[Show abstract][Hide abstract] ABSTRACT: The temperature limit defining fever (TLDF) is based on scarce evidence. This study aimed to determine the rate of fever in neutropenia (FN) episodes additionally diagnosed by lower versus standard TLDF.
In a single center using a high TLDF (39.0°C tympanic temperature, LimitStandard), pediatric patients treated with chemotherapy for cancer were observed prospectively. Results of all temperature measurements and CBCs were recorded. The application of lower TLDFs (LimitLow; range, 37.5°C to 38.9°C) versus LimitStandard was simulated in silicon, resulting in three types of FN: simultaneous FN, diagnosed at both limits within 1 hour; earlier FN, diagnosed >1hour earlier at LimitLow; and additional FN, not diagnosed at LimitStandard.
In 39 patients, 8896 temperature measurements and 1873 CBCs were recorded during 289 months of chemotherapy. Virtually applying LimitStandard resulted in 34 FN diagnoses. The predefined relevantly (≥15%) increased FN rate was reached at LimitLow 38.4°C, with total 44 FN, 23 simultaneous, 11 earlier, and 10 additional (Poisson rate ratioAdditional/Standard, 0.29; 95% lower confidence bound, 0.16). Virtually applying 37.5°C as LimitLow led to earlier FN diagnosis (median, 4.5 hours; 95% CI, 1.0 to 20.8), and to 53 additional FN diagnosed. In 51 (96%) of them, spontaneous defervescence without specific therapy was observed in reality.
Lower TLDFs led to many additional FN diagnoses, implying overtreatment because spontaneous defervescence was observed in the vast majority. Lower TLDFs led as well to relevantly earlier diagnosis in a minority of FN episodes. The question if the high TLDF is not only efficacious but as well safe remains open.
PLoS ONE 02/2015; 10(2):e0117528. DOI:10.1371/journal.pone.0117528 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fatal hyperammonemia secondary to chemotherapy for hematological malignancies or following bone marrow transplantation has been described in few patients so far. In these, the pathogenesis of hyperammonemia remained unclear and was suggested to be multifactorial. We observed severe hyperammonemia (maximum 475 μmol/L) in a 2-year-old male patient, who underwent high-dose chemotherapy with carboplatin, etoposide and melphalan, and autologous hematopoietic stem cell transplantation for a neuroblastoma stage IV. Despite intensive care treatment, hyperammonemia persisted and the patient died due to cerebral edema. The biochemical profile with elevations of ammonia and glutamine (maximum 1757 μmol/L) suggested urea cycle dysfunction. In liver homogenates, enzymatic activity and protein expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) were virtually absent. However, no mutation was found in CPS1 cDNA from liver and CPS1 mRNA expression was only slightly decreased. We therefore hypothesized that the acute onset of hyperammonemia was due to an acquired, chemotherapy-induced (posttranscriptional) CPS1 deficiency. This was further supported by in vitro experiments in HepG2 cells treated with carboplatin and etoposide showing a dose-dependent decrease in CPS1 protein expression. Due to severe hyperlactatemia, we analysed oxidative phosphorylation complexes in liver tissue and found reduced activities of complexes I and V, which suggested a more general mitochondrial dysfunction. This study adds to the understanding of chemotherapy-induced hyperammonemia as drug-induced CPS1 deficiency is suggested. Moreover, we highlight the need for urgent diagnostic and therapeutic strategies addressing a possible secondary urea cycle failure in future patients with hyperammonemia during chemotherapy and stem cell transplantation.
[Show abstract][Hide abstract] ABSTRACT: Autologous stem cell transplantation (ASCT) is applied to consolidate first remission in patients with acute myeloid leukaemia (AML). However, outcome after ASCT widely varies among AML patients. We analyzed the prognostic significance of haematological recovery for neutrophils [absolute neutrophil count (ANC) >1·0 × 109/l] and platelets (platelet count >20·0 × 109/l), stratifying at day 20 after ASCT in 88 consecutive and homogeneously treated AML patients in first remission. We observed that patients with delayed recovery had better overall survival (OS; ANC: P < 0·0001 and platelets: P = 0·0062) and time to progression (TTP; ANC: P = 0·0003 and platelets: P = 0·0125). Delayed recovery was an independent marker for better OS and TTP in a multivariate analysis including age, gender, number of transfused CD34+ cells, cytogenetics, FLT3-internal tandem duplication and NPM1 mutation. Our results suggest that delayed neutrophil and platelet recovery is associated with longer OS and TTP in AML patients consolidated with ASCT in first remission.
British Journal of Haematology 09/2014; 168(2). DOI:10.1111/bjh.13118 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
In children and adolescents with fever in neutropenia (FN) during chemotherapy for cancer, hemoglobin ≥90 g/L at presentation with FN had been associated with adverse events (AE). This analysis explored three hypothetical pathophysiological mechanisms potentially explaining this counterintuitive finding, and further analyzed the statistical association between hemoglobin and AE.
Two of 8 centers, reporting on 311 of 421 FN episodes in 138 of 215 patients participated in this retrospective analysis based on prospectively collected data from three databases (SPOG 2003 FN, transfusion and hematology laboratories). Associations with AE were analyzed using mixed logistic regression.
Hemoglobin was ≥90 g/L in 141 (45%) of 311 FN episodes, specifically in 59/103 (57%) episodes with AE, and in 82/208 (39%) without (OR, 2.3; 99%CI, 1.1–4.9; P = 0.004). In FN with AE, hemoglobin was bimodally distributed with a dip around 85 g/L. There were no significant interactions for center, age and sex. In multivariate mixed logistic regression, AE was significantly and independently associated with leukopenia (leukocytes <0.3 G/L; OR, 3.3; 99%CI, 1.1–99; P = 0.004), dehydration (hemoglobinPresentation/hemoglobin8–72 hours ≥1.10 in untransfused patients; OR, 3.5; 99%CI, 1.1–11.4; P = 0.006) and non-moderate anemia (difference from 85 g/L; 1.6 per 10 g/L; 1.0–2.6; P = 0.005), but not with recent transfusion of packed red blood cells (pRBC), very recent transfusion of pRBC or platelets, or with hemoglobin ≥90 g/L as such.
Non-moderate anemia and dehydration were significantly and relevantly associated with the risk of AE in children with cancer and FN. These results need validation in prospective cohorts before clinical implementation.
PLoS ONE 07/2014; 9(7):e101696. DOI:10.1371/journal.pone.0101696 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Current practice in Switzerland for the mobilization of autologous stem cells in myeloma patients is combining vinorelbine chemotherapy and G-CSF cytokine stimulation. We prospectively investigated adding intravenous plerixafor to the vinorelbine/G-CSF combination (VGP), and compared it to vinorelbine/plerixafor (VP) and G-CSF/plerixafor (GP) combinations. In a final cohort (VP-late), plerixafor was given on the first day of CD34+ cells rising >15'000/ml peripheral blood. Four consecutive cohorts of ten myeloma patients were studied. We observed that intravenously administered plerixafor can be safely combined with vinorelbine/G-CSF. VGP was superior in mobilizing peripheral stem and progenitor cells compared to the three double combinations (VP, GP and VP-late), and GP mobilized better than VP. Our data indicate that the triple combination of vinorelbine, G-CSF and plerixafor is an efficient strategy to collect autologous CD34+ cells, with G-CSF contributing predominantly in this concept. Plerixafor can be safely added to G-CSF and/or to vinorelbine chemotherapy.
Leukemia and Lymphoma 06/2014; 56(3):1-24. DOI:10.3109/10428194.2014.927454 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Gamma irradiation is currently the standard care to avoid transfusion-associated graft-versus-host disease. Guidelines on gamma irradiation of blood components state that platelets (PLTs) can be irradiated at any stage in their 5-day storage and can thereafter be stored up to their normal shelf life of 5 days after collection. In this study, we explored whether the timing of irradiation has an effect on transfusion efficacy of apheresis PLT concentrates (APCs).
Based on the 1-hour percent PLT recovery (PPR1h), transfusion efficacy of 1,000 eligible APCs transfused to 144 children were evaluated retrospectively. PPR1h was compared in transfused APCs irradiated at the day of transfusion and APCs irradiated in advance.
In univariate analysis, transfusion efficacy of APCs irradiated in advance was significantly lower than that of APCs irradiated at the day of transfusion (mean PPR1h 27.7 vs. 35.0%; p = 0.007). This was confirmed in multivariate analysis (p = 0.030). Compared to non-irradiated APCs, transfusion efficacy of APCs irradiated at the day of transfusion was not significantly inferior (mean difference -2.8%; 95% CI -6.1 to 0.5%; p = 0.092), but APCs irradiated in advance were clearly less efficient (mean difference -8.1%; 95% CI -12.2 to -4.0%; p < 0.001).
Our data strongly support that APCs should not be irradiated in advance, 1.e., ≥24 h before transfusion.
Transfusion Medicine and Hemotherapy 06/2014; 41(3):176-81. DOI:10.1159/000363484 · 1.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECT: Resection of lesions close to the primary motor cortex (M1) and the corticospinal tract (CST) is generally regarded as high-risk surgery due to reported rates of postoperative severe deficits of up to 50%. The authors' objective was to determine the feasibility and safety of low-threshold motor mapping and its efficacy for increasing the extent of lesion resection in the proximity of M1 and the CST in children and adolescents.
METHODS: The authors analyzed 8 consecutive pediatric patients in whom they performed 9 resections for lesions within or close (≤ 10 mm) to M1 and/or the CST. Monopolar high-frequency motor mapping with train-of-five stimuli (pulse duration 500 μsec, interstimulus interval 4.0 msec, frequency 250 Hz) was used. The motor threshold was defined as the minimal stimulation intensity that elicited motor evoked potentials (MEPs) from target muscles (amplitude > 30 μV). Resection was performed toward M1 and the CST at sites negative to 1- to 3-mA high-frequency train-of-five stimulation.
RESULTS: The M1 was identified through high-frequency train-of-five via application of varying low intensities. The lowest motor thresholds after final resection ranged from 1 to 9 mA in 8 cases and up to 18 mA in 1 case, indicating proximity to motor neurons. Intraoperative electroencephalography documented an absence of seizures during all surgeries. Two transient neurological deficits were observed, but there were no permanent deficits. Postoperative imaging revealed complete resection in 8 patients and a very small remnant (< 0.175 cm3) in 1 patient.
CONCLUSIONS: High-frequency train-of-five with a minimal threshold of 1-3 mA is a feasible and safe procedure for resections in the proximity of the CST. Thus, low-threshold motor mapping might help to expand the area for safe resection in pediatric patients with lesions located within the precentral gyrus and close to the CST, and may be regarded as a functional navigational tool. The additional use of continuous MEP monitoring serves as a safety feedback for the functional integrity of the CST, especially because the true excitability threshold in children is unknown.
[Show abstract][Hide abstract] ABSTRACT: Fever and neutropenia (FN) often complicate anticancer treatment and can be caused by potentially fatal infections. Knowledge of pathogen distribution is paramount for optimal patient management.
Microbiologically defined infections (MDI) in pediatric cancer patients presenting with FN by nonmyeloablative chemotherapy enrolled in a prospective multi-center study were analyzed. Effectiveness of empiric antibiotic therapy in FN episodes with bacteremia was assessed taking into consideration recently published treatment guidelines for pediatric patients with FN.
MDI were identified in a minority (22%) of pediatric cancer patients with FN. In patients with, compared to without MDI, fever (median, 5 [IQR 3-8] vs. 2 [IQR1-3] days, p < 0.001) and hospitalization (10 [6-14] vs. 5 [3-8] days, p < 0.001) lasted longer, transfer to the intensive care unit was more likely (13 of 95 [14%] vs. 7 of 346 [2.0%], p < 0.001), and antibiotics were given longer (10 [7-14] vs. 5 [4-7], p < 0.001). Empiric antibiotic therapy in FN episodes with bacteremia was highly effective if not only intrinsic and reported antimicrobial susceptibilities were considered but the purposeful omission of coverage for coagulase negative staphylococci and enterococci was also taken into account (81% [95%CI 68 - 90] vs. 96.6% [95%CI 87 - 99.4], p = 0.004) CONCLUSIONS: MDI were identified in a minority of FN episodes but they significantly affected management and the clinical course of pediatric cancer patients. Compliance with published guidelines was associated with effectiveness of empiric antibiotic therapy in FN episodes with bacteremia.
[Show abstract][Hide abstract] ABSTRACT: Background:
The definition of fever, and thus fever and neutropenia (FN), varies between different pediatric oncology centers. Higher temperature limit should reduce FN rates, but may increase rates of FN with complications by delaying therapy. This study determined if different fever definitions are associated with different FN rates.
Two pediatric oncology centers had used three fever definitions in 2004-2011: ear temperature ≥38.5 °C persisting ≥2 hours (low definition); axillary temperature ≥38.5 °C ≥ 2 hours or ≥39.0 °C once (middle); and ear temperature ≥39.0 °C once (high). Clinical information was retrospectively extracted from charts. FN rates were compared using mixed Poisson regression.
In 521 pediatric patients with cancer, 783 FN were recorded during 6,009 months cumulative chemotherapy exposure time (501 years; rate, 0.13/month [95% CI, 0.12-0.14]), 124 of them with bacteremia (16%; 0.021/month [0.017-0.025]). In univariate analysis, the high versus low fever definition was associated with a lower FN rate (0.10/month [0.08-0.11] vs. 0.15/month [0.13-0.16]; rate ratio, 0.66 [0.45-0.97]; P = 0.036), the middle definition was intermediate (0.13/month [0.11-0.15]). This difference was not confirmed in multivariate analysis (rate ratio, 0.94 [0.67-1.33]; P = 0.74). The high versus low definition was not associated with an increased rate of FN with bacteremia (multivariate rate ratio, 1.39 [0.53-3.62]; P = 0.50).
A higher fever definition was not associated with a lower FN rate, nor with an increased rate of FN with bacteremia. These may be false negative findings due to methodological limitations. These questions, with their potential impact on health-related quality of life, and on costs, need to be assessed in prospective studies.
[Show abstract][Hide abstract] ABSTRACT: This systematic review and meta-analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty-nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66-0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51-0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91-1·16; P = 0·63). Higher-dose DNR, compared to lower-dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60-0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75-0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high-dose DNR (90 mg/m(2) daily × 3 or 50 mg/m(2) daily × 5) and IDA (12 mg/m(2) daily × 3) can achieve 5-year survival rates of between 40 and 50 percent.
British Journal of Haematology 02/2013; 161(2). DOI:10.1111/bjh.12233 · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The standard treatment of fever in chemotherapy-induced neutropenia (FN) includes emergency hospitalization and empirical intravenous antimicrobial therapy. This study determined if first-day step-down to oral outpatient treatment is not inferior to continued standard regarding safety and efficacy in children with low-risk FN.
In a randomized controlled non-blinded multicenter study, pediatric patients with FN after non-myeloablative chemotherapy were reassessed after 8-22 hours of inpatient intravenous antimicrobial therapy. Low-risk patients were randomized to first-day step-down to experimental (outpatient, oral amoxicillin plus ciprofloxacin) versus continued standard treatment. Exact non-inferiority tests were used for safety (no serious medical complication; non-inferiority margin of difference, 3.5%) and efficacy (resolution of infection without recurrence, no modification of antimicrobial therapy, no adverse event; 10%).
In 93 (26%) of 355 potentially eligible FN episodes low-risk criteria were fulfilled, and 62 were randomized, 28 to experimental (1 lost to follow-up) and 34 to standard treatment. In intention-to-treat analyses, non-inferiority was not proven for safety [27 of 27 (100%) vs. 33 of 34 (97%; 1 death) episodes; 95% upper confidence border, 6.7%; P = 0.11], but non-inferiority was proven for efficacy [23 of 27 (85%) vs. 26 of 34 (76%) episodes; 95% upper confidence border, 9.4%; P = 0.045]. Per-protocol analyses confirmed these results.
In children with low-risk FN, the efficacy of first-day step-down to oral antimicrobial therapy with amoxicillin and ciprofloxacin in an outpatient setting was non-inferior to continued hospitalization and intravenous antimicrobial therapy. The safety of this procedure, however, was not assessable with sufficient power.
[Show abstract][Hide abstract] ABSTRACT: Fever and chemotherapy-induced neutropenia (FN) is the most frequent potentially lethal complication of therapy in children with cancer. This study aimed to describe serious medical complications (SMC) in children with FN regarding incidence, clinical spectrum, and associated characteristics.
Pediatric patients presenting with FN induced by non-myeloablative chemotherapy were observed in a prospective multicenter study. SMC was defined as potentially life-threatening complication (PLTC), transfer to the pediatric intensive care unit (PICU), or death.
A total of 443 FN episodes were reported from 8 centers. Of these, 411 episodes were reported from 4 centers recruiting consecutively and without bias regarding the risk of complications. They were used for calculation of proportions. An SMC was reported in 23 episodes [5.6%; 95% confidence interval (CI): 3.7-8.1], usually defined by more than one criterion. These were PLTC in 13 episodes, PICU in 22, and death in 3 (mortality, 0.7%; 95% CI: 0.2-2.1). Both a delayed onset of SMC (14 of 23 episodes, 61%) and a biphasic clinical course (11 of 23, 48%) were frequently observed. In a multivariate logistic regression analysis, 4 characteristics were significantly and independently associated with the risk of SMC: diagnosis of acute myeloid leukemia, interval since chemotherapy ≤7 days, severely reduced general condition, and hemoglobin ≥9.0 g/dl at presentation.
In children with FN, SMC were rare, and mortality was very low. Those with SMC often had a delayed onset and biphasic clinical course with secondary deterioration.
[Show abstract][Hide abstract] ABSTRACT: Voriconazole is used in antifungal prophylaxis. We performed a retrospective review of immunocompromised children receiving prophylaxis with voriconazole during major hospital renovation, who developed phototoxic skin reactions. The overall incidence of phototoxic skin reactions was 33%. A voriconazole dose of ≥6 mg/kg of body weight per dose twice daily was associated with a significantly greater risk to develop phototoxic skin reactions compared with lower doses.
[Show abstract][Hide abstract] ABSTRACT: To develop a score predicting the risk of bacteremia in cancer patients with fever and neutropenia (FN), and to evaluate its performance.
Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of bacteremia was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules.
Bacteremia was reported in 67 (16%) of 423 FN episodes. In 34 episodes (8%), bacteremia became known only after reassessment after 8 to 24 hours of inpatient management. Predicting bacteremia at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The reassessment score predicting future bacteremia in 390 episodes without known bacteremia used the following 4 variables: hemoglobin ≥ 90 g/L at presentation (weight 3), platelet count <50 G/L (3), shaking chills (5), and other need for inpatient treatment or observation according to the treating physician (3). Applying a threshold ≥ 3, the score--simplified into a low-risk checklist--predicted bacteremia with 100% sensitivity, with 54 episodes (13%) classified as low-risk, and a specificity of 15%.
This reassessment score, simplified into a low-risk checklist of 4 routinely accessible characteristics, identifies pediatric patients with FN at risk for bacteremia. It has the potential to contribute to the reduction of use of antimicrobials in, and to shorten the length of hospital stays of pediatric patients with cancer and FN.
[Show abstract][Hide abstract] ABSTRACT: Kinetic investigations in pediatric acute lymphoblastic leukemia (ALL) are based on all blast cells and, therefore, reflect the proliferative characteristics of the predominant immunophenotype of leukemic cells. Nothing is known about proliferation of immunologically defined rare subpopulations of leukemic cells. In this study, mononuclear cells from the bone marrow of 15 children with untreated CD19 B-cell precursor ALL were examined for proliferative features according to the immunophenotype. After exclusion of highly proliferating residual normal hematopoietic cells, ∼ 3% of blast cells were CD19 and showed a low percentage of cells in S-phase assessed by the bromodeoxyuridine labeling index (BrdU-LI): median BrdU-LI, 0.19% [interquartile range (IQR), 0.15-0.40%]. In contrast, a median BrdU-LI of 7.2% (IQR, 5.7-8.8%) was found for the major CD19 blast cell compartment. Staining smears of sorted CD19 cells for CD10 or CD34 revealed a small fraction of CD19CD10 or CD19CD34 blast cells. These cells were almost nonproliferating with a median BrdU-LI of <0.1% (IQR, 0-0.2%). This proliferative behavior is suggestive of a stem/progenitor cell function and, in addition, the low proliferative activity might render them more resistant to an antiproliferation-based chemotherapy. However, xenotransplantation experiments will be necessary to demonstrate a possible stem cell function.
Pediatric Research 03/2011; 69(3):194-9. DOI:10.1203/PDR.0b013e3182092716 · 2.31 Impact Factor