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Focussing of the serine protease urokinase (uPA) to the tumor cell surface via interaction with its receptor (uPAR) is an important step in tumor invasion and metastasis. The human ovarian cancer cell line OV-MZ-6#8 was stably transfected with expression plasmids either encoding cell-associated uPAR (GPI-uPAR) or a soluble form of uPAR (suPAR) lacking its glycan lipid anchor. In vitro, high level synthesis of functionally active recombinant suPAR inhibited cell proliferation and led to reduced cell-associated fibrin matrix degradation, whereas fibrinolytic activity was increased in OV-MZ-6#8 cells overexpressing GPI-uPAR. Both OV-MZ-6#8-derived clones were inoculated into the peritoneum of nude mice and tested for tumor growth and spread. High level synthesis of recombinant suPAR (without altering the physiological expression levels of GPI-uPAR and uPA in these cells) resulted in a significant reduction of tumor burden (up to 86%) in the xenogeneic mouse model. In contrast, overexpression of GPI-uPAR in tumor cells did not affect tumor growth. Our results demonstrate that high levels of suPAR in the ovarian cancer cell vicinity can act as a potent scavenger for uPA, thereby significantly reducing tumor cell growth and cancer progression in vivo.

Single-chain urokinase-type plasminogen activator (pro-uPA) is bound to a specific surface receptor on ovarian cancer HOC-I cells that is incompletely saturated. Saturation of uncovered receptors by uPA polypeptides with intact amino-terminal fragment (ATF) derived from pro-uPA by limited proteolysis (human leucocyte elastase [HLE] or V8 protease) has been studied. HOC-I cells preferentially invaded reconstituted basement membranes in a time- and plasminogen-dependent manner. This process was inhibitable by preincubation with uPA polypeptides in the medium at levels which suggested that complete saturation of cell surface uPA receptors occurred. This result indicates that occupation of uPA receptors by enzymatically inactive uPA fragments or prevention of rebinding of pro-uPA synthesised by tumour cells to the receptors specifically reduces the invasion of the tumour cells through basement membranes in vitro. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6

The glycosylphosphatidylinositol (GPI)-anchored, multifunctional receptor for the serine proteinase, urokinase plasminogen activator (uPAR, CD87), regulates plasminogen activation and cell migration, adhesion, and proliferation. uPAR occurs in functionally distinct, membrane-anchored and soluble isoforms (s-uPAR) in vitro and in vivo. Recent evidence indicates that s-uPAR present in the circulation of cancer patients correlates with tumor malignancy and represents a valuable prognostic marker in certain types of cancer. We have therefore analyzed the mechanism of uPAR shedding in vitro. We present evidence that uPAR is actively released from ovarian cancer cells since the rate of receptor shedding did not correlate with uPAR expression. While s-uPAR was derived from the cell surface, it lacked the hydrophobic portion of the GPI moiety indicating anchor cleavage. We show that uPAR release is catalyzed by cellular GPI-specific phospholipase D (GPI-PLD), an enzyme cleaving the GPI anchor of the receptor. Thus, recombinant GPI-PLD expression increased receptor release up to fourfold. Conversely, a 40% reduction in GPI-PLD activity by GPI-PLD antisense mRNA expression inhibited uPAR release by more than 60%. We found that GPI-PLD also regulated uPAR expression, possibly by releasing a GPI-anchored growth factor. Our data suggest that cellular GPI-PLD might be involved in the generation of circulating prognostic markers in cancer and possibly regulate the function of GPI-anchored proteins by generating functionally distinct, soluble counterparts.

The purpose of the study was to compare myocardial blood flow (MBF) in hyperlipidemic postmenopausal women and age-matched hyperlipidemic men, and to analyze the relationship between cholesterol subfractions and myocardial blood flow in men and women.Women are protected from coronary artery disease (CAD) events until well after menopause, in part due to gender-specific differences in lipid profiles.To examine the effect of these influences on coronary microcirculation, MBF was quantitated with N-13 ammonia/PET (positron emission tomography) at rest and during adenosine hyperemia in 15 women and 15 men, all nondiabetic, who were matched for age and total cholesterol levels (53+/-4 vs. 50+/-8 years, p = NS, 6.44+/-1.1 vs. 6.31+/-0.85 mmol/liter, or 249+/-41 vs. 244+/-33 mg/dl, p = NS).Women had significantly higher high density lipoprotein (HDL) and lower triglyceride (Tg) levels than did men, and they showed significantly higher resting MBF and stress MBF levels. Significant correlations were found between resting and hyperemic MBF and HDL and Tg levels (r = 0.44, p0.02 for stress MBF vs. HDL; r = 0.48, p0.007 for stress MBF vs. Tg). Gender was the strongest predictor of hyperemic MBF in multivariate analysis. Women responded to adenosine hyperemia with a significantly higher heart rate than did men, and hemodynamic factors correlated significantly with blood flow both at rest and during stress.These data suggest that the favorable lipid profile seen in women may be associated with preserved maximal blood flow in the myocardium.

Granular cell tumor is a rare, usually benign neoplasm of neural origin that may arise in virtually any site and, when situated in the breast, can mimic breast carcinoma. We describe a case of granular cell tumor of the breast in a 57-yr-old woman. Clinical evaluation, mammography, sonography and MRI suggested a carcinoma with infiltration of skin and muscle. However, the tumor did not display increased glucose metabolism on PET. Clinical findings, imaging results, histological characteristics and surgical management are discussed.

In node-negative breast cancer, 70% of patients are cured by surgery alone and thus should be spared the necessity of systemic adjuvant treatment. Histomorphological and tumor biological prognostic factors may be employed to assess the patient's risk profile with regard to disease recurrence and death. To evaluate the relationship between tumor biological factors and the metastatic potential of primary breast cancer, proteolytic factors uPA, PAI-1, and cathepsin L, which are associated with tumor invasion and metastasis, were determined in breast cancer tissue extracts by ELISA and the values assessed by uni- and multivariate analysis as well as CART (classification and regression trees) in comparison with traditional prognostic factors. Cysteine protease cathepsin L, serine protease uPA, and the protease inhibitor PAI-1 were determined by ELISA in extracts of primary tumors of 103 node-negative breast cancer patients and values assessed by univariate and multivariate analysis in comparison with traditional prognostic factors (tumor size, steroid hormone receptor status, grading, vessel invasion, menopausal status). Median follow-up of patients still alive at time of follow-up was 56.5 months (range 34-88). PAI-1, cathepsin L, tumor size, grading, and steroid hormone receptor status but not uPA, vessel invasion, and menopausal status were of prognostic relevance for disease-free survival (univariate analysis). Multivariate analysis of disease-free survival (Cox proportional hazards model) disclosed PAI-1 (relative risk of 8.6, p = 0.0001) to be the only strong and statistically independent prognostic factor. By CART-analysis, however, the combination of PAI-1 (or = 14 ng/mg protein) and cathepsin L (or = 1,100 ng/mg protein) allowed the identification of a subgroup comprising 68% of the node-negative breast cancer patients having a very low risk of disease recurrence (2/70; incidence of 0.8% per year) versus the high-risk group with PAI-1 (14 ng/mg protein) and cathepsin L (1,100 ng/mg protein) showing an increased recurrence rate (14/33; incidence of 8.6% per year). We conclude that by the combined determination of PAI-1 and cathepsin L tumor levels low-risk node-negative breast cancer patients may be identified. These patients most probably will not benefit from systemic adjuvant therapy.

Primary therapy of advanced ovarian cancer is standardized, the therapy in relapsed ovarian cancer however is still controversial. In a prospective study the benefit of secondary surgery and/or second-line chemotherapy were evaluated. 139 patients with relapsed ovarian cancer were stratified according to a treatment plan: patients with early relapse (recurrence-free interval 12 months) or primary progression during chemotherapy (n=43) were treated chemotherapeutically with etoposide (p.o. vs. i.v.). Patients with late relapse (recurrence-free interval12 months, n=96) were referred, if possible, to a secondary debulking operation, followed by a platinum-based chemotherapy. Remission-rate, toxicity and survival time were analyzed. Median survival time in theearly relapsegroup was 15 months compared to 30 months in patients with late relapse (p=0.0004). Within thelate relapsegroup patients with secondary debulking and chemotherapy (n=59) had a statistically significant survival advantage compared to patients who had only chemotherapy (n=37) (38 vs. 12 months, p0.0001). The unfavorable group of patients with early relapse should be treated chemotherapeutically, whereas in patients with late relapse a secondary debulking seems to improve prognosis.

Thrombomodulin (TM), recognized as an essential vessel wall cofactor of the antithrombotic mechanism, is also expressed by a wide range of tumor cells. Tumor cell lines subcloned from four patients with malignant melanoma displayed a negative correlation between TM expression and cell proliferation in vitro and in vivo. Overexpression of wild-type TM decreased cell proliferation in vitro and tumor growth in vivo. TM mutants with altered protein C activation capacity lead to a similar effect. In contrast, transfection of melanoma cells with mutant TM constructs, in which a portion of the cytoplasmic or lectin domain was deleted, abrogated the antiproliferative effect associated with overexpression of wild-type TM. Experiments performed with either peptide agonists/antagonists of the thrombin receptor, with hirudin, or with inhibitors of thrombin-TM interaction did not alter the growth inhibitory effect of TM overexpression. These data suggest that TM exerts an effect on cell proliferation independent of thrombin and the thrombin receptor, possibly related to the binding of novel ligands to determinants in the lectin domain which might trigger signal transduction pathways dependent on the cytoplasmic domain.

uPAR (CD87), the receptor for the urokinase-type plasminogen activator (uPA) facilitates tumor cell invasion and metastasis by focusing uPA proteolytic activity to the cell surface. As uPAR exists in various molecular forms, it is desirable to use well defined antibodies for analyses of uPAR antigen expression in human malignant tumors by immunological methods. Therefore, twelve monoclonal antibodies (MAbs) directed against uPAR were generated by using nonglycosylated, recombinant human uPAR (spanning amino acids 1 to 284), expressed in Escherichia coli, as the immunogen. The reaction pattern of these MAbs with the immunogen and a series of carboxyl-terminally truncated versions of uPAR demonstrated that at least six different epitopes of uPAR are recognized. All MAbs reacted under reducing conditions in immunoblot analyses with E. coli-expressed uPA and also with highly glycosylated, functionally intact, recombinant human uPAR expressed in Chinese hamster ovary (CHO) cells. Seven of the MAbs recognized CHO uPAR under nonreducing conditions as well. By flow cytofluorometric analyses, three of these MAbs were shown to bind to native human uPAR present on the cell surface of monocytoid U937 cells with MAb IIIF10 being the best. Saturation of uPAR with uPA on U937 cells completely blocked interaction of MAb IIIF10 with uPAR (mapped epitope, amino acids 52 to 60 of domain I of uPAR). In turn, preincubation of U937 cells with MAb IIIF10 efficiently reduced binding of uPA to uPAR, indicating that the epitope detected by MAb IIIF10 is located within or closely to the uPA-binding site of uPAR, and thus, this site may be a target to influence uPA/uPAR-mediated proteolysis in tumors. Binding of MAbs IID7 or IIIB11 (mapped epitope, amino acids 125 to 132 of domain II of uPAR) to uPAR is not affected when uPAR is occupied by uPA. As these MAbs reacted strongly with cellular uPAR antigen in formalin-fixed paraffin-embedded tumor sections, the domain-II-specific antibodies IID7 and IIIB11 may be useful for immunohistochemical studies of uPAR expression in tissue remodeling processes in tumor invasion. In conclusion, we have devised well defined and epitope-mapped MAbs to uPAR that are highly specific tools for detection and targeting of uPAR in tumor tissue.

121 patients with advanced ovarian cancer resistant to or relapsing following platinum-based chemotherapy participated in this prospective randomised multicenter study. The second-line treatment was indicated according to the relapse-free interval. 36 assessable patients were resistant to platinum-based chemotherapy or relapsed within 12 months following primary surgery. This group of patients with early relapse was randomized to oral or parenteral etoposide. 82 patients relapsed within an interval longer then 12 months following primary surgery; these patients with delayed relapse underwent a secondary tumour-debulking surgery. The data of this group of patients with delayed relapse will be published as soon as the time of observation allows adequate results. In this paper the efficiency of etoposide in the patients with early relapse is analysed according to the application form of the drug (oral vs. parenteral). No statistically significant difference in response rate, toxicity, and median survival time was found between the oral (n = 18) and parenteral (n = 18) treatment. In both application groups the response rate was 22%, the median survival time 14 and 13 months respectively. Alopecia and leucopenia were the most frequent toxicities. As a result etoposide is efficient in unfavorable ovarian cancer patients with early relapse. Because of better compliance etoposide should be administered parenterally. In respect of response rate and median survival time, etoposide is comparable with paclitaxel.

The relevance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI) type 1 in predicting the survival probability of patients with advanced ovarian cancer after radical surgery and adjuvant chemotherapy by assessing the patients' primary tumors has recently been shown by us (W. Kuhn et al., Gynecol. Oncol., 55: 401-409, 1994). In the present study, we determined uPA, uPA receptor, PAI-1, and PAI-2 concentrations in primary tumors and tumor-infiltrated omentum and retroperitoneal lymph nodes of ovarian cancer patients. The group consisted of 39 patients with advanced ovarian carcinoma stages Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) IIIc or IV; for comparison 7 patients with early carcinoma stage FIGO I were also included. In metastases of the omentum from ovarian cancer stage FIGO IIIc or IV patients, we noted a 4-fold elevated uPA content, a 2-fold increase in PAI-1, and also a significant increase in uPA receptor and PAI-2 over primary tumors. In metastases of the lymph nodes the levels of the respective antigens were also increased when compared to primary tumors. These data may indicate that elevated levels of components of the fibrinolytic system at sites of metastases may contribute to the aggressive potential of cancer cells by favoring their reimplantation and/or the consolidation of a new tumor stroma.

The lysosomal cysteine proteases cathepsin B and cathepsin L have been implicated in tumor spread and metastasis. To evaluate the prognostic impact of these proteases for disease-free survival and overall survival in breast cancer, the antigen content of cathepsin B and cathepsin L was determined using ELISA in tumor cytosol fractions of 167 breast cancer patients and in cytosols of 29 benign breast tissue specimens. Median values of 856 ng versus 76 ng cathepsin B/mg protein and of 428 ng versus 56 ng cathepsin L/mg protein were found in tumor versus benign cytosol fractions. A positive correlation between cathepsin B and cathepsin L (r = 0.32, P = 0.0000, Spearman test) was found. Cathepsin L was inversely correlated to hormone receptor status (P = 0.0014, Mann-Whitney U test) and to the presence of tumor necrosis (P = 0.009, Mann-Whitney U test). There were no correlations of cathepsin B or cathepsin L to tumor size, axillary lymph node status, age, menopausal status, tumor grading, and vessel invasion. To perform univariate analyses of disease-free survival, optimal cutoff points were determined by isotonic regression and classification and regression trees analysis. Patients with a high content of cathepsin B (1092 ng/mg protein) or cathepsin L (376 ng/mg protein) in their primary tumors had a statistically significantly higher risk of recurrence than patients with a low content of cathepsin B or cathepsin L (5-year disease-free survival: cathepsin B, 70% versus 52%, P = 0.04; cathepsin L, 83% versus 52%, P = 0.0002). Median follow-up was 39 (range, 6-73) months. Multivariate analysis for disease-free survival showed that cathepsin L is a strong and independent prognostic factor with a prognostic impact comparable to that of axillary lymph node status and grading. We conclude that both cathepsin B and cathepsin L may serve as prognostic factors for tumor recurrence in human breast cancer. These data underline the significance of tumor-associated proteolysis for invasion and metastasis.

In 90 patients with primary node-negative breast carcinomas we compared the prognostic impact of total S-phase fraction (SPF) and MIB1 proliferation rate (MIB1-PR) after a median follow-up of 34 months (9-72 months).SPF was determined flow cytometrically and MIB1 (Ki-67) immunohistochemically in parallel-cut, paraffin-embedded tissue sections.SPF was significantly correlated to tumor size and steroid hormone receptor status, MIB1-PR to grading. In univariate analysis both SPF and MIB1-PR were significant prognostic factors for disease-free survival. In multivariate analysis however, S-phase fraction was the only significant prognostic factor when compared to MIB1-PR, tumor size, steroid hormone receptor status, menopausal status, grading, lymph vessel invasion, and tumor necrosis.In our study SPF was of higher prognostic strength and may therefore be better suited for clinical application than MIB1-PR in node-negative breast cancer.

This study was performed to prove, if the use of methods, that are based on procedures for analysis of chaotic systems ("complexity analysis"), can give information on the fetal condition during birth and predict both the course of delivery and fetal outcome.Fetal ECG was derived in 37 pregnancies (36-42 weeks of gestation) during birth for two to seven hours. In 12 cases delivery was uncomplicated, in 24 cases FHR tracings had been pathological.Complexity analysis of fetal ECG signals showed within short observation intervals criteria that may be a hint for imminent fetal distress and acidosis.Application of complexity analysis in the future may give additional information for evaluation of intrapartum CTG in cases of suspicious FHR patterns.

Study Objective. To compare the outcome of laparoscopic treatment of adnexal masses with treatment by laparotomy. The procedures, their duration, and associated complications also were evaluated. Design. Women were randomized to undergo either procedure based on the ward to which they were admitted. Setting. A university teaching hospital. Patients. The 192 patients were admitted with a preoperative diagnosis of adnexal mass. Interventions. Surgical procedures were cystectomy, salpingectomy, oophorectomy, and unilateral or bilateral salpingo-oophorectomy. Organ-preserving techniques were used wherever possible. All tissue specimens were examined histologically. Measurements and Main Results. The mean duration of surgery was statistically not significantly different between the groups, 96.8 minutes for minimally invasive surgery, and 116 minutes for laparotomy. Organ preservation did reach statistical significance at 65.7% and 17.2%, respectively (p

The efficacy and safety of two antibiotic regimens for the treatment of acute pelvic inflammatory disease (PID) was compared in a prospective and randomised study. 57 patients received either 0.2 gms ciprofloxacin intravenously b.i.d. in combination with 0.5 g metronidazole intravenously t.i.d. (n = 26), or alternatively 2 g cefoxitin intravenously t.i.d. in combination with doxycycline 0.1 g b.i.d. (n = 31). After commencing therapy intravenously, medication with ciprofloxacin, metronidazole and doxycycline was continued orally after two or three days. In the ciprofloxacin/metronidazole group, PID was found to be severe in 7, moderate in 12 and mild in 7 patients. The numbers in the cefoxitin/doxycycline group were 8, 20 and 3 respectively. The clinical result after treatment with ciprofloxacin/metronidazole was resolution of all symptoms in 24 patients and improvement in 2 others. In the cefoxitin/doxycycline treated group, resolution was found in 27 patients, improvement in 2 others. Failure occurred in 2 patients. 53 different microorganisms as the suspected cause of PID were isolated in the ciprofloxacin/metronidazole group and 56 in the cefoxitin/doxycycline group. According to our clinical and bacteriological criteria, treatment for PID was successful in 97% of the ciprofloxacin/metronidazole group and in 87% of the cefoxitin/doxycycline group. Adverse reactions were found in 4 patients in the ciprofloxacin/metronidazole treated group. Therapy had to be terminated in 3 of these patients. In the cefoxitin/doxycycline group 2 patients had adverse reactions, and therapy had to be terminated in one of these patients. According to our results, both antibiotic regimens can be recommended for the treatment of PID.

The serine protease urokinase-type plasminogen activator (uPA) plays a key role in tumor-associated proteolysis in malignant solid tumors. Proteolytic activity of uPA is controlled by its naturally occurring plasminogen activator inhibitor type 1. As an initial observation, a correlation of enzymatic uPA activity in breast cancer cytosols with prognosis was described in 1988 (Duffy et al., Cancer (Phila.), 62: 531-533, 1988). A pronounced prognostic impact of uPA, independent of classical risk parameters, was then first demonstrated in detergent-extracted (Triton X-100) breast cancer tissues by applying enzyme-linked immunosorbent assay techniques (Jänicke et al., Lancet, 2: 1049, 1989; Fibrinolysis, 4:69-78, 1990; Duffy et al., Cancer Res., 50: 6827-6829, 1990). In addition, not only uPA but also plasminogen activator inhibitor type 1 were shown to be of prognostic value in breast cancer (Jänicke et al., Semin. Thromb. Hemostasis, 17: 303-312, 1991; Breast Cancer Res. Treat., 24: 195-208, 1993). Subsequently, the prognostic value of uPA and plasminogen activator inhibitor type 1 was also confirmed in studies using archived "cytosol fractions" of breast cancer tissues (Foekens et al., Cancer Res., 52: 6101-6105, 1992; Spyratos et al., J. Natl. Cancer Inst., 84: 1266-1272, 1992; Grondahl-Hansen et al., Cancer Res., 53: 2513-2521, 1993; Sumiyoshi et al., Int. J. Cancer, 50: 345-348, 1992). A direct comparison of both methods with regard to prognosis, however, was lacking. We therefore prepared both the detergent-treated tissue extracts and the cytosol fractions from the same breast cancer specimens to allow a direct comparison of both methods. In 247 breast cancer patients investigated, the Triton X-100-extracted tissues revealed about twice as much uPA antigen (uPATx: median, 2.32 ng/mg protein) than the cytosol fractions (uPAcyt: median, 1.07 ng/mg protein). In contrast, the presence of Triton X-100 did not result in an increase of PAI-1 (PAI-1Tx: median, 6.34 ng PAI-1/mg protein) compared to the cytosol fractions (PAI-1cyt: median, 7.15 ng PAI-1/mg protein). Good correlations between uPATx and uPAcyt (R = 0.72) and between PAI-1Tx and PAI-1cyt (R = 0.88) were observed. Furthermore, PAI-1 and uPA are moderately correlated with each other (uPATx versus PAI-1Tx: R = 0.40; uPAcyt versus PAI-1cyt: R = 0.39). The prognostic power of uPA showed its best advantage in Triton X-100-extracted tissues (RR = 3.22), most pronounced in the subgroups of node-negative and premenopausal patients, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Hydronephrosis as the first symptom of primary metastasised breast cancer is described in two case reports. The literature regarding this topic is also discussed. Although retroperitoneal metastases are rarely found, patients with breast cancer should undergo a regular sonographic control of the kidneys, simultaneously with the routine ultrasound of the upper abdomen.

Various parameters associated with fibrinolysis were examined in plasma and placenta tissue extract in 18 patients with HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count). A significant increase in plasma concentrations of tPA and PAl-1 was observed in the HELLP patients in comparison to 18 pregnant women of the control group (equal duration of pregnancy). In contrast, there was no difference in plasma concentrations of uPA, uPA-receptor and D-dimer. In placenta tissue extract, significant differences were found just as rarely for uPA, uPA-receptor and PAl-1 as for tPA and D-dimer. Our findings indicate, that endothelial damage with release of tPA may be involved in the pathophysiological pathway of HELLP syndrome. Increased plasma levels of PAl-1 may reflect deficient fibrinolysis resulting in impairment in microcirculation. Clinical relevance of tPA and PAl-1 plasma concentration as possible predictor of hypertensive pregnancy complications will have to be studied further.

Accumulation of p53 protein resulting in levels detectable by immunohistochemistry (IHC) has been proposed as an indicator of mutation of the p53 gene. We have investigated a panel of 23 fresh-frozen breast cancers by IHC (PAb 1801), Southern and Northern blot analysis, and direct sequencing of the mutation hot spot regions (exons 5-8) of the p53 gene. Three tumors (13%) showed an intense nuclear staining in the majority of malignant cells, but only one of these showed a mutation of the p53 gene (codon 237, Arg to His). Furthermore, a mutation (5-bp deletion) was identified in a tumor that showed no p53 immunoreactivity. Our results indicate that accumulation of p53 protein, as detectable by IHC, is not a reliable indicator for p53 gene mutation in human breast cancer.

The aetiology of preterm rupture of membranes is not yet completely understood. Local infections of the vagina and cervix have attracted special attention during the last years. Ascending infection with subsequent chorioamnionitis is a common complication of preterm rupture of membranes. Recognition of the beginning of a chorioamnionitis is usually based on clinical symptoms and laboratory findings like white blood cell count and C-reactive protein. The purpose of this study was to find out the diagnostic value of elastase, a protease of polymorphonuclear granulocytes, which is known to be involved in inflammatory processes. Fifteen out of thirty-three patients with preterm rupture of membranes developed a chorioamnionitis. Elastase plasma concentration levelsor = 32 ng/ml one day before delivery showed a significant correlation (p = 0.02) to the development of a chorioamnionitis. At this time neither white blood cell count, nor rectal body temperature showed significant correlations. Low elastase levels do not exclude an infection, whereas high levels indicate an infectious process. We conclude that elastase is a relevant marker of chorioamnionitis.

There is plenty of evidence that survival time associated with advanced ovarian cancer is predominantly related to the amount of residual tumor after primary operation. However, there are only few and inconclusive reports concerning the effect of second debulking procedures on survival time after relapse.To evaluate the effect of radical second operation, 30 patients with clinically diagnosed relapses had second operations after a median recurrence-free interval of 16 months. Considerable efforts were made to resect all tumor tissue. Complete resection was achieved in 14 of 39 (47%) patients, and residual tumors smaller than 2 cm remained in 12 (40%) patients. In 19 (63%) patients, intestinal resections were necessary. Operation time, blood units needed, hospital stay, and complication rates were comparable to those associated with primary debulking procedures.Survival time after second operation was closely correlated with the residual tumor remaining after second surgical procedure and also with the length of the recurrence-free interval. Patients with complete resections had significantly longer survival times than those with residual tumors of less than 2 cm (median, 29 months versus 9 months; P = 0.004). Patients with a recurrence-free interval of more than 12 months had a longer survival time than those with a shorter disease-free time (median, 29 months versus 8 months; P = 0.002). Postoperative treatment also was shown to influence survival time, whereas grade of the tumor (P = 0.74), age of the patient (P = 0.87), and initial FIGO stage (P = 0.58) had no influence on survival time after second operation. Multivariate analysis (Cox regression) revealed that residual tumor after second surgical procedure (relative risk, 4.7) was the most important independent variable predicting survival time after second surgical procedure. Recurrence-free interval (relative risk, 2.7) and postoperative (second-line) treatment (relative risk, 3.0) were equally potent variables. Residual tumor after primary operation, was almost significant (P = 0.06) in the univariate analysis, but was canceled in the multivariate setting by the recurrence-free interval. Again, FIGO stage, grade of the tumor, and patient age had no predictive value.The authors conclude that radical surgical procedure can prolong survival times in patients with recurrent ovarian cancer. Patients who had a complete resection of cancer tissue in the primary operation or those who experienced a disease-free interval of more than 12 months after primary operation are most likely to benefit from second operation in recurrent ovarian cancer. Radical surgical procedure should be offered to these patients to enhance efficacy of second-line chemotherapy, which is of limited value in bulky recurrent disease.

23 healthy smokers with uneventful singleton pregnancies underwent Doppler-flow measurements of the foetal umbilical artery and middle cerebral artery before and ten minutes after smoking one cigarette. In both arteries the resistance indices (RI) did not change significantly. Maternal mean arterial blood pressure and heart rate increased significantly after the smoking of the cigarette. Neither the group with an RI increase of greater than or equal to 5% in the foetal umbilical artery (n = 7) nor the group with an increase of the RI in the foetal umbilical artery and, at the same time, a decrease of the RI in the arteria cerebri media (n = 5), showed a significant difference concerning maternal haemodynamic parameters and the number of cigarettes smoked before and during pregnancy. The results suggest, that the smoking of one cigarette in uneventful pregnancy does not produce acute haemodynamic effects in the foetus.

The Hellp syndrome is a complication of toxemia. It may occur before, during or after childbirth and may not be accompanied by any sign of toxemia. The main clinical sign is pain in the hepatic region. Haptoglobin is the most reliable parameter to demonstrate hemolysis, which is one of the disorders related to this syndrome. In the authors' opinion, early diagnosis and immediate delivery by Cesarean are the appropriate methods to use to reduce maternal and perinatal mortality. Conservative treatment is not generally effective and is dangerous.

26 women with an uneventful singleton pregnancy near term underwent scheduled Caesarean section with lumbar epidural anaesthesia (PDA). Doppler-flow measurements of the foetal umbilical artery and the maternal hypogastric artery were taken before and after sympathicolysis was established. The mean arterial blood pressure was maintained unchanged between the measurements. Both measurements were performed by the same examiner. Three patients received additional general anaesthesia during the operation because of inadequate analgesia. The resistance index (RI) with PDA decreased significantly in 23 patients by a mean of 7.6% (p less than 0.05). The RI in those patients (n = 3) with inadequate analgesia increased by a mean of 27%. The physiologically reversed diastolic flow in the maternal hypogastric artery was mathematically taken into consideration by applying the quotient of the systolic flow and the diastolic reversed flow (V/R-quotient). The V/R-quotient increased with established sympathicolysis by more than 180% in all but one patient. The neonates' mean umbilical artery pH was 7.32 (7.27 to 7.41), the mean five minute Apgar score was 10 (8 to 10).

Obstetrical management and fetal outcome were individually analysed annually from 1987 to 1990, using computerised equipment. The individual results were discussed anonymously with all colleagues, but every colleague knew his own results. Clinical methods and obstetrical management had not been changed during the investigation period. The number of high-risk pregnancies increased significantly, whereby the incidence of risk-related surgical interventions decreased at the same rate. The number of FBA and EDA increased significantly (p less than 0.001). The mean umbilical artery pH increased during the last four years from 7.27 to 7.30 (p less than 0.05), i.e. that each colleague achieved an improvement. The incidence of acidotic values in the umbilical artery decreased significantly (pH less than 7.20 from 13.2% to 7.1%, pH less than 7.10 from 3.6% to 1.2% p less than 0.01). The rate of caesarean section increased (p less than 0.05) and the number of vaginal operative deliveries did not change significantly. As early as one year after the introduction of the individual efficiency control, a significant improvement in obstetrical results could be demonstrated.

Lupus erythematosus first diagnosed in pregnancy or puerperium is a problem both for the obstetrician and for the internist. We report on a case of lupus manifestation with signs and symptoms similar to sepsis diagnosed in the puerperium.

The capacity of solid tumours to invade the surrounding tissue and to metastasize, is correlated with the formation and degradation of structural elements in the vicinity of the tumour cells. Substances with both procoagulant activity and fibrinolytic activity are important factors in the formation or degradation of a "fibrin-fibronectin-gel matrix". This gel is subsequently transformed into the extracellular matrix, which, together with cells, will form the tumour stroma. When analyzing tumour stroma degradation products, it is obvious that the protease plasmin catalyses the disintegration of fibrin and fibronectin. Additional compounds of the tumour stroma and of the basal membrane are also, at least in part, broken down by plasmin or other proteases, such as collagenase IV and cathepsin D. The plasminogen activator urokinase (uPA) seems to play a central role as it was shown that elevated content of uPA is correlated with a high risk of early relapse and shorter overall survival, at least in breast cancer. It has been shown, that by means of quantifying uPA, patients with a relative high or low risk can even be selected within the classical risk groups, which so far are defined by the locoregional extension of the tumour and the hormone receptor status only. Evidently, as uPA content in human breast cancer tissue is an independent prognostic factor, one may speculate, that those experimental or in vitro data, which correlated increase in uPA-synthesis with malignancy, may be of direct relevance for human tumour biology. Moreover, due to these recent observations on the prognostic significance of tumour-associated proteases, new aspects for the selection of risk collectives within the node-negative breast cancer patients for adjuvant therapy have to be considered. It may well be possible, that one may affect tumour invasion and metastasis by inhibiting protease action of solid tumours by disturbing the binding of proteases to tumour cell surface receptors. As it is only a quantitative aspect, which separates benign physiological processes from tumour cell pathophysiology, experimental evidence suggests, that less drastic forms of palliative therapy can be proposed.

Increased sialic acid levels reflecting tumor burden are found on the surface of T-lymphocytes and in the plasma of patients with carcinoma of the mammary gland. The data of the determinations of sialic acid content and distribution on T-cells, using microanalytical methods such as HPLC and a colorimetric test, show that the total sialic acid content is increased by about 60% and that nearly 80-90% of the sialic acids consist of N-acetyl-9-O-acetyl-neuraminic acid, in comparison to the healthy controls (not containing O-acetylated neuraminic acid). Investigations on lymphocytes of malignant melanoma patients show similar changes of sialic acid content and distribution on the cell surface. Increased sialic acid levels are also found in the plasma of patients with cancer but no O-acetylated derivative can be found. Furthermore the examinations show that the separation of the T-lymphocytes from the total lymphocyte fraction is not required. Determination of sialic acids in the total lymphocyte fraction can be a simplification in carrying out further diagnostic investigations. A high level of sialic acids as "antirecognition factor" seems to be not only a marker of tumor cells but also an attribute of T-lymphocytes, involved in the defence against the malignoma (malignant melanoma, breast cancer). Considering the possible contribution of sialic acid to the immunoregulatory protective mechanism during the first stage of pregnancy, sialic acid content and distribution on T-cells of pregnant women are investigated. Both an increase and a change in the distribution of sialic acids can be excluded.

When human granulocytes were stimulated with the chemotactic peptide FNLPNTL (N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosinyl- lysin; in the presence of cytochalasin B), proteolytic enzymes were released which prevented activation of tumor-cell derived pro-uPA by plasmin. Elastase was identified by use of eglin C (elastase inhibitor) and an inhibitory monoclonal antibody to elastase as the functional proteolytic enzyme in these granulocyte supernatants. Purified human granulocyte elastase cleaves pro-uPA at amino acid position lle159-lle160 thus generating an enzymatically inactive two-chain form of uPA, as judged by N-terminal amino acid sequence analysis. An additional minor elastase-mediated cleavage site was detected at position Thr165-Thr166. This form of uPA was indistinguishable by SDS-PAGE from plasmin-generated enzymatically active HMW-uPA. Action of plasmin on the proenzyme form of uPA (pro-uPA) generates an enzymatically active uPA-molecule (high molecular weight form; HMW-uPA) which is cleaved at amino acid position Lys158-lle159 (Mr = 33,000 (B-chain) and 22,000 (A-chain). Thus elastase cannot substitute for plasmin in the proteolytic activation of pro-uPA to enzymatically active HMW-uPA. Enzymatically active HMW-uPA, however, was not affected by elastase. Elastase-containing granulocytes were identified by immunohistochemical staining of elastase in breast cancer tissue. Granulocytes were located close to the tumor cells and also in the tumor stroma surrounding the tumor nests. These tumor cells contain pro-uPA. Evidently, the conversion of tumor cell pro-uPA into enzymatically active HMW-uPA is controlled by elastase released from granulocytes into the tumor tissue.

The risk of thrombo-embolic complications increases in surgical gynaecological oncology as a consequence of difficult and long-lasting interventions. In gynaecologic operations without any drug prophylaxis thrombosis has been reported by 24-29%, whereas in operations of progressed oncological findings thrombo-embolic complications arise in almost every second case. Such complications have to be taken seriously due to difficulty treatable sequelae (post-thrombic syndrome) and due to potentially lethal pulmonary embolism. Furthermore, they are important causes of postoperative early mortality. Diagnosis of a deep thrombosis is insecure even for experienced clinicians. We have various diagnostical means at our disposal, such as phlebography, sounding and 125-iodine-fibrinogen-testing. Differentiated drug medication for the prevention and therapy of thrombo-embolism is definitely indicated. There are also different kinds of physical and drug-aided means, which can be applied according to the individual situation.