N. Lang

Nitric Oxide Synthase Activity and Doppler Parameters in the Fetoplacental and Uteroplacental Circulation in Preeclampsia

OBJECTIVEnWe investigated the hypothesis that changes in blood flow in the uteroplacental and fetoplacental circulation in preeclampsia are associated with an abnormality of placental or uterine placental bed nitric oxide (NO) synthesis.nnnMETHODSnWe measured pulsatility indices on Doppler waveform analysis from uterine and umbilical arteries in 20 patients with preeclampsia and 14 healthy pregnant controls before elective cesarean section. During cesarean section, biopsies from the uterine placental bed and the placenta were taken and the nitric oxide synthase (NOS) activity was measured by the [3H] L-arginine-[3H] L-citrulline conversion assay in these samples.nnnRESULTSnThe NOS activity was significantly lower in the uterine placental bed in comparison to the placental tissue (p < 0.01). Placental NOS activity was similar between patients with preeclampsia and healthy controls and in the groups with either a pathological or a normal Doppler flow in the umbilical artery. In the uterine placental bed however, NOS activity from patients with preeclampsia was significantly lower (p < 0.01), whereas the blood flow resistance in the uterine arteries was elevated (p < 0.01) in comparison to healthy controls.nnnCONCLUSIONSnOur data show that pathological Doppler waveforms in the uterine arteries of patients with preeclampsia are paralleled by diminished NOS activity in the uterine placental bed. Therefore, the compromised NO production in the uterine placental bed may play an important role in the impaired uteroplacental blood flow and potentially in some pathological features of preeclampsia such as intervillous thrombosis formation and fetal growth retardation.

Some observations on the effect of a GnRH analog in ovarian cancer

Observations in healthy women led us to suppose that the increase of the tumor marker CA 125 observed during progression of ovarian cancer could be dependent on pituitary gonadotropins. Therefore we administered the GnRH-analog, DTrp 6-LH-RH, to 19 patients with progressive ovarian cancer and increasing CA 125 serum levels. When compared to 11 untreated patients, CA 125 levels increased at a considerably slower rate in 9 of 11 patients who were treated with the substance for more than 3 months. This was associated with stable disease, ranging from 4 to 20 months so far. The further analysis of 2 patients who developed an increase in CA 125 serum levels and a progression of disease during treatment demonstrated that FSH and LH levels had escaped suppression. The results support our assumption, that gonadotropins may be involved in the mechanisms leading to increasing CA 125 concentrations in ovarian cancer. The reduced increase of CA 125 and the observed stabilisation of disease during pituitary blockade offers a rationale for GnRH analogues in the therapeutic approach to this disease.

CA 125 production and release by ovarian cancer cells in vitro.

The antigenic determinant CA 125 is a high molecular weight glycoprotein which is elevated in more than 80% of patients with epithelial ovarian cancer. Despite its good performance as a human tumor marker, only little is known about its physiological function. According to recent publications, CA 125 production and release appear to be related to cellular growth. In order to investigate this putative relationship more closely, we analyzed the pattern of CA 125 production and release by ovarian cancer cells during exponential cell growth, during cell cycle arrest by colchicine and during inhibition of cellular protein synthesis by cycloheximide. The results were correlated with the cell cycle distribution. According to our results, the main determinant of CA 125 release into the culture supernatant is the total cell count. Although cell cycle arrest in the G2 + M phase by means of colchicine treatment resulted in the death of most cells, which was reflected by an increased release of CA 125, no differences in the intracellular production rate between colchicine treated and untreated cells were seen. In contrast, treatment of cells with cycloheximide not only resulted in decreasing cell numbers but also in a complete inhibition of CA 125 production by surviving cells.

Influence of Human Luteinizing Hormone on Cell Growth and CA125 Secretion of Primary Epithelial Ovarian Carcinomas in vitro

In the present study, the influence of human luteinizing hormone(hLH) on the growth and the CA 125 secretion of primary ovarian carcinoma cell cultures derived from 11 previously untreated patients was investigated. Two different patterns of in vitro growth of unstimulated ovarian carcinoma cells could be detected: 5 cell cultures in which no changes of cell number were observed during an incubation period of 6 days (group A) and 6 cell cultures which grew without any hormonal support (group B). All tumors of group A showed enhanced cell proliferation when hLH was added to the culture medium, reaching a maximum at dosages of 100 mIU/ml on day 2 after incubation, while such an effect was not observed in group B. In most cases, no positive correlation was found between hLH-induced cell growth and CA 125 release. Our findings demonstrated a dose-dependent hLH-induced stimulation of epithelial ovarian tumors in vitro.

Prognosis of children born to mothers with HELLP-syndrome

In literature there have been differences in the assessment of the outcome of children born to mothers with HELLP syndrome. In a retrospective study we investigated six annual groups (1989-1994) at the Perinatal Center in Erlangen (11,235 births, 68 children of mothers with HELLP syndrome), 53 children were treated in our neonatal intensive care unit (NICU). The control group (n = 219) consisted of a complete age group in our NICU. The gestational age (mean 33 weeks, p < 0.003) and the birth weight (mean 1671 g, p < 0.001) were significantly lower in the HELLP group. No significant differences were detected with respect to the frequency of leucocytopenia (p = 0.518) and thrombocytopenia (p = 0.215). Despite a relatively high rate (37.7%) of RDS there was only a significant tendency to the disadvantage of HELLP children (p = 0.075). There was no difference in frequency of intracranial hemorrhage (ICH) (p = 0.566). Infections were diagnosed less frequently in HELLP children (p = 0.042). Mortality in the control group was higher only as a tendency (p = 0.07). The follow-up examinations of the neurological development covered 31 of the 53 treated children. After 6-72 months (median 24 months), 90.3% of these children showed normal development or only minor disabilities. The prognosis of children of mothers with HELLP syndrome is not as bad as has been assumed so far.

Mammographisch/stereotaktisch gezielte Vakuum-/Exzisionsbiopsie Interventionelle Methoden in der Mammadiagnostik

ZusammenfassungSowohl im Rahmen der komplementären Mammadiagnostik (Klinik, Mammographie, Sonographie) einschließlich der dynamischen MRT als auch von Mammakarzinom-Screening-Projekten haben interventionelle Methoden wie die mammographisch/stereotaktisch gezielte Vakuum-/Exzisionsbiopsie ihren festen Stellenwert zur Vermeidung unnötiger offener Operationen und gehören zum klinischen Alltag. Unter Beachtung strenger Kriterien ist dies ein Weg, die Spezifität und den negativen Vorhersagewert in der Mammadiagnostik zu verbessern. Darüber hinaus sind interventionelle Methoden kostengünstiger, zeitsparender und mit geringerer Morbidität belastet als ein operativer Eingriff.AbstractAs well as in the complementary mamma diagnosis (clinical examination, mammography, sonography) including the dynamic MRI and the mammography screening projects the interventional methods like mammographically/stereotactically guided vacuumbiopsy/excisional biopsy are established methods to avoid unnecessary open operations and they are integrated in the clinical routine. By using strict criterias it is a way to improve the specificity and the negative predictive value in the mamma diagnosis. In addition the interventional methods requires less costs, less time and reduces the morbidity in comparison to an open operation.

Immunohistochemical detection of P-glycoprotein in normal and malignant tissues: a comparative study of three monoclonal antibodies, JSB-1, C 219 and 265/F4, against different epitopes using frozen and paraffin tissue sections.

In this study, the reactivity of three different monoclonal antibodies (MAbs) against the multiple-drug resistance (MDR)-related P-glycoprotein (P-170) were compared with each other using a collection of frozen and paraffin-embedded tumors, normal tissues and metastatic cells of malignant pleural and peritoneal effusions. The MAbs JSB-1, C 219 and 265/F4 were used in an indirect immunoperoxidase technique on frozen material. In addition, MAb C 219 was used on formalin-fixed, paraffin-embedded material from the same tumors, of which frozen sections were studied, and in a retrospective study C 219 was tested on paraffin blocks of the primary tumors that were responsible for the malignant effusions. The results show different staining patterns for all three MAbs to some extent. Results in frozen and paraffin sections obtained with MAb C 219 were comparable. MAb C 219 performs well both in frozen and formalin-fixed, paraffin-embedded material, making it a useful candidate for application in routine laboratory analysis. The retrospective analysis did not show consistency of P-170 expression in the same patients. This leads to the hypothesis that the actual status of P-170 expression in recurrent disease should be obtained before continuing or modifying chemotherapy. Clinical studies aimed at the correlation of immunohistochemistry with therapy response have to evaluate the relevance of P-170 expression in drug resistance of primary and metastatic tumors.

Induction of Ovarian Tumors by Endogenous Gonadotropins in Rats Bearing Intrasplenic Ovarian Grafts

In this study the role of gonadotropins for the induction of ovarian tumors in rats was examined. The rats were castrated and one ovary was transplanted under the splenic capsule. Rats remained untreated or received a GnRH analog for gonadotropin suppression either immediately, 90 or 180 days after castration. Under these conditions the untreated rats developed ovarian tumors while the treated rats only developed tumors when the stimulation of gonadotropins lasted for more than 90 days. The first appearing tumors were theca cell tumors while during the further course of the experiment the granulosa cell compartment increased; however, no histological signs of malignancy could be detected in these tumors. GnRH analogs could block the induction of granulosa cell tumors when administered 150 days after transplantation. After a period of 210-240 days the tumors grew independently of elevated LH and FSH levels. The causes of this growth autonomy need to be studied further.

Serum CA-125 as a guideline for the timing of a second-look operation and second-line treatment in ovarian cancer

SummaryIn the assessment of response to treatment of ovarian cancer patients, clinical examination is unreliable in detecting small tumor masses. The second-look laparotomy is therefore an accepted procedure. The optimal timing of second-look laparotomy, however, is uncertain. We therefore examined the usefulness of serial serum CA-125 estimations in the timing of second-look laparotomies in 33 patients suffering from ovarian cancer. Increasing CA-125 concentrations were always followed by relapses or progressive disease, whereas decreasing serum concentrations indicated response to treatment. In future we propose to perform second-look laparotomies when CA-125 levels have declined to a steady plateau and to star a secondary treatment when CA-125 levels start to rise again.

Beckenwandrezidive des Zervixkarzinoms

ZusammenfassungHintergrundDie Prognose von Patientinnen mit Beckenwandrezidiv eines Zervixkarzinoms ist schlecht. Die Fünf-Jahres-Überlebensrate liegt nach ausschließlich operativer Primärtherapie für diese Patientinnen zwischen 5 und 25%. Die kombinierte operative und strahlentherapeutische Behandlung (CORT) konnte die Prognose verbessern. Zur Optimierung der Behandlungsergebnisse beim Zervixkarzinomrezidiv der Beckenwand wurde ein neues Konzept, bestehend aus radikaler Chirurgie und einer strahlenbiologisch optimierten Radiochemotherapie, entwickelt — CORCT (combined operative-and radiochemotherapy).Patienten und MethodeNach radikaler Operation eines Beckenwandrezidivs erfolgte eine interstitielle HDR-(Ir-192-)Brachytherapie in Afterloadingtechnik (2,5 Gy, zwei Fraktionen/Tag an fünf Tagen). Additiv wurde eine Kombinationschemotherapie mit Cisplatin 25 mg/m2 KOF/Tag an fünf Tagen und 5-Fluorouracil 1000 mg/Tag an fünf Tagen durchgeführt. Nach Abschluß der Gesamttherapie wurden die Patientinnen in dreimonatigen Abständen nachuntersucht.ErgebnisseDrei von drei ausschließlich operativ, und strahlentherapeutisch behandelten Patientinnen verstarben innerhalb von im Median acht Monaten an einer progredienten Fernmetastasierung. Nach additiver Radiochemotherapie lebten nach einer medianen Beobachtungszeit von 14 (zwölf bis 30) Monaten noch, drei von vier Patientinnen ohne Hinweis auf lokale Rezidive oder Fernmetastasen.SchlußfolgerungDie ersten Behandlungsergebnisse mit dem neu entwickelten CORCT-Verfahren lassen auf eine Verbesserung der Prognose für Patientinnen mit Beckenwandrezidiv eines Zervixkarzinoms hoffen.AbstractPurposeThe prognosis of patients with pelvic wall recurrences after primary therapy of cervical cancer is bad. In selected patients treated exclusively by surgery as primary therapy the 5-year survival rate was between 5 and 25%. Additionally the combination of operation and radiotherapy (CORT) improved the survival so far. We developed a new concept for the treatment of pelvic wall recurrences. This concept includes the combination of radical surgery, interstitial radiation and chemotheray — CORCT (combined operative- and radiochemotherapy).Patients and MethodsAfter radical surgery, interstitial HDR (Ir-192) brachytherapy in afterloading technique (2.5 Gy, 2 fractions/day in 5 days) was performed. Additionally a chemotherapy with cisplatin 25 mg/m2/day in 5 days and 5-fluorouracil 1000 mg/day in 5 days was applicated.ResultsAfter combined operative- and radiotherapy 3 of 3 patients died after treatment within 8 months (median) because of distant metastases. After additive radiochemotherapy 3 of 4 patients had no evidence of disease (NED) after a follow-up period of 14 (12 to 30) months.ConclusionThe first treatment results of the new designed combined operative- and radiochemotherapy concept (CORCT) led us to expect an improvement of the prognosis of patients with recurrences of cervical cancer at the pelvic wall.PURPOSEnThe prognosis of patients with pelvic wall recurrences after primary therapy of cervical cancer is bad. In selected patients treated exclusively by surgery as primary therapy the 5-year survival rate was between 5 and 25%. Additionally the combination of operation and radiotherapy (CORT) improved the survival so far. We developed a new concept for the treatment of pelvic wall recurrences. This concept includes the combination of radical surgery, interstitial radiation and chemotheray--CORCT (combined operative- and radiochemotherapy).nnnPATIENTS AND METHODSnAfter radical surgery, interstitial HDR (Ir-192) brachytherapy in afterloading technique (2.5 Gy, 2 fractions/day in 5 days) was performed. Additionally a chemotherapy with cisplatin 25 mg/m2/day in 5 days and 5-fluorouracil 1000 mg/day in 5 days was applicated.nnnRESULTSnAfter combined operative- and radiotherapy 3 of 3 patients died after treatment within 8 months (median) because of distant metastases. After additive radiochemotherapy 3 of 4 patients had no evidence of disease (NED) after a follow-up period of 14 (12 to 30) months.nnnCONCLUSIONnThe first treatment results of the new designed combined operative- and radiochemotherapy concept (CORCT) led us to expect an improvement of the prognosis of patients with recurrences of cervical cancer at the pelvic wall.