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.     

Intratemporal vascular tumors: detection with CT and MR imaging

The diagnostic contributions of computed tomography (CT) and magnetic resonance (MR) imaging were compared in 12 patients with benign intratemporal vascular tumors (hemangioma or vascular malformation). The tumors included six in the internal acoustic canal and six in the geniculate ganglion region. Clinical and histologic correlations were made. Two of the six patients with tumors in the internal acoustic canal underwent CT, and both required gas cisternography to show the tumor. Five patients in that group underwent MR imaging, and all five studies showed the tumor. All six patients with geniculate ganglion tumors underwent CT. Results in one study were questionable, and five showed the tumor. Five patients in this group underwent MR imaging, but the MR findings were positive in only two cases. MR imaging should therefore be performed before CT in the evaluation of facial nerve dysfunction, as it demonstrated all tumors in the internal acoustic canal and some in the geniculate ganglion region. If MR findings are negative, CT should then be performed to rule out a possible geniculate ganglion lesion.     

Vertebroplasty and Kyphoplasty in Spinal Trauma

Abstract Kyphoplasty and vertebroplasty have become recognized procedures for the treatment of vertebral fractures, especially in patients with osteoporosis. In most cases of osteoporotic spinal vertebral fracture in elderly patients, polymethylmethacrylate (PMMA) cement is used to fill the defect and stabilize the vertebral body. The techniques of vertebroplasty and kyphoplasty differ in the possibility of realignment and reconstruction of the vertebral body and spinal column. Long-term results in terms of integration of the cement and bioreactivity of the vertebral body are still lacking; so, these procedures are still no options in the treatment of younger patients. Vertebroplasty and kyphoplasty show different success in the management of fresh traumatic spine fractures. The acute traumatic vertebral fracture has to be classified sensitively, to find the right indication for cement augmentation. Mild acute compression fractures can be treated by vertebroplasty or kyphoplasty, severe compression and burst fractures by combination of internal fixation and kyphoplasty. The indications for use of biological or osteoinductive cement in spinal fracture management must still be regarded as restricted owing to the lack of basic biomechanical research data. Such cement should not be used except in clinical studies.     

Posttraumatisches septisches Abdomen

Abdominal infection has the fifth highest incidence of all posttraumatic infections but has the second highest mortality rate with 25%,pneumonia,with 29%, being the only posttraumatic infection that is more frequently lethal.Posttraumatic abdominal sepsis, on the other hand, has a mortality rate of almost 50%.This rate cannot be reduced except by prompt identification of the correct diagnosis of the underlying injury or complication.This means that delayed laparotomy is strikingly detrimental in these patients, with 46% mortality as opposed to 11% in patients who undergo laparotomy promptly. In parallel with this, the mortality of fresh-onset and localized peritonitis is 14%,whereas that of diffuse purulent peritonitis is up to a devastating 42%.     

Blood donation behavior of Hispanics in the lower Rio Grande Valley

This study was designed to determine the blood donation behavior and attitudes of Hispanic residents of the Lower Rio Grande Valley for the purpose of developing promotional and educational approaches to enhance levels of donor participation. Personal interviews of 545 respondents were conducted in English and Spanish using quota sampling and standard intercept techniques at lower- and middle-income supermarkets in five cities during a payday weekend. A number of research hypotheses were established to test for demographic, behavioral, and attitudinal differences that were observed in donors and nondonors using chi-square analysis and multiple discriminant analysis. After analyzing the difference between Hispanics and non-Hispanics for blood donation rates, all non-Hispanics were eliminated from analysis, and the remaining 419 Hispanics were evaluated on the basis of their donor behavior. Donation among Hispanics was most likely to be by better- educated, English-speaking, higher-job-status individuals who had participated in a blood donation drive. Donors tend to have parent(s) who were donors, and they were also more likely to carry an organ donor card. Donors were found to vary in their behaviors as well as their attitudes and beliefs. Perceptions of a lack of safety in donating, the risk of contracting acquired immune deficiency syndrome, and the financial motivation of donors were most pronounced among Hispanics, which indicated a need for improved education on these issues.     

Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchange

Their glycolytic metabolism imposes an increased acid load upon tumour cells. The surplus protons are extruded by the Na⁺/H⁺ exchanger (NHE) which causes an extracellular acidification. It is not yet known by what mechanism extracellular pH (pH_e) and NHE activity affect tumour cell migration and thus metastasis. We studied the impact of pH_e and NHE activity on the motility of human melanoma (MV3) cells. Cells were seeded on/in collagen I matrices. Migration was monitored employing time lapse video microscopy and then quantified as the movement of the cell centre. Intracellular pH (pH_i) was measured fluorometrically. Cell–matrix interactions were tested in cell adhesion assays and by the displacement of microbeads inside a collagen matrix. Migration depended on the integrin α2β1. Cells reached their maximum motility at pH_e∼7.0. They hardly migrated at pH_e 6.6 or 7.5, when NHE was inhibited, or when NHE activity was stimulated by loading cells with propionic acid. These procedures also caused characteristic changes in cell morphology and pH_i. The changes in pH_i, however, did not account for the changes in morphology and migratory behaviour. Migration and morphology more likely correlate with the strength of cell–matrix interactions. Adhesion was the strongest at pH_e 6.6. It weakened at basic pH_e, upon NHE inhibition, or upon blockage of the integrin α2β1. We propose that pH_e and NHE activity affect migration of human melanoma cells by modulating cell–matrix interactions. Migration is hindered when the interaction is too strong (acidic pH_e) or too weak (alkaline pH_e or NHE inhibition).     

Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study

The role that maternal and fetal human leukocyte antigen (HLA) genes play in pregnancy is unknown, but it has been suggested that fetuses whose HLA alleles do not differ from maternal alleles (i.e. histocompatible fetuses) are more likely to be aborted than fetuses with HLA alleles that differ from maternal alleles (i.e. histoincompatible fetuses). To elucidate the role of HLA compatibility in pregnancy, we tested the hypothesis that couples who match for HLA alleles or haplotypes would have reduced fertility because only these couples could produce histocompatible fetuses. We conducted a 10 year prospective study of HLA matching and pregnancy outcome in 111 Hutterite couples, providing information on 251 pregnancies. A logistic regression analysis was performed to determine the effects of HLA matching at HLA regions and loci on pregnancy outcome (fetal loss versus delivery). Significantly increased fetal loss rates were observed among couples matching for the entire 16-locus haplotype (P = 0.002). Among the individual loci, loss rates were increased among couples matching for HLA-B (P = 0.019), HLA-C (P = 0.033) and the complement component, C4 (P = 0.043). We interpret these results as evidence that matching for the entire 16-locus haplotype and/or alleles at an HLA-B-linked locus confers significant risk for fetal loss.