose level, 3/6 patients developed grade 3 neutropenia (absolute granulocyte count less than 1 x 10(9)/liter). Myelosuppression was transient, with no documented infections being associated with neutropenia. Hypotension was mild; a single patient was treated with a vasopressor, but all other cases of hypotension responded to fluid administration. No significant pulmonary toxicity was produced. Fever, chills, and malaise were universal but not dose-limiting. Three partial responses and one minor response were observed in patients with malignant melanoma, renal cell carcinoma, and breast cancer. Immunological studies suggested that natural killer activity was related to both the dose of rIL-2 and the dose of rHuIFN-alpha 2a, with natural killer activity being positively related to the dose of rIL-2 and maximal at the lowest dose of rHuIFN-alpha 2a of 0.1 x 10(6) units/m2.
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PMID:Phase I clinical trial of interleukin 2 and alpha-interferon: toxicity and immunologic effects. 280 86

Large granular lymphocyte (LGL) leukemia is a rare disease characterized by clonal expansion of LGL associated with chronic neutropenia, multiple auto-antibodies, and occasionally polyarthritis. We studied cell surface antigen expression and functional activity of leukemic LGL from ten such patients. Using two-color flow cytometric analysis, we found that leukemic LGL from all ten patients expressed the CD3 and HNK-1 markers, while cells from only four patients expressed IgG Fc receptors (FcR). The LGL leukemic cells had little or no NK activity (defined as MHC-nonrestricted cytotoxicity against K562 target cells); however, NK activity could be induced in leukemic LGL by in vitro treatment with as little as 0.05 microgram/mL of anti-CD3 monoclonal antibody. Cell sorting experiments demonstrated that NK activity was induced in CD3+ leukemic LGL (either CD3+, HNK-1+ or CD3+, FcR+) with anti-CD3 monoclonal antibody but not in normal CD3+, FcR- T cells. Treatment with purified interleukin 2 (IL 2) also caused direct activation of some CD3+ leukemic LGL. Despite induction with anti-CD3 MAb or IL 2, activated leukemic LGL did not proliferate or express high density IL 2 receptors detectable by cell sorter analysis. Treatment with alpha interferon had minimal effect on NK activity of LGL leukemic cells. These results suggest that leukemic LGL may provide a useful model for examining the signals required for LGL maturation and activation.
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PMID:Induction of NK activity in large granular lymphocyte leukemia: activation with anti-CD3 monoclonal antibody and interleukin 2. 309 27

Natural killer (NK) cell activity was measured by a 51Cr-release assay using K562 target cells in 12 neutropenic children. NK cell activity was depressed in four patients who had childhood chronic neutropenia with abnormal neutrophil morphology and chemotaxis. The percentage of lysis at a 40:1 effector-target ratio was 28.4% to 42.1% (P less than .001) of the normal lymphocyte value during the study period (32 to 40 months). NK cell activity was normal in the other eight children with chronic neutropenia without any of these neutrophil abnormalities: lazy leukocyte syndrome, Shwachman syndrome, or dysgammaglobulinemia type I with neutrophil defects. NK cell activity of the four patients was depressed at 5:1 to 40:1 effector-target ratios. The NK cells responded to in vitro interferon (IFN)-alpha and interleukin 2, as did normal lymphocytes, but the activated levels were still lower than those of normal lymphocytes (P less than .01). Because NK cells kill a target through recognition, binding, killing, and detaching, and they repeat this lytic sequence (ie, recycling), the localization of the NK cell defect was further analyzed in the four patients using both 51Cr-release and single cell-in-agarose assays. The patients' NK cells were normal in recognizing, binding, and killing a target but were defective in recycling; the estimated maximum recycling capacity (MRC) values in a four-hour assay were 1.8 to 2.4 (P less than .01), as compared with the normal lymphocyte value of 5.5 +/- 0.6 (mean +/- SD). The stimulation of the effector cells with 1,000 U/mL IFN-alpha did not significantly increase the estimated MRC. These results demonstrate that NK cells are defective in recycling in some type of childhood chronic neutropenia with abnormal neutrophil morphology and chemotaxis. The NK cell deficiency is of clinical interest in terms of its relationship to the recurrent infections, development of malignancy, and dysgranulopoiesis in the disorder.
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PMID:Impaired natural killer cell recycling in childhood chronic neutropenia with morphological abnormalities and defective chemotaxis of neutrophils. 387 72

In an effort to develop a biochemotherapy regimen for metastatic melanoma suitable for testing in a cooperative group setting, we modified the concurrent biochemotherapy regimen of S. S. Legha et al. (J. Clin. Oncol., 16: 1752-1759, 1998) by providing enhanced supportive care and developing a strict, conservative approach to the management of treatment-related toxicities. Patients received cisplatin, vinblastine, and dacarbazine (CVD: cisplatin (20 mg/m2) and vinblastine (1.2 mg/m2) on days 1-4, dacarbazine (800 mg/m2) on day 1 only) concurrently with interleukin 2 (9 MIU/m2/day) by continuous i.v. infusion on days 1-4 and IFN-alpha (5 MU/m2/day) on days 1-5, 8, 10, and 12. Prophylactic antibiotics and a maximum of four cycles were administered. Routine granulocyte colony-stimulating factor and aggressive antiemetics were initiated after patients 7 and 14, respectively. Forty-four patients were enrolled in this study. No patients had received prior chemotherapy or interleukin 2; however, 23 (53%) had received prior IFN-alpha, mostly in the adjuvant setting. A total of 131 treatment cycles was administered. Significant toxicities requiring dose modification included: hypotension requiring pressors (15 episodes in 11 patients), grades 3/4 vomiting (12 episodes in 15 cycles; 5 episodes in 12 patients (6 episodes in 9 cycles after initiation of the modified antiemetic regimen), transient renal insufficiency (5 episodes in 5 patients), grade 4 thrombocytopenia (24 episodes, 1 associated with bleeding), neutropenia with or without fever (15 instances, only 11 in 112 cycles after routine use of granulocyte colony-stimulating factor), and catheter-related bacteremia (2 patients). Five (16%) of 30 patients who were treated after the last protocol modification experienced what we defined as unacceptable toxicity for a cooperative group setting. Responses were seen in 19 of 40 evaluable patients (relative risk, 48%) with 8 complete responses (20%). The median response duration was 7 months (range, 1-17+ months) with one currently ongoing. The central nervous system was the initial site of relapse in 11 responding patients. The median survival duration was 11 months (range, 2-31 months). This modified, concurrent biochemotherapy regimen is active and tolerable for use in a cooperative group setting. Central nervous system relapse, however, remains a concern for responders. This regimen is being compared with CVD in a Phase III Intergroup Trial (Eastern Cooperative Oncology Group/Southwest Oncology Group 3695).
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PMID:A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2B in patients with metastatic melanoma. 1087 69

Serum levels of interleukin-1 beta (IL-1beta), soluble interleukin 2 receptors (sIL-2R), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha) were measured to predict some characteristics of febrile episodes in children with cancer and neutropenia. Forty-eight episodes of febrile neutropenia were determined in 23 pediatric cancer patients, including 35 febrile episodes without identifiable source, 7 episodes of bacteremia due to Gram-negative organisms and 4 due to Gram-positive organisms, and 2 fungal infections. Interleukin-6, sIL-2R, and IL-8 levels were significantly higher at the beginning of the febrile episodes than those of controls (p < 0.001, p < 0.001, and p < 0.001). Interleukin-6, slL-2R, and IL-8 levels were higher in patients with bacteremia due to Gram-negative organisms than in those with Gram-positive ones (p = 0.042, p = 0.006, and p = 0.023, respectively). TNF-alpha and IL-1beta levels were similar in febrile episodes and controls (p > 0.05). In conclusion, sIL-2R, IL-6, and IL-8 levels may be helpful in the prediction of infection in febrile cancer patients with neutropenia and measurements of IL-1beta and TNF-alpha were not useful for identifying the presence and the type of infection in febrile neutropenic episodes in children.
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PMID:Serum levels of IL-1 beta, sIL-2R, IL-6, IL-8, and TNF-alpha in febrile children with cancer and neutropenia. 1177 70

A new symptom-complex is described characterized by manifestations of autoimmune disease, infectious lymphadenopathy, double negative T cells, and impaired activation-induced cell death that developed in late adolescence. Similarities, but also significant differences, to autoimmune lymphoproliferative syndromes (ALPS, Canale-Smith syndrome) and autoimmune lymphoproliferative disease (ALD, Dianzani syndrome), were observed. The main clinical features were recurrent bacterial infections with subsequent lymphadenopathy due to autoimmune neutropenia. Laboratory results revealed a large proportion of alphabetaTCR positive, CD4 negative, CD8 negative, peripheral T cells, and a decreased apoptosis upon activation with phytohemagglutinin and interleukin 2, but normal Fas-mediated apoptosis. Genetic investigations excluded mutations in Fas gene death domain and in the 4 exons of Fas ligand gene. Despite unknown pathogenesis, this new syndrome might belong to the growing group of diseases with defects in apoptosis.
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PMID:A new disorder of lymphocyte apoptosis: combination of autoimmunity, infectious lymphadenopathy, double negative T cells, and impaired activation-induced cell death. 1260 26

Severe fungal infections remain a significant cause of morbidity and mortality in neutropenic patients undergoing dose-intensive chemotherapy for malignant diseases. Chronic disseminated candidiasis (CDC) is a life-threatening complication in neutropenic patients because of the lack of responsive hematopoietic precursor cells. Resolution of Candida organ lesions after hematopoietic reconstitution may take months. Here, we report the case of a 19-year-old neutropenic woman with relapsed acute myelogenous leukemia and candidiasis of liver, spleen, and kidneys. Antifungal treatment was initiated using fluconazole and caspofungin but was changed to itraconazole and caspofungin. Despite elevated C-reactive protein (CRP) levels and detectable Candida organ lesions, antileukemic therapy was restarted with interleukin 2 at the same time as antimicrobial treatment. Eight weeks after the start of interleukin therapy, CRP levels and organ lesions were decreased significantly irrespective of continuing neutropenia. This case report describes the successful treatment of CDC during neutropenia using combination antifungal therapy and suggests controlled studies to establish optimal therapeutic strategies.
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PMID:Successful treatment of chronic disseminated candidiasis with caspofungin and itraconazole in a patient with progressive acute leukemia and prolonged neutropenia. 1516

Cytokines are essential regulators of hematopoesis and the immune system. Genetic engineering of recombinant cytokines has facilitated their implementation in many clinical areas. In the field of oncology the granulopoetic human growth factors G-CSF and GM-CSF are of particular importance. They can be applied to prevent chemotherapy induced neutropenia. Furthermore, they allow for mobilization of hematopoetic stem cells in order to obtain peripheral blood stem cell transplants. Another class of cytokines, the interferons, possess immunomodulating, antiproliferative, and antiviral properties. While the significance of interferon alfa as an antitumor agent is dwindling, it still plays a very important role in the therapy of chronic hepatitis b and c. Interferon beta is successfully used to treat multiple sclerosis. Among the heterogenous group of interleukines in particular interleukin 2 has reached clinical practice as an immunostimulating agent in the therapy of metastatic renal cell carcinoma. Many other cytokines have yet to undergo clinical trials.
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PMID:[Immunostimulating drugs and cytokines]. 2204 28

Background Early diagnosis of infection is essential for the initial management of cancer patients with chemotherapy-associated febrile neutropenia (FN). In this study, we have evaluated two emerging infection biomarkers, pancreatic stone protein (PSP) and soluble receptor of interleukin 2, known as soluble cluster of differentiation 25 (sCD25), for the detection of an infectious cause in FN, in comparison with other commonly used infection biomarkers, such as procalcitonin (PCT). Methods A total of 105 cancer patients presenting to the emergency department were prospectively enrolled. We observed 114 episodes of chemotherapy-associated FN. At presentation, a blood sample was collected for the measurement of PCT, PSP and sCD25. In order to evaluate the discriminatory ability of these markers for the diagnosis of infection, the area under the curve (AUC) of the receiver operating characteristic curves was calculated. Results Infection was documented in 59 FN episodes. PCT, PSP and sCD25 levels were significantly higher in infected patients. PCT was the biomarker with the highest diagnostic accuracy for infection (AUC: 0.901), whereas PSP and sCD25 showed a similar performance, with AUCs of 0.751 and 0.730, respectively. In a multivariable analysis, PCT and sCD25 were shown to be independently associated with infection. Conclusions Two novel biomarkers, PSP and sCD25, correlated with infection in cancer patients with chemotherapy-associated FN, but neither PSP nor sCD25 improved the performance of PCT. Based on the results obtained, the introduction of these novel biomarkers as a tool for the diagnosis of infection in this patient group is not recommended.
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PMID:Analyzing the capability of PSP, PCT and sCD25 to support the diagnosis of infection in cancer patients with febrile neutropenia. 3024 Mar 55


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