Luteinizing hormone-releasing hormone agonist triptorelin in combination with cytotoxic chemotherapy in patients with advanced ovarian carcinoma. A prospective double blind randomized trial. Decapeptyl Ovarian Cancer Study Group.

BACKGROUND: Several lines of evidence suggest that the proliferation of ovarian carcinoma might be stimulated by gonadotrophins. A number of Phase I/Phase II clinical trials have reported that the suppression of endogenous luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone (LHRH) analogs induced objective remissions and/or disease stabilization in 10-30% of patients with advanced refractory ovarian carcinoma. The current study was performed to evaluate whether the addition of LHRH agonist treatment to standard platinum-based chemotherapy could prolong survival of patients with surgically treated Stage III or IV epithelial ovarian carcinoma. METHODS: One hundred and thirty-five patients with Stage III or IV epithelial ovarian carcinoma participated in this prospective randomized double blind trial. After cytoreductive surgery, 69 patients received monthly injections of a depot preparation of the LHRH agonist [D-Trp6] LHRH (triptorelin, 3.75 mg) and 66 patients received placebo until their deaths or termination of trial, respectively. All patients were treated with a standard platinum-based chemotherapy, and, if necessary, with second- or third-line cytotoxic regimens. RESULTS: Endogenous gonadotrophins were reliably suppressed in patients treated with triptorelin. However, their progression free and overall survival were not significantly different from that of patients receiving placebo injections (statistical power > 80% for a difference between both groups of > or = 20%). CONCLUSIONS: The results of this trial suggest that the suppression of endogenous gonadotrophins by conventional doses of an LHRH agonist produces no relevant beneficial effects in patients with advanced ovarian carcinoma who receive standard surgical cytoreduction and cytotoxic chemotherapy.

Craniofacial anomalies, abnormal hair, camptodactyly, and caudal appendage (Teebi-Shaltout syndrome): clinical and autopsy findings.

Teebi and Shaltout [1989: Am J Med Genet 33: 58-60] described a new syndrome of craniofacial anomalies, abnormal hair, camptodactyly, and caudal appendage in children born to a consanguineous couple. We report on a second family with the same pattern of anomalies occurring in a liveborn female and 3 spontaneously aborted fetuses, and include autopsy findings. As additional findings 2 of our cases had unilateral microphthalmia and kidney anomalies. Our observation confirms that this pattern of anomalies is a distinct syndrome with autosomal recessive inheritance; we suggest the synonym Teebi-Shaltout syndrome.

[In vivo and in vitro effects of GnRH analogs on ovarian Leydig cell tumor]. / In-vivo- und In-vitro-Effekte von GnRH-Analoga auf einen ovariellen Leydigzelltumor.

A 65-year old patient, suspected to be suffering from an androgen producing ovarian tumour, was treated preoperatively with the GnRH agonist triptorelin (500 micrograms/day s.c.) for 7 days. After an initial rise, gonadotrophin levels were suppressed under this treatment. The elevated serum testosterone concentrations were reduced by approx. 50% by the triptorelin injections. After the extirpation of the tumour (histologically a Leydig cell tumour of the ovary without signs of malignancy), primary cell cultures which secreted testosterone and androstenedione were prepared. Coincubation of the tumour cells with the GnRH agonist triptorelin had no effect on their androgen secretion. Treatment of the tumour cells with high concentrations (10(-5) M) of a GnRH antagonist, however, resulted in a 100% increase of their testosterone and androstenedione secretion. GnRH-binding sites of low affinity (Ka = 0.54 x 10(5) M-1) and high capacity (B max = 1364 x 10(-12) M/mg membrane protein) were identified in the tumour. These findings suggest that GnRH analogues might modify androgen secretion of sex-cord stromal tumours of the ovary via the suppression of endogenous gonadotrophin secretion and possibly also via direct effects on the tumour cells.

Intracellular actions of gonadotropic and peptide hormones and the therapeutic value of GnRH-agonists in ovarian cancer.

During the last two decades, considerable experimental evidence has been collected indicating that epithelial ovarian cancer might be gonadotropin dependent. LH and FSH receptors have been described in some of these tumors. The proliferation of ovarian cancer cells could be stimulated in vitro by gonadotropins. Suppression of endogenous LH and FSH secretion by GnRH-agonist treatment inhibited the growth of experimental or heterotransplanted ovarian cancers in various animal models. A number of recent phase II clinical trials have shown that the application of GnRH-agonists can lead to remission or stable disease in patients with relapsed advanced ovarian cancer. At present, prospective controlled clinical studies are being performed to assess the efficacy of GnRH-agonist treatment in addition to conventional surgical and cytostatic therapy in ovarian cancer in FIGO stages III and IV. Also, direct effects of GnRH analogues on ovarian cancer seem possible: a GnRH-like protein has been found in the human ovary. Our group discovered and partially characterized a specific GnRH-binding site (mol. wt 63.2 kDa) in ovarian cancer which is very similar to other human extrapituitary GnRH-binding sites of the low affinity, high capacity type, e.g. in breast cancer or the placenta. Recently, other groups have described also high affinity GnRH-agonist binding sites in ovarian cancer as well as in other extrapituitary tissues. First results from our laboratory indicate that the proliferation of certain ovarian cancer cell lines in vitro is reduced by both agonistic and antagonistic analogues of GnRH. Other authors were able to inhibit gonadotropin-induced in vitro proliferation of ovarian cancer cell lines by co-incubation with a GnRH-agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Specific low affinity binding sites for gonadotropin-releasing hormone in human endometrial carcinomata.

Specific low-affinity high-capacity binding sites for gonadotropin-releasing hormone (GnRH) have recently been discovered in human breast and ovarian carcinomata. We checked whether similar binding sites are present in human endometrial cancer. Plasma membrane preparations were incubated with [125I,D-Ala6-desGly10]-GnRH-ethylamide in the presence or absence of unlabelled GnRH agonists or other peptides. GnRH-binding could be demonstrated in all 12 tumor samples tested. The mathematical analysis of the binding data was consistent with a single class of low affinity (Ka = (0.8-1.4) x 10(5) M-1) and high-capacity (Bmax = (134-142) x 10(-12) M/mg membrane protein) binding sites. Native GnRH had a similar affinity to the binding sites as the GnRH agonist used. Other peptides such as oxytocin, somatostatin and thyrotropin-releasing hormone did not crossreact with the binding sites. A photolabelled derivative of [D-Lys6]-GnRH was prepared with the bifunctional photolabile reagent (4-azidobenzyl)-N-hydroxysuccinimide. Photoaffinity labelling of endometrial carcinoma membranes and subsequent sodium dodecyl sulfate electrophoresis in 10% polyacrylamide gel revealed the presence of a single molecular mass component of 62 +/- 1.9 kDa. The appearance of this photolabelled binding site could be largely suppressed by the addition of unlabelled GnRH-agonist (10(-4) M) and thus represents the specific binding site for GnRH in endometrial cancer.

LHRH-receptors and LHRH-agonist treatment in ovarian cancer: an overview.

Considerable evidence exists that ovarian cancer might be gonadotrophin-dependent. Receptors for LH and FSH have been discovered in these tumors. Proliferation of ovarian cancer cells in vitro could be stimulated by gonadotrophins. Withdrawal of LH and FSH in animal models of ovarian cancer inhibited growth of these tumors. Phase-II clinical studies have shown that suppression of endogenous gonadotrophins by LHRH-agonists can be beneficial in women with advanced ovarian cancer. Respective controlled clinical trials are performed at present. Also direct effects of LHRH analogues on ovarian tumors have been reported. An LHRH like protein was found in human ovarian tissue. We discovered a specific LHRH binding site (mol. wt 63.2 kDa) in ovarian cancer tissue which is very similar to other human extrapituitary LHRH binding sites, of the low-affinity, high-capacity type, e.g. in breast cancer and the placenta. In the latter tissues, LHRH or a related substance has been proposed as an autocrine regulator of cellular function. If this was also the case in ovarian cancer, direct effects of LHRH analogs on the tumor cells could be used as additional therapeutical points of attack.

[Chemosensitivity studies with soft agar culture systems in ovarian cancer]. / Chemosensibilitätsuntersuchungen mit Weichagarkultursystemen beim Ovarialkarzinom.

Since 1982, chemosensitivity studies have been conducted in our laboratory with 181 tumour samples from 132 woman patients suffering from carcinoma of the ovaries, using the colony test and capillary assays. Colonisation rates were 67% and assay rates between 60 and 47%; in 36 cases the in vitro result was compared with the course of the disease observed in vivo. Whereas in 11 of 12 patients it was possible to correctly assess chemoresistance (in vitro growth inhibition less than or equal to 49%) pretherapeutically, chemosensitivity (growth inhibition greater than or equal to 50%) proved more difficult to confirm, 15 predictions being true and 9 false. To assess the prognostic significance of the test results, survival curves were calculated from the data of 33 patients. With a p-value of 0.49, the courses of disease of "in vitro resistant" and "in vitro sensitive" patients differed only slightly from one another. We can conclude from our experiments, that an important indication for performing the colony test in ovarian carcinoma should always be assumed in patients with a poor prognosis, e.g. in women having a large postoperative residual tumour. If, in such cases, the possibility of chemosensitivity testing via the colony test is considered, this examination may offer the chance of sparing the patient additional strain due to the side effects of a treatment with cytostatics if the latter is most likely to be of no significant use.

Gonadotropin releasing hormone binding sites in human epithelial ovarian carcinomata.

As a first step to investigate whether gonadotropin releasing hormone (GnRH) analogs might be able to modulate directly the proliferation of human epithelial ovarian carcinomata, we checked if binding sites for GnRH are present in these malignancies. Specific binding of [125I][D-Ala6-des Gly10]-GnRH-ethylamide (GnRH agonist = GnRH-A) could be demonstrated in plasma membranes from 32 out of 40 ovarian carcinomata tested. This binding was dependent on temperature, time and plasma membrane concentration. Mathematical analysis of the binding data showed that the interaction of GnRH-A with the binding sites was consistent with a single class of low affinity, high capacity binding sites (Ka = 1.42 +/- 0.14 X 10(5) M-1; range: 0.3-3.8 X 10(5) M-1; R = 209 +/- 69 X 10(-12) M/mg membrane protein; range 16-400 X 10(-12) M/mg MP; means +/- S.E., n = 32). Native GnRH and the GnRH antagonist [D-p-Glu1, D-Phe2, D-Trp3,6]-GnRH had Ka values comparable to those of the GnRH-A used. [125I]GnRH-A binding could not be displaced by oxytocin, thyrotropin releasing hormone and corticotropin releasing factor in concentrations up to 10(-4) M. Somatostatin cross-reacted with binding sites from some carcinomata, while it did not displace GnRH-A binding in membranes from others. Though the functional role of this specific binding site for GnRH in human epithelial ovarian carcinomata is still obscure, it might be part of an autocrine regulatory system and provide a possible point of attack for therapeutic approaches using GnRH analogs in this malignancy.

[Risk of infection in premature infants with premature rupture of fetal membranes in correlation to respiratory distress syndrome]. / Infektionsrisiko bei Frühgeburten mit vorzeitigem Blasensprung in Korrelation zum Atemnotsyndrom.

The spectrum of infective agents in 58 preterm deliveries with premature rupture of the membranes (PROM) is examinated by assessment of bacteriological swabs. In the earliest weeks of gestation all children had severe RDS. Nearly 40% of the detected pathogens belonged to the non pathogenic vaginal flora. E. coli, Streptococcus species, Klebsiella and Candida were predominant in the group of facultative pathogenic infective agents. There is an enlarged colonization in maternal swabs after greater than 24 h. In nearly 80% of the children with severe RDS pathogens could be detected. Ascending infection is followed more often by severe RDS. In case of premature labor refractory to tocolytic therapy or slight vaginal bleeding, cervical swabs should be taken. Pathological findings must be treated by local antiseptic agents or antibiotic therapy. If there are any signs of intrauterine infection the pregnancy must be terminated to avert damage from the newborn.

[Blood coagulation and fibrinolytic factor activities in the amniotic fluid]. / Aktivitäten von Gerinnungs-und Fibrinolysefaktoren im Fruchtwasser.

Plasma and 138 samples of amniotic fluid were obtained from 129 patients during the 15th to 39th pregnancy week and during parturition. Factor activities of the coagulation and fibrinolytic system were studied by means of enzymatic-kinetic measurement methods to differentiate the haemostaseological properties of the amniotic fluid. The factor X activity drops in the amniotic fluid during the third trimester and during parturition. The activities of plasminogen, alpha 1-antitrypsin, alpha 2-antiplasmin, antithrombin III and alpha 2-macroglobulin in the amniotic fluid do not change significantly during gestation and parturition. None of these factors seems to show any difference between the activities in the maternal placenta and in the amniotic fluid. The most striking change in activity was seen with prothrombin. There is a marked increase between the second and third trimester. In the maternal plasma the activity is relatively constant within the standard range of non-pregnant women. Further studies will be necessary to find out whether the increase in prothrombin activity in the amniotic fluid correlates with the increased surfactant production in the fluid and may thus be of diagnostic importance.

Effects of intralipid and hydrocortisone upon human fetal lung cell cultures.

Organotypic cell culture systems of human fetal lungs of 15, 18, and 26 weeks' gestational age were treated with Intralipid, a phosphatidylcholine-containing lipid mixture, and with hydrocortisone of varying concentrations. The lamellar bodies found in the pneumocytes type II were ultrastructurally identified. Their amount was quantitated by point-counting, a morphometrical method. Intralipid had a stimulating effect upon the surfactant production depending on the concentration admitted. This effect was quantitatively compared to the known effect of hydrocortisone. Intralipid at a concentration of 10(-2%) produced a significant increase of the relative volume of lamellar bodies (P = 0.05) at a gestational age of 18 weeks. This effect is comparable to hydrocortisone treatment at a concentration of 10(-1%) (P = 0.05) and 10(-3%) (P = 0.01). At a gestational age of 26 weeks, Intralipid at a concentration of 10(-1%) (P = 0.01) stimulated lamellar body production. Hydrocortisone had a similar effect at a concentration of 10(-1%) (P = 0.01). Intralipid does not pass the placenta-barrier and is locally applied by amniocentesis. Therefore, complications to the maternal organism and probably to the fetuses are negligible. The application of Intralipid represents an alternative method to accelerate antenatal surfactant production and to improve the rate of survival of preterm infants.

[Puncture of the chorionic villi. Technic--experiences--risks]. / Chorionzottenpunktion. Technik--Erfahrungen--Risiken.

Chorion villi biopsy is a recently introduced method for first trimester prenatal diagnosis. Based on 435 cases of chorionic villi biopsies, obtained during a 3 year period, we report our experiences with the technique of chorionic villi sampling, chromosomal analysis from trophoblast tissue and possibly associated complications, such as spontaneous abortions, vaginal bleeding, and chromosomal mosaicism. The rate of spontaneous abortions in our group of patients was 3%. This appears low, considering the high overall spontaneous abortion rate in early pregnancy of women over 35 years. The cytogenetic diagnosis is complicated by a high rate (2.8%) of chromosomal mosaicism, which were found to be not representative for the fetus, but required control amniocentesis. From our experiences with this method we conclude that chorion villi biopsy can be offered as a reliable alternative method to amniocentesis in the hands of an experienced team of obstetric surgeons and cytogenetists.

[Experiences with PAC and PEC polychemotherapy in the treatment of advanced and recurrent breast cancers]. / Erfahrungen mit einer PAC- und PEC-Polychemotherapie bei der Behandlung fortgeschrittener und rezidivierender Mammakarzinome.

At the department of gynecology of the universities of Lübeck and Bonn 18 in part pretreated patients with advanced or relapsing cancer of the breast were treated with a DDP-containing polychemotherapy. For 14 of the 18 women the PAC or PEC regime was beneficial: 9 had complete or partial remission and 1 patient had a no change situation; 4 women showed no evidence of disease. The time of survival after the chemotherapy treatment was two month in the minimum and more than 50 month in the maximum (20 month in the average). As side effects, in particular leucocyte-depression and nausea as well as vomiting of various degrees were observed; alopecia was seen in every case. The success of DDP-containing chemotherapy in the treatment of breast cancer is of note, but in the future it will be important to define subgroups that would most benefit from PAC- or PEC-treatment without substantial negative side effects.

[Bacteriologic studies in premature rupture of fetal membranes and correlation with the clinical aspects of chorioamnionitis and the amnion infection syndrome]. / Bakteriologische Untersuchungen bei vorzeitigem Blasensprung und Korrelation zur Klinik von Chorioamniotitis und Amnioninfektionssyndrom.

One of the major complications following premature rupture of the membranes (PROM) is ascending infection. In this aspect the bacteria of the vaginal flora play a major part. Bacterial spectra of a group with PROM and another control group with punctual rupture of the membranes are comparatively analysed. This analysis is based on swabs taken from vagina and newborns. Data are interpreted in correlation to clinical picture of chorioamnionitis and amnion infection syndrome (AIS). Twelve newborns clinical suspected to have a neonatal infection are retrospectively judged. In the group with pregnant women with PROM potential pathological germs such as group B streptococci and E. coli are found more often, whereas physiological flora, specially Lactobacillus species, are clearly reduced. In newborns with AIS even germs can be detected, which so far have seemed to be more apathogenic, such as Gardnerella vaginalis. Bacteriological findings are discussed in connection with clinical parameters, specially group B streptococci are looked at more precisely. In newborns with AIS microbiological results are demonstrated including course of pregnancy and delivery. For the management of PROM alternatives are shown and advice for prophylaxis is given.

[Bacteriologic studies of the amniotic fluid following amniocentesis]. / Bakteriologische Fruchtwasseruntersuchungen nach Amniozentese.

After transabdominal amniocentesis puncture needles and samples of amniotic fluid were microbiologically examined. The antibacterial activity of the amniotic fluid after inoculation of different germs was compared. Positive microbiological results were found in 43 of total 573 puncture needles, but there were germs of the skin flora in 40 cases. Five amniotic fluid samples out of total 424 were contaminated, whereby skin commensals were detected in four samples. The bacteriostatic activity against the examined germs was individually. Complete growth inhibition over 24 hours was observed in cultures with coagulase-negative Staphylococcus, Staph. aureus and E. coli, a less growth inhibition over nearly 10 hours for Pseudomonas aeruginosa. The growth of Strep. faecalis was not suppressed. As result of the frequent observation of skin commensals in amniocentesis puncture needles and amniotic fluid samples clear lines for the performance of the amniocentesis on antiseptic condition basis and for the diagnostic and therapeutic procedure in case of positive microbiological findings were recommended.

[Significance of atypical hemorrhage in ovarian cancer]. / Die Bedeutung von atypischen Blutungen für das Ovarialkarzinom.

UNLABELLED: In a retrospective study on 167 ovarian cancer patients the presenting symptom was defined via anamnesis. This parameter was correlated to others characterising the cancer and the patient: age, parity, menopause, stage, extent of operation, tumor residue, postoperative therapy, induction of remission and several morphological data. The prognostic significance was analysed using Hazard-models (Cox 1972, Carter 1983) and contingency tables. RESULTS: The presenting signs and symptoms were: atypical bleeding in 44 patients, pain in 75 patients and other signs in 48 patients. These signs and symptoms were significantly correlated with tumor residue, and were more frequently seen in mucinous and endometrioid carcinomas. There were no significant correlations to the other examined parameters, but there was a trend for patients with atypical bleedings to be diagnosed at early stages and their survival prognosis was significantly (p less than 0.01) better compared with that for patients with pain or other presenting signs or symptoms.

[Ivemark syndrome]. / Das Ivemark-Syndrom.

The Ivemark-Syndrome (Alienie Syndrome) is defined by the characteristic association of splenic aplasia, organsymmetry and other malformations especially of the cardiovascular system. More than 200 cases are reported. The incidence of Ivemark-Syndrome is very low. The aetiology is not yet clearly defined. As a main cause exogen factors between the 31st and 38th day of gestation are discussed, but a genetic cause has not been detected yet. Due to the unfavourable prognosis an intensive ultrasonographic screening is to be asked for.

[Gynecologic and cytogenetic aspects of prenatal diagnosis in the 1st trimester of pregnancy]. / Gynäkologische und zytogenetische Aspekte der Pränataldiagnostik im ersten Schwangerschafts-trimenon.

The article reports on a new method in prenatal diagnosis during the first three months of pregnancy. The gynaecological as well as the cytogenetic aspects are discussed on the basis of 74 transcervical trophoblast aspirations. Two different experimental preliminary examination series were conducted. In the first study, the failure rate in respect of recovery of material was 12.5%, whereas in the second examination series all aspirations were successful. Thanks to these favourable results, transcervical trophoblast aspiration was adopted as the only method used in prenatal diagnosis. In cytogenetic processing, direct chromosome preparation was found to be rather costly and time-consuming, whereas the short-term culture of chorionic villi usually yielded more favourable results in respect of mitotic rate and quality of the metaphase plates. It must be considered a drawback of transcervical trophoblast aspiration that it is not possible to conduct alpha-foetoprotein determination or determination of acetylcholine esterase as part of prenatal neural tube diagnosis. However, this can be subsequently done-with suitable disposition--during the 16th week of pregnancy, or can be replaced by a determination of alpha-foetoprotein in the serum of pregnant women.