Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer.

PURPOSE: Urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor (PAI)-1, have been shown to be related to poor prognosis in a variety of malignant solid tumors. Studies on the prognostic relevance of uPA and PAI-1 in ovarian cancer, however, have been inconclusive. The current study tests the hypothesis that elevated expression of uPA and PAI-1 is associated with prognosis and disease progression. EXPERIMENTAL DESIGN: uPA and PAI-1 were prospectively measured by quantitative ELISA in tumor samples from 103 ovarian cancer patients (82 primary invasive epithelial carcinomas, 9 low malignant potential tumors, and 12 recurrent ovarian carcinomas). RESULTS: uPA but not PAI-1 levels were consistently associated with malignant progression, with levels increased from low malignant potential tumors to primary tumors (uPA, P = 0.04; PAI-1, P = 0.019), from early to advanced disease stages (uPA, P = 0.014; PAI-1, P = 0.23), and from primary to intra-abdominal metastatic tumors (uPA, P = 0.001; PAI-1, P = 0.16). High uPA and PAI-1 levels were associated with residual tumor volumes of >1 cm (P = 0.001 and P = 0.016, respectively). Among invasive International Federation of Gynecologists and Obstetrician stages I-IV tumors, elevated levels of uPA (>5.5 ng/mg) and PAI-I (>18.8 ng/ml) were associated with a shortened progression-free survival (uPA, P = 0.003; PAI-1, P = 0.039) and overall survival (uPA, P = 0.0002; PAI-1, P = 0.007). In multivariate analysis, uPA retained prognostic independence for progression-free survival (P = 0.037) and overall survival (P = 0.006). CONCLUSIONS: These data suggest that the uPA/PAI-1 axis may play an important role in the intra-abdominal spread and reimplantation of ovarian cancer cells. The prognostic relevance of uPA and PAI-1 supports their possible role in the malignant progression of ovarian cancer.

Her-2/neu and urokinase-type plasminogen activator and its inhibitor in breast cancer.

PURPOSE: Recent studies suggest that HER-2/neu specifically promotes the invasive capacity of tumor cells by up-regulating secretion of the proteolytic enzyme, urokinase-type plasminogen activator (uPA), or its inhibitor, plasminogen activator inhibitor-1 (PAI-1), in colon and gastric cancer. It was the purpose of this study to: (a) evaluate the association between HER-2/neu and uPA and PAI-1 expression in a large primary breast cancer cohort; (b) perform the first multivariate analysis, including HER-2/neu, uPA, and PAI-1 in breast cancer; and (c) define the effect of HER-2/neu overexpression on uPA and PAI-1 expression in breast cancer cells. EXPERIMENTAL DESIGN: HER-2/neu, uPA, and PAI-1 were measured as continuous variables by ELISA in primary breast cancer tissue extracts from 587 patients with clinical follow-up and analyzed for correlations with clinical outcome. Furthermore, a full-length human HER-2/neu cDNA was introduced into five human breast cancer cell lines to define the effects of HER-2/neu overexpression on uPA and PAI-1 expression. In addition, we tested whether HER-2/neu antibodies could reverse any given alteration of uPA and PAI-1 levels. RESULTS: Our findings indicate a weak positive association between HER-2/neu and uPA (r = 0.147; P < 0.001) and no association between HER-2/neu and PAI-1 (r = 0.07; P = 0.085). HER-2/neu overexpression (> or =400 fmol/mg) and high levels of uPA/PAI-1 (> or =5.5 ng/mg and/or > or =14 ng/mg, respectively) were significantly associated with shorter disease-free survival (DFS; P < 0.001 and P = 0.003) and metastasis-free survival (MFS; P = 0.015 and P < 0.001). Multivariate analysis revealed prognostic independence between HER-2/neu and the uPA/PAI-1 axis for DFS and MFS. Both uPA and PAI-1 had no significant discriminatory effect among HER-2/neu-positive patients for DFS. The prognostic value of HER-2/neu overexpression for MFS, however, was significantly enhanced by elevated uPA expression (P = 0.053). Stable transfection of the HER-2/neu gene into multiple human breast cancer cell lines resulted in consistent down-regulation of uPA or PAI-1 expression. In addition, anti-HER-2/neu antibodies did not significantly affect uPA or PAI-1 expression in human cancer cell lines naturally overexpressing HER-2/neu. CONCLUSIONS: The present findings suggest that the invasive phenotype elicited by HER-2/neu overexpression in breast cancer is not a direct effect of uPA or PAI-1 expression. HER-2/neu and the uPA/PAI-1 axis have been shown to affect the invasive capacity of breast cancer independently. Determination of uPA can provide significant additional prognostic information for MFS in HER-2/neu-positive and -negative patients.

[Contraception in young adolescents]. / Schwangerschaftspravention bei jungen Patientinnen.

The continuing increase in teenage pregnancies and abortions calls for more effective sex education on the one hand, including a detailed explication of the (perfectly normal) changes an adolescent body is undergoing, but we also need to understand the way teenagers actually do use contraceptives. Modern contraception for teenagers should not cause any side effects and its efficacy must not be linked to compliance. Gynaecologists must acquaint themselves with the laws covering the prescription of contraceptives to adolescents. Whether hormonal contraceptives for men are also suitable for teenage boys remains to be seen. Advising mentally or physically handicapped teen-agers or those with chronic diseases on their contraceptive options is particularly challenging. Adolescents are more prone to contract HPV infections and thus need to be screened, counselled and told about the association between HPV and cervical dysplasia.

Cancer in pregnancy: maternal-fetal conflict.

The occurrence of malignancies during pregnancy has increased over the last decades. They complicate approximately 1 per 1000 pregnancies. The most common malignancies associated with pregnancy include malignant melanoma, malignant lymphomas and leukemia, and cancer of the cervix, breast, ovary, colon and thyroid. Since it is impossible for prospective randomized clinical trials to be conducted in this field, relevant data have been generated from case reports and matched historical cohort studies in order to evaluate the treatment outcomes and the issues complicating the management of malignancy in the pregnant patient. There is almost always a conflict between optimal maternal therapy and fetal well-being. The maternal interest is for an immediate treatment of the recently diagnosed tumor. However, the optimal therapy, be it chemotherapy, radiotherapy or surgery, may impose great risks on the fetus. Consequently, either maternal or fetal health, or both, will be compromised. Therefore, both the pregnant patient and her physician are often in a dilemma as to the optimal course. On the basis of the medical facts, we discuss the issues raising potential ethical conflicts and present a practical ethical approach which may help to increase clarity in maternal-fetal conflicts. We review the available data informing the incidence and impact of the most common malignancies during pregnancy and their treatment on both the pregnant woman and her fetus. The optimal therapy for the tragic diagnosis of cancer in pregnancy requires a collaborative and interdisciplinary approach between gynecologists, oncologists, obstetricians, surgeons, neonatologists, psychologists, nursing staff and other disciplines. The purpose of this article is not to answer specific questions or to construct management schemes for specific tumors but to provide a framework for approaching some of these complex issues.

DNA cell-cycle analysis of cervical cancer by flow cytometry using simultaneous cytokeratin labelling for identification of tumour cells.

DNA ploidy and cell-cycle distribution were determined by flow cytometry in fresh tumour tissue of 53 cervical carcinomas. Epithelial cells were labelled by a fluorescein-isothiocyanate-conjugated cytokeratin antibody (CK6, CK18) to study the influence of contaminating stromal and inflammatory cells on results of cell-cycle analysis of tumour cells. Without identification of cytokeratin-positive cells 30/53 (57%) tumours were found to be DNA-aneuploid compared to 43/53 (81%) after gating for cytokeratin. Only 7 of 15 DNA-multiploid tumours could be detected without cytokeratin staining. In addition, cytokeratin-negative cells, which are found in all tumours, can be used as an internal standard for the calculation of ploidy and for quality control (coefficient of variation, linearity) of each individual sample. Cell-cycle analysis revealed significantly higher S-phase and G2M-phase fractions in cytokeratin-gated compared to ungated samples (13.1% versus 10.0% and 8.0% versus 5.4%; P < 0.001). This difference was more pronounced in DNA-diploid than DNA-aneuploid tumours. In conclusion, about 30% of DNA-aneuploid tumours could only be detected after cytokeratin labelling of epithelial cells. Owing to the identification of cytokeratin-positive cells the influence of non-tumoural cell elements on cell-cycle analysis was reduced markedly. Therefore, in cervical cancer, cytokeratin labelling can optimize both the determination of DNA ploidy and cell-cycle analysis.

The Stroop effect in schizophrenic patients.

Schizophrenic patients (n = 44) and normal controls (n = 50) performed a computerized version of the Stroop color-word interference task. Schizophrenic patients generally showed more Stroop interference than normal subjects. The effect was neither related to demographic variables, nor to actual psychopathology. However, the course of the disorder was related to the Stroop effect, in that acute, chronic, and schizoaffective patients displayed a larger interference effect than patients with a recurrent episode. From a methodological perspective, the computerized version of the Stroop task proved to be more sensitive to interference effects in the patient group. The finding of enhanced reverse Stroop interference in patients strongly preoccupied with colors is discussed within the framework of MacLeod and Dunbar's (MacLeod and Dunbar, 1988) theory of Stroop interference involving differential practice effects.

Carboplatin/etoposide as first-line chemotherapy in advanced ovarian carcinoma: a pilot study.

In a pilot study, 18 patients with advanced ovarian cancer were evaluated for tolerance and response to a combination treatment with a fixed dose of carboplatin (350 mg/m2 given i.v. on day 1) and escalated doses of etoposide (70-130 mg/m2 daily given i.v. on days 1-3) as first-line chemotherapy. The maximum tolerated dose of etoposide was 130 mg/m2 when given i.v. on days 1-3 in combination with 350 mg/m2 carboplatin given i.v. every 4 weeks. At these dose levels, bone marrow toxicity was manageable and did not appear to be cumulative. In all, 12 objective responses, including 9 complete responses (CRs) and 3 partial responses (PRs), were achieved in 18 patients; 6 of the 9 CRs were confirmed as pathological CRs by second-look surgery.

Fertility after organ-preserving surgery of ectopic pregnancy: results of a multicenter study.

OBJECTIVE: To evaluate the postoperative fertility rate after ectopic pregnancy (EP) and to compare the impact of different surgical techniques. DESIGN: Prospective, multicenter trial. SETTING: Twenty-five centers with microsurgical facilities. PATIENT(S): A total of 1,025 patients with EP were enrolled between 1984 and 1990. INTERVENTION(S): Organ-preserving operation and at least one patent remaining tube. Evaluation of postoperative outcome by standardized questionnaires. MAIN OUTCOME MEASURE(S): Postoperative fertility in terms of pregnancy rate (PR) and recurrent ectopic implantation. RESULT(S): The PR was similar after wedge resection (45.9%) and salpingotomy or milk out (42.0%). The recurrence rates did not differ between both groups (7.5% versus 8.2%). In patients with a blocked or absent contralateral tube, the PR was poor (31.2%), and the recurrence rate of EP was high (16.0%), indicating that most pregnancies are achieved through the contralateral tube. CONCLUSION(S): The postoperative fertility rate after an EP is reduced. The type of surgery usually has no significant impact. In the case of a blocked or absent contralateral tube, the patient must be informed about the significantly reduced fertility rate and the elevated risk for EP recurrence.

Experimental anastomosis of the rabbit fallopian tube using fibrin glue.

Experimental end-to-end anastomosis was performed in 20 rabbits with biologic tissue adhesive allogenic fibrinogen, after removal of 1 to 2 cm of the isthmus. A standardized insemination procedure was undertaken to achieve pregnancies in the animals upon which operations were performed. Without any intervention, the fertility rate was 80% after repeated inseminations in ten nonexperimental rabbits. After anastomosis of the fallopian tube using fibrin glue, the patency rate was 75% (30 of 40 fallopian tubes), and the subsequent pregnancy rate was 60% (12 of 20 animals). No spontaneous recanalization nor subsequent pregnancy was observed in the control group after removal. Histologic findings demonstrated mild to moderate tissue reactions, comparable to those observed when microsutures were used.

Chemosensitivity testing in gynecologic oncology--dream or reality?

Cell culture and animal models have played an essential role in the research of new principles of therapy. Many methods for the individualized testing of therapy sensitivity and resistance have been developed, for example, the clonogenic assay. Presently, the ATP-TCA is commercially available as a testing kit. This review gives an overview of the tumor samples that were tested in the oncologic laboratory in the Department of Obstetrics and Gynecology, Munich Grosshadern between 1993 and 2001. All target parameters show a clear trend in favor of sequential, dose-intensified Epirubicin/Paclitaxel therapy. If this trend remains valid for the total number of patients, a significant impact of this new principle of therapy can be expected. By individualized planning of therapy with ATP-TCA testing, therapy in the individual patient could already be performed by the examination of sensitivity in the preoperative biopsy specimen.

Low-dose FSH stimulation in polycystic ovary syndrome: comparison of 3 FSH-preparations.

In patients with PCOS low dose administration of follicle stimulating hormone is accepted as a safe treatment modality with low risk for an ovarian hyperstimulation syndrome or a multiple pregnancy. In this study we have retrospectively compared the efficacy of 3 different FSH preparations in low dose protocols-urinary FSH (FSH), highly purified urinary FSH (FSHHP) and recombinant FSH (rec. FSH). A total of 68 PCOS-patients, 36 lean and 32 moderately obese patients, were treated in 116 stimulation cycles. The mean age did not differ between the groups. A mean number of 1.7 cycles per patient was performed. PCOS was diagnosed in all patients by hormonal and sonographic means. Treatment was performed with daily injections of one ampoule FSH from day 3 onwards. Ovulation was induced with 10,000 IU HCG, when the leading follicle exceeded 16 mm in diameter and no more than 3 follicles were seen. The rate of monofollicular cycles was lowest in obese patients after FSHHP stimulation (30%) and after rec. FSH (66.6% in lean and 58.3% in obese patients, respectively). The number of FSH ampoules did not differ significantly between the groups. No severe hyperstimulation syndrome was registered. 21 pregnancies were achieved without significant differences between the different FSH preparations. Besides two abortions and one ectopic implantation, 12 pregnancies were ongoing singleton pregnancies, 3 twin pregnancies and 3 sets of triplets were noted. In conclusion, low-dose stimulation with FSH offers a safe and successful treatment option in patients with PCOS with an acceptable risk for multiple gestations.

Dose-dense and sequential strategies in adjuvant breast cancer therapy.

Several attempts have been made to improve the survival rates of breast cancer patients. The benefit of adjuvant chemotherapy was clearly shown, but the absolute difference of 2% to 11% in overall survival, depending on the patient group, is disappointingly small. In particular, high-risk patients, such as those with > or = 10 involved lymph nodes, extracapsular spread, or vascular invasion, still have an excessive risk of recurrence even after standard adjuvant chemotherapy. To increase the survival rates after adjuvant therapy, new chemotherapeutic agents and new strategies of application are currently being evaluated in clinical trials. Chemotherapy with cyclophosphamide (Cytoxan, Neosar), methotrexate, and fluorouracil (CMF) seems to be safe and effective in patients with breast cancer. In addition, in metastatic patients, dose-intensified chemotherapy is being investigated. The introduction of epirubicin (Ellence), an agent less cardiotoxic and equally active compared to doxorubicin, enabled the escalation of anthracyclines in adjuvant therapy without serious cardiotoxic effects. The combination of dose-intensified chemotherapy and sequential application in the treatment of breast cancer is reviewed.

Experimental animal model for readhesion formation study.

The problem of postoperative adhesions remains unsolved. The formation of readhesions after tubal reconstructive surgery reduces the success rate. We have developed a modified uterine horn model in the rat to study the influence of peritoneal transplants on readhesion formation. A total of 58 rats were operated. In 25 animals (group III) the uterine horn was scratched on both sides and then sutured together. During relaparotomy 14 days later the tight connection between both sides was cut. The resulting defect was covered by a peritoneal transplant on one side (group IIIb) and was left open on the control side (group IIIa). After 14 days the presence or absence of adhesions was explored. There was a significant difference (p < .001) between the covered (28%) and uncovered (84%) peritoneal defects with respect to incidence of adhesions. To compare the different characteristics of visceral and parietal peritoneum, a pelvic sidewall defect was induced in 33 animals. There was no significant difference between covering the defect by a peritoneal transplant (group II; 42.9%) and the control side (group I; 33.3%). These data suggest that defects on visceral peritoneum should be closed to prevent adhesion formation. The incidence of adhesions after injury of parietal peritoneum seems to be much lower and of less clinical significance.

Prenatal diagnosis of congenital heart disease and neonatal outcome--a six years experience.

BACKGROUND: Prenatal diagnosis of congenital heart disease (CHD) is important for proper perinatal and neonatal management, as CHD occurs in approximately eight of 1000 live births. Antenatal detection of cardiac malformations is crucial as altered obstetric and neonatal management may be required and the neonate will benefit from delivery at a tertiary care center. METHODS: A retrospective comparison between pre- and postnatal diagnoses was accomplished. All fetal echocardiographic scans performed and CHD's detected postnatally between January 1994 and December 1999 by the department of obstetrics and gynecology and pediatric cardiology - Grosshadern, Munich University Hospital were reviewed. RESULTS: The incidence of CHD was 1.5% (116/ 7913). CHD was suspected by prenatal ultrasound in 57 fetuses. Postnatally, 116 congenital cardiac anomalies were diagnosed. Overall, the intrauterine detection rate was 38% (44/116). 72% (84) of the diagnosed anomalies were Septal Defects, 16% (19) disorders of the Atrioventricular Valves and 11% (13) Anomalies of the Great Vessels. In 10% (11) of fetuses chromosomal abnormalities were found. 8% (9) newborns suffered from congenital syndromes. In 55% (64) children were delivered preterm (<37 weeks of gestation). 5% (6) of the neonates required surgery within their first year of life. 28% (33) of children with CHD did not survive the first year of life. CONCLUSION: As the prenatal diagnosis is important for pre-, peri- and postnatal management, diagnostic accuracy is essential. Nevertheless, the accuracy of postnatal pediatric echo still exceeds that of the prenatal scan.

Low-dose follicle stimulating hormone for ovulation induction in polycystic ovary syndrome.

In 20 patients with clinically, sonographically and endocrinologically proven polycystic ovary syndrome, ovulation induction with low doses of follicle stimulating hormone (FSH) was attempted by administration for 27 menstrual cycles. One ampule FSH was administered from day 3 onwards. If the ovarian response was inadequate after days 10-12, the daily FSH dose was increased by half an ampule until ovulation induction. Of the cycles, 55.5% were monofollicular, whereas 4 cycles had to be cancelled due to a multifollicular response or failure of ovarian stimulation. On average, 14.4 ampules was used, and human chorionic gonadotropin was given on day 16. Seven pregnancies were established, with all of them ongoing at this writing. One twin pregnancy and one triplet pregnancy occurred. Even in polycystic ovary syndrome patients, low-dose administration of FSH allows safe stimulation, with a low incidence of ovarian hyperstimulation, a high pregnancy rate and an acceptably low risk of multiple pregnancies.

[Aporia of prenatal medicine]. / Aporie der Pränatalmedizin.

Prenatal medicine touches upon elementary questions of the quality of life - of the mother as well as of the unborn child and of the physician. In essence, it is always about the determination of human worth by human beings. Each prenatal care examination is a measure of prenatal medicine. Prenatal medicine has gained today, and rightly so, a high and positive position in obstetrics and within our society. Without a doubt however, the advancements of prenatal medicine have also awakened demands and desires. We are increasingly faced with the 'demand for a healthy child'. In the ethical evaluation, intrauterine diagnostic measures are questionable as long as no intrauterine therapy is possible and only the killing of the child follows as 'therapy'. The contents of the 'indication', especially with respect to what can reasonably be demanded from the mother or the parents, are discussed with respect to liability law - 'the child as damage'. The reform of 218 StGB (German criminal law code) has provoked, among other issues, the pre- and postnatal problem of iatrogenic preterm birth. The ever present question is becoming more transparent with the liveborn sick child, which should have actually died, i.e. why instead the life of this child suddenly assumes the full legal protection so that active handling is replaced by passiveness. The two-facedness of prenatal medicine appears even more clearly when picturing the current political discussions concerning what is newly feasible in prenatal medicine, namely preimplantation diagnostics.

[Child and adolescent gynecology. Introduction to the focal topic 'Child and adolescent gynecology']. / Kinder- und Jugendgynäkologie. Einführung zum Schwerpunkt <>.

Valuable knowledge from the subspecialty of child and adolescent gynecology is of considerable importance for the clinically active pediatrician and gynecologist. Focal topics such as sexual violence to children and young adults, undesired pregnancies and pregnancy termination should not only be made known in the media, but also to specialists, so that successful prevention and treatment can be carried out. Furthermore, endocrinological problems and genital malformations in adolescence should be detectable and treatable.

[Breast diagnosis: new acquisitions and developments]. / Mammadiagnostik: Neue Erkenntnisse und Entwicklungen.

The development and refinement of breast diagnosis have increased the significance of breast ultrasound, have led to the establishment of mammographic classification criteria (BI-RADS) and to the standardisation of the terminology used for reporting the results and thus its codification. Targeted stereotactic biopsies (Mammotome and SiteSelect) have become established methods of pretreatment diagnosis.

[Cesarean section on demand or elective. Cesarean section: request for rethinking]. / Sectio nach Wunsch oder elektive. Sectio: Aufforderung zum Umdenken.

Nowadays, the mortality and morbidity of caesarean section, particularly elective caesarean section, are hardly different from those of vaginal delivery. 'Section on request' is so extremely rare that it is of no importance and that these terms should not be used at all. A change in thinking is necessary because only real misgivings make the pregnant woman wish for this procedure. In this context, the increasing importance of autonomy and the right to self-determination of the woman lead to a fundamental shift in the relationship between doctor and patient. Long-term sequelae after vaginal delivery, e.g. injury to the pelvic floor with functional impairment and disturbances of sexual function, but also considerations about the safety of the child become more and more important for the pregnant woman and have to be taken seriously by the physician. Although there are no precise bases for assessment, a global comparison of costs between vaginal delivery and elective caesarean section with regard to the long-term sequelae will hardly show any true differences, and therefore the health insurances are not entitled to refuse the reimbursement of costs.

[Must the postgraduate medical training for specialists of gynecology and obstetrics be reconsidered?]. / Muss die Weiterbildung zum Facharzt Gynäkologie und Geburtshilfe in der Schweiz überdacht werden?

Our specialty is based on a 3-pillared concept. The professional political development again requires a discussion on the separation of 'nonoperating' and 'operating' specialists. In addition, the future model of the 'gynecologist as family doctor for women' becomes an interesting topic. The guidelines for the proceedings in the case of suspect and positive cytological smears of the cervix have been revised with regard to the Bethesda nomenclature and will be published this year.