Risk factors for symptomatic venous thromboembolism during therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: Symptomatic venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity, which occurs early in childhood acute lymphoblastic leukemia (ALL) therapy. Approximately 5% of children will experience VTE which is treated with anticoagulation. Asparaginase and corticosteroids are etiologic factors for VTE, however other clinical factors may modify this risk. PROCEDURE: We sought to i) assess published pre-treatment VTE risk factors ii) identify early clinical factors that were associated with VTE and iii) determine whether single nucleotide polymorphisms (SNPs) associated with VTE in non-cancer patients contributed to VTE in children with ALL. We performed a detailed, retrospective analysis of 1021 ALL patients treated between 1998 and 2013. Individual patient records were reviewed to ascertain VTE incidence and document treatment-related clinical variables. RESULTS: The incidence of VTE was 5.1%. Extremes of weight at diagnosis (<5th or >95th centile) was an independent risk factor in multivariable analysis, when added to published risk factors of age ≥10 years and mediastinal mass. When factors during induction/consolidation were considered separately: bacteremia, elevated serum gamma-glutamyl transferase and bilirubin were associated with VTE occurrence. None of the SNPs associated with VTE in non-cancer populations were significantly associated with VTE in our cohort. CONCLUSION: We found two known risk factors (age ≥ 10 years and mediastinal mass) in a large cohort of children treated for ALL and identified other factors associated with VTE such as weight extremes at diagnosis, bacteremia, and abnormal liver function which warrant further study. These VTE risk factors may form the basis of future thromboprophylaxis trials.

Stepped-wedge cluster randomised controlled trial to assess the effectiveness of an electronic medication management system to reduce medication errors, adverse drug events and average length of stay at two paediatric hospitals: a study protocol.

INTRODUCTION: Medication errors are the most frequent cause of preventable harm in hospitals. Medication management in paediatric patients is particularly complex and consequently potential for harms are greater than in adults. Electronic medication management (eMM) systems are heralded as a highly effective intervention to reduce adverse drug events (ADEs), yet internationally evidence of their effectiveness in paediatric populations is limited. This study will assess the effectiveness of an eMM system to reduce medication errors, ADEs and length of stay (LOS). The study will also investigate system impact on clinical work processes. METHODS AND ANALYSIS: A stepped-wedge cluster randomised controlled trial (SWCRCT) will measure changes pre-eMM and post-eMM system implementation in prescribing and medication administration error (MAE) rates, potential and actual ADEs, and average LOS. In stage 1, 8 wards within the first paediatric hospital will be randomised to receive the eMM system 1 week apart. In stage 2, the second paediatric hospital will randomise implementation of a modified eMM and outcomes will be assessed. Prescribing errors will be identified through record reviews, and MAEs through direct observation of nurses and record reviews. Actual and potential severity will be assigned. Outcomes will be assessed at the patient-level using mixed models, taking into account correlation of admissions within wards and multiple admissions for the same patient, with adjustment for potential confounders. Interviews and direct observation of clinicians will investigate the effects of the system on workflow. Data from site 1 will be used to develop improvements in the eMM and implemented at site 2, where the SWCRCT design will be repeated (stage 2). ETHICS AND DISSEMINATION: The research has been approved by the Human Research Ethics Committee of the Sydney Children's Hospitals Network and Macquarie University. Results will be reported through academic journals and seminar and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR) 370325.

Leukocyte count as a predictor of death during remission induction in acute myeloid leukemia.

Acute myeloid leukemia (AML) presenting with a high leukocyte count has been associated with an increase in induction mortality and poor results in a number of other survival measures. However, the level at which an elevated leukocyte count has prognostic significance in AML remains unclear. In this report on a series of 375 adult (non-M3) AML patients undergoing induction chemotherapy at a single institution, leukocyte count analyzed as a continuous variable is shown to be a better predictor of induction death (ID) and overall survival (OS) than a leukocyte count of > or = 100 x 10(9)/L, a value characteristically associated with "hyperleukocytosis" (HL). In this patient cohort, a presenting leukocyte count of > or = 30 x 10(9)/L had high sensitivity and specificity for predicting ID, and both performance status (PS) and leukocyte count more accurately predicted for ID than age. Considering these parameters in newly-diagnosed AML patients may facilitate the development of strategies for reducing induction mortality.

A reliable method for total RNA extraction from frozen human bone marrow samples taken at diagnosis of acute leukaemia.

This report describes a newly developed method using Trizol LS reagent that can reliably extract high quality total RNA from frozen human leukaemic bone marrow samples. Extraction of total RNA from 71 frozen leukaemic bone marrow samples obtained at the time of diagnosis produced a median yield of 145 micro g/ml leukaemic bone marrow. Total RNA samples could be reverse transcribed into cDNA and used successfully in the reverse transcription polymerase chain reaction amplification of B2M transcripts in 68 of 71 cases. A multivariate linear regression analysis revealed that significant predictors of RNA yield were both sample volume (< 1 ml v > 1 ml; p = 0.003) and peripheral blood white cell count (< 5 x 10(9) v >or= 5 x 10(9) white blood cells/litre; p = 0.011). The percentage of blasts present, leukaemia subtype, and sample storage period at -80 degrees C (up to 945 days) were not predictors of total RNA yield. This method of total RNA extraction should be of interest to diagnostic and research staff using frozen bone marrow samples for molecular analyses. Similarly, the lack of association between sample storage period at -80 degrees C and total RNA yield should be of interest to the administrators of tumour banks housing frozen bone marrow samples.

Scedosporium infection in immunocompromised patients: successful use of liposomal amphotericin B and itraconazole.

BACKGROUND: Invasive fungal disease is a major cause of death in immunocompromised patients. The filamentous fungus Scedosporium consists of two species, S. prolificans and S. apiospermum, which can cause infections in immunocompromised patients that are often fatal. A significant feature of this pathogen is its broad resistance to many antifungal agents, including amphotericin B. PROCEDURE AND RESULTS: Five cases of infection with Scedosporium spp. occurred in patients with haematologic malignancies over a 10-month period. Three patients with S. prolificans were severely immunosuppressed and neutropenic; two were in relapse and another was early post-matched unrelated bone marrow transplant. All three died despite treatment with various combinations of amphotericin B and itraconazole. Two patients who were less immunosuppressed and had a normal neutrophil count developed S. apiospermum infection. Both were successfully treated with liposomal amphotericin B and itraconazole. CONCLUSIONS: Disseminated infection in immunocompromised hosts with Scedosporium spp. is often fatal. However, in patients with a lesser degree of immunocompromise and particularly in those infected with the less virulent S. apiospermum, intensive antifungal therapy with liposomal amphotericin B and itraconazole may be associated with complete eradication of infection. Med Pediatr Oncol 2001;37:122-125.