Neutropenia In Cancer Patients Research Articles

Use of antimicrobial agents and granulocyte colony stimulating factors for febrile neutropenia in cancer patients in a tertiary care hospital in India

Use of antimicrobials (AM) and granulocyte colony stimulating factors (G-CSF) affect the outcome and cost of treatment of febrile neutropenia (FN). There are no studies describing the AM utilization pattern or the use of G-CSF and cost incurred on them in cancer patients with FN from India. A study was conducted in a tertiary care, teaching hospital in New Delhi, India, with the objectives of describing the utilization pattern of AM and G-CSF in cancer patients with FN. The efficacy and costs of AM and G-CSF prescribed were also assessed. A total of 211 patients with FN were enrolled in the study. A majority of 207 (98.1%) were in the low-risk category. The average number of AM used per patient was 2.45 ± 0.02 and the AM exposure density was 1.19. All patients were administered five different combinations of AM regimens and G-CSF, irrespective of the risk category. No difference in the time to defervesence or in the recovery of ANC counts were observed with the different AM regimens. The average drug cost per febrile neutropenia episode (FNE) was Rs 4694.45 ± 296.35 (113.95 ± 7.19$). G-CSF accounted for 76.14 - 97.58% of the total costs. Large variations in the pattern of AM prescribed with routine use of G-CSF, irrespective of the risk status, was observed. Guidelines for the rational and cost-effective use of AM and G-CSF in patients with FN needed to be prepared. This was especially important as treatment was given free of cost to all patients admitted in the government health facility.

Retrospective cost analysis of management of febrile neutropenia in cancer patients in Spain

Background:Febrile neutropenia (FN) is associated with disruption of planned chemotherapy and increased management costs. However, the economic impact of FN in Spanish clinical practice has not been documented hitherto.Research design and methods:A multicenter, retrospective chart review of adults with breast or lung cancer or non-Hodgkin's lymphoma (NHL) who had ≥1 FN episode during chemotherapy. Resource use, direct costs, and FN effect on planned chemotherapy were assessed.Main outcome measures:238 episodes of FN were analyzed in 194 patients. The mean ± SD length of FN-related hospitalization was 8.7 ± 6.9 days (median [p25–p75] = 7 [5–11] days). At least one transfusion was needed in 77 (32.3%) FN episodes, blood tests were done in 233 (97.9%) and blood cultures in 207 (87.0%). Antibiotics were used in all episodes (100%), other drugs in 186 (78.2%) episodes and the granulocyte colony-stimulating factor (G-CSF) in 161 (67.7%) episodes. The distribution of costs per episode of FN were: hospitalization 79%, antibiotics 10%, G-CSF 5%, complementary tests 4%; other drugs 1%, blood transfusions 1%. The estimated mean (95% CI) cost per FN episode was €3841 (95% CI: €3476–4206). FN management was costlier in NHL patients €4514 (95% CI: €3805–5223) than in breast or lung cancer patients (€3519 [95% CI: €2976–4061] and €3311 [95% CI: €2817–3805] respectively) (P < 0.05 both comparisons). Planned chemotherapy was disrupted in 139 (58.4%) episodes (dose reductions in 75 [34.9%], dose delays in 60 [28.0%] and withdrawal in 33 [14.7%]).Conclusions:FN substantially affects healthcare resource use and costs in breast cancer, lung cancer and, NHL. In this study, hospitalization and antibiotics were the main drivers of cost. A limitation of the analysis was that it did not include the indirect costs associated with FN episodes.

Pharmacodynamic Genes do not Influence Risk of Neutropenia in Cancer Patients Treated with Moderately High-Dose Irinotecan

A recent study found that variation in camptothecin pharmacodynamic genes (TOP1, PARP1, TDP1 and XRCC1) correlated with efficacy and risk of neutropenia in irinotecan-treated cancer patients (median dose: 180 mg/m2), which suggests that these genes might predict outcomes to irinotecan-based therapies. The present study was conducted to evaluate previous gene associations using an independent sample of patients receiving irinotecan. DNA was isolated from 85 advanced cancer patients treated with 300 or 350 mg/m2 irinotecan and genotyped for haplotype-tag polymorphisms across TOP1, PARP1, TDP1 and XRCC1. Associations between genotypes and haplotypes and log(absolute neutrophil count nadirs) were assessed by linear regression. No associations were observed. Our findings suggest that the genes we tested do not influence toxicity of irinotecan when adminstered at 300-350 mg/m2.

Should the indications for the use of myeloid growth factors for the prevention of febrile neutropenia in cancer patients be extended?

Prevention of infectious complications of chemotherapy-induced granulocytopenia is a major issue in preventive medicine, as febrile neutropenia is still associated with an overall 10% mortality and extensive morbidity and cost. The prescription of granulocyte colony-stimulating factors should not be determined according to a risk prediction of febrile neutropenia considering solely type of chemotherapy and according to cost-effectiveness; other factors appear now to be important for making the decision, namely age and the presence of various comorbid factors. It is likely that the consideration of these newly recognized risk factors and the availability of more affordable granulocyte colony-stimulating factors will lead, in the near future, to an extension of the presently recognized indications for the prescription of granulocyte colony-stimulating factors.

CLONING AND EXPRESSING HG-CSF (HUMAN GRANULOCYTE COLONY STIMULATING FACTOR) BEING FUSED WITH FERRITIN HEAVY-CHAIN IN E. COLI

G-CSF is a cytokine that stimulates the proliferation, differentiation, function of mature neutrophils and is generally used for treatment of neutropenia in cancer patients under chemotherapy. In this study, we report results on the cloning and expression of hG-CSF being fused with the heavy-chain (FTN-H) of human ferritin, which had been showed to be capable of facilitate the folding of several human protein expressed in E. coli. The hg-csf gene and gene encoding FTN-H were inserted into plasmid pET28a to form expression vector PET-FHG. 6xHis tag and TEV sequence (being recognized and cleaved by TEV protease) was added between of G-CSF and FTN-H to facilitate G-CSF purification and recovery afterwards. PET-FHG was transformed into E. coli BL21(DE3). The expression of hG-CSF was induced by IPTG and confirmed by SDS-PAGE and Western blot using anti-hG-CSF antibody.

Comprehensive Pharmacogenetic Analysis of Irinotecan Neutropenia and Pharmacokinetics

We aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients. Pharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg/m(2) (n = 20) and 350 mg/m(2) (n = 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated. Almost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 -48C>T, SLCO1B1*1b, ANC baseline levels, sex, and race (P < .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 -24C>T, SLCO1B1*5, HNF1A 79A>C, age, and CPT-11 dose (P < .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684T>C, ABCB1 IVS9 -44A>G, and UGT1A1*93 (P = .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes. On the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required.

Pharmacodynamic genes do not influence risk of neutropenia in cancer patients treated with moderately high-dose irinotecan

Pharmacodynamic genes do not influence risk of neutropenia in cancer patients treated with moderately high-dose irinotecan

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Neutropenia during Phase I Development of Liposome-Entrapped Paclitaxel

To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients. LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m(2)). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection. The MTD of LEP-ETU was identified as 325 mg/m(2). DLTs occurring at 375 mg/m(2) consisted of febrile neutropenia and neuropathy. The C(max) and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 mug/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m(2) q3w. For a dose of 110 mg/m(2) given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w. LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m(2) LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m(2) Taxol q3w. A 275 mg/m(2) dose may offer an improved therapeutic index.

Multiple-pool cell lifespan models for neutropenia to assess the population pharmacodynamics of unbound paclitaxel from two formulations in cancer patients

Our objective was to build a mechanism-based pharmacodynamic model for the time course of neutropenia in cancer patients following paclitaxel treatment with a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol). A randomized two-way crossover trial was performed with 35 adult patients who received 175 mg/m(2) paclitaxel as either 15 min (Tocosol Paclitaxel) or 3 h (Taxol) intravenous infusions. Paclitaxel concentrations were measured by LC-MS/MS. NONMEM VI was used for population pharmacodynamics. The cytotoxic effect on neutrophils was described by four mechanism-based models predicated on known properties of paclitaxel that used unbound concentrations in the central, deep peripheral or an intracellular compartment as forcing functions. Tocosol Paclitaxel was estimated to release 9.8% of the dose directly into the deep peripheral compartment (DPC). All models provided reasonable fitting of neutropenic effects. The model with the best predictive performance assumed that this dose fraction was released into 22.5% of the DPC which included the site of toxicity. The second-order cytotoxic rate constant was 0.00211 mL/ng per hour (variability: 52% CV). The relative exposure at the site of toxicity was 2.21 +/- 0.41 times (average +/- SD) larger for Tocosol Paclitaxel compared to Taxol. Lifespan was 11.0 days for progenitor cells, 1.95 days for maturating cells, and 4.38 days for neutrophils. Total drug exposure in blood explained half of the variance in nadir to baseline neutrophil count ratio. The relative exposure of unbound paclitaxel at the site of toxicity was twice as large for Tocosol Paclitaxel compared to Taxol. The proposed mechanism-based models explained the extent and time course of neutropenia jointly for both formulations.

Pegfilgrastim Administered on the Same Day with Dose-Dense Adjuvant Chemotherapy for Breast Cancer Is Associated with a Higher Incidence of Febrile Neutropenia as Compared to Conventional Growth Factor Support: Matched Case-Control Study of the Hellenic Cooperative Oncology Group

Objective: Recombinant human granulocyte-colony-stimulating factors such as filgrastim and pegfilgrastim have been employed as primary and secondary prophylaxis against neutropenia in cancer patients receiving chemotherapy. This study was conducted to evaluate the rate of febrile neutropenia in patients with high-risk early breast cancer receiving dose-dense chemotherapy and, as primary prophylaxis, either pegfilgrastim 6 mg fixed dose on the same day as chemotherapy or filgrastim on days 2–10 of each cycle. Secondary objectives included the rate of severe neutropenia, treatment delays and dose reductions. Methods: This was a nonrandomized matched case-control study with 214 patients receiving dose-dense chemotherapy. Each group receiving supportive therapy included 107 patients (pegfilgrastim and filgrastim groups). Results: Fourteen patients (13%) in the pegfilgrastim group developed febrile neutropenia as compared to 1 patient (1%) in the filgrastim group (p = 0.001). No statistically significant differences regarding the rate of severe neutropenia, treatment delays and dose reductions were observed. Conclusion: The results demonstrate that pegfilgrastim administered as primary prophylaxis on the same day as dose-dense chemotherapy is less efficacious than filgrastim administered on days 2–10 of each chemotherapy cycle. For the particular regimens given in this retrospective matched case-control study, the current recommendation for administering pegfilgrastim at least 24 h after chemotherapy completion seems justified. However, further randomized controlled trials are needed to clarify this finding.

GlycoPEGylated Filgrastim XM22 Demonstrates Dose-Dependent Activity in Comparison to Pegfilgrastim in a Dose-Escalating Study in Healthy Volunteers after Body-Weight Dependent Single Dose.

XM22 is a glycoPEGylated recombinant human G-CSF that interacts with the G-CSF receptor by binding and activation. In pilot studies in non-neutropenic animals, XM22 demonstrated a similar PK/PD profile compared to pegfilgrastim. Because of its longer duration of action compared to filgrastim, XM22 is intended to be dosed once per cycle for the reduction of duration of severe neutropenia and incidence of febrile neutropenia in cancer patients undergoing chemotherapy.METHODS: A single center, randomized, single-blind study of XM22, administered as single escalating body-weight (bw) dependent doses given by the s.c. route was conducted to assess safety, pharmacokinetic profile and pharmacodynamic properties based on absolute neutrophil count (ANC) and CD34+ cell count. Male or female healthy volunteers were assigned to one of 3 XM22 dose groups, at 25 μg/kg bw dose (n=8), at 50 μg/kg bw (n=15), and 100 μg/kg bw (n=15) compared to 100 μg/kg bw pegfilgrastim (n=15).RESULTS: 53 healthy volunteers were enrolled in the three dose groups and completed 21 day follow-up. Injections were generally well-tolerated with no discontinuations due to adverse events or serious adverse events. XM22 at a dose of 100 μg/kg bw exhibited a PK profile with increased bioavailability and extended half life compared to the same dose of pegfilgrastim. ANC area over baseline effect curve (AOBEC) and CD34+ AOBEC were higher after treatment with XM22 100 μg/kg bw (6818.55 hr*neut./nl and 7340.16 hr*cell count/μl geometric mean respectively) compared to the same dose of pegfilgrastim. Antibody data will be presented.CONCLUSIONS: Single body-weight dependent doses up to 100 mg/kg of XM22 administered to healthy volunteers were generally well-tolerated with regard to the expected side effect profile and demonstrated dose-dependent increases in absolute neutrophil count and CD34+ cell count. These data supplement results from another study in healthy volunteers in which XM22 was administered as a fixed dose.

Daptomycin Use in Cancer Patients with Neutropenia.

Infections occurring during neutropenia in cancer patients (pts) frequently involve Gram-positive pathogens and are complicated by antibiotic resistance. Outcomes for infections due to either methicillin-resistant or -susceptible Staphylococcus aureus (MRSA, MSSA) treated with vancomycin are considered suboptimal by many clinicians (Sakoulas G. J Clin Microbiol 2004; 42:2398–402). New effective agents are needed for treatment. Data were collected retrospectively as part of an ongoing registry (Cubicin Outcomes Registry and Experience; CORE, 2005 and 2006 program years). Data were collected on demographic and microbiologic characteristics; prior, concomitant and follow-up antibiotics; DAP regimen; and clinical data. Outcomes were assessed at the end of DAP therapy by the investigator who, in most cases, was the infectious disease physician involved in the treatment of the patient. The definitions for clinical outcome were: Cure - clinical signs and symptoms resolved (and/or) no additional antibiotic therapy necessary (or) negative culture reported at the end of therapy; Improved - partial resolution of clinical signs and symptoms (and/or) additional antibiotic therapy warranted at the end of therapy; Failure - inadequate response to therapy: worsening or new/recurrent signs and symptoms (or) need for a change in antibiotic therapy (or) positive culture reported at the end of therapy. Pts reported with neutropenia during DAP, a history of cancer, and evaluable for outcome (cure, improved, failure) were analyzed. Eighty-four pts had a history of cancer and had neutropenia during DAP treatment, of these, 72 (86%) were evaluable for DAP outcome. Sixty-five of 72 (90%) pts had either cure (n=40, 56%) or improved (n=25, 35%) as an outcome. Success rates (cure plus improved) stratified by the lowest WBC during DAP were; 29/34 (85%) for < 100 cells/m3, 26/28 (93%) for 100–499 cells/m3, and 10/10 (100%) for 500–1000 cells/m3, P=0.32. The median (range) time to clinical response in those successfully treated (data reported in 47 pts) was 4 days (1–21). Fifty-nine of 72 (82%) had a hematological malignancy. Fifty-eight percent were male, 22% were ≥66 yrs old, 7% had an initial CrCl <30 mL/min, 18% received DAP in an ICU. Eighty-eight percent of pts received antibiotics before DAP, most frequently with vancomycin (83%), cefepime (17%), and linezolid (16%). The most frequent reason for switching to DAP was prior clinical failure / resistance (54%). The major infections being treated with DAP were bacteremia (76%), UTI / pyelonephritis (10%), and uncomplicated skin and skin structure (6%). Seventy-four percent of pts with a WBC < 100 cells/m3 had a bacteremia. The most common Gram-positive pathogens reported were vancomycin-resistant enterococci (52%), coagulase-negative staphylococci (21%), and S. aureus (14%; 7/11, 64% were MRSA). The median (range) initial DAP dose was 6.0 mg/kg (3–7). The median (range) DAP duration of therapy was 13 days (1–86). Nineteen percent of the pts received DAP as an outpatient at some time during their therapy. There were 37 adverse events (AE) reported in 20 (28%) pts; however, only three AEs in 3 pts (4%) were assessed as possibly related to DAP. The data from the registry provide useful information about the clinical characteristics of neutropenic cancer patients treated with DAP for primarily bacteremia. Most of the pts were bacteremic and there was no difference in outcome regardless of the degree of neutropenia. These data require confirmation via prospective clinical trials.

The Role of Sargramostim (rhGM-CSF) as Immunotherapy

GM-CSF stimulates the differentiation of hematopoietic progenitors to monocytes and neutrophils, and reduces the risk for febrile neutropenia in cancer patients. GM-CSF also has been shown to induce the differentiation of myeloid dendritic cells (DCs) that promote the development of T-helper type 1 (cellular) immune responses in cognate T cells. This review summarizes some of the immunological effects of GM-CSF relevant to antitumor immunity in cancer patients. GM-CSF has been used to augment the activity of rituximab in patients with follicular lymphoma and to induce autologous antitumor immunity in patients with hormone-refractory prostate cancer. GM-CSF causes upregulation of costimulatory molecule expression on leukemia blasts in vitro, enhancing their ability to present antigen to allogeneic T cells, and, in combination with interferon-alpha, can induce antitumor immune responses in patients whose acute leukemia has relapsed following allogeneic hematopoietic progenitor cell transplant. Tumor cells engineered to secrete GM-CSF are particularly effective as antitumor vaccines, and the addition of GM-CSF to standard vaccines may increase their effectiveness by recruiting DCs to the site of vaccination. However, a significant limitation in the use of GM-CSF as an immunostimulatory agent is that objective antitumor responses are infrequent, and are often not durable. Effective and durable antitumor immunity will likely require novel methods to eliminate counterregulatory immune responses that limit activation and expansion of cytotoxic T cells with antitumor activity.

Revisiting therapeutic strategies in radiation casualties

Nuclear/radiological threats have evolved and scenarios for terrorist attacks involving radioactive material have been identified as complex situations. Mass casualty scenarios may happen, and individuals may be exposed to intentionally hidden sources of high activity, resulting in delayed diagnosis and treatment of acute radiation syndrome (ARS). Moreover, ARS must be considered as an emergency in order to better anticipate delayed radiation toxicity. In this context, therapeutic strategies in radiation casualties have to be revisited and new pharmacological approaches developed. B6D2F1 mice were total-body irradiated (TBI) with a 9 Gy gamma dose and then received intraperitoneal doses of either early (stem cell factor + FLT-3 ligand + thrombopoietin + interleukin-3 [SFT3] +/- keratinocyte growth factor (KGF); stem cell factor + erythropoietin + Peg-filgrastim [SEG]) or delayed treatments (SFT3 +/- KGF, erythropoietin, or hyaluronic acid). Survival was monitored and bone marrow hematopoiesis evaluated at 300 days following early treatments. SFT3 anti-apoptotic cytokine combination administered early (2 hours and 24 hours) after lethal TBI induced 60% survival versus 5% in controls. Early SEG treatment may be an alternative to SFT3 in terms of survival (55%), but SEG benefit might be obtained at the expense of long-term hematopoiesis. SFT3 + KGF induced 75% survival. No effectiveness was observed, over antimicrobial supportive care, when administration of SFT3 or its tested combinations was delayed at 48 hours. As a potentially multi-organ failure, ARS requires global therapy, beyond the hematopoietic syndrome, which may include pleiotropic cytokines such as KGF.

Early hospital discharge versus continued hospitalization in febrile pediatric cancer patients with prolonged neutropenia: A randomized, prospective study

Hospitalization with single or multi-agent antibiotic therapy has been the standard of care for treatment of febrile neutropenia in cancer patients. We hypothesized that an empiric antibiotic regimen that is effective and that can be administered once-daily will allow for improved hospital utilization by early transition to outpatient care. Febrile pediatric cancer patients with anticipated prolonged neutropenia were randomized between a regimen of once-daily ceftriaxone plus amikacin (C + A) and imipenem monotherapy (control). Afebrile patients on C + A satisfying "Early Discharge Criteria" at 72 hr continued treatment as outpatients. We compared the outcome, adverse events, duration of hospitalization, and cost between both groups. A prospective randomized controlled clinical trial was conducted on 129 febrile episodes in pediatric cancer patients with prolonged neutropenia. No adverse events were seen in 32 children (84% of study arm) treated on an outpatient basis. We found a statistically significant difference between the duration of hospitalization of the C + A group [median 5 days] and control [median 9 days](P < 0.001), per episode antibiotic cost (P < 0.001) and total episode cost (P < 0.001). There was no statistically significant difference in the response to treatment at 72 hr or after necessary antimicrobial modifications. We conclude that pediatric febrile cancer patients initially considered at risk for sepsis due to prolonged neutropenia can be re-evaluated at 72 hr for outpatient therapy. The convenience, low incidence of adverse effects, and cost benefit of the once-daily regimen of C + A may be particularly useful to reduce the overall treatment costs and duration of hospitalization.

Risk-adapted strategy for the management of febrile neutropenia in cancer patients

Among patients who develop fever and neutropenia after having received cancer chemotherapy, we have to distinguish at least three categories of risk levels for complications and death: patients at low risk and eligible for oral treatment and possibly outpatient management, patients at low risk who require intravenous therapy, and patients at higher risk. The Multinational Association for Supportive Care in Cancer scoring system identifies patients at low risk (<5%) of severe complications with very low mortality (<1%) during an episode of febrile neutropenia; this group represents roughly 70% of an unselected population of patients with febrile neutropenia. A significant percentage (approximately 50%) of these patients are eligible for treatment with orally administered antibiotics and can be discharged early and safely from the hospital after a short (24-48 h) observation period.

Neutropenia febril en niños con cáncer en un centro asistencial en Santiago, Chile

Febrile neutropenia in cancer patients is a common complication associated to chemotherapy and can be the first manifestation of a potentially lethal infection. In order to adapt our clinical practice to national clinical guidelines, we performed a retrospective review of clinical charts of all children admitted to the Pediatric Unit of Clinica Davila, from May 1, 2003 to December 31, 2004, with cancer, fever and neutropenia. A total of 57 febrile neutropenic episodes occurred in 25 children and in 44% (25/57) of them an infectious focus could be identified; respiratory infections were the most common (11/25). A microorganism could be identified in 16/57 (x%) of episodes, e.g. 12 recovered from blood cultures (42% coagulase negative Staphylococcus, 17% group viridans Streptococci, 17% Escherichia coli and Enterococcus sp, Candida albicans y Pseudomonas aeruginosa in 8% each one), 3 from a catheter (coagulase negative Staphylococci) and 1 from a bronchoalveolar lavage (Pneumocystis jiroveci). At admission, 63% of children received treatment with 2 antibiotics, mostly ceftazidime and amikacin (39%) and 21% received vancomycin. In 37% of patients therapy required adjustment due to a poor response. Fifty six episodes had a favorable resolution with one patient diying of septic shock. Frequency of microorganism detection, the distribution of species recovered and the favorable resolution are comparable to that reported from industrialized countries.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important hematopoietic growth factor and immune modulator. GM-CSF also has profound effects on the functional activities of various circulating leukocytes. It is produced by a variety of cell types including T cells, macrophages, endothelial cells and fibroblasts upon receiving immune stimuli. Although GM-CSF is produced locally, it can act in a paracrine fashion to recruit circulating neutrophils, monocytes and lymphocytes to enhance their functions in host defense. Recent intensive investigations are centered on the application of GM-CSF as an immune adjuvant for its ability to increase dendritic cell (DC) maturation and function as well as macrophage activity. It is used clinically to treat neutropenia in cancer patients undergoing chemotherapy, in AIDS patients during therapy, and in patients after bone marrow transplantation. Interestingly, the hematopoietic system of GM-CSF-deficient mice appears to be normal; the most significant changes are in some specific T cell responses. Although molecular cloning of GM-CSF was carried out using cDNA library of T cells and it is well known that the T cells produce GM-CSF after activation, there is a lack of systematic investigation of this cytokine in production by T cells and its effect on T cell function. In this article, we will focus mainly on the immunobiology of GM-CSF in T cells.

Prevention of febrile neutropenia in cancer patients by probiotic strain Enterococcus faecium M-74. Phase II study

Febrile neutropenia (FN) remains a potentially life-threatening complication of anticancer chemotherapy. Bacterial translocation via intestinal mucosa is a significant mechanism of FN development. Competitive inhibition of bowel colonization by pathogenic microorganisms by lactic acid bacteria could be a useful prevention of FN. The aim of the study was the prevention of FN by probiotic strain Enterococcus faecium M-74 enriched with selenium in leukemic patients. Fourteen (six males/eight females) patients with myelogenous leukemia treated by induction or consolidation chemotherapy were included in the study. Patients received prophylaxis with E. faecium M-74 during one cycle of chemotherapy. The daily dose was 36 x 10(9) CFU tid. Prophylaxis started between day -2 and day +2 of chemotherapy and continued until the absolute neutrophile count (ANC) was >1,000/microl. All patients experienced febrile neutropenia. During 231 days of severe neutropenia, 30 febrile episodes occurred. No any febrile episode or infection provoked by the strain tested was noticed. Tolerance of therapy was excellent without significant adverse effects. Our results demonstrate the safety of the probiotic strain E. faecium M-74 enriched with selenium in leukemic patients with severe neutropenia. However, its administration was not effective in the prevention of febrile neutropenia, but this does not preclude the protective effect of other probiotic strains.

A risk model for first cycle febrile neutropenia in cancer patients receiving systemic chemotherapy

8122 Introduction: Myelosuppression remains the major dose-limiting toxicity of cancer chemotherapy. A prospective, nationwide study was undertaken to develop and validate a risk model for febrile neutropenia (FN) in cancer patients receiving chemotherapy. Methods: More than 2,300 patients with cancers of the breast, lung, colon and ovary or lymphoma initiating a new regimen have been prospectively registered at 137 randomly selected sites. Data on at least 1 cycle of chemotherapy are available on 2,106. A standard regimen has been defined in 1,464 patients permitting an estimation of planned dose intensity (PDI). A logistic regression model for cycle 1 FN in those with known PDI was developed and test performance characteristics estimated. Results: Of 222 patients experiencing FN events, 125 (56%) did so in cycle 1 with prophylactic growth factors reported in only 3.5%. Major independent clinical factors in the risk model include: anthracycline chemotherapy (OR=7.80;P=.001); immune disorders (OR=5.14;P=.014); pretreatment neutropenia (OR=4.00;P<.001); elevated bilirubin (OR=3.73;P=.009); ECOG PS ≥2 (OR=2.84;P=.010); stage 1–2 disease (OR=2.66;P=.009); pretreatment lymphopenia (OR=2.51;P=.001); elevated alkaline phosphatase (OR=2.15; P=.012); pretreatment thrombocytopenia (OR=1.5;P=.024), and anemia (OR=1.43;P=.069). The risk model was adjusted for practice, planned dose intensity, BSA and patient demographics. The risk model accounted for over 80% of the variability (R2=0.829) with a c-statistic of 0.874 [0.847,0.902](P<.0001). Model discrimination was optimized for an estimated risk ≥5% distinguishing high and low risk groups with average cycle 1 FN risks of 20% and 1%, respectively. The model was associated with a sensitivity[±95%CL] of 93%[86–96], specificity of 66%[63–68], predictive value + and - of 20%[17–24] and 99%[98–100], respectively and diagnostic odds ratio of 22[12–43]. Discussion: Based on excellent test performance characteristics, the risk model identified patients at increased risk for first cycle FN for possible targeted prophylaxis with filgrastim or pegfilgrastim. Validation of the model in phase 2 of this ongoing registry study is currently underway. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen