Is quantitative oestrogen receptor expression useful in the evaluation of the clinical prognosis? Analysis of a homogeneous series of 797 patients with prospective determination of the ER status using simultaneous EIA and IHC

ObjectiveOestrogen receptor (ER) determination in breast cancer (BC) is a major yardstick for the prognosis and for response to hormonal therapy (HT). As several techniques have been proposed for ER quantification, the purpose of our study was to assess whether the qualitative or quantitative analysis of ER expression might influence the prognosis and response to treatment.Materials and methodsWe analysed overall survival (OS) and disease-free survival (DFS) in 797 primary BC cases with ER determination by enzyme immunoassay (EIA) and immunohistochemistry (IHC). The clinical impact according to qualitative or quantitative analysis of ER expression was assessed. Response to HT was evaluated according to quantitative EIA-determined ER expression levels.ResultsAccording to the qualitative analysis of ER expression, patients with EIA-determined and IHC-determined ER-positive tumours had significantly longer OS and DFS (p < 0.001). The analysis stratified on quartiles of ER levels showed significantly different outcomes according to EIA- and IHC-determined subgroups. In the group of patients who received adjuvant treatment, 5-year OS was significantly different between the groups, with a clear benefit for the highest EIA-determined ER quartiles (p < 0.001). Comparatively, in terms of 5-year DFS, a clear separation was noted between groups for adjuvant treatment (p < 0.001). The group with moderate ER+ values was clearly distinct from the ER-negative population. Quantitative ER expression helped to better distinguish the beneficial or detrimental effect of HT within quartiles of ER-expressing tumours. Based on the STEPP analysis which showed a trend towards an ER effect on DFS as a function of HT assignment, we confirm the benefit of HT in patients with a very high EIA-determined ER level and a detrimental impact on negative and weakly positive groups.ConclusionQuantitative ER expression in BC helps to better discriminate heterogeneity in clinical outcome and response to HT.     

Termination of pregnancy in patients with previous cesarean section

Objective

To evaluate the safety and efficacy of termination of pregnancy using mifepristone and misosprostol at more than 15 weeks' gestation in patients with uterine scar due to previous cesarean section.

Materials and Methods

This retrospective study was conducted in a tertiary maternity ward between January 2000 and October 2004. A total of 252 women at more than 15 weeks' gestation underwent termination of pregnancy including 50 women with uterine scar due to previous cesarean section (Group 1) and 202 control patients (Group 2) without known uterine scar. Abortion was induced with mifepristone and a prostaglandin analogue. Women between 15 and 34 weeks' gestation received misoprostol intravaginally every 3 h at doses of 200 μg (Group 1) or 400 μg (Group 2). Women at more than 34 weeks' gestation received Prostin E2 vaginal gel. Main end points were hemorrhage, fever, retained placenta, occurrence of complications including uterine rupture and dehiscence, and final outcome.

Results

A total of 13 (26%) patients in Group 1 and 79 (39.1%) in Group 2 were at more than 24 weeks' gestation. The abortion failure rate was 2% (1/50) in Group 1 and 0.5% (1/202) in Group 2 (p=.28). The median induction-to-delivery interval was 8.5 h (range, 3.0-114.2 h) for Group 1 and 9.0 h (range, 1.3-124.3 h) in Group 2 (p=.26). One case of uterine rupture and one case of dehiscence were observed, both in women in Group 1. The incidence of hemorrhage was not significantly different between Group 1 and Group 2 (2% vs. 0.9%, respectively, p=.56). The incidence of retained placenta was higher in the Group 1 (70% vs. 52.5%, respectively, p=.025).

Conclusion

In this retrospective series of women who underwent abortion at 15-35 weeks' gestation using mifepristone and a prostaglandin analogue for labor induction abortion, history of cesarean section was not associated with higher morbidity except risk of uterine rupture. However, dose and interval of misoprostol should be determined. A larger study is needed before drawing definitive conclusions about the safety of these regimens.     

Conservative treatment of cervical intraepithelial neoplasia using a cold-knife section technique

OBJECTIVE: The purpose of this study was to evaluate a conservative cold-knife section technique for treatment of cervical intraepithelial neoplasia (CIN). This procedure can be adapted to patient age, preservation of childbearing potential and extent of dysplasia. DESIGN: Prospective study. SETTING: Gynecological Oncology Department in French Public Hospital. POPULATION: A total of 460 women treated for CIN between 1985 and 1999 were included. METHODS: A conservative cold-knife cervical section followed by blanket suture reconstruction was used in all cases. MAIN OUTCOME MEASURES: Immediate operative results, recurrence and reproductive function were assessed. RESULTS: The mean length of the cervical specimen was 11.4 mm (range, 4-22 mm). Mean specimen thickness was strongly correlated with age: 10.6 +/- 4.1 mm in women <40 years versus 12.1 in women >40 years; p < 0.001. Complete excision was achieved in 395 cases (85.8%). Post-operative bleeding was observed in 5 cases (1.1%). The mean duration of follow-up was 62 months (range, 12.3-156.5 months). Recurrences developed in 26 patients (6.6%) including CIN 1 in 9 cases, CIN 2 in 9 and CIN 3 in 8. No patient developed carcinoma. The actuarial risk of recurrence was 2.4% (+/- S.D., 0.9) at 24 months and 7.8% (+/-S.D., 1.9) at 60 months. A total of 52 pregnancies were observed in 39 patients. No case of de novo infertility was reported post-operatively. Amenorrhea was noted in 1 patient (0.1%) and dysmenorrhea in 1 patient (0.1%). CONCLUSIONS: This conservative cold-knife section technique is effective for treatment of CIN with low morbidity and little adverse effect on childbearing potential. Exposure of the squamocolumnar junction (SCJ) greatly facilitates follow-up.     

Risk factors for forceps delivery in nulliparous patients

OBJECTIVE: To identify risk factors for forceps delivery during first pregnancy. MATERIALS AND METHODS: A retrospective case-control study was carried out in a tertiary maternity ward between January 2001 and December 2003. A total of 582 nulliparous women, with full-term (>37 weeks gestation), singleton, cephalic pregnancies, who delivered by the vaginal route with or without instrumental assistance were evaluated. RESULTS: The strongest risk factors for forceps delivery were birth weight greater than 4000 g (OR: 6.5; 95% CI: 1.6, 26.9), the occiput posterior position of the fetal head (OR: 5.8; 95% CI: 2.5, 13.8), and epidural analgesia (OR: 7.7; 95% CI: 4.1, 14.7). Other significant risk factors for forceps delivery were age over 35 years (OR: 2.4; 95% CI: 1.1, 5.1), induction of labor (OR: 2.1; 95% CI: 1.4, 3.1), first stage of labor longer than 420 min (OR: 2.3, 95% CI: 1.3,4.2), and a prolonged second stage of labor (OR: 1.6, 95% CI: 1.1, 2.4). CONCLUSION: Age over 35 years and induction of labor are risk factors for forceps delivery at admission. Epidural use, fetal head in occiput posterior position, and birth weight >4000 g are strong intrapartum risk factors for instrumental delivery in nulliparous women.     

Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential

Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.