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.     

Cost-effective reduction of neuromuscular-blocking drug expenditures

BACKGROUND: Anesthetic drug expenditures have been a focus of cost-containment efforts. The aim of this study was to determine whether expenditures for neuromuscular-blocking agents could be reduced without compromising outcome, and to determine whether such a cost-effective pattern of neuromuscular blocker use could be sustained. METHODS: Education, practice guidelines, and paperwork barriers were used to persuade anesthesiologists to substitute low-cost neuromuscular-blocking drugs (pancuronium or a metocurine-pancuronium combination) for a more costly neuromuscular-blocking drug (vecuronium). Neuromuscular-blocking drug use in all patients during a historical control period (6 months; n = 4,804) was compared with that during two consecutive 1-yr periods of intervention (n = 9,761/n = 10,695). Expenditures for vecuronium and for all neuromuscular-blocking drugs were compared for the control and intervention periods. The rate of complications related to neuromuscular-blocking drugs was determined by an ongoing continuous quality improvement program. RESULTS: Vecuronium use decreased by 76% during the first and second yr of intervention, compared with the historical period (P < 0.01). The cost of neuromuscular-blocking drugs decreased by 31% (P < 0.01) and 47% (P < 0.01) for the first and second yr, respectively. The complication rate related to neuromuscular-blocking drugs was 0.081% in the historical period and 0.11% and 0.093% during the intervention periods (P = 0.29 and 0.41). CONCLUSION: Practice guidelines, education, and paperwork barriers used together substantially reduced the expenditures for neuromuscular-blocking drugs for 2 yr without adversely affecting clinical outcome.     

Influence of an oligodendroglial component on the survival of patients with anaplastic astrocytomas: a report of Radiation Therapy Oncology Group 83-02

PURPOSE: Seven percent of patients with high grade gliomas enrolled in RTOG 83-02 had mixed astrocytoma/oligodenroglial elements on central pathology review. It has often been assumed that the most aggressive histologic component of a tumor determines biologic behavior; however in this trial, the survival of patients who had mixed glioblastomas/oligodenrogliomas was significantly longer than that of patients with pure glioblastomas (GBM). We therefore evaluated the effect of an oligodendroglial component on the survival of patients who had anaplastic astrocytomas (AAF) treated in the same trial. METHODS AND MATERIALS: One hundred nine patients who had AAF and 24 patients with mixed AAF/oligodendrogliomas (AAF/OL) were enrolled in a Phase I/II trial of randomized dose-escalation hyperfractioned radiotherapy plus BCNU. AAF/OL patients were older and more likely to have had more aggressive surgery than AAF patients. Other pretreatment characteristics were balanced between groups, as was assigned treatment. RESULTS: The median survival time for AAF was 3.0 years versus 7.3 years for AAF/OL (p = 0.019). In a multivariate analysis, adjusting for extent of surgical resection and age, an oligodendroglial component was an independent prognostic factor for survival. CONCLUSION: The results support the concept that AAFs with an oligodendroglial component have a better prognosis than pure AAF tumors, similar to the effect seen among patients with glioblastoma multiforme tumors. This better survival outcome should be taken into consideration in the design and stratification of future trials. Additionally, in contrast to patients with GBMs, patients who have AAF/OL have the potential for prolonged survival; therefore, late sequelae of treatment (both radiation and chemotherapy) must be weighed more heavily in the benefits to risks analysis.     

Etiology of bloody diarrhea in Bolivian children: implications for empiric therapy. Bolivian Dysentery Study Group

In Bolivia, few data are available to guide empiric therapy for bloody diarrhea. A study was conducted between December 1994 and April 1995 to identify organisms causing bloody diarrhea in Bolivian children. Rectal swabs from children <5 years old with bloody diarrhea were examined for Salmonella, Shigella, and Campylobacter organisms; fecal specimens were examined for Entamoeba histolytica. A bacterial pathogen was identified in specimens from 55 patients (41%). Shigella organisms were found in 39 specimens (29%); 37 isolates (95%) were resistant to ampicillin, 35 (90%) to trimethoprim-sulfamethoxazole, and 24 (62%) to chloramphenicol, but all were susceptible to nalidixic acid. Only 1 of 133 stool specimens contained E. histolytica trophozoites. Multidrug-resistant Shigella species are a frequent cause of bloody diarrhea in Bolivian children; E. histolytica is uncommon. Clinical predictors described in this study may help identify patients most likely to have Shigella infection. Laboratory surveillance is essential to monitor antimicrobial resistance and guide empiric treatment.     

The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor

BACKGROUND: In muscle and liver, glycogen concentrations are regulated by the reciprocal activities of glycogen phosphorylase (GP) and glycogen synthase. An alkyl-dihydropyridine-dicarboxylic acid has been found to be a potent inhibitor of GP, and as such has potential to contribute to the regulation of glycogen metabolism in the non-insulin-dependent diabetes diseased state. The inhibitor has no structural similarity to the natural regulators of GP. We have carried out structural studies in order to elucidate the mechanism of inhibition. RESULTS: Kinetic studies with rabbit muscle glycogen phosphorylase b (GPb) show that the compound (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5, 6-tricarboxylate (Bay W1807) has a Ki = 1.6 nM and is a competitive inhibitor with respect to AMP. The structure of the cocrystallised GPb-W1807 complex has been determined at 100K to 2.3 A resolution and refined to an R factor of 0.198 (Rfree = 0.287). W1807 binds at the GPb allosteric effector site, the site which binds AMP, glucose-6-phosphate and a number of other phosphorylated ligands, and induces conformational changes that are characteristic of those observed with the naturally occurring allosteric inhibitor, glucose-6-phosphate. The dihydropyridine-5,6-dicarboxylate groups mimic the phosphate group of ligands that bind to the allosteric site and contact three arginine residues. CONCLUSIONS: The high affinity of W1807 for GP appears to arise from the numerous nonpolar interactions made between the ligand and the protein. Its potency as an inhibitor results from the induced conformational changes that lock the enzyme in a conformation known as the T' state. Allosteric enzymes, such as GP, offer a new strategy for structure-based drug design in which the allosteric site can be exploited. The results reported here may have important implications in the design of new therapeutic compounds.     

The mini-micro-epididymal sperm aspiration for sperm retrieval: a study of urological outcomes

Susceptible adults (n = 105) were enrolled into a randomized double-blind study of rimantadine treatment of experimental influenza A infection. Subjects were cloistered for 8 days and challenged with a rimantadine-sensitive strain of influenza A H1N1 virus at the end of the first day. Forty-eight hours after challenge and for 8 days, 54 subjects received placebo and 51 received rimantadine (100 mg orally, twice a day). Symptoms, signs, and pathophysiologies were monitored. Nine subjects were not infected. Seventeen subjects (38%) in the rimantadine and 26 (53%) in the placebo group became ill. A beneficial effect of rimantadine was documented for virus shedding, symptom load, and sinus pain. Rimantadine had no effect on nasal patency, mucociliary clearance, nasal signs, or on symptoms and signs of otologic complications. These results do not support a preventive effect of rimantadine on the development of otologic manifestations of influenza A infection in adults.     

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.