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Biomedical subjects

R L Edwards

Publications and source records attributed to R L Edwards.

At least 55 records · Page 3Linked to original sources
PubMed1988

Effect of mopidamol on survival in carcinoma of the lung and colon: final report of Veterans Administration Cooperative Study No. 188.

Mopidamol (RA-233), a derivative of dipyridamole, is a phosphodiesterase inhibitor that has been shown previously to limit progression of malignancy in certain experimental animal models and in a pilot study in humans. RA-233 plus chemotherapy was compared with chemotherapy alone in a 5-year double-blind trial involving 719 patients with advanced carcinomas of the lung and of the colon. RA-233 treatment was associated with a statistically significant prolongation of survival in patients with non-small cell lung cancer (N-SCLC) limited to one hemithorax and with reduction in mean plasma fibrogen concentration. RA-233 was not toxic. The favorable effects on survival could not be explained by any factor other than the RA-233 treatment. In other tumor categories tested, no differences in survival were observed. These results suggest that RA-233 is useful in the treatment of N-SCLC of limited extent. They also suggest that therapeutic intervention aimed at modified intracellular pathways might constitute a novel investigative approach to the treatment of cancer.

Carcinoma↗
PubMed1988

Monocyte procoagulant activity as a peripheral marker of clotting activation in cancer patients.

Peripheral blood monocytes generate the procoagulant tissue factor in vitro and in vivo in response to stimulation by a variety of agents. Monocytes from cancer patients generate significantly increased tissue factor and a quantitative relationship exists between the levels of monocyte tissue factor (MTF) and levels of circulating fibrinopeptide A (FPA), a marker of in vivo clotting activation. Furthermore, monocytes from cancer patients have a greater procoagulant response to stimulation by endotoxin in vitro, which appears independent of lymphocyte regulation. These findings suggest a priming process in vivo, and may reflect exposure of monocytes to tumor antigen(s) or components of the immune response to tumors.

Animals↗
PubMed1987

Abnormalities of blood coagulation tests in patients with cancer.

Routine blood coagulation tests were performed on 431 consecutive patients enrolled in a study of the role of anticoagulation in cancer treatment (VA Cooperative Study #75). Two hundred sixteen control patients were treated with standard therapy, and 215 patients were treated with standard therapy plus sodium warfarin. At the time of entry into the study, the most common abnormalities were elevated fibrinogen levels, platelet counts, and fibrinopeptide A levels. Serial studies demonstrated a steady increase in platelet count and fibrinogen levels before death. Anticoagulation lowered FPA levels but had no significant effect on fibrinogen levels, platelet counts, or euglobulin clot lysis times. An unexpected finding was a dramatic increase in fibrin split product levels after institution of anticoagulation (means +/- SEM = 42.6 +/- 116.4 vs. 2.9 +/- 7.0 mg/L in control subjects; P less than 0.02). This study supports the presence of subclinical activation of blood coagulation in most patients with cancer. Moreover, the preferential activation of fibrinolysis in anticoagulated patients suggests a role for a vitamin K-dependent factor(s) in the regulation of fibrinolysis in patients with cancer.

Blood Coagulation Tests↗
PubMed1987

Activation of blood coagulation in Crohn's disease. Increased plasma fibrinopeptide A levels and enhanced generation of monocyte tissue factor activity.

We have examined the relationships among activation of blood coagulation, generation of monocyte procoagulant activity, and clinical activity in patients with Crohn's disease. Subclinical activation of blood coagulation was measured using a radioimmunoassay for fibrinopeptide A. Fibrinopeptide A levels were strongly correlated with the level of disease activity as measured by the Crohn's disease activity index. Patients with active disease who were successfully treated either medically or surgically demonstrated a reduction of fibrinopeptide A levels. Failure of fibrinopeptide A to return to the normal range predicted an early relapse. Monocyte tissue factor generation was assessed in both unstimulated and lipopolysaccharide-stimulated mononuclear cell cultures obtained from the peripheral blood of patients with Crohn's disease. A strong correlation (r = 0.89) was observed between plasma fibrinopeptide A levels and monocyte tissue factor generation. These results suggest that monocyte procoagulant generation may contribute to the activation of blood coagulation in this inflammatory bowel disease. Moreover, fibrinopeptide A levels in Crohn's disease may provide a useful quantitative measure of inflammatory activity.

Adolescent↗
PubMed1986

The effect of sodium warfarin on rabbit monocyte tissue factor expression.

A rabbit model was developed to examine the effect of sodium warfarin on peripheral blood monocyte tissue factor (MTF) activity. After three days of treatment with sodium warfarin, MTF expression was significantly impaired (p less than 0.003). Vitamin K reversed this inhibition despite continued treatment with warfarin. Animals resistant to warfarin did not become anticoagulated and failed to demonstrate inhibition of MTF expression. Cells grown in plasma from warfarin-treated animals expressed reduced amounts of MTF activity, while cells grown in normal rabbit plasma demonstrated procoagulant activity in assays using both normal and factor VII-deficient substrate plasmas. These studies suggest that normal factor VII binds to monocytes during the culture period. Moreover, a plasma component in warfarin-treated animals, possibly abnormal factor VII, may bind to monocytes and block expression of MTF activity. This may represent another mechanism for warfarin-mediated inhibition of cell-mediated coagulation reactions in vivo.

Animals↗
PubMed1985

Synthesis of PGE2, collagenase and tissue factor by fibroblast substrains: substrains are differentially activated for different metabolic products.

Metabolic heterogeneity has previously been demonstrated for cloned fibroblast populations. It is unclear whether a "high producer" or "activated" phenotype for one cell product reflects general metabolic activation or whether activated phenotypes for different metabolic markers segregate independently among cloned populations. We examined human foreskin fibroblast substrains, isolated by limiting dilution cloning, for heterogeneity in biosynthesis of PGE2 and collagenase (stimulated by Interleukin 1-containing mononclear cell supernates), and tissue factor. Synthesis of these products varied 5- to 10-fold among 16 substrains isolated from two parent lines (AT and WB). Metabolic phenotypes (high versus low levels of synthesis) were stable for the substrains over multiple weeks of culture. In neither group of substrains was there a correlation between levels of stimulated PGE synthesis and stimulated collagenase synthesis (r = -0.24 and 0.29 for AT and WB substrains, respectively). Similarly, tissue factor generation did not correlate with either PGE production (r = 0.12 and -0.38 for AT and WB substrains, respectively) or collagenase synthesis (r = 0.17 and 0.21 for AT and WB substrains, respectively). The discordance between high producer phenotypes for the different products was observed even when all three products were measured in the same culture. Activated phenotypes for different metabolic markers thus appear to segregate among cells independently. The process of connective tissue activation by immune cell-derived mediators may depend on the constituent makeup of the responding connective tissue cell population.

Cells, Cultured↗
PubMed1985

Bleeding complications from warfarin anticoagulation in patients with malignancy.

Bleeding complications from warfarin anticoagulants were analyzed in 431 patients with carcinoma of the lung, colon, prostate and head and neck who were admitted to a randomized, controlled therapeutic trial of this agent. A total of 215 patients were randomized to the warfarin-treated group and 216 to the control groups. The mean prothrombin time was significantly prolonged (p = 0.0001) for warfarin-treated patients. The duration of warfarin administration was 64.9% of the total followup period providing 101 patient-years of experience with warfarin in cancer. Both the overall incidence of bleeding episodes (58% of warfarin-treated versus 30% of control) and the incidence of major bleeding episodes (42% versus 14%, respectively) were significantly increased in the warfarin-treated group (p = less than 0.001). The incidence of major bleeding was 1.86 per patient-year on warfarin. The most common sites of bleeding (in descending order) were the gastointestinal tract, the urinary tract, the nasal passages and skin. Hemorrhage occurred in association with the terminal event in 10 warfarin-treated and 12 control patients. Warfarin anticoagulation may have contributed to terminal bleeding in 3 (1.4%) patients. There was no difference in mean hemoglobin or hematocrit values for patients with versus patients without bleeding episodes.

Clinical Trials as Topic↗
PubMed1984

Safety of influenza vaccination in adults with asthma.

The results of a study to investigate whether influenza vaccination produces symptoms or exacerbations in adults with asthma are reported. Twenty-eight subjects with asthma were followed up over three-week periods, during which they received both influenza vaccinations and placebo injections. Subjective assessment of asthma symptoms and objective assessment of bronchoconstriction by means of peak expiratory flow rate measurements were carried out each day. No evidence for the asthmagenicity of influenza vaccination was found. The relevance of this finding in the assessment of patients for influenza vaccination is discussed.

Adolescent↗
PubMed1984

Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75.

VA Cooperative Study #75 was established to test in a controlled, randomized trial the hypothesis that warfarin anticoagulation would favorably affect the course of certain types of malignancy. No differences in survival were observed between warfarin-treated and control groups for advanced non-small cell lung, colorectal, head and neck and prostate cancers. However, warfarin therapy was associated with a significant prolongation in the time to first evidence of disease progression (P = 0.016) and a significant improvement in survival (P = 0.018) for patients with small cell carcinoma of the lung, including the subgroup of patients with disseminated disease at the time of randomization (P = 0.013). A trend toward improved survival with warfarin treatment was observed for the few patients admitted to this study with non-small cell lung cancer who had minimal disease at randomization. These results suggest that warfarin, as a single anticoagulant agent, may favorably modify the course of some, but not all, types of human malignancy, among which is small cell carcinoma of the lung. Further trials of warfarin may be indicated in patients with limited disease who have cell types that failed to respond when advanced disease was present.

Adenocarcinoma↗
PubMed1984

Molecular structure of 5,10-dimethoxybenzo[j]fluoranthene.

The molecular and crystal structure of the synthetic 5,10-dimethoxy derivative of the carcinogen benzo[j]fluoranthene has been determined by direct methods from X-ray diffractometric data and refined to an R index 0.041 over 2788 independent reflections. The benzo ring is inclined at approximately 3 degrees to the almost planar fluoranthene moiety (carbon atoms have r.m.s. deviation of 0.02 A from the carbon-atom plane); the methoxy carbon atoms lie within 0.2 A of the molecular plane. Corresponding bond lengths (e.s.d. 0.004 A for carbon-oxygen and carbon-carbon) and angles lie within 3 sigma for the two independent molecules, with mean dimensions of methoxy groups: C-C = 1.422, C-O = 1.372 A, C-O-C = 117.4 degrees.

Carcinogens↗
PubMed1984

Accrual of patients into a multihospital cancer clinical trial and its implications on planning future studies.

Little information exists on the population of cancer patients from which individual patients are selected for admission to a clinical trial. In fact, most reports of clinical trials of cancer chemotherapeutic agents begin by describing samples of treated patients but neglect to collect data and describe the population from which the samples were taken. In a multi-institutional VA Cooperative Study in which two different cancer treatments were compared, an attempt was made to screen all lung, colorectal, prostate, and head and neck patients seen at participating hospitals prior to randomization to a therapeutic regimen. Of a total of 2687 patients screened, 437 (16.3%) were randomized and 2250 (83.7%) were excluded for 2981 reasons. Protocol reasons were the basis for 68.6% of all exclusions, 21.3% were physician refusals, and 10.1% were patient refusals. The number of patients randomized did not correlate well with number of patients screened across participating centers. Patients admitted to the study tended to be younger and in better health than excluded patients. Overestimates of randomization rates projected initially from published information point to the need for improved screening data in the planning of future studies. Factors such as screening methods, physician acceptance of the experimental approach, number of competing protocols within each center, and cooperation among medical center departments and personnel all are important ingredients in any screening effort.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Comparison of local versus central tumor measurements in a multicenter cancer trial.

Four hundred nineteen solid tumors from 92 patients were measured by a local team consisting of a physician and nurse oncologist or physician's assistant, and centrally by one radiologist. The central radiologist also remeasured 137 tumors on 30 patients to assess intraexaminer agreement. Tumor measurements at specific points in time as well as changes in tumor measurements over time were evaluated. When signed differences were calculated, there was little overall difference between local and central examiners, although three of the eight centers did show a significant difference. However, when absolute differences were calculated, the relative errors of the width times length products ranged from 35 to 55%. Although local and central examiners agreed 75% of the time on change in disease, there was only 42% agreement on the subset of patients who had a remission. In general, the intraexaminer agreement was slightly better than the interexaminer agreement. This study suggests that solid tumor measurements are not particularly reliable, and that survival time remains the most satisfactory endpoint in a cancer clinical trial.

Clinical Trials as Topic↗
PubMed1984

Pulsatile administration of GnRH for the treatment of hypogonadotrophic hypogonadism.

Fourteen patients, aged 22-35 years, complaining of infertility and failing to ovulate on clomiphene, were treated with GnRH administered in pulses at 90 min intervals. Four patients received a total of eight courses of GnRH given subcutaneously and 13 were given a total of 20 months of treatment with GnRH given intravenously. Serum concentrations of immunoreactive GnRH were measured in six patients before administration of the drug and at regular intervals for 60 min after subcutaneous and intravenous injections of 5, 10 and 20 micrograms GnRH. Maximum concentrations of GnRH were reached by 5-10 min after subcutaneous injections and within 2 min after intravenous injections. The peak concentrations were 3.6-6.3 times and the sums of increments were 2.0-3.9 times greater following intravenous injections than after subcutaneous injections. Subcutaneous treatments extended for 15-29 days with doses of 5-20 micrograms per pulse. Only one patient ovulated as judged by the luteal phase progesterone and ultrasonic scanning of the follicle. Intravenous treatments were from 12-22 days with doses of 10 micrograms per pulse and 16 treatments out of 20 were ovulatory with four pregnancies. HCG (5000 i.u.) was given when ultrasonic scanning indicated adequate follicular growth, but in eight of the cycles, including three of the pregnancies, the follicle had ruptured before HCG was given. Pulsatile administration of GnRH proved to be an effective treatment for infertility in hypogonadotrophic hypogonadism. Possible reasons for the better results by intravenous rather than subcutaneous injections are discussed.

Adult↗
PubMed1984

Review of 59 patients with hypergonadotrophic amenorrhoea.

Fifty-nine patients presented with elevated concentrations of gonadotrophins and secondary amenorrhoea before the age of 35 years. Fifty-three underwent laparoscopic examination and primordial follicles were observed in 16. Two others had follicles as they later became pregnant and a third showed biochemical evidence of spontaneous ovulation. There were streak ovaries in 12, two with follicles and three others with chromosomal abnormalities, two being 47XXX and one XO/XX. Two other patients had only one ovary each but no follicles. Chromosomal abnormalities were detected in two further patients one being XO/XX and the other a recombinant. Six patients became pregnant, two of them twice, resulting in four term deliveries and four spontaneous abortions. Three other patients showed biochemical evidence of ovulation; one spontaneously, one after oestrogen therapy and the third after treatment with gonadotrophin releasing hormone analogue.

Adolescent↗