Flow cytometry in primary breast carcinomas. Prognostic impact of proliferative activity

From 1990 to 1996, 607 previously untreated, node-negative, invasive breast carcinomas were sampled by a pathologist for flow-cytometric DNA analysis. The aim of the present work was to study the correlations between flow cytometric results obtained thanks to the American Consensus (AC) guidelines of 1993 and the established clinico-pathological prognostic factors (T, grade, receptors), and despite a short global follow-up (mean of 4 years), to correlate flow cytometry with the outcome of the patients. In this study S-phase fraction (SPF) correlated strongly with tumor size, histological grade, lack of steroid receptors, histological type and was together with the mitotic activity a paramount prognostic factor even after multivariate analysis. This study compared also the technical criteria proposed by the AC with our own more stringent ones and concluded that the criteria of the AC are relevant and allow, thanks to the use of tertiles in the reporting of SPF values, a comparison of values obtained by different teams. Our review of the literature, focused on series using fresh material, enabled us to show that there is a rather wide agreement concerning the relationship between SPF and prognosis most often after multivariate analysis. This despite the lack of standardization in the design of the studies (implementation of the technical steps or reporting of results). When estimated from fresh or frozen material following ACs guidelines, SPF along with mitotic activity should become a prognostic factor used in the daily practice by oncologists in the management of breast carcinomas.     

Population pharmacokinetics of topotecan: intraindividual variability in total drug

The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.5 l per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of −2 ± 17%, and +5 ± 20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring. Received: 23 February 2000 / Accepted: 22 May 2000     

Identification of N-myc regulatory regions involved in embryonic expression.

Our knowledge on the regulation of the N-myc proto-oncogene expression comes mostly from in vitro studies. Very few in vivo analyses have been performed to identify the regulatory elements involved in N-myc developmental expression. In the present study, we defined DNA regions required for the regulated expression of N-myc during early embryogenesis. We showed that the expression of N-myc driven by the human N-myc sequences previously described to control N-myc expression in appropriate cell types in vitro cannot rescue the mouse N-myc mutant phenotype, suggesting that regulatory elements necessary for N-myc embryonic expression were missing. To identify the regulatory DNA regions involved in N-myc expression, transgenic mouse lines carrying N-myc/lacZ reporter constructs were generated. Beta-galactosidase staining analysis at different stages of gestation revealed that >16 kb of mouse N-myc genomic sequences are required to recapitulate the entire spatiotemporal expression pattern of the endogenous N-myc gene between embryonic d 8.5 and 11.5. This observation supported the notion that the sequences previously identified by in vitro assays were not sufficient to reproduce the N-myc embryonic expression pattern. However, regulatory elements that can direct specific expression in the visceral arches, the limb buds, the CNS, and the dorsal root ganglia are included into the mouse N-myc genomic sequences tested. Altogether, these findings indicated that the regulation of the spatiotemporal expression pattern of N-myc during development necessitates multiple regulatory DNA elements.     

Low posttrauma GABA plasma levels as a predictive factor in the development of acute posttraumatic stress disorder.

BACKGROUND: Gamma amino-butyric acid (GABA) regulates the intensity and the duration of the central hyperadrenergic response in times of high stress and has been negatively associated with anxiety, depression, and sleep problems. We hypothesized that individuals with low plasma GABA levels may be more prone to develop posttraumatic stress disorder (PTSD) in the aftermath of trauma exposure. METHODS: To test this hypothesis, we measured plasma GABA levels in a population of 108 road traffic accident victims on arrival at a traumatology department and assessed them for PTSD 6 weeks later. RESULTS: The mean GABA level (nmol/mL) in the PTSD group (n = 55; M =.20; SD =.08) was significantly lower compared with members of the trauma-exposed group who did not develop PTSD [n = 17; M =.30; SD =.09), t(70) = 3.94, p =.0002]. CONCLUSIONS: Provided that GABA levels in the brain are genetically predetermined, our results would suggest that individuals with low plasma GABA levels are premorbidly more vulnerable to stress-related disorders such as acute PTSD. If replicated, plasma GABA levels measured in the aftermath of trauma exposure might help to identify individuals at high risk for developing PTSD.     

Effects of Surgical Sympathectomy on Skin Blood Flow in a Rat Model of Chronic Limb Ischemia

p < 0.05), NSBF ( p < 0.05), and SO ( p < 0.05) were found to be drastically reduced at day 2 after ligation compared to preligation values. This reduction partially recovered during the following weeks. TSBF ( p < 0.05) and NSBF ( p < 0.05), however were still reduced at day 28 after ligation compared to preligation values, whereas the SO at this time tended to be lower ( p = 0.11). In the sympathectomy group the TSBF was found to be increased at day 2 ( p < 0.05) and day 28 ( p < 0.05) after sympathectomy, both compared to values obtained at day 28 after ligation. Sympathectomy did not have an effect on NSBF and SO. The sham procedure had no effect on the TSBF, NSBF, or SO. These results indicate that in case of lower limb ischemia, sympathectomy improves skin blood flow at the thermoregulatory but not the nutritive level of skin microcirculation. This may be related to the fact that the thermoregulatory vessels are mainly sympathetically controlled, whereas the nutritive capillaries are mainly controlled by local (nonneural) factors.     

Study of the female urethra's submucous vascular plexus by color Doppler

A total of 67 patients, including 44 continent patients and 23 patients suffering from stress incontinence, underwent color Doppler examination of the urethra. The maximal urethral pressure and the amplitude of the urethral pulse were measured in 35 of the patients. Linear endovaginal sonography was performed in 25 of the patients to define the position of the urethrovesical unit at rest. The submucous vascular sheath was clearly visible. Its average thickness was 3.42 mm and its average length was 11.75 mm. The measurement reproducibility was good. The dimensions of the submucous vascular plexus and its pulsatility decreased with age and increased with maximal urethral pressure and the manometric amplitude of the urethral pulse. By coupling the sonographic data obtained with color Doppler and linear endovaginal sonography in 25 patients, we obtained a good estimate of the urethral pressure in 83% of the cases and could correctly diagnose all cases of continence in our series (n=9) and 15 of 16 stress-incontinent patients.     

Electrophysiological studies before and after argon-laser photocoagulation in diabetic retinopathy

50 eyes with diabetic retinopathy were studied before and after treatment with argon-laser coagulation. After treatment, decreases of the L/D ratios of the EOGs and of the amplitudes of all ERG components were found. The scotopic b waves were more involved than the photopic b waves. The peak times were hardly modified. The dark-adaptation curves were not modified. Interesting was the fact that in the pretreatment findings the EOGs were involved before the ERGs. The decreases of the L/D ratios started when avascular and ischemic zones were seen on fluorescein angiography.