Relationship between response and survival in patients with advanced ovarian cancer.
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Female↗
Biomedical subjects
M Friedman
Publications and source records attributed to M Friedman.
Statistical model to determine the relationship of response and survival in patients with advanced ovarian cancer treated with chemotherapy.
BACKGROUND: A statistically appropriate analysis of the association between survival and response measures in patients with ovarian cancer could help to define the role of response rate in planning, monitoring, and interpreting the results of clinical trials. PURPOSE: This study was designed to investigate the relationship between antitumor response determined by clinical or pathological means and survival in patients with advanced ovarian cancer with no previous treatment. We focused on avoiding the limitations of the usual approach of comparing durations of survival for patients responding to therapy with those for nonresponders. METHODS: A new meta-analytic statistical model we developed was used to analyze data from 26 randomized clinical trials published between 1975 and 1989. Our model incorporates intra-study and inter-study sources of variability in the estimates of response and survival. The study also addresses the methodological problems of evaluating response as a surrogate end point and the relevance of this association to clinical decision making and the design of clinical trials. RESULTS: For 13 studies in which response was pathologically assessed, an improvement in surgically documented complete response rate was associated with an increase in median survival. A similar but apparently smaller effect was found for the association between objective clinical response and median survival in the 25 studies reporting these data. CONCLUSIONS: These results suggest that therapeutic measures must produce large improvements in clinical response rates to achieve meaningful effects on median survival. Improvement in surgically documented complete response rate appears to be more strongly associated with increased median survival and, hence, might be used for interim monitoring in clinical trials, but the role of second-look procedures in clinical management is controversial.
Antineoplastic Combined Chemotherapy Protocols↗
Differences in arachidonic acid metabolism by human myelomonocytic cell lines.
The production of arachidonic acid metabolites by the HL60, ML3, and U937 human phagocyte cell lines was determined after incubation with interferon-gamma (IFN-gamma, 500 U/ml) or vehicle for 4 days. Cells were prelabeled with tritiated arachidonic acid, [3H]AA, for 4 h, and media supernatants were analyzed by high-performance liquid chromatography. None of the cell lines produced [3H]AA metabolites in large amounts during an unstimulated, basal release period (30 or 60 min). In response to 10 microM calcium ionophore A23187 incubation (30 min), undifferentiated and IFN-gamma-differentiated HL60 cells formed both cyclooxygenase products (thromboxane and prostaglandins) and lipoxygenase products (leukotrienes and hydroxyeicosatetraenoic acids). In contrast to the HL60 cells, IFN-gamma-differentiated U937 cells formed primarily cyclooxygenase products and undifferentiated and IFN-gamma-differentiated ML3 cells did not form any [3H]AA metabolites in response to A23187. These results indicate the need to be careful in selecting a cell line for use in a phagocyte assay system when cyclooxygenase and/or lipoxygenase products could influence the assay results.
Antigens, CD↗
Physicochemical properties of albumin microspheres determined by spectroscopic studies.
The interactions of a family of fluorescein dyes of varying hydrophobicities and polarizabilities (as well as those of several model drugs) with native and colloidal denatured albumin systems from various sources were monitored spectroscopically. The use of colloidal denatured albumin systems allowed direct determination of spectral shifts induced by the interactions of the dyes or drugs with the albumins. Large bathochromic shifts were observed upon interaction of hydrophobic dyes or drugs with bovine and human albumin systems. Egg albumin systems, on the other hand, did not induce such shifts. The hydrophobicities of the albumin surfaces estimated using bathochromic shifts were in the order bovine greater than human greater than egg, in agreement with literature values. The changes in absorbances of the dyes or drugs following interaction with the albumins allowed estimation of the polarizabilities of the albumins; these were in the order bovine greater than human greater than egg. The similar interactions of dyes and model drugs with albumin microspheres suggest that fluorescein dyes serve as excellent probes of the physicochemical state of denatured albumin systems and as good models for studying drug interaction with albumin microspheres. These studies also indicate that it may be possible to predict drug uptake by albumin microspheres from physicochemical properties of the drugs and carriers. Such predictions would be of great potential value for screening the suitability of carriers, especially for drugs which are highly sensitive to the preparation conditions of the microspheres, such as heating and cross-linking agents.
Adsorption↗
Effect of ozone on platelet activating factor metabolism in phorbol-differentiated HL60 cells.
The mechanisms of ozone (O3) toxicity in the lung may involve the formation of lipid inflammatory mediators. We have previously demonstrated that exposure to O3 in vitro results in increased accumulation and release of platelet activating factor (PAF) in the macrophage-like cell line HL60 differentiated with phorbol ester (dHL60). In the present study we have examined possible biochemical mechanisms responsible for the O3-induced increase in PAF levels in dHL60 cells. Specifically, we studied the effect of O3 on phospholipase A2 (PLA2), acetyltransferase, acetylhydrolase, and reacylation activities. dHL60 cells were exposed to 1.0 ppm O3 or air alone. O3 exposure was found to significantly decrease dHL60 cell acetylhydrolase activity by 36%. Additional experiments demonstrated that extracellular acetylhydrolase activity, but not intracellular acetylhydrolase activity, was inhibited by O3 exposure of dHL60 cells. O3 exposure resulted in a small (13%) but statistically significant reduction in reacylation activity in dHL60 cells. In addition, a significant (22%) contribution of PLA2 activation to the O3-induced increase in PAF levels was also found. Basal and calcium ionophore-induced acetyltransferase activity was found to be unaffected by exposure of dHL60 cells to O3. These data suggest that in vitro exposure to O3 affects both synthetic and degradative pathways of PAF metabolism in dHL60 cells.
Acetylation↗
Absence of genotoxicity of potato alkaloids alpha-chaconine, alpha-solanine and solanidine in the Ames Salmonella and adult and foetal erythrocyte micronucleus assays.
To assess whether reported toxicities of potato-derived glycoalkaloids could be the result of interactions with cellular DNA, the genotoxic effects of alpha-solanine, alpha-chaconine and solanidine were studied, using the Ames test (Salmonella strains TA98 and TA100), the mouse peripheral blood micronucleus test and the mouse transplacental micronucleus test. The Ames test for mutagenicity with alpha-solanine was weakly positive in TA100 with S-9 activation (29 revertants per millimole per plate). However, pooled data from duplicate tests gave a negative effect. Pooled data from two experiments with alpha-chaconine gave a weak positive response in TA98 without microsomes (17 revertants per millimole per plate). The micronucleus tests for clastogenicity using male mouse and foetal blood were negative. The absence of mutagenicity and clastogenicity suggests lack of damage to intracellular DNA for potato alkaloid toxicity.
Animals↗
Partial amino acid sequence of potato solanidine UDP-glucose glucosyltransferase purified by new anion-exchange and size exclusion media.
Solanidine UDP-glucose glucosyltransferase (SGT) is involved in the biosynthesis of steroidal glycoalkaloids in potatoes. This enzyme is present at an extremely low level, is inherently unstable, and copurifies with the major storage protein patatin during isolation. We describe an improved method for isolating SGT from greening potato peel using two new chromatographic supports, Macro-Prep 50 Q anion-exchange and Superdex 75HR size exclusion media, under medium-pressure conditions at room temperature. The enzyme preparation was further resolved by SDS-PAGE and the proteins transferred to PVDF membrane (Immobilon-P). Two protein bands corresponding to active forms of SGT (36 and 37 kDa) were excised and cleaved with cyanogen bromide in trifluoroacetic acid. The resultant peptide mixtures were then separated by Tricine-SDS-PAGE and transferred to a PVDF membrane (Pro-Blott). The two major peptide bands observed in both digests (17 and 19 kDa) were sequenced. Identical N-terminal sequences were obtained from the 19-kDa peptides from both digests.
Amino Acid Sequence↗
Adsorption of fluorescein dyes on albumin microspheres.
The surface characteristics of bovine and egg albumin microspheres were examined using four anionic dyes; sodium fluorescein, eosin, erythrosin, rose bengal, and the cationic dye rhodamine B. The adsorption isotherms of the dyes on unloaded albumin microspheres exhibited Langmuir behavior for dilute solutions of rose bengal, erythrosin, and eosin, suggesting monolayer formation in the initial stages of the sorption process. The adsorption capacity of the microspheres for the dyes (k2) and the affinity constants of the dyes for the microspheres (k1) were found to depend on both the polarizability and the hydrophobic properties of the dye, presumably reflecting the heterogeneous character of the microsphere surface. Further, the extent of sorption at higher dye concentrations was found to depend on the ability of the dye to form stable aggregates inside the microspheres and on environmental long-range forces acting at these sites. At both low and high dye concentrations, the amount adsorbed to the microsphere surface increased with increasing hydrophobicity of the dyes. The lowest adsorption was observed for the nonsubstituted dye fluorescein, whereas the most hydrophobic dye used, rose bengal, was completely adsorbed onto the microsphere surface. The data suggest that the bovine albumin microsphere surfaces are highly hydrophobic and less porous than egg albumin microsphere surfaces.
Adsorption↗
The use of a patient note to evaluate clinical skills of first-year residents who are graduates of foreign medical schools.
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Clinical Competence↗
Microbiological evaluation of the efficacy of chlorhexidine in a sustained-release device for dentine sterilization.
The aim of this in-vitro study was to evaluate the effect of chlorhexidine in solution and in a sustained-release device as an intracanal medication. Hollow cylindrical dentine specimens prepared from bovine incisors were incubated with Streptococcus faecalis for a period of 3 weeks. The intracanal medicaments tested were 0.2% chlorhexidine gluconate solution (CH), chlorhexidine in a sustained-release device (1.2 mg) (SBD), camphorated paramonochlorophenol (CMCP), and a control (no medication). Each medicament was introduced into the lumen of one dentine specimen and incubated for 5 min, 24 h, 48 h or 7 days at 37 degrees C. The bacteriological samples were taken by shaving the dentine inside the lumen with dental burs ranging in size from ISO 023-033. The dentine powder was collected in test-tubes containing growth medium and incubated for 24 h. The optical density of the medium was recorded by means of a spectrophotometer at a wavelength of 540 nm. There was a statistically significant difference between the control group and all the medicaments tested.
Animals↗
Efficacy of a sustained-release device containing chlorhexidine and Ca(OH)2 in preventing secondary infection of dentinal tubules.
This study was conducted to evaluate the efficacy of the antibacterial activity of Ca(OH)2 and a sustained-release device containing chlorhexidine (SRD) in both sterilization and prevention of secondary infection of the root canal system. Bovine root dentine specimens previously incubated with Streptococcus faecalis were used in this experiment. Two different formulations of the SRD (differing in their cross-linkage), Ca(OH)2 and normal saline (control) were evaluated. The degree of bacterial infection of the root canal was tested after incubation periods of 24 h, 72 h and 7 days with these medicaments. Their efficacy in preventing secondary infection after recontamination was tested after 72 h and 7 days. The results demonstrated that both formulations of the SRD significantly reduced the bacterial population in the primary infected groups, as well as preventing secondary infection of the dentinal tubules in the recontaminated group. By contrast, Ca(OH)2 did not show any antibacterial activity, and failed to sterilize the dentinal tubules or prevent secondary infection after recontamination at the time periods examined.
Animals↗
Effect of cervical coating of ethyl cellulose polymer and metacrylic acid copolymer on the radicular penetration of hydrogen peroxide during bleaching.
Extraradicular leakage of oxidizing agents during bleaching is an undesirable event and thus need to be prevented. The effect of external cervical coating of ethyl cellulose (EC) and metacrylic acid copolymer (MAC) on the radicular penetration of hydrogen peroxide during intracoronal bleaching was examined. Single rooted human premolars extracted for orthodontic reasons were used. The cementum covering the cemento-enamel junction was mechanically removed and the teeth treated endodontically and bleached with 30% hydrogen peroxide. Radicular hydrogen peroxide penetration was measured before coating the teeth and after applications of 1-3 layers of EC or 3 layers of MAC external cervical coatings. It was found that the radicular penetration of 30% hydrogen peroxide was related to the number of layers of cervical EC coatings. Application of one layer of EC did not reduce the hydrogen peroxide penetration. Two and three layers of EC reduced the hydrogen peroxide penetration by 38% and 85% respectively. Three layers of MAC reduced the radicular hydrogen peroxide penetration in 83%. Statistically, a highly significant difference was found between the teeth coated with three layers of either EC or MAC and the noncoated teeth (p < 0.001). It was concluded that application of ethyl cellulose or metacrylic acid copolymer to exposed cervical root surfaces may effectively prevent extraradicular leakage of bleaching agents.
Cellulose↗
Dietary impact of food processing.
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Amino Acids↗
Effect of slow-release chlorhexidine mouthguards on the levels of selected salivary bacteria.
This study evaluated the effect of an alternate delivery system for chlorhexidine on salivary levels of mutans streptococci (MS) and other selected oral bacteria. On the basis of salivary MS levels > or = 10(4) CFU/ml, 22 subjects were enrolled. All caries lesions were restored prior to treatment. Two pretreatment paraffin-stimulated saliva samples were obtained for culturing at least 1 week apart. Complete-arch vacuum-adapted mouthguards were individually fabricated and coated internally with a 3% w/v chlorhexidine varnish. Mouthguards were worn for an average of 7 h/night for 7 nights. Saliva samples were obtained immediately after treatment and 1 and 3 months later. There was no significant change in levels of any of the monitored bacteria between the two pretreatment samples. A significant and specific reduction in salivary MS levels was observed in the three after-treatment samples as compared with baseline values (p < 0.001, p < 0.001, p < 0.05, respectively). The levels of Actinomyces viscosus were also measured, and there was a significant reduction immediately after treatment (p < 0.05), a return to baseline values at 1 month, and a significant increase above baseline values at 3 months, (p < 0.001). There was no significant change in saliva volume, in total numbers of facultatively anaerobic bacteria, or in levels of lactobacilli or Streptococcus sanguis. This treatment system is capable of significant and specific suppression of MS levels for up to 3 months without retreatment.
Actinomyces viscosus↗
Interleukin-2 directly increases albumin permeability of bovine and human vascular endothelium in vitro.
The direct effects of interleukin-2 (IL-2) on albumin permeability of cultured bovine pulmonary artery endothelial cell (BPAEC) and human arterial endothelial cell (HAEC) monolayers were studied. BPAEC were exposed to IL-2 (500 to 25,000 U/ml) for 4 h. The steady-state transfer rate of [125I]albumin across the BPAEC monolayer was 3.3 +/- 0.4%/h (n = 10) in control BPAEC (diluent alone), was significantly increased in BPAEC exposed to 500 U/ml of IL-2 (72 +/- 3% above control values, n = 6, P less than 0.02), and further increased in BPAEC exposed to 5,000 U/ml (60 +/- 2% increase above 500 U/ml values, n = 5, P less than 0.02). No further increase was noted after exposure to 25,000 U/ml of IL-2. Additionally, no further increase in [125I]albumin transfer rates was noted in BPAEC exposed to 5,000 U/ml of IL-2 for 24 versus 4 h. Similar changes were found using HAEC. Preincubation of HAEC with an anti-IL-2 low-affinity receptor antibody (anti-IL-2R alpha) inhibited the IL-2-induced permeability increase. Expression of IL-2R alpha receptors in HAEC incubated with 5,000 U/ml of IL-2 for 4 h was also found. Thus, IL-2 appears to have a direct effect on cultural arterial endothelial monolayers not requiring the presence of other cell types or serum proteins. IL-2-induced increases in endothelial macromolecular permeability may play an important role in the pathogenesis of the IL-2-induced vascular leak syndrome seen in vivo.
Albumins↗
Effect of ozone on platelet-activating factor production in phorbol-differentiated HL60 cells, a human bronchial epithelial cell line (BEAS S6), and primary human bronchial epithelial cells.
Platelet-activating factor (PAF) is a phospholipid with a wide spectrum of pro-inflammatory properties. In the lung, PAF induces airway hyperresponsiveness, neutrophil sequestration, and increased vascular permeability. The alveolar macrophage and the bronchial epithelium are tissues that are exposed to inhaled ozone (O3). We studied the effect of an in vitro O3 exposure on PAF production in a macrophage-like HL60 human cell line (dHL60), a human bronchial epithelial cell line (BEAS S6), and also in primary human bronchial epithelial cells. PAF was quantified by thin-layer chromatographic separation of lipid extracts from cells radiolabeled with [3H]lysoPAF and by radioimmunoassay. In vitro exposure of dHL60 cells to 0.05 to 1.0 ppm O3 for 15 to 120 min was found to significantly increase PAF levels above air control values at all exposure levels and time points (average increase of 92%). Similarly, BEAS S6 cells grown on collagen-coated filter supports and exposed to 0.05 to 1.0 ppm O3 for 60 min released an average increase in PAF of 626% above control values. Primary human bronchial epithelial cells also demonstrated significant increases in [3H]PAF release (average increase of 289% after exposure to 1.0 ppm O3 for 60 min) compared with paired air controls. These findings suggest that some of the effects of O3 inhalation may be mediated by PAF.
Bronchi↗
Laryngotracheal reconstruction in adults with the sternocleidomastoid myoperiosteal flap.
Subglottic or tracheal reconstruction may be required in cases of subglottic stenosis, invasive thyroid carcinoma, or trauma. The sternocleidomastoid myoperiosteal flap uses clavicular periosteum on a muscle pedicle to provide vascularity. Clavicular periosteum is fibrous and durable and will conform to the shape of the trachea, forming bone to provide stability to the airway. The procedure is relatively simple and involves single-stage reconstruction. Success has been achieved in reconstruction of long-standing subglottic and/or tracheal stenosis and in cases of extreme tracheal defects. On the basis of 8 years' experience with this flap, we present the results from a series of 26 patients who underwent subglottic or tracheal reconstruction with the sternocleidomastoid myoperiosteal flap. Twenty-five of the 26 patients were successfully decannulated. Complications have been expanded to include one case of osteomyelitis of the sternum with mediastinitis, and 1 patient required revision. Subsequently, modifications of technique and patient management have been adopted. The complications compare favorably in frequency and in seriousness with those of other techniques for laryngotracheal reconstruction. We describe additional experience with this procedure and longer follow-up to establish its position as a first-line reconstructive approach for widespread clinical use.
Adult↗
Effects of ozone exposure on lipid metabolism in human alveolar macrophages.
Alveolar macrophages (AM) store arachidonic acid (AA), which is esterified in cellular phospholipids until liberated by phospholipase A2 or C after exposure to inflammatory stimuli. After release, there can be subsequent metabolism of AA into various potent, biologically active mediators including prostaglandins and platelet-activating factor (PAF). To examine the possibility that these mediators may account for some of the pathophysiologic alterations seen in the lung after ozone (O3) exposure, human AM were collected by bronchoalveolar lavage of normal subjects, plated into tissue culture dishes, and the adherent cells were incubated with [3H]AA or [3H]lysoPAF. Human AM exposed to 1.0 ppm O3 for 2 hr released 65 +/- 12% more tritium, derived from [3H]AA, than paired, air-exposed controls into media supernatants. In other studies using a similar O3 exposure protocol, there was also a significant increase in human AM prostaglandin E2 production (2.0 +/- 0.5-fold increase above air-exposure values, p less than 0.01, n = 17). In additional studies, using a similar O3 exposure protocol (1.0 ppm for 1 hr), there was also a significant increase in human AM PAF content (1.7 +/- 0.2-fold increase above air-exposure values, p less than 0.02, n = 5). These potent lipid mediators, originally derived from human AM, may play an important role in the mechanisms of O3 lung toxicity.
Adult↗