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H Graeff

Publications and source records attributed to H Graeff.

At least 19 recordsLinked to original sources
PubMed1992

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.

Adult↗
PubMed1992

Effective activation of the proenzyme form of the urokinase-type plasminogen activator (pro-uPA) by the cysteine protease cathepsin L.

Increased levels of both the cysteine protease, cathepsin L, and the serine protease, uPA (urokinase-type plasminogen activator), are present in solid tumors and are correlated with malignancy. uPA is released by tumor cells as an inactive single-chain proenzyme (pro-uPA) which has to be activated by proteolytic cleavage. We analyzed in detail the action of the cysteine protease, cathepsin L, on recombinant human pro-uPA. Enzymatic assays, SDS-PAGE and Western blot analysis revealed that cathepsin L is a potent activator of pro-uPA. As determined by N-terminal amino acid sequence analysis, activation of pro-uPA by cathepsin L is achieved by cleavage of the Lys158-Ile159 peptide bond, a common activation site of serine proteases such as plasmin and kallikrein. Similar to cathepsin B (Kobayashi et al., J. Biol. Chem. (1991) 266, 5147-5152) cleavage of pro-uPA by cathepsin L was most effective at acidic pH (molar ratio of cathepsin L to pro-uPA of 1:2,000). Nevertheless, even at pH 7.0, pro-uPA was activated by cathepsin L, although a 10-fold higher concentration of cathepsin L was required. As tumor cells may produce both pro-uPA and cathepsin L, implications for the activation of tumor cell-derived pro-uPA by cathepsin L may be considered. Different pathways of activation of pro-uPA in tumor tissues may coexist: (i) autocatalytic intrinsic activation of pro-uPA; (ii) activation by serine proteases (plasmin, kallikrein, Factor XIIa); and (iii) activation by cysteine proteases (cathepsin B and L).

Amino Acid Sequence↗
PubMed1992

[The effect of smoking on the resistance index of the umbilical artery and the middle cerebral artery].

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.

Adult↗
PubMed1992

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.

Animals↗
PubMed1992

[HELLP syndrome].

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Asphyxia Neonatorum↗
PubMed1992

[The Hellp syndrome. Clinical and laboratory test results].

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.

Adolescent↗
PubMed1991

Cathepsin B efficiently activates the soluble and the tumor cell receptor-bound form of the proenzyme urokinase-type plasminogen activator (Pro-uPA).

Action of purified human cathepsin B on recombinant single-chain urokinase-type plasminogen activator (pro-uPA) generated enzymatically active two-chain uPA (HMW-uPA), which was indistinguishable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot from plasmin-generated HMW-uPA and from elastase- or thrombin-generated inactive two-chain urokinase-type plasminogen activator. Preincubation of cathepsin B with E-64 (transepoxysuccinyl-L-leucylamino- (4-guanidino)butane, a potent inhibitor for cathepsin B) prior to the addition of pro-uPA prevented the activation of pro-uPA. The cleavage site within the cathepsin B-treated urokinase-type plasminogen activator (uPA) molecule, determined by N-terminal amino acid sequence analysis, is located between Lys158 and Ile159. Pro-uPA is cleaved by cathepsin B at the same peptide bond that is cleaved by plasmin or kallikrein. Binding of cathepsin B-activated pro-uPA to the uPA receptor on U937 cells did not differ from that of enzymatically inactive pro-uPA, indicating an intact receptor-binding region within the growth factor-like domain of the cathepsin B-treated uPA molecule. Not only soluble but also tumor cell receptor-bound pro-uPA could be efficiently cleaved by cathepsin B to generate enzymatically active two-chain uPA. Thus, cathepsin B can substitute for plasmin in the proteolytic activation of pro-uPA to enzymatically active HMW-uPA. In contrast, no significant activation of pro-uPA by cathepsin D was observed. As tumor cells may produce both pro-uPA and cathepsin B, implications for the activation of tumor cell-derived pro-uPA by cellular proteases may be considered.

Blotting, Western↗
PubMed1991

[Change in acylneuraminic acid content of T-lymphocytes and in plasma in breast cancer].

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.

B-Lymphocytes↗
PubMed1991

Human tumor cell urokinase-type plasminogen activator (uPA): degradation of the proenzyme form (pro-uPA) by granulocyte elastase prevents subsequent activation by plasmin.

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.

Breast Neoplasms↗
PubMed1991

Fluorescent probes as tools to assess the receptor for the urokinase-type plasminogen activator on tumor cells.

Flow cytofluorometric protocols (FACScan) are described for the rapid and quantitative real-time analysis of binding of FITC-pro-u-PA to cell surface receptors (u-PAR) on living, resting, and also on PMA-stimulated human monocytic U937 cells. Binding of pro-u-PA was visualized by CLSM. This fairly new technique is superior over conventional fluorescence microscopy and is an alternative to electron microscopic approaches. Both flow cytofluorometry and confocal laser scanning microscopy allow the analysis quantitatively and with high-sensitivity binding of FITC-pro-u-PA to single suspended or adherent cells. By CLSM u-PA/u-PAR were found to be located in heterogeneously distributed discrete patches at the cell surface on U937 and not inside the cell. This is in agreement with previous studies by Hansen et al, who applied radioiodinated u-PA and electron microscopy to locate u-PAR on microvilli of fixed U937 cells. By flow cytofluorometry, it was possible to quantify the time-dependent and temperature-dependent binding of FITC-pro-u-PA to living single U937. Apparent saturation of u-PAR was achieved at 5 nM FITC-pro-u-PA for both nonstimulated and PMA-stimulated U937 cells. Half saturation of u-PAR was also determined. Nonstimulated U937 was 0.7 nM, and PMA-stimulated U937 was 1.1 nM of FITC-pro-u-PA. This increase in half-saturation concentration in PMA-stimulated cells is paralleled by a steep increase in binding sites (3.6-fold). The use of fluoresceinated reference beads is recommended to verify changes in affinity and binding sites. Using CLSM or flow cytofluorometry, it is also possible to study the structure relationship of u-PA/u-PAR in the presence of competitive binding analogues or inhibitors. Fluorescence techniques will also permit the identification of u-PAR-positive cells in blood, ascitic fluid, or biopsies obtained from cancer patients.

Amino Acid Sequence↗
PubMed1991

[Clinical and prognostic significance of tumor-associated proteases in gynecologic oncology].

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.

Biomarkers, Tumor↗
PubMed1991

[Clinic interns, individual performance appraisal and obstetric quality assurance].

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.

Clinical Competence↗
PubMed1991

[Doppler flow changes in maternal and fetal blood vessels before and during peridural anesthesia].

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).

Anesthesia, Epidural↗
PubMed1991

Immunolocalization of urokinase-type plasminogen activator in adenomas and carcinomas of the colorectum.

Carcinogenesis in the human colon is associated with a marked increase in the tissue content of the urokinase-type plasminogen activator (u-PA). This study was performed to determine the type of cells responsible for the u-PA increase in carcinomas of the colon and in their precursor lesions, the adenomas, by immunohistological evaluation applying monoclonal antibody 3689 directed to the beta-chain of u-PA. Normal intestinal mucosa (n = 17) showed hardly any staining of u-PA, but some lamina propria cells were faintly positive. Carcinomas (n = 17) and adenomas (n = 16) showed a considerable and comparable staining intensity of u-PA in neoplastic columnar epithelial cells, and this staining was found to be diffuse and cytoplasmic. In a majority of the neoplastic tissues the u-PA staining was found to be patchy and not related to known risk markers of malignancy such as dysplasia in the adenomas, or to prognostic determinants such as Dukes' classification or differentiation in the carcinomas. The observation of strong u-PA positive lamina propria cells in adenomas but infrequently observed in normal mucosa and carcinomas was noteworthy. u-PA staining intensity of the tissue sections was found to correlate well with the u-PA antigen level in the tissue extracts determined by ELISA (r = 0.52, P = 0.0001) but poorly with the u-PA activity determined enzymatically (r = 0.28, P = 0.05). In conclusion, the u-PA increase in neoplasia of the human colon can be attributed to an increased diffuse cytoplasmic content of u-PA in neoplastic columnar epithelial cells.

Adenocarcinoma↗