Acute Cardiac Failure due to Intra-Atrial Mass Caused by Zygomycetes in an Immunocompromised Paediatric Patient.

Cardiac zygomycosis can be a critical condition with sudden onset of severe congestive heart failure followed by severe hemodynamic deterioration. We report a fatal course of disseminated fungal infection with a massive intra-atrial thrombosis caused by a zygomycete, in a five year old boy treated for acute lymphoblastic leukaemia. In addition, we discuss the literature concerning infections caused by zygomycetes involving the heart. Prognosis is poor. A high index of suspicion and an aggressive diagnostic and therapeutic approach with the prompt start of preemptive antifungal therapy are key factors to improve outcome.

[Pneumatosis intestinalis in 9 children with an oncologic disease]. / Pneumatosis intestinalis bij 9 kinderen met een oncologische aandoening.

OBJECTIVE: To acquire knowledge regarding the rare condition pneumatosis intestinalis (PI) in children treated for malignant disease. DESIGN: Retrospective. METHOD: In 1998-1999 PI was diagnosed in 9 of the 140 children with malignant disease in the department of Paediatric Oncology of the UMC St Radboud, Nijmegen, the Netherlands. By examination of the records of these 9 children, data were collected on the symptomatology, diagnostics, treatment and prognosis of PI. RESULTS: The 9 children included 7 boys and 2 girls, varying in age from 2 to 12 years. In 7 patients the underlying disease was acute lymphocytic leukaemia and in 2 it was a stage IV neuroblastoma. The presenting symptoms were nonspecific and included: a distended abdomen, abdominal pain, diarrhoea and constipation. In all children, PI was located in the colon. Supplemental blood and microbiological analysis did not reveal any typical abnormalities. 8 children were treated with lactitol because of constipation. A laparotomy was performed in the first patient, while the other 8 were treated with gastric suctioning, parenteral nutrition and antibiotics. All 9 children recovered within a few weeks. CONCLUSION: With supportive care, PI in children with malignant disease is mostly a self-limiting condition. A pneumoperitoneum in PI is no indication for surgery, except in the presence of an acute abdomen. Chemotherapy can be continued.

Bacteria in blood smears: overwhelming sepsis or trivial contamination.

It is unusual to find microorganisms in peripheral blood smears, and their presence is frequently associated with overwhelming sepsis and consequently a poor prognosis. In this report, we demonstrate 4 cases with bacteria in blood smears. Two of them had a fatal outcome, but the other 2 were caused by a contamination either via the central venous catheter or in vitro, both without dramatic outcome. The finding of bacteria in blood smears has to be interpreted carefully, and thorough examination of peripheral blood smears may be of great importance in the early diagnosis of bacteremia; however, in vitro contamination must be excluded.

An automated method for the bioanalysis of vincristine suitable for therapeutic drug monitoring and pharmacokinetic studies in young children.

Pharmacokinetic studies in young children require very sensitive methods using low plasma volumes. Although vincristine has been used as an antineoplastic drug for almost 40 years, data on vincristine pharmacokinetics and pharmacodynamics are scarce, especially in young children. One of the reasons for this is the lack of a specific and sensitive assay suitable for small plasma volumes. Therefore the authors aimed to improve an existing high-performance liquid chromatography (HPLC) assay by changing the solid-phase extraction material and by using a more sensitive and controlled electrochemical detector. An on-line solid-phase extraction was used with a preconcentration column of 10 * 3 mm ID containing octadecyl silane (ODS) reversed-phase material and an analytical microsphere C18 column. The mobile phase was unchanged and consisted of 35% phosphate buffer 0.02 mol (pH 7.00 +/- 0.10), 50% methanol, and 15% acetonitrile. Detection was performed with a new electrochemical detector. This detector comprised a highly stable Faraday-shielded oven compartment that accommodated a column and flowcell. The flowcell had a spacer thickness of 0.25 microm set at 830 mV. It also had an excellent signal-to-noise ratio, which resulted in very sensitive electrochemical analysis. These improvements resulted in a lower required sample volume of only 0.3 mL instead of 1.2 mL plasma with a very low limit of quantitation of 0.483 microg/L according to good laboratory practice (GLP) rules. The intraday coefficients of variation were 6.2% (0.483 microg/L) and 4.2% (18.4 microg/L). The interday coefficients of variation were 10.3% (0.483 microg/L) and 8.5% (18.4 microg/L).

Mild axonal neuropathy of children during treatment for acute lymphoblastic leukaemia.

Neurophysiological functioning was studied prospectively in children treated for acute lymphoblastic leukaemia with a low dose vincristine regime (8 x 1.5 mg/m2/dose), to obtain more insight into vincristine neuropathy. A WHO neurotoxicity score was estimated and vibration sense and electrophysiological measurements were taken at standardized times during vincristine treatment. The WHO neurotoxicity score showed decreased or disappearance of Achilles tendon reflexes, and mild sensory disturbances, but a grade 3-4 neurotoxicity was not demonstrated by any of the children. Vibration perception thresholds increased progressively during treatment and amplitudes of action potentials of peroneal and sensory ulnar and median nerves decreased, whereas nerve conduction velocities stayed unchanged. Both vibration perception thresholds and the electrophysiological findings hardly exceeded the limits of normality. We conclude that children treated for acute lymphoblastic leukaemia with a low dose vincristine regimen have mild axonal neuropathy which may be responsible for the motor problems in these children.

The influence of recombinant human insulin-like growth factor-I (rhIGF-I) on cell growth and cytotoxicity of drugs in childhood rhabdomyosarcoma cell lines and xenograft models.

PURPOSE: Recombinant human insulin-like growth factor I (rhIGF-I) has been reported to ameliorate vincristine-induced neuropathy, the dose-limiting side effect of this antimitotic anticancer drug. However, rhIGF-I also might have adverse effects, as has been shown in vitro, where it stimulates growth of cancer cells and protects them from cytotoxicity of anticancer drugs. The influence of rhIGF-I on the cytotoxicity of vincristine has not yet been studied. Furthermore, studies performed have been done under serum-free conditions, which are far from physiological. METHODS: We studied the influence of rhIGF-I on the growth of two rhabdomyosarcoma cell lines (Rh30 and Rh1) and on the antitumor effects of vincristine, cisplatin, etoposide, doxorubicin, and topotecan under serum-free and serum-containing conditions. To extend the in vitro data, we grew Rh30 cells as xenografts in mice and determined the effects of vincristine. rhIGF-I or their combination on tumor growth. RESULTS: In vitro, both cell lines demonstrated a functional type I IGF receptor, as shown by the rapid activation of ribosomal p70 S6 kinase after stimulation with rhIGF-I. Under serum-free conditions, rhIGF-I stimulated growth of both cell lines. Exposure to cytotoxic drugs with and without rhIGF-I resulted in higher cell numbers in cultures exposed to rhIGF-I. However, relative to the appropriate control, fractional growth inhibition and or cell kill of the cytotoxic drugs was identical with and without rhIGF-I. Under serum-containing conditions, rhIGF-I had no effect on cell growth or drug cytotoxicity. In vivo we did not find a significant influence of rhIGF-I on HxRh30 cell growth, or on the antitumor activity of vincristine. CONCLUSIONS: These studies show that rhIGF-I has no adverse effects on human rhabdomyosarcoma growth or on the antitumor effect of cytotoxic drugs under serum-containing conditions in vitro or in tumor-bearing mice. Potentially, therefore, rhIGF-I may ameliorate vincristine-induced neuropathy without adversely influencing tumor growth or vincristine cytotoxicity in children.

Vincristine pharmacokinetics after repetitive dosing in children.

PURPOSE: We studied vincristine disposition after 169 weekly i.v. bolus injections in 32 children with acute lymphoblastic leukemia, non-Hodgkin lymphoma, or Wilms' tumor. The aim of the study was to determine intrapatient and interpatient variability in vincristine disposition and demographic, clinical, and biochemical characteristics influencing this variability. METHODS: Vincristine plasma concentrations were measured by a high-performance liquid chromatography assay with electrochemical detection. A limited sampling strategy was used based on a bayesian parameter estimation algorithm that is part of the ADAPT II software package. A two-compartment, first-order model was fitted to the data, and pharmacokinetic parameters were calculated from the model using the ADAPT II software. For statistical analysis, analysis of variance (ANOVA), t test, simple and multiple regression analysis, and non-parametric or robust equivalents were used. RESULTS: Results showed a large intrapatient and interpatient variability in distribution half-life, elimination half-life, total body clearance, apparent volume of distribution at steady state, and area under the concentration-time curve. Intrapatient variability was significantly smaller than interpatient variability for all these parameters except distribution half-life. The diagnosis or treatment protocol turned out to be the most predictive characteristic; leukemia and non-Hodgkin lymphoma patients had a significantly higher total body clearance than Wilms' tumor patients. CONCLUSIONS: We conclude that both intrapatient and interpatient variability in vincristine pharmacokinetics is large in pediatric cancer patients and that variability, although significantly influenced by diagnosis, largely remains unpredictable.

N-methyladrenaline: age-dependent urinary excretion, perinatal organ content and relation with 'classical' catecholamines.

Using high performance liquid chromatography with electrochemical detection we determined free dopamine, noradrenaline, adrenaline and N-methyladrenaline in: (1) urines from newborns (n = 32), children (n = 45) and adults (n = 19) and (2) adrenals, organ of Zuckerkandl, dorsal roots and perirenal brown adipose tissue from deceased fetuses (n = 2), very premature (n = 6) and term (n = 2) newborns and infants (n = 2). Data from children and adults showed that contributions of adrenaline and N-methyladrenaline to the sum of urinary free catecholamines increase with age. Relative amounts of adrenaline and N-methyladrenaline increased in both adrenal and extra adrenal chromaffin tissues from late gestation up to several months of postnatal life. Increase of adrenal N-methyladrenaline content follows endocrine maturation of the medulla, phenylethanolamine-N-methyltransferase induction and subsequent adrenaline synthesis. Relative amounts of N-methyladrenaline in extra adrenal chromaffin tissue increase in a period that is associated with its regression. Further investigations are necessary to elucidate the function and possible clinical chemical usefulness of N-methyladrenaline.

A comparison of high-frequency oscillation superimposed onto backup mechanical ventilation and conventional mechanical ventilation on the distribution of exogenous surfactant in premature lambs.

Twenty-six premature lambs were treated by tracheal instillation of [14C]labeled natural sheep surfactant before the onset of breathing or after the establishment of respiratory distress syndrome 30 min after birth. Half of both groups were subsequently ventilated for 3 h with 100% O2 by conventional mechanical ventilation (CMV) and half by high frequency oscillation superimposed onto backup mechanical ventilation (HFOV). Mean airway pressure, arterial blood pressures, and heart rate were recorded continuously. Arterial blood gases and pH were obtained every 15 min. After sacrifice, the distribution of radiolabeled surfactant was quantified and alveolar expansion was evaluated by morphometrics. At comparable oxygenation, mean airway pressures were significantly lower in the lambs treated with surfactant at birth (groups CMV-B and HFOV-B) than in lambs on CMV and treated with surfactant during RDS (group CMV-R). Mean airway pressures in both groups of lambs on HFOV (groups HFOV-B and HFOV-R) were comparable at values lower than in group CMV-R and higher than in group CMV-B. The distribution of radiolabeled surfactant was more homogeneous in lambs treated at birth and not different for both types of ventilatory assistance. Morphometrics demonstrated significantly better expansion of the alveoli of lambs ventilated with HFOV than of those on CMV, irrespective of the timing of surfactant administration. These results indicate that prophylactic surfactant administration at birth leads to a better distribution of surfactant than rescue treatment with surfactant after the establishment of respiratory distress syndrome and is not affected by a subsequent type of ventilatory assistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of oxygen toxicity with superoxide dismutase and catalase in premature lambs.

The use of high oxygen concentrations and high mean airway pressures during mechanical ventilation of premature newborn infants with respiratory distress syndrome leads in 20%-30% of the survivors to chronic lung disease. This study explores if exogenous polyethylene glycol conjugated superoxide dismutase (PEG-SOD) and catalase (PEG-CAT) mitigate oxygen toxicity in premature lambs with respiratory distress syndrome. Six pairs of premature lambs were delivered by cesarean section and treated by tracheal instillation of 60 mg natural sheep surfactant/kg/body weight. After birth, all lambs were ventilated with 100% oxygen, and one of each pair received a single intravenous injection of 1 million U/kg PEG-CAT and 50,000 U/kg PEG-SOD. At 8 h of age or after respiratory failure was established, the lambs were killed and the lungs were removed intact. Lung damage was assessed by microscopy. The arterial blood gases, pH, and mean airway pressures of the lambs treated with PEG-SOD/PEG-CAT did not differ from those of the controls. Mean PaO2 was greater than 140 mmHg during the first 4 h of the experiments. In the lambs treated with PEG-SOD/PEG-CAT, SOD and CAT levels were very high during the study period and less bronchiolar epithelial damage and lung hemorrhages were found at microscopy.