Voriconazole-induced phototoxicity in children Bernhard, Sara; Kernland Lang, Kristin; Ammann, Roland A ...
The Pediatric infectious disease journal,
2012-July, Letnik:
31, Številka:
7
Journal Article
Recenzirano
Odprti dostop
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.
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 475μmol/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 1757μmol/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.
•Chemotherapy and/or stem cell transplantation can cause fatal hyperammonemia.•Chemotherapeutics may cause carbamoyl phosphate synthetase 1 (CPS1) deficiency.•Chemotherapy-induced hyperammonemia may be caused by acquired CPS1 deficiency.•Chemotherapy-induced hyperammonemia requires urgent diagnosis and therapy.
Abstract
Current practice in Switzerland for the mobilization of autologous stem cells in patients with myeloma is combining vinorelbine chemotherapy and granulocyte-colony stimulating factor (G-CSF) ...cytokine stimulation. We prospectively investigated adding intravenous plerixafor to the vinorelbine/G-CSF combination (VGP), and compared it with 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 increasing to > 15 000/mL peripheral blood. Four consecutive cohorts of 10 patients with myeloma 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 VGP 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 vinorelbine chemotherapy.
BACKGROUND: ABO major compatibility is essential in transfusions of red blood cells but is not requisite in PLT transfusions. In adults there is some evidence that transfusion efficacy of ABO blood ...group–identical platelets (PLTs) is superior to major‐mismatched PLTs. However, in children this question has not been investigated for more than 30 years.
STUDY DESIGN AND METHODS: In a prospective study, the efficacy (based on the 1‐hour percentage of PLT recovery PPR1hr) of 400 eligible ABO blood group–identical or out‐of‐group apheresis PLT concentrates (APCs), transfused mainly prophylactically to 50 children with hematologic malignancies, solid tumors, or aplastic anemia was investigated. The primary objective was to compare PPR1hr between ABO‐identical and major‐mismatched transfusions.
RESULTS: After ABO major‐mismatched transfusions, PPR1hr was significantly lower than after ABO blood group–identical transfusions (median 21% vs. 32%; p = 0.034). Multivariate analysis showed major‐mismatched transfusions to be significantly more often unsuccessful than identical transfusions (odds ratio OR, 3.97; 95% confidence interval CI, 1.52‐10.39; p = 0.005). Using flow cytometry and fluorescent microscopy, it could be demonstrated that PLTs of subgroup A1, significantly expressing A antigen on their surface, were rapidly cleared from the circulation of group O or B recipients. In contrast, major‐mismatched transfusions of A2 PLTs, expressing no detectable A antigen, were as successful as identical transfusions (OR, 1.13; 95% CI, 0.16‐7.88; p = 0.90).
CONCLUSION: These data clearly indicate that in children ABO major‐mismatched PLT transfusions result in inferior transfusion efficacy, with the only exception of group A2 PLTs. ABO minor‐mismatched PLTs showed comparable efficacy to identical transfusions.
Rationale
Autologous stem cell transplantation for adult acutemyelogenousleukemia (AML) is a therapeutic option for good and intermediate risk patients. New compounds and new formulations in ...conjunction with pre andpost transplant targeted therapy may improve outcome.
A recent EBMT retrospective survey investigating on Busulfan administered IV (Nagler A et al:Haematologica. 2014 ) pre autologous stem cell transplantation (ASCT) suggested that the combination of Busulfan and High dose Melphalan (BUMEL) was associated with the best overall survival. To address this question, we compared this regimen with the historical Busulfanand Cyclophosphamide (BUCY) association.
Methods
Eligibilitycriteria consistedof all adult patients (age >18 years) with AMLautograftedin CR1, following a preparative regimen consisting of either BUCY or BUMEL, reported to the EBMT registry in the period from January 2005 to December 2013. The doses of Busulfan were either oral at 16 mg/kg over 4 days or IV at 12.8 mg/kg over 4 days. High dose Melphalan was 140mg/m². The data came from 231 centers 23 ofwhich usedboth regimens. The relationships between outcomes and patient, disease and transplant characteristics was evaluated in multivariate analyses using the Cox model.
Results
1120 patients received BUCY and 436 BUMEL prior to autografting in first remission. Patients receiving BUMEL were older (median 52 years versus 50 years, p=0.01) with less good risk diseases by cytogenetics (16% versus 28%, p=0.001). They were autografted with a longer interval from CR1 to autografting (120 days versus 104 days, p=0.001) and they were more frequently in a negative minimal residual disease (MRD) status by molecular biology (89% versus 82%, p= 0.03).
The nature of the pretransplant regimen interacted with the interval from diagnosis to autografting on both relapse incidence (p=0.005) and leukemia free survival (p= 0.02): the outcome post BUMEL was superior to BUCY only in patients transplanted within less than six months post diagnosis. In these patients, following BUMEL and BUCY respectively, the RI was 35%versus 50.6% (p< 10-3), the LFS 61.1% versus 46.2% (p< 10-3) and the OS 79.4% versus 64.8% (p= 0.003). There was no difference for NRM.
When considering only patients autografted at the time when MRD detection was negative, the LFS at two years was 75.8% for 134 patients receiving BUMEL and 58.6% in the 371 patients receiving BUCY, with no significant difference (p= 0.1). The major cause of death in the two groups was leukemia recurrence.
Conclusion
We conclude that the BUMEL combination pre ASCT in AML CR1 is superior to BUCY when the transplant is performed less than 6 months after diagnosis. These registry data should be confirmed in a well designed two arm study assessing the role of ASCT in good risk and possibly intermediate -1 risk adult patients with AML.
TablepHR95% CINRMBUMEL vs BUCY0.4501.3760.5993.16Age atTx/ 10years0.0011.0641.0251.10Time from diagnosis to Transplant.0.9000.9990.9841.01Cytogenetics :Intermediatevs good0.6100.7090.1912.63Poor versus good0.7100.7080.1124.46Missing0.4200.5910.1642.11centre (frailty)0.360RIBUMEL vs BUCY0.0010.6020.4450.816Age at Transplant / 10years0.0051.0121.0031.020Time from diagnosis to Transplant:0.7201.0000.9961.004Cytogenetics : Intermediatevs good0.5101.1450.7641.714Poor versus good0.0311.7991.0553.067Missingversus good0.4801.1500.7791.699centre (frailty)0.110OSBUMEL vs BUCY0.0020.6140.4490.841Age at Transplant / 10years<10-41.0251.0141.036Time from diagnosis toransplant0.940.9990.9951.004Intermediatevs good0.881.0360.6491.653Poor versus good0.111.6320.9012.956Missingversus good0.811.0580.6721.665centre (frailty)0.29LFSBUMEL vs BUCY0.0020.6490.4900.858Age at Transplant / 10years<10-41.0151.0061.023Time from diagnosis to Transplant0.7401.0000.9961.004Cytogenetics : Intermediatevs good0.5901.1100.7551.630Poor vs good0.0461.6791.0082.796Missingversus good0.5901.1060.7631.604centre (frailty)0.170
Multivariate analyses of prognostic factors in patients autografted within 6 months
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Nemet:Celgene: Honoraria; Pliva: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Mohty:Janssen: Honoraria; Celgene: Honoraria. Nagler:Biokine LTD: Consultancy.
Fever in neutropenia (FN) is the most frequent potentially life threatening complication of chemotherapy for cancer. Prediction of the risk to develop FN during chemotherapy would allow for targeted ...prophylaxis. This retrospective, single centre cohort study in pediatric patients diagnosed with cancer before 17 years covered two decades, 1993 to 2012. The 583 (73%) of 800 patients diagnosed with cancer who had received chemotherapy were studied here. Data on 2113 observation periods was collected, defined by stable combinations of 11 predefined characteristics potentially associated with FN. They covered 692 years of cumulative chemotherapy exposure time, during which 712 FN episodes were diagnosed, 154 (22%) of them with bacteremia. The risk to develop FN and FN with bacteremia remained stable over time. These data can mainly be used to study FN risks over time and between centers, and to derive or externally validate FN risk prediction rules.
In childhood acute lymphoblastic leukemia, treatment failure is associated with resistance to glucocorticoid agents. Resistance to this class of drugs represents one of the strongest indicators of ...poor clinical outcome. We show that leukemic cells, which are resistant to the glucocorticoid drug methylprednisolone, display a higher demand of glucose associated with a deregulation of metabolic pathways, in comparison to sensitive cells. Interestingly, a combinatorial treatment of glucocorticoid and the glucose analog 2-deoxy-D-glucose displayed a synergistic effect in methylprednisolone-resistant cells, in an oxygen tension-independent manner. Unlike solid tumors, where 2-deoxy-D-glucose promotes inhibition of glycolysis by hexokinase II exclusively under hypoxic conditions, we were able to show that the antileukemic effects of 2-deoxy-D-glucose are far more complex in leukemia. We demonstrate a hexokinase II-independent cell viability decrease and apoptosis induction of the glucose analog in leukemia. Additionally, due to the structural similarity of 2-deoxy-D-glucose with mannose, we could confirm that the mechanism by which 2-deoxy-D-glucose predominantly acts in leukemia is via modification in N-linked glycosylation, leading to endoplasmic reticulum stress and consequently induction of the unfolded protein response.
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