Prostacyclin deficiency and reduced fetoplacental blood flow in pregnancy-induced hypertension and preeclampsia.

BACKGROUND: Low endothelial generation of prostacyclin (PGI(2)) is a typical feature of pregnancy-induced hypertensive disorders. The aim of the current study was to establish whether changes in PGI(2) are accompanied by alterations in fetoplacental blood flow and to test the hypothesis that PGI(2) deficiency contributes to reduced fetoplacental perfusion in pregnancy-induced hypertension (PIH) and preeclampsia. METHODS: The study included 11 women with normal pregnancies, 12 with PIH/preeclampsia, and 7 with otherwise complicated pregnancies. Fetoplacental blood flow was assessed both by umbilical artery Doppler sonography measuring the resistance index (RI) and by means of neonatal birth weight. PGI(2) formation was measured in umbilical arteries prepared immediately after birth. PGI(2), RI and birth weight were correlated with and without correction for gestational age. Furthermore, data from patients with PIH/preeclampsia were compared with normal pregnancies as controls. RESULTS: A significant inverse correlation was found between umbilical PGI(2) formation and umbilical RI and between birth weight and RI, whereas PGI(2) and birth weight were directly related. Patients with PIH/preeclampsia showed reduced PGI(2) formation, markedly increased gestational age-corrected RI and significantly reduced percentile birth weight. CONCLUSIONS: These results provide evidence showing that PGI(2) is a relevant mediator of fetoplacental blood flow and suggest an important role of PGI(2) deficiency in PIH/preeclampsia.

Reliability and clinical application of fetal RhD genotyping with two different fluorescent duplex polymerase chain reaction assays: three years' experience.

OBJECTIVE: This study was designed to evaluate accuracy and clinical usefulness of fetal RhD genotyping with fluorescent duplex polymerase chain reaction. STUDY DESIGN: Two RhD-specific gene fragments (exon 10 in polymerase chain reaction 1 and exon 7 in polymerase chain reaction 2) were amplified in samples from 213 fetuses. RESULTS: Amplification failed in 0.9% of the specimens, and equivocal results were found in 1.4% of the specimens. Of the analyses, 6.6% had to be repeated. The concordance of genotyping and serotyping was 99.0% for each polymerase chain reaction. False-positive results were noted in 4 fetuses. Concordant findings from both assays indicated the correct serotype for all fetuses. In 44 alloimmunized pregnancies, further invasive procedures were avoided for 5 of the 6 genotypically RhD-negative fetuses. Only two of 38 RhD-positive fetuses had a hemoglobin level <8 g/dL at first fetal blood sampling. CONCLUSIONS: Fetal genotyping at distinct regions of the RhD gene is reliable and improves the care management of sensitized women.

Interstitial pregnancy treated with local and systemic methotrexate.

We present a case of an intact interstitial pregnancy at 6 postmenstrual weeks and 4 days, which was successfully treated by combined local and systemic methotrexate administration. The embryonic cardiac activity stopped within 1 min after uneventful ultrasound-guided puncture and methotrexate instillation of the chorionic sac. While the beta-hCG serum values returned to normal 59 days after local, and 52 days after systemic treatment, the echogenic lesion has reduced in size by 50%, but is still sonographically detectable 7 months after the procedure. This report shows that medical treatment of interstitial pregnancy may be an effective alternative to the surgical approach.

[Measuring bone density with ultrasound osteodensitometry--results of a pilot study]. / Knochendichtemessung mittels Ultraschallosteodensitometrie--Ergebnisse einer Pilotstudie.

Osteoporosis is a systemic bone disease with a decrease in bone structure and increased risk of fractures. The primary diagnosis of osteoporosis and the surveillance of therapeutic interventions is based either on laboratory or on radiological diagnosis. In a pilot study encompassing 274 women the routine use of ultrasound osteodensitometry (QUS, Lunar Achilles) of the os calcaneus was validated and tested. Velocity of the ultrasound signal (SOS) and frequency attenuation (BUA) were measured and the proprietary index stiffness calculated. In 47 women ultrasound data were compared with the DXA measurements. Results from both methods correlated significantly. Postmenopausal patients with HRT had significant better QUS values than those without HRT. Results from both diagnostic methods (QUS versus DXA) correlated significantly. Women with HRT showed significantly increased bone measurements compared to those without HRT. This correlated with an increase in bone metabolism. QUS of the os calcaneus was easy to perform, without time spent or inconvenience for and with high acceptance by the volunteers/patients. The conformity of the results of the different methods (DXA, QUS) may--if the follow up study confirms these results--lead to a routine use of QUS for screening and therapy monitoring.

[Considerations in rational use of tumor markers in breast carcinoma]. / Uberlegungen zum rationellen Einsatz von Tumormarkern beim Mammakarzinom.

The objective of this review is to determine clinical practical guidelines for the use of serum tumor markers in the care of breast cancer patients outside of clinical trials. Mucin antigens (CA 15-3, MCA, CA 549) and CEA are established markers in breast cancer. Owing to their low sensitivity, none of these markers can be recommended for screening, diagnosis or staging. During follow-up, increasing marker levels may indicate recurrence 3-6 months earlier than clinical and radiological examinations in about 40-50% of patients. However, the clinical benefit of this lead-time is not established. Tumor markers are able to monitor response to treatment in 70-80% of patients with metastatic breast cancer. However, paradoxical changes of the markers especially in the beginning of treatment, the insufficient concordance with tumor activity in 20-30% of the women, and the lack of curative therapy regimens limit the prospective clinical use of the markers in the individual patient. Therefore, marker changes require confirmation by radiological methods in most cases. The present data are insufficient to recommend routine use of tumor markers alone for monitoring breast cancer patients after primary treatment or during palliative therapy. However, in the absence of readily measurable disease (e. g. bone metastases) continuously increasing marker levels may be used to indicate treatment failure. If high-dose chemotherapy in metastatic breast cancer renders to be effective, the clinical impact of tumor markers will increase considerably. Until that time, the analytical performance and the sensitivity of the established marker assays should be improved, and the clinical role of newer marker tests (TPS, CA 27.29) should be evaluated.

Estimation of probability of malignancy using a logistic model combining physical examination, ultrasound, serum CA 125, and serum CA 72-4 in postmenopausal women with a pelvic mass: an international multicenter study.

BACKGROUND: To assess the differential diagnostic potential of physical examination, ultrasound, the serum CA 125 assay, and serum CA 72-4 assay, and the contribution of each parameter to a logistic model predicting the probability of malignancy in postmenopausal patients presenting with a pelvic mass. PATIENTS AND METHODS: In a multicenter, prospective study a total of 155 patients were evaluated preoperatively using a standard protocol for pelvic examination, transvaginal (occasionally additional abdominal) ultrasound, and serum CA 72-4 (cutoff level 3 U/ml) and CA 125 (cutoff level 35 U/ml). RESULTS: Fifty-nine malignant (39%) and 92 benign (61%) pelvic tumors were found in addition to 4 borderline tumors (3%). Forty-three patients appeared to have ovarian carcinoma, FIGO Stage III or IV in 28 cases. Borderline tumors were excluded from the statistical calculations. The diagnostic accuracy of each single parameter, i.e., pelvic examination, ultrasound, and serum CA 125 and CA 72-4 in discriminating between benign and malignant pelvic masses gave highly similar results (81, 76, 78, and 81% respectively). Best sensitivity was found in pelvic examination (92%); best specificity was found in CA 72-4 (93%). Using logistic regression analysis the power of pelvic examination appeared to be the most relevant (adjusted odds ratio 12.1), followed by ultrasound (odds ratio 9.7), serum CA 125 (odds ratio 5.0), and serum CA 72-4 (odds ratio 4.9). Age appeared to be nonpredictive. The logistic model gives a correct prediction in 87% of all cases. CONCLUSIONS: The addition of serum CA 72-4 to the combination of pelvic examination, ultrasound, and serum CA 125 leads to an improved discrimination between malignant and benign pelvic masses.

Constriction of an extremity after amnioreduction in a TRAP-like sequence.

We present an unusual case of TRAP sequence (twin reversed arterial perfusion) with persistent polyhydramnios despite spontaneous thrombosis of the vena umbilicalis of the acardius. Serial amnioreduction was performed owing to considerable maternal discomfort and preterm labor. After three procedures, spontaneous abortion occurred. Unexpectedly, the normal twin had an apparently recent constriction of the right forearm. We hypothesize that limb constriction could be a rare but specific complication of aggressive amnioreduction.

Fetal Rhesus D genotyping on amniocytes in alloimmunised pregnancies using fluorescence duplex polymerase chain reaction.

OBJECTIVE: 1. To establish the reliability of fetal amniocyte Rhesus D (RhD) genotyping using fluorescence duplex polymerase chain reaction (PCR) and 2. to assess the potential clinical impact on management of alloimmunised pregnancies. DESIGN: Multicentre observational study. SETTING: Four departments of obstetrics and gynaecology in Germany. METHODS: Fourty-four amniotic fluid samples were obtained by amniocentesis from a retrospective group of 27 RhD alloimmunised pregnancies and 15 samples from 14 women treated prospectively. Two RhD gene specific fragments (exon 7 and 10) were amplified using two separate fluorescence duplex PCR assays, and laser detected in an automated DNA sequence analyser. RESULTS: Amplification of the Rh gene sequences was successful in all samples. PCR at the two RhD gene regions resulted in complete concordance. Genotyping correctly predicted the RhD status of all fetuses serotyped (n = 41). After intrauterine transfusions, PCR identified the RhD type of two fetuses more accurately than serotyping. Earlier knowledge of a negative RhD status would have rendered unnecessary 12 amniocenteses in four fetuses of the retrospective study group, and prevented further invasive testing in one fetus treated prospectively. In the latter group, women with a positive fetal RhD genotype underwent intensive prenatal care including serial invasive monitoring and intrauterine treatment. CONCLUSIONS: Fetal RhD genotyping of amniocytes is a reliable technique with the potential to improve routine management of alloimmunised pregnant women.

Early cancer detection programmes for women at high risk for breast and ovarian cancer: a proposal of practical guidelines.

Women from families with multiple breast and/or ovarian cancers may be at increased risk to develop breast/ovarian cancer themselves. Due to personal experience with family members having these diseases they are anxious and ask for specific prophylactic measurements or treatment. The detection of two susceptibility genes, BRCA1 and BRCA2, has given insight into the genetic background of part of the familial breast/ovarian cancer syndromes. This has led to an increased demand in genetic counselling, testing, and early cancer detection programmes. Prospective data from early cancer detection programmes in this high risk population are yet not available. Based on data from epidemiological risk studies, breast and ovarian screening programmes and follow up data from breast cancer trials recommendations for an early cancer detection programme have been summarized. At the present these recommendations are tested in a prospective trial.

Metastatic choriocarcinoma in a postmenopausal woman.

Trophoblastic disease is usually related to pregnancy and occurs in about 1 in 1300 pregnancies in Western countries. Since the advent of methotrexate therapy, trophoblastic tumors have become one of the most curable malignancies. Trophoblastic disease can develop independently of gestation, but this is very rare. We report the unusual case of a 58-year-old woman who had a metastatic choriocarcinoma 6 years after menopause and 29 years after her last pregnancy. The tumor proved to be primarily resistant to monochemotherapy and developed chemoresistance to three different polychemotherapeutic regimens. Eleven months after the diagnosis of uterine choriocarcinoma the patient died from advanced metastatic disease.

Comparative prognostic value of Cathepsin D and urokinase plasminogen activator, detected by immunohistochemistry, in primary breast carcinoma.

The lysosomal protease Cathepsin D and the serine protease urokinase plasminogen activator (uPA) are suspected to indicate poor prognosis in primary breast carcinoma. We tested Cathepsin D and uPA immunohistochemically in 281 surgical specimens of primary ductal infiltrating breast carcinomas. Staining was evaluated, taking intracytoplasmic immunoreactions into account, in tumour cells and tumour infiltrating macrophages. Positivity was established in 48.4% and 58.0% of tissue samples for cathepsin D and uPA respectively (co-expression: 67.6%). In patients with cathepsin D- or uPA-positive tumours, relapses were more frequent and disease-free survival was shorter irrespective of nodal status, receptor status or menopausal status, (median observation time 74 months). However, this trend was statistically significant only for cathepsin D. With stepwise cox regression analysis, borderline significance (p = 0.07) was calculated for cathepsin D only in node-negative patients. The combination of cathepsin D with uPA measurements did not enhance its prognostic value. Immunohistochemical detection of Cathepsin D could potentially be used to identify patients with poor prognosis in the group of node negative breast cancer patients.

Relationship between amniotic fluid insulin and maternal blood glucose concentrations in patients with carbohydrate intolerance during pregnancy.

In contrast to maternal blood glucose, amniotic fluid insulin (AFI) directly reflects the functional state of the fetal pancreas. In a prospective study we evaluated the correlation of AFI with maternal metabolic control in 70 amniotic fluid specimens from 61 women having carbohydrate intolerance during pregnancy (White A n = 44, B0 n = 17). AFI was measured with the Insulin RIA 100 kit from Pharmacia (Freiburg). The normal range of AFI was established in 304 healthy pregnant women (16th-42nd gestational week). AFI concentrations increased by a factor of 1.5 to 2 during gestation reflecting the maturation of the fetal pancreas. Elevated AFI levels (> 97th centile) were found in 11% of normoglycemic diabetics and in 50% of women with insufficient metabolic control. Despite a high overall concordance (81%) no direct relationship could be found between fetal and maternal parameters. Patients with increased AFI values had a 5-fold higher rate of large-for-gestational age (LGA) infants than women with normal levels. This finding confirms the pathogenetic role of hyperinsulinism in the development of fetal macrosomia.

Prognostic value of cathepsin D in breast cancer: comparison of immunohistochemical and immunoradiometric detection methods.

AIM: To test whether immunoradiometric or immunohistochemical detection of lysosomal protease cathepsin D in breast cancer is more predictive of outcome. METHODS: Tumour tissues from 270 primary breast cancer patients were evaluated for the expression of cathepsin D using immunohistochemistry (IH; paraffin embedded tissues) and an immunoradiometric assay (IRMA; cytosol from frozen tissues). Immunohistochemical scores were based on immunoreaction in tumour cells and tumour associated macrophages. RESULTS: IRMA values (cut off 40 fmol/mg cell protein) correlated significantly with IH values. Recorded incidences of positive immunoreaction in tumour cells using two different cut off values were 52% and 35%, respectively. Macrophages stained positive in 31% of tissues. Combined evaluation of tumour cells and macrophages resulted in positivity rates of 59% and 48%, respectively. Node status was the only variable found to correlate with cathepsin D expression. IH results correlated significantly with clinical outcome (median observation time 68 months) in node negative patients (n = 120) but not in node positive patients (n = 145). Cathepsin D positivity as measured by IRMA was not related to clinical outcome in either group. On multivariate analysis in the node negative group, IH detection of cathepsin D appeared to be the only independent factor indicating prognosis. For node positive patients, tumour grade, size, and receptor status were of prognostic relevance. CONCLUSIONS: Because of the simple methodology and the minimal amount of tissue used for analysis, immunohistochemistry was preferred to immunoradiometry for cathepsin D measurement; it also provided more predictive data with respect to prognosis.

[Prenatal determination of fetal rhesus factor in amnionic cells using polymerase chain reaction]. / Pränatale Bestimmung des fetalen Rhesusfaktors in Amnionzellen mittels Polymerase-Ketten-Reaktion.

In Rhesus incompatibility, prenatal RhD typing of the fetus requires intrauterine blood sampling by cordocentesis or by chorionic villus biopsy. Amniocentesis is easier to perform, and carries a lower risk of enhancement of maternal immunization. Therefore, we evaluated polymerase chain reaction (PCR) for fetal RhD typing in amniocytes which were isolated from amniotic fluid (18-40 gw) obtained by amniocentesis (n=26) or during delivery (n=27). In the clinically most important group of children from RhD-negative women (n=25) and in 28 newborns of RhD- positive mothers, we found a 100 percent agreement between the findings of PCR and the results of serologic typing. If these encouraging results are confirmed in a larger series, the method could be used for the clinical management of RhD-negative women with Rhesus incompatibility and a heterozygous RhD-positive partner.

Immunohistochemical detection of epidermal growth factor receptor lacks prognostic significance for breast carcinoma.

OBJECTIVE: We sought to determine whether the immunohistochemical detection of epidermal growth factor receptor (EGF-R) in primary cancer tissues is of prognostic significance in patients with breast carcinoma. METHODS: Paraffin-embedded tissues from 244 study subjects with primary breast carcinomas were tested immunohistochemically for the presence of EGF-R and were compared in a retrospective study with clinical outcome. RESULTS: Epidermal growth factor receptor was detected in the tumors of 49 (20.1%) of the 244 study subjects. The incidence of EGF-R detection was comparable in subjects with disease-free lymph nodes (T1-4, N0, M0, n = 111; EGF-R present 22.5%) or those whose nodes contained carcinoma (T1-4, N+, M0, n = 133; EGF-R present 18.9%). No reliable correlation was found in either group between EGF-R detection and clinical, functional, or morphologic prognostic indicators that included age, menopausal status, tumor size, tumor grade, nodal status, and hormone receptor status. Relapse-free survival and overall survival (median observation time 62.5 months) did not differ between patients with EGF-R-positive or EGF-R-negative breast carcinoma specimens. CONCLUSIONS: In our experience, the immunohistochemical determination of EGF-R in routine formalin-fixed, paraffin-embedded tumor specimens fails to provide useful information concerning the prognosis of patients with primary breast carcinoma.

[Immunohistochemical detection of pS2 protein in paraffin sections of breast carcinoma tissue. Comparison with results of an immunoradiometry assay]. / Immunhistochemischer Nachweis des pS2-Proteins an Paraffinschnitten von Mammakarzinomgeweben. Vergleich mit den Ergebnissen eines immunoradiometrischen Assays.

The synthesis of pS2 protein is induced through estrogen-dependent transcription of the pS2 gene. The presence of the pS2 protein in breast cancer is thought to be as valuable as receptor status, or even more so, in predicting the response to hormonal therapy. Furthermore, pS2 appears to be a prognostic factor for primary breast cancer. In 162 cases of primary breast cancer, pS2 was tested by immunohistochemical procedures on formalin-fixed and paraffin-embedded tissues. Staining was evaluated semi-quantitatively using an immunoreactive score (IRS). The concentrations of pS2 in tumor cytosol were determined using an immunoradiometric assay. Positive staining for pS2 (IRS > or = 2) was seen in 27% of the tumors. Comparison of immunohistochemical and biochemical detection (26% of tumors had pS2 cytosol concentrations above the cut-off value of 26 ng/mg cell protein) revealed an 81% concordance rate (r = 0.76; P < 0.0001). Univariate analysis showed no significant correlation of immunohistochemical pS2 detection and age or menopausal status of patients, tumor size, tumor grade or nodal status. However, the immunohistochemical pS2 status correlated significantly with the immunohistochemical detection of the estrogen (ER; P < 0.001) and progesterone receptor status (PR; P < 0.0001). pS2-positive tumors were ER-positive in 66% of cases and PR-positive in 73%; 89% of pS2-positive tumors were positive for ER and/or PR. The incidence of immunohistochemical pS2 detection was 41% in the group of steroid receptor positive carcinomas (ER- and/or PR-positive) in contrast to 7% in steroid receptor negative tumors (ER- and PR-negative).

P53 protein in 204 patients with primary breast carcinoma--immunohistochemical detection and clinical value as a prognostic factor.

In a retrospective study, 204 formalin-fixed and paraffin-embedded biopsies of primary breast carcinomas were tested immunohistochemically for the expression of p53 protein (PAb 1801). 38% of the carcinomas were positive with respect to p53. The expression of p53 correlated significantly with the loss of tumor differentiation (P = 0.013), but not with menopausal status, patients' age, tumor size, axillary lymph node involvement or hormone receptor status. The influence of p53 expression on prognosis was evaluated in 197 patients (T1-4 N0-2 M0, median observation time 72 months). Detection of p53 protein was associated with a significantly longer disease-free survival in node-positive women (P = 0.03). However, p53 protein did not prove to be a prognostic factor in node-negative patients. The results demonstrate the prognostic value of p53 expression in breast cancer which appears to be limited to patients with node-positive tumors.