Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1.

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)

Primary tumor and metastasis in ovarian cancer differ in their content of urokinase-type plasminogen activator, its receptor, and inhibitors types 1 and 2.

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.

Prognostic value of the cysteine proteases cathepsins B and cathepsin L in human breast cancer.

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.

Disease-adapted relapse therapy for ovarian cancer: results of a prospective study.

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 interval >12 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 the group was 15 months compared to 30 months in patients with late relapse (p=0.0004). Within the group 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, p<0.0001). 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.

[Prognostic significance of the S-phase and MIB1 (Ki-67) proliferation parameters in node-negative breast carcinoma]. / Prognostische Bedeutung der Proliferationsparameter S-Phase und MIB1 (Ki-67) beim nodal-negativen Mammakarzinom.

OBJECTIVE: 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). METHODS: SPF was determined flow cytometrically and MIB1 (Ki-67) immunohistochemically in parallel-cut, paraffin-embedded tissue sections. RESULTS: 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. CONCLUSIONS: 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.

Insights into adenovirus host cell interactions from structural studies.

Human adenoviruses cause a significant number of acute respiratory, enteric and ocular infections, however they have also served as useful model systems for uncovering fundamental aspects of cell and molecular biology. In addition, replication-defective forms of adenovirus are being used in gene transfer and vaccine clinical trials. Over the past decade, steady advances in structural biology techniques have helped reveal important insights into the earliest events in the adenovirus life cycle as well as virus interactions with components of the host immune system. This review highlights the continuing use of structure-based approaches to uncover the molecular features of adenovirus-host interactions.

Tumour cell detection in the bone marrow of breast cancer patients at primary therapy: results of a 3-year median follow-up.

We examined bone marrow aspirates from 100 metastasis-free primary breast cancer patients. In 38/100 patients (38%), tumour cells were detected in the marrow using an immunocytochemical technique with a cocktail of two monoclonal antibodies: anti-EMA and anti-cytokeratin. Median follow-up was 34 months: 15/38 (39%) tumour cell-positive patients have since relapsed, but only 9/62 (15%) tumour cell-negative patients. The median interval between tumour cell detection and relapse was 11.4 months. No statistically significant correlation existed between tumour cell presence and 'established' prognostic factors. However, relapse-free survival was significantly shorter in tumour cell-positive patients. Multivariate analysis showed tumour cell presence as a strong, significant prognostic factor for relapse-free as well as overall survival. We conclude that screening for tumour cells in bone marrow of primary breast cancer patients identifies high-risk patients for early relapse. In particular, patients with node-negative tumours who have tumour cells in their bone marrow may require subsequent systemic therapy.

[Importance of plasma PMN granulocyte elastase concentration determination in pregnant patients with premature rupture of fetal membranes]. / Die Bedeutung der PMN-Granulozyten-Elastase-Konzentrationsbestimmung im Plasma von Schwangeren mit vorzeitigem Blasensprung.

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 levels > or = 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.

Urokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum-based chemotherapy.

Fifty-one patients with advanced ovarian cancer FIGO III were studied to determine new tumor biology-oriented prognostic factors. The tumor-associated protease urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 were detected in malignant ovarian cancer tissue extracts. The concentration of both factors was significantly higher in malignant tissue compared with benign ovarian tissue specimens (P < 0.01). According to a cutoff value for uPA and PAI-1, patients could be subdivided into risk groups: patients with low uPA and PAI-1 (uPA < 0.9 ng/mg protein and PAI-1 < 13.5 ng/mg protein) had a statistically significant better prognosis than patients with high uPA and/or high PAI-1 (P = 0.01). Especially in patients without residual tumor, uPA and PAI-1 were strong prognostic parameters (P = 0.03). In multivariate analysis the residual tumor was the most powerful prognostic indicator (P = 0.013) closely followed by uPA and PAI-1 (P = 0.047). Moreover, there is a strong correlation between uPA levels and lymph node involvement (P = 0.004) and a trend to higher uPA-levels in poorly differentiated (G3 + G4) cancers (P = 0.059) and in tumors with increased ascites production (P = 0.09). A trend to higher PAI-1 levels was also noted in the above-mentioned tumor situations. The differences, however, were of no statistical significance. From these data it can be concluded that the pattern of tumor spread (mainly intraabdominally versus additional extensive lymph node involvement) and tumor biological appearance (ascites production, differentiation) are reflected by the expression of the tumor-associated proteolytic factors uPA and PAI-1. Adjuvant therapy might be adjusted to uPA and PAI-1 not only in advanced ovarian cancer but also in carcinoma of low malignant potential or early-stage ovarian carcinoma.

Tumor-associated urokinase-type plasminogen activator: biological and clinical significance.

Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. Receptor-bound urokinase-type plasminogen activator (uPA) appears to play a key role in these events. uPA converts plasminogen into plasmin and thus mediates pericellular proteolysis during cell migration and tissue remodeling under physiological and pathophysiological conditions. uPA is secreted as an enzymatically inactive proenzyme (pro-uPA) by tumor cells and stroma cells. uPA exerts its proteolytic function on normal cells and tumor cells as an ectoenzyme after having bound to a high-affinity cell surface receptor. After binding, pro-uPA is activated by serine proteases (e.g. plasmin, trypsin or plasma kallikrein) and by the cysteine proteases cathepsin B or L, resp. Receptor-bound enzymatically active uPA converts plasminogen to plasmin which is bound to a different low-affinity receptor on tumor cells. Plasmin then degrades components of the tumor stroma (e.g. fibrin, fibronectin, proteoglycans, laminin) and may activate procollagenase type IV which degrades collagen type IV, a major part of the basement membrane. Hence receptor-bound uPA will promote plasminogen activation and thus the dissolution of the tumor matrix and the basement membrane which is a prerequisite for invasion and metastasis. Tissues of primary cancer and/or metastases of the breast, ovary, prostate, cervix uteri, bladder, lung and of the gastrointestinal tract contain elevated levels of uPA compared to benign tissues. In breast cancer uPA and PAI-1 antigen in tumor tissue extracts are independent prognostic factors for relapse-free and overall survival.

Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer.

Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. The serine protease urokinase-type plasminogen activator (uPA), which is elevated in solid tumors, appears to play a key role in these processes. We used enzyme-linked immunoassays (ELISA) to test for uPA antigen and its inhibitor PAI-1 in tumor tissue extracts of 247 breast cancer patients who were enrolled in a prospective study. The relation of these data to known prognostic factors and to other variables such as DNA analysis and cathepsin D was studied. Disease-free and overall survival were analyzed according to Cox's proportional hazard model. The major new finding is that breast cancer patients with either high uPA (> 2.97 ng/mg protein) or high content of the uPA inhibitor PAI-1 (> 2.18 ng/mg protein) in their primary tumors have an increased risk of relapse and death. Multivariate analyses revealed uPA to be an independent and strong prognostic factor. The impact of uPA is as high as that of the lymph node status. In node-negative patients the impact of uPA is closely followed by that of PAI-1. Since uPA and PAI-1 are independent prognostic factors, the node-negative patients could be subdivided further by combining these two variables. In this refined analysis, patients whose primary tumors have lower levels of both antigens evidently have a very low risk of relapse (93% disease-free survival at three years) in contrast to patients with high uPA and high PAI-1 (55% disease-free survival at three years). The combination of uPA and PAI-1 in our group of patients with axillary node-negative breast cancer allows us to identify the 45 percent of patients having an increased risk of relapse. Consequently, more than half of the patients had less than a 10% probability of relapse and thus would possibly be candidates for being spared the necessity of adjuvant therapy.

[Occupational cancer study of asbestos: possibilities and limits of epidemiologic studies on the causes of death in West Germany]. / Berufskrebsstudie Asbest: Möglichkeiten und Grenzen epidemiologischer Todesursachenforschung in der Bundesrepublik Deutschland.

The study is based on 3990 men and women exposed to asbestos dust for at least three years at their place of work, and prospectively and epidemiologically examined since 1 January, 1977. By 31 December, 1983, 336 had been registered as having died. Calculation of standard mortality rates indicates that the incidence of malignant tumour as cause of death was much higher than in the general population of the FRG, that of fatal mesothelioma about 100 times as high. Standard mortality rate for lung cancer was increased by 48% and 175%, respectively, depending on whether exposure to asbestos dust had ended after (subgroup I) or before (subgroup II) 1 January, 1972. Proportional mortality rate of 43% of tumours at all locations, with about 14% lung cancer and about 9% fatal mesothelioma cases in subgroup II, approaches the internationally recognized frequency of asbestos-associated tumours.

Radical surgical procedure improves survival time in patients with recurrent ovarian cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

-Intravenous or oral etoposide therapy of platinum refractory ovarian cancer with early recurrence. Results of a prospective randomized study-. / Die intravenöse oder orale Etoposid-Therapie des Platin-refraktären Ovarialkarzinom-Frührezidivs. Ergebnisse einer prospektiven randomisierlen Studie.

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.

Mortality rates in the Federal Republic of Germany following previous occupational exposure to asbestos dust.

In 1972, a procedure was introduced by the Industrial Injuries Insurance Institutes (Berufsgenossenschaften) of the Federal Republic of Germany, which is to be used by the special occupational health service for employees exposed to asbestos dust. Since 1 January 1972, occupational health examinations are performed when exposure to asbestos dust has been of at least 3 years' duration. On 1 January 1977, a prospective cohort study was started with employees formerly exposed to asbestos dust whilst working for companies manufacturing or using asbestos. Data on these persons are collected in the Central Register of Employees Exposed to Asbestos Dust of the Industrial Injuries Insurance Institutes. A total of 3,070 male and female employees in whom asbestos exposure terminated after 1 January 1972 formed subcohort I of the study. For comparison, 665 persons whose exposure terminated before 1 January 1972 served as subcohort II. In addition to several other inclusion criteria, each individual's permission was required before personal data could be evaluated. Of the subjects in the two subcohorts, 185 and 71, respectively, had died by 31 December 1982. Tumours were more frequently than this cause of death is expected in the general population. In addition to a high incidence of mesothelioma, the standard mortality rate was especially increased for lung cancer. The proportional mortality rates of about 40% for tumours of all sites (with about 17% lung cancer and 8% mesothelioma) especially in subcohort II, seemed to be comparable to the international figures for epidemiological mortality.

Prognostic impact of proliferation-associated factors MIB1 (Ki-67) and S-phase in node-negative breast cancer.

MIB1 proliferation rate (MIB1-PR) and total S-phase fraction (SPF) were retrospectively determined in formalin-fixed, paraffin-embedded sections of 90 primary node-negative breast carcinomas. None of the patients had received adjuvant systemic therapy. Median follow-up in patients still alive at the time of analysis was 37.5 months (16-72 months). Immunostaining of Ki-67 antigen was performed using the monoclonal antibody MIB1 and the APAAP technique. An adjacent 50-microm paraffin section was used for flow cytometric S-phase determination. Results were compared to established clinicopathological prognostic factors. MIB1-PR was significantly correlated to grading (P = 0.018); SPF was significantly correlated with tumour size (P = 0.041) and inversely with steroid hormone receptor status (P = 0.03). A significant correlation between MIB1-PR and SPF was found in aneuploid (P = 0.025) but not in diploid tumours (P = 0.164). In univariate analysis, both MIB1-PR (optimized cut-off of 25%) and SPF (optimized cut-off of 8%) were significant prognostic factors for disease-free survival (DFS) (MIB1-PR, P = 0.0224; SPF, P = 0.0028). In multivariate analysis, however, only SPF remained significant; it was the strongest prognostic factor for DFS (P = 0.0073), stronger than MIB1-PR or established clinicopathological prognostic factors. We thus conclude that MIB1-PR and SPF provide additional prognostic information in node-negative breast cancer. However, in our study, flow cytometrically determined SPF had the greater prognostic impact.

[Developments in the therapy of advanced FIGO III ovarian cancer]. / Entwicklungen in der Therapie des fortgeschrittenen Ovarialkarzinoms FIGO III.

From 1982 to 1992 103 patients with ovarian cancer stage FIGO III have been treated. In 38% of the patients there was no residual tumour postoperatively, in 40.8% the residual tumour was smaller than 2 cm. In 51.5% bowel resections were necessary, a stoma was unavoidable in just one case. A lymphadenectomy (pelvic, paraaortic or combined) was done in 46.6% of the patients. Postoperatively, 54.4% of the patients received a platinum-based chemotherapy, in the other patients other kinds of chemotherapy were applied. A radiation of the whole abdomen was done only in 3.9%. A median survival time for more than 60 months could be achieved in tumour-free patients due to the increased radical operations in combination with the platinum based chemotherapy. The lymphadenectomy seems to prolong the survival time of the patients. The positive nodal status is definitely unfavourable for the prognosis. By this therapeutic approach, an increased survival time with a good life quality can be achieved.

Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc.

Strong evidence has accumulated on the prognostic value of tumour-associated proteolytic factors in patients afflicted with solid malignant tumours, including advanced ovarian cancer. We evaluated the prognostic impact of the protease urokinase plasminogen activator (uPA) and its inhibitor PAI-1 on overall survival in patients with advanced ovarian cancer stage FIGO IIIc in order to select patients at risk. uPA and PAI-1 antigen were determined by ELISA in primary tumour tissue extracts of 86 ovarian cancer patients FIGO stage IIIc enrolled in a prospective study. Univariate and multivariate analyses were performed using the Cox proportional hazard model. The time-varying coefficient model of Gray was used to assess the time-dependent strength of prognostic factors tumour mass, uPA and PAI-1 on overall survival. In all patients, uPA and PAI-1 (optimized cut-offs of 2.0 and 27.5 ng mg(-1) protein respectively), in addition to the traditional prognostic parameters of residual tumour mass, nodal status, grading and ascites volume, were of prognostic significance in univariate analysis for overall survival. Even in patients with residual tumour mass (n = 43), the statistically independent prognostic impact of PAI-1 persisted, allowing further discrimination between low- and high-risk patients. In multivariate analysis, residual tumour mass (P < 0.001, relative risk (RR) 4.5), PAI-1 (P < 0.001; RR 3.1) and nodal status (P = 0.022, RR 2.6) turned out to be strong, statistically independent prognostic parameters. Evaluation of the time-dependent prognostic impact of residual tumour mass and PAI-1 on overall survival (n = 86, 50 months) revealed that the prognostic power of these factors increased with time. In patients with advanced ovarian cancer, both residual tumour mass and PAI-1 are statistically independent strong prognostic factors. Even within patient subgroups with or without residual tumour mass, PAI-1 allowed selection of patients at risk who might benefit from individualized therapy protocols.