Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.     

Surgical management of dysrhythmias in infants and small children.

Surgery for cardiac dysrhythmias is infrequently reported in infants and children as compared with adults. This report reviews 55 infants and small children (age, less than or equal to 5 years) operated on during the interval July 1, 1984 to December 31, 1991 for Wolff-Parkinson-White Syndrome (41), atrioventricular node reentry (two), atrial automatic tachycardia (two), and ventricular tachycardia (nine). Ages ranged from 3 weeks to 71 (mean, 29) months. Associated congenital heart defects were present in five (10%). Indications for surgery included failure of medical therapy, life-threatening dysrhythmias, and more recently, failure of catheter ablation. There were no hospital or late deaths. One patient sustained perioperative central nervous system injury. Surgery was successful in 52 of 55 (94.5%) (Wolff-Parkinson-White, 38/41 (93%); atrioventricular node reentry, 2/2 (100%); atrial automatic tachycardia, 3/3 (100%); ventricular tachycardia, 9/9 (100%). Ventricular function returned to normal in all 12 patients in whom it was abnormal before operation. Thus, surgical ablation is highly successful in the management of various forms of refractory or life-threatening dysrhythmias in infants and small children. Catheter ablation techniques require significant fluoroscopic time, are more difficult in infants, and as yet do not have adequate long-term follow-up. Accordingly, surgery may continue to play a role in this particular group of patients.     

Long-term treatment of anxiety and risk of withdrawal. Prospective comparison of clorazepate and buspirone

Risk of withdrawal was investigated in a prospective, double-blind comparison of clorazepate dipotassium, a benzodiazepine with a long half-life, and the nonbenzodiazepine buspirone hydrochloride in the long-term treatment of anxious outpatients. Patients were treated with therapeutic doses of clorazepate dipotassium (15 to 60 mg/d) or buspirone hydrochloride (10 to 40 mg/d) for six continuous months before their tranquilizer therapy was blindly and abruptly stopped. There was a significant increase in symptom severity consistent with a withdrawal reaction for the clorazepate group but not the buspirone group. For the clorazepate group, there was a suggestion that previous discontinuous exposure to benzodiazepines might sensitize patients to subsequent withdrawal effects. For the buspirone group, a higher dropout rate raised questions about patient satisfaction with therapy in this rather chronically anxious population.     

Pediatric cardiac pacing.

Cardiac pacing in children has undergone many improvements in the last decade. The differences between adult and pediatric pacing have narrowed. Children are no longer being denied pacemakers because of size. This article discusses techniques for pacing pediatric patients successfully that will allow them to lead normal lives.     

A Bayesian iterative transmission gradient reconstruction algorithm for cardiac SPECT attenuation correction

Background  High-quality attenuation maps are critical for attenuation correction of myocardial perfusion single photon emission computed tomography studies. The filtered backprojection (FBP) approach can introduce errors, especially with low-count transmission data. We present a new method for attenuation map reconstruction and examine its performance in phantom and patient data. Methods and Results  The Bayesian iterative transmission gradient algorithm incorporates a spatially varying gamma prior function that preferentially weights estimated attenuation coefficients toward the soft-tissue value while allowing data-driven solutions for lung and bone regions. The performance with attenuation-corrected technetium 99m sestamibi clinical images was evaluated in phantom studies and in 50 low-likelihood patients grouped by body mass index (BMI). The algorithm converged in 15 iterations in the phantom studies. For the clinical studies, soft-tissue estimates had significantly greater uniformity of mediastinal coefficients (mean SD, 0.005 cm⁻¹ vs 0.011 cm⁻¹; P<.0001). The accuracy and uniformity of the Bayesian iterative transmission gradient algorithm were independent of BMI, whereas both declined at higher BMI values with FBP. Attenuation-corrected perfusion images showed improvement in myocardial wall variability (4.8% to 4.1%, P=.02) for all BMI groups with the new method compared with FBP. Conclusion  This new method for attenuation map reconstruction provides rapidly converging and accurate attenuation maps over a wide spectrum of patient BMI values and significantly improves attenuation-corrected perfusion images.     

Trust, but verify. The accuracy of references in four anesthesia journals.

To determine the accuracy of bibliographic citation in the anesthesia literature, we reviewed all 1988 volumes of ANESTHESIOLOGY, Anesthesia and Analgesia, British Journal of Anaesthesia, and Canadian Journal of Anaesthesia and sequentially numbered all references appearing in that year (n = 22,748). One hundred references from each of the four journals were randomly selected. After citations to nonjournal articles (i.e., books or book chapters) were excluded, the remaining 348 citations were analyzed in detail. Six standard bibliographic elements--authors' names, article title, journal title, volume number, page numbers, and year--were examined in each selected reference. Primary sources were reviewed, unless our institution did not own the source or could not obtain it through interlibrary loan, in which case standard indexes, abstracting services, and computerized databases were consulted. Each element was checked for accuracy, and references were classified as either correct or incorrect. A reference was correct if each element of the citation was identical to its source. Of the examined references, more than half (50.3%) contained an error in at least one element. The elements most likely to be inaccurate were, in descending order, article title, author, page numbers, journal title, volume number, and year. No significant differences (P = 0.283) existed in the error rates of the four journals; the percentage of citations containing at least one error ranged from 44% (Anesthesia and Analgesia) to 56% (British Journal of Anaesthesia). The citation error rate of anesthesia journals is similar to that reported in other specialties, where error rates ranging from 38% to 54% have been documented.     

Gene Delivery to Human B-Precursor Acute Lymphoblastic Leukemia Cells

Autologous leukemia cells engineered to express immune-stimulatingmolecules may be used to elicit antileukemia immune responses. Genedelivery to human B-precursor acute lymphoblastic leukemia (ALL) cellswas investigated using the enhanced green fluorescent protein (EGFP) asa reporter gene, measured by flow cytometry. Transfection of the Nalm-6and Reh B-precursor ALL leukemia cell lines with an expression plasmidwas investigated using lipofection, electroporation, and a polycationiccompound. Only the liposomal compound Cellfectin showed significantgene transfer (3.9% to 12% for Nalm-6 cells and 3.1% to 5% for Rehcells). Transduction with gibbon-ape leukemia virus pseudotyped Moloneymurine leukemia virus (MoMuLV)-based retrovirus vectors wasinvestigated in various settings. Cocultivation of ALL cell lines withpackaging cell lines showed the highest transduction efficiency forretroviral gene transfer (40.1% to 87.5% for Nalm-6 cells and 0.3%to 9% for Reh cells), followed by transduction with viral supernatant on the recombinant fibronectin fragment CH-296 (13% to 35.5% for Nalm-6 cells and 0.4% to 6% Reh cells), transduction on human bonemarrow stroma monolayers (3.2% to 13.3% for Nalm-6 cells and 0% to0.2% Reh cells), and in suspension with protamine sulfate (0.7% to3.1% for Nalm-6 cells and 0% for Reh cells). Transduction of bothNalm-6 and Reh cells with human immunodeficiency virus-type 1 (HIV-1)-based lentiviral vectors pseudotyped with the vesicular stomatitis virus-G envelope produced the best gene transfer efficiency, transducing greater than 90% of both cell lines. Gene delivery intoprimary human B-precursor ALL cells from patients was then investigatedusing MoMuLV-based retrovirus vectors and HIV-1-based lentivirusvectors. Both vectors transduced the primary B-precursor ALL cells withhigh efficiencies. These studies may be applied for investigating genedelivery into primary human B-precursor ALL cells to be used forimmunotherapy.