Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: A phase I study

Background: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin. Methods: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m², three patients were treated at 90 mg/m², and five patients received 120 mg/m². A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation. Results: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p<0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m². Conclusions: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC. The results of this study were presented at the 46th Annual Cancer Symposium of The Society of Surgical Oncology, Los Angeles, California, March 18–21, 1993.     

Shelf-lives and factors affecting the stability of morphine sulphate and meperidine (pethidine) hydrochloride in plastic syringes for use in patient-controlled analgesic devices

Published reports regarding the stability of morphine are at variance, especially in syringes used in patient-controlled analgesia (PCA) devices. In addition to the effects of container type and vehicle, reasons for this variation include the effect of excipients temperature and light during storage. Furthermore, the literature varies regarding the mechanisms of decomposition for morphine. To our knowledge, the stability of meperidine (pethidine) stored in plastic syringes has not been reported. The purposes of this study were to investigate the stability of morphine sulphate (1 and 5 mg/ml) and meperidine hydrochloride (5 and 10 mg/ml) in plastic syringes for use in PCA devices for a duration of 12 weeks, and evaluate the influence of light (240 foot-candies), temperature (-20, 4 and 23d?C), diluent (5% dextrose or normal saline), and drug concentration on the stability of these narcotic analgesics. Samples were taken bi-weekly for solutions protected from light and weekly for solutions exposed to light. Morphine sulphate and meperidine hydrochloride concentrations were quantified using independent, stability-indicating, high performance liquid chromatographic assays. The within-day and between-day coefficients of variation for these assays were 4% over each of the concentration ranges studied. Under the conditions of this study, it is proposed that although decomposition of morphine to its main product, pseudomorphine, can be interpreted using first-order kinetics, consecutive (to form the N-oxide) and parallel mechanisms (to form apomorphine) exist. Morphine solutions were more stable in normal saline than in 5% dextrose. SheIf-life data indicate that morphine is stable for at least 6 weeks when protected from light. Exposure to light accelerates morphine decomposition two to six-fold depending on the concentration, and the shelf-life is reduced to about 1 week in some instances. Meperidine solutions in both vehicles under all conditions had shelf-lives of at least 12 weeks. No effects of light were detected and no changes in solution colour were observed. This study illustrates that patients using PCA devices must be advised about shelf-lives as well as correct storage conditions to protect solutions of these drugs from environmental factors that may alter shelf-lives. Pharmacists should also note that other formulation factors such as: antioxidants, preservations, buffers, impurities, and the source and quality of containers, may significantly alter the shelf-lives of these drugs.     

Comparison between Low Frequency Magnetic Field Stimulation and Nerve Growth Factor Treatment of Cultured Chromaffin Cells, on Neurite Growth, Noradrenaline Release, Excitable Properties, and Grafting in Nigrostriatal Lesioned Rats

Adrenal chromaffin cells in vitro respond to nerve growth factor (NGF) by expressing neuronal traits. Low frequency magnetic (LFM) field stimulation, while inducing a variety of effects on several cell types, has never been studied as to its effects on chromaffin cell cultures. The purpose of this study was to compare the effects of LFM field stimulation with that of NGF on the morphological phenotype, on noradrenaline (NA) release, and on membrane excitability of cultured chromaffin cells. We also tested the effects of grafting LFM and NGF-treated chromaffin cells into the caudate nucleus of rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. The results of this study showed that LFM field stimulation produced neurite growth of cultured chromaffin cells in a manner similar to that of NGF exposure. The combination of the two procedures did not induce changes above those observed by NGF alone. Both NGF- and LFM-treated chromaffin cells released [³H]NA equally in response to a depolarizing concentration of KCl. On the other, Na⁺ current density of LFM field stimulation increased, but to a lesser extent than that seen in NGF-treated cells. In addition both types of cells when transplanted into nigrostriatal-lesioned animals induced a similar decrease in the motor asymmetries produced by the lesion. When NGF- or LFM-treated chromaffin cells where compared to untreated control cells, no significant differences were observed in [³H]NA release, on Na⁺ current densities, or on postgraft motor asymmetries. The results are discussed in terms of the fact that LFM-stimulated cells can be differentiated in a manner similar to NGF-treated cells, by acquiring sympathetic like traits which in turn can diminish motor asymmetries when grafted into nigrostriatal-lesioned rats.     

Cerebral lateralization and color perception: a transcranial Doppler study.

Eight normal subjects were examined in dark, light and color conditions. Mean cerebral blood flow velocity (MBFV) were recorded almost simultaneously from their posterior cerebral arteries (PCA) using transcranial Doppler (TCD) ultrasound. The side-to-side difference was significant during the dark (p = 0.0159) and color stimulation (p = 0.0001) but not in light condition. This side-to-side difference in MBFV was used to characterize lateralization of color perception. This showed that the right PCA was always greater than the left during the presentation of color stimuli. Primary psychological colors (blue, yellow, red and green) induced greater lateralization as compared with color resulting from a mixed blue-green wavelength. This suggests that the right visual cortex is selectively sensitive to wavelengths.     

Neuropsychological detection of cognitive impairment: inter-rater agreement and factors affecting clinical decision-making.

The agreement between neuropsychologists identifying cognitive impairment (CI) in older adults was examined, as were factors influencing the classification process. Twenty four neuropsychologists in 18 study centers classified cases with or without CI after reviewing neuropsychological findings and other relevant information. All cases were participants in the third wave of the Canadian Study of Health and Aging, a study of CI in later life. For 117 randomly selected cases, a second neuropsychologist reviewed the same material and reclassified the cases. Cases given the same (concordant) or different (discordant) classifications were compared with respect to patient and rater characteristics. The inter-rater agreement was moderate (77.7% agreement, kappa = .49). On all measures of cognitive functioning, the concordant group without impairment obtained a higher mean score than the discordant group, and the discordant group obtained a higher mean score than the concordant group with impairment. For 5 out of 8 cognitive measures, the concordant group with impairment differed from the concordant group without impairment and the discordant group, but the latter two groups did not differ significantly. The findings are comparable to others in the field and highlight the need for neuropsychologists to further clarify procedures for identifying subtle, or mild, forms of cognitive impairment.     

Analysis of the inflammatory response in endovascular treatment of aortic aneurysms.

OBJECTIVE: The objective of this study is to evaluate the inflammatory response caused by endovascular stents in the treatment of aortic aneurysms. METHODS: Twenty-five patients underwent endovascular stent treatment from March through December 2005. The evolution of mediators (sedimentation velocity, C reactive protein, interleukin-6, interleukin-8, tumor necrosis factor-alpha, intercellular adhesion molecule-1, l-selectin), inflammatory cells (leukocytes, lymphocytes, platelets), serum creatinine and body temperature within preoperative period and in the following postoperative periods--1, 6, 24 and 48 h, 7 days, 1-3 months, was analyzed. In order to achieve statistic significance, Friedman test and Wilcoxon test were used, with index of significance of 5% (p<0.05). RESULTS: Peak values of sedimentation velocity, C reactive protein and interleukin-6 were observed at 7 days (p<0.0001), 48 h (p<0.0001) and 24h (p<0.0001), respectively. Tumor necrosis factor-alpha and interleukin-8 did not show statistically significant variability during the entire follow-up. In terms of intercellular adhesion molecule-1 and l-selectin, their expressive values were found in late phase of follow-up, although without statistical significance. Elevation of leukocytes count occurred in premature phase of follow-up (p<0.0001), while lymphocyte and platelet count occurred in a late phase of follow-up (p<0.0001). Serum levels of creatinine did not show significant variability during follow-up. The period between 24 and 48 h corresponded to major frequency for fever (p<0.0001). CONCLUSION: Individual mediators analysis and inflammatory cells demonstrated variability of their values during postoperative follow-up. This could help in the analysis of the inflammatory response evolution caused by endovascular stent treatment for aortic aneurysms in premature and late phases after implantation of the vascular prosthesis.     

Effects of negative pressure wound therapy on fibroblast viability, chemotactic signaling, and proliferation in a provisional wound (fibrin) matrix

Vacuum Assisted Closure brand Negative Pressure Wound Therapy (V.A.C. NPWT) has been shown to be an effective therapeutic option for the treatment of recalcitrant wounds; however, the mechanism of action at the cellular level remains to be elucidated. Here, we examined the effects of negative pressure wound therapy, manifolded with two different dressings, on fibroblast viability, chemotactic signaling, and proliferation in a fibrin clot matrix. Fibroblasts were grown in a three-dimensional fibrin matrix and were treated for 48 hours with either V.A.C. NPWT and GranuFoam Dressing, or with gauze under suction, or as static controls without negative pressure or dressings. Cells treated by gauze under suction showed significantly greater cell death and stimulated less migration and proliferation than static and V.A.C. NPWT-treated cells (p<0.05). Apoptosis was also significantly higher in gauze under suction than in static treatments. These results indicate that the dressing material has a significant effect on cell response following negative pressure wound therapy. The ability to support cell growth, stimulate chemotaxis, and proliferation without increasing apoptosis may provide an insight into the mechanisms of action of V.A.C. NPWT.