Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients.

The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.     

The accompanying male parent in the intensive care unit

A study is made in the Intensive Care Unit of "José L. Miranda" Provincial Pediatric Teaching Hospital in Santa Clara in order to know the sequence with which the father occupies the place of the mother in the care of hospitalized children. With this objective, 54 male companions are surveyed in the first trimester of 1987. The prevailing occupational profile was that of worker. A higher number of the respondents were between 17 and 25 years of age. The school level of secondary school prevailed among patient companions. Most of them reported no economic inconveniences during the child's disease. The desire to remain at the bedside and the inability of the mother to do so were the major reasons for their stay. The advantages recognized by the nursing personnel in male companions are made known.     

A case-control study of risk factor for renal cell cancer in northern Italy

A hospital-based case-control study of renal cell cancer was conducted in northern Italy betwen 1986 and 1989, with 240 cases of renal cell cancer (150 males and 90 females), and 665 controls (445 males and 220 females) chosen on the basis of age, sex, and area of residence. No associations were found between renal cell cancer and: body mass index (BMI); number of cigarettes smoked; age at starting to smoke; years of smoking; consumption of wine, beer, spirits, coffee, decaffeinated coffee; tea; intake of animal protein, fruits, and vegetables; various resproductive factors; hormonal use; sexual habits; sexually transmitted diseases; or selected occupational exposures. The odds ratio (OR) was above unity in smokers (OR=1.34 for 15 cigarettes/day), but the trends in risk with dose or duration were not statistically significant. Significant positive associations were found between renal cell cancer and sources of fat intake, especially margarine (OR for highest vs lowest intake = 1.71), and oils (OR=1.89) whereas carrot intake showed a negative association (OR=0.62). Also, a history of nephrolithiasis and multiple episodes of cystitis showed weak positive associations (OR=2.00, 95 percent confidence interval (CI) 1.07–3.73; and OR=1.60, 95 percent CI 0.95–2.70, respectively).Address reprint requests to Dr Talamini. The work was conducted with the contribution of the Italian Association for Cancer Research, Milan, Italy and the CNR (Italian National Research Council) Applied Projects Oncology (Contract n. 85.02209.44).Drs Talamini, Barón, Barra, Bidoli, Serraino, and Franceschi are in the Epidemiology Unit, Aviano Cancer Center, Via Pedemontana Occ. 33081 Aviano (PN) Italy. At the time of this work, Dr Barón was a visiting biostatistician from the Department of Preventive Medicine and Biometrics, University of Colorado, Health Science Center, CO, funded by the National Cancer Institute (US) and the Italian National Research Council. Dr Franceschi is also chief of the Hormones and Sexual Factors and Cancer Working Group of the European Organization for Cooperation in Cancer Prevention Studies, Bruxelles, Belgium. Drs La Vecchia and Negri are in the Mario Negri Institute for Pharmacological Research, Milan, Italy. Dr La Vecchia is also in the Institute of Social and preventive Medicine, University of Lausanne, Switzerland.     

When it's hard to be sure of the patient's own goals

As the new world of managed care transforms your professional life, it also poses new ethical problems. This month, Managed Care welcomes to its pages columnist John La Puma, M.D., who will address the ethical concerns introduced by capitation and similar features of a fast-changing environment.     

Evidence against a role of nitric oxide in the indirect negative inotropic-effect of M-cholinoceptor stimulation in human ventricular myocardium

Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with N^G-monomethyl-l-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37°C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 mol/l) was studied in the presence of the \-adrenoceptor agonist isoprenaline (0.03 mol/l).After stimulation with isoprenaline, carbachol significantly (P < 0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to \-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 mol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 mol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction. Basal force of contraction, as well as the positive inotropic effect of isoprenaline remained unaffected by NMMA or methylene blue.The present study provides evidence that the indirect negative inotropic effect of M-cholinoceptor agonists is not due to an effect of NO in the human myocardium. Furthermore, the well known enhancement of cGMP in response to M-cholinoceptor stimulation appears not to be involved in this antiadrenergic effect.