Acute neurologic dysfunction associated with high-dose chemotherapy and autologous bone marrow rescue for primary malignant brain tumors

Acute neurologic complications occurred 103 times in 50 (54%) of 92 patients (primarily children) treated with high-dose chemotherapy and autologous bone marrow rescue for primary central nervous tumors. Different types of neurologic compromise occurred during the chemotherapy infusion as compared to the first 100 days after the chemotherapy and the greater-than-100-day time period. The causes of the neurologic compromise were also time sensitive. BACKGROUND: Results of treatment for children with primary brain tumors using high-dose chemotherapy with autologous marrow rescue (ABMR) have been encouraging. However, the neurotoxicity associated with this technique remains a major concern. We reviewed the records of 92 patients who underwent ABMR for malignant brain tumors between 1986 and 1992 for the occurrence and timing of acute neurologic dysfunction (AND). METHODS: Individual investigators at the participating institutions retrospectively completed standardized forms on each patient. The manner in which the distribution of AND versus time of treatment emerged led to the establishment of distinct time periods for data analysis and discussion. The pre-ABMR period included those events that occurred during the chemotherapy infusion, the early posttreatment period included the first 100 days following bone marrow rescue, and the late posttreatment period was greater than 100 days following bone marrow rescue. RESULTS: Fifty patients (54%) had 103 episodes of AND. AND included encephalopathies with or without hallucinations or coma (32), seizures (23), headaches (9), ataxia-tremor-dysarthria syndrome (7), anorexia and nausea syndrome (7) and others (25). During the chemotherapy infusion, encephalopathies and seizures were most common. Hallucinations occurred primarily related to drug infusion, while encephalopathies without hallucinations were usually due to demonstrable dysmetabolic states. In the 100 days following ABMR, dysmetabolic states and iatrogenic factors caused 45% and progressive disease caused 33% of AND. Greater than 100 days from ABMR, progressive disease caused 55% of AND; 7 patients were noted to develop chronic anorexia and nausea of unclear etiology. The occurrence of neurologic compromise was not related to the chemotherapy regimens, tumor histology, tumor location, patient age, prior treatment, or the amount of tumor at time of treatment. Dexamethasone use was the only clinical factor associated with AND (p < 0.004). CONCLUSIONS: The cause of AND was definable for 95% of instances that occurred within 100 days of ABMR. Early AND was often iatrogenic and reversible. The greater the time from ABMR the more likely AND was due to progressive disease. Clinical factors could not predict the occurrence of AND as only the concurrent use of dexamethasone at the time of treatment proved significant. Although frequent, AND should not be considered a limiting toxicity of this approach or preclude the use of this technique.     

Localization and characterization of the human ADP-ribosylation factor 5 (ARF5) gene

ADP-ribosylation factor 5 (ARF5) is a member of the ARF gene family. The ARF proteins stimulate the in vitro ADP-ribosyltransferase activity of cholera toxin and appear to play a role in vesicular trafficking in vivo. We have mapped ARF5, one of the six known mammalian ARF genes, to a well-defined yeast artificial chromosome contig on human chromosome 7q31.3. In addition, we have isolated and sequenced an approximately 3.2-kb genomic segment that contains the entire ARF5 coding region, revealing the complete intron-exon structure of the gene. With six coding exons and five introns, the genomic structure of ARF5 is unique among the mammalian ARF genes and provides insight about the evolutionary history of this ancient gene family.     

Successful outcome in Swan-Ganz catheter-induced rupture of pulmonary artery

Swan-Ganz catheter-induced pulmonary artery (PA) rupture is rare, with an incidence of 0.016 to 0.2 per cent, but it remains the most dreaded complication in the placement of these catheters with a mortality above 50 per cent. We report two cases of PA rupture after catheter placement. Both patients were managed nonoperatively and without any invasive procedure. They both stopped bleeding after the initial episode and were discharged a few days later. We believe that in the absence of high-risk factors, such as pulmonary hypertension and systemic anticoagulation, PA rupture from a Swan-Ganz catheter can be successfully treated by withdrawal of the catheter and supportive care.     

High dose fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily, in patients with chronic severe asthma. International Study Group

Airway inflammation is now regarded as fundamental in the pathogenesis of asthma and treatment with inhaled corticosteroids has proved effective. There is a need for drugs in this category with higher topical potency but fewer side-effects than those presently available. A double-blind, parallel group study was conducted in 671 patients with severe asthma (already taking between 0.8-2.0 mg of inhaled corticosteroid daily) to compare the safety and efficacy of 6 weeks of treatment with inhaled fluticasone propionate (FP), 1 mg daily, to fluticasone propionate, 2 mg daily, and budesonide (BUD), 1.6 mg daily, delivered via a metered-dose inhaler. Peak expiratory flow (PEF), asthma symptoms, and usage of rescue medication were recorded daily by the patient. At each clinic visit (-2, 0, 3 and 6 weeks) morning serum cortisol levels, bone markers and spirometry were assessed. The changes in mean morning PEF from baseline (weeks 1-6) were: FP 2 mg daily +24 l.min-1; FP 1 mg daily +21 l.min-1; BUD 1.6 mg daily +13 l.min-1. A similar rank order for the three treatments was seen for evening PEF, clinic spirometry, reduction of diurnal PEF variation, symptom scores, and requirement for rescue bronchodilators. The mean serum cortisol levels remained well within the normal range in all three groups. Analysis of the geometric mean cortisol ratio (treatment/baseline ratio after 6 weeks treatment) showed a changed rank order, the values being: FP 1 mg daily 1.04; BUD 1.6 mg daily 0.97; FP 2 mg daily 0.88.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kinetic analysis of dynamic 13C NMR spectra: metabolic flux, regulation, and compartmentation in hearts

Control of oxidative metabolism was studied using 13C NMR spectroscopy to detect rate-limiting steps in 13C labeling of glutamate. 13C NMR spectra were acquired every 1 or 2 min from isolated rabbit hearts perfused with either 2.5 mM [2-13C]acetate or 2.5 mM [2-13C]butyrate with or without KCl arrest. Tricarboxylic acid cycle flux (VTCA) and the exchange rate between alpha-ketoglutarate and glutamate (F1) were determined by least-square fitting of a kinetic model to NMR data. Rates were compared to measured kinetics of the cardiac glutamate-oxaloacetate transaminase (GOT). Despite similar oxygen use, hearts oxidizing butyrate instead of acetate showed delayed incorporation of 13C label into glutamate and lower VTCA, because of the influence of beta-oxidation: butyrate = 7.1 +/- 0.2 mumol/min/g dry wt; acetate = 10.1 +/- 0.2; butyrate + KCl = 1.8 +/- 0.1; acetate + KCl = 3.1 +/- 0.1 (mean +/- SD). F1 ranged from a low of 4.4 +/- 1.0 mumol/min/g (butyrate + KCl) to 9.3 +/- 0.6 (acetate), at least 20-fold slower than GOT flux, and proved to be rate limiting for isotope turnover in the glutamate pool. Therefore, dynamic 13C NMR observations were sensitive not only to TCA cycle flux but also to the interconversion between TCA cycle intermediates and glutamate.