Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate.

Although ovarian cancer treatment has advanced in the last 20 years, long-term survival remains stable. The purpose of this study was to determine whether survival has improved in line with treatment advances in a population-based prospective cohort of ovarian cancer patients (1978-1997, with a follow-up through to 2000). The 10-year overall survival rate for cancer patients was similar before and after 1988: 32.2% (n=1661) and 34.4% (n=2089). For patients after 1988, a 12-month prolongation of median survival was observed. In terms of stage according to the International Federation of Gynecology and Obstetrics (FIGO), only FIGO I and FIGO II patients showed, in addition to a prolongation in survival, an absolute improvement of 12.9 and 12.6% after 5 years and of 13.2 and 8.6% after 10 years. This hardly affected the survival of the total sample. For the most frequent stage FIGO III patients and for FIGO IV patients, a prolongation in survival time, but no improvement in survival rate, was seen after five or 10 years. The progress in FIGO I and II patients may be due to more accurate staging. More effective chemotherapy may also explain some of the improvement. The prolongation in FIGO-stages III-IV may be due to more radical surgery. Patient selection criteria, not only the treatment modalities, may be responsible for the superior results reported in clinical trials. Cancer registries are important for evaluating the quality of healthcare delivery.

Induction of the bradykinin B2-receptor, but not of the bradykinin B1-receptor, by interleukin-1beta in cultivated human decidua-derived cells.

Aspects of the pathophysiological steps leading to preterm labor after intrauterine infection can be studied in a cell culture model of decidua-derived cells. In this model, bradykinin (BK) increases the release of arachidonic acid (AA), the precursor of labor-promoting prostaglandins. The release is more than additively increased when cells are pretreated with interleukin-1beta (IL-1beta). Binding studies indicate that the expression of the bradykinin B2-receptor (B2R) protein rises to up to 300% of control after incubation with IL-1beta for 24 h. Thus, there is an increased capacity of mediating the response to BK. These findings suggest a pivotal role for the kallikrein-kinin system (KKS) during labor caused by intrauterine infection. However, there was no binding to the bradykinin B1-receptor (B1R), and it could not be induced by IL-1R, which is a unique finding compared with other cell systems.

Successful treatment of malignant placental site trophoblastic tumor with combined cytostatic-surgical approach: case report and review of literature.

OBJECTIVE: Although rare among gestational trophoblastic diseases, the clinical relevance of malignant placental site trophoblastic tumor (PSTT) derives from its potential malignancy associated with early systemic tumor cell dissemination and manifestation of fatal metastases. Because of the low number of cases reported so far worldwide, several treatment strategies have been under consideration, which will be debated following this case report. METHOD: We present the case of a 33-year-old female with PSTT and metastases to the vagina and lung. A 9-month delay in accurate diagnosis was caused by a misinterpretation of her symptoms as signs of a spontaneous abortion. Specialized pathological examination finally led to the diagnosis of PSTT. Primary surgical treatment consisting of abdominal hysterectomy and unilateral salpingo-oophorectomy was followed by multiple resections of recurrent vaginal disease. After the completion of six cycles of EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine) chemotherapy, hCG titers stayed within the normal range. The patient is without evidence of disease 39 months after primary diagnosis. RESULT: This is the third case of documented long-term remission (>1 year) in metastatic PSTT after combined cryostatic-surgical treatment. CONCLUSION: Since the few previously reported cases with prolonged remission have been treated with the described combined cytostatic-surgical approach consisting of cytoreductive surgery and adjuvant chemotherapy, this approach may be recommended for metastatic PSTT.

The bradykinin B2-receptor in human decidua.

Bacterial infection of the amniotic cavity is one of the most frequent causes of preterm delivery. Bacterial products activate a network of autocrine and paracrine mediators in fetal membranes and decidua, with prostaglandins finally inducing contractions of the myometrium. Bradykinin and its B2-receptor (B2R) seem to be part of this network. In cultured decidua-derived cells, bradykinin stimulates the release of arachidonic acid, interleukin-6 (IL-6), and interleukin-8 (IL-8). These effects are prevented by the specific B2R antagonist Hoe 140. Using a pooled antiserum against peptide sequences of the B2R protein, the receptor can be visualized immunocytochemically. The cells contain mRNA for the B2R, as shown by reverse transcriptase polymerase chain reaction (RT-PCR). Binding studies reveal specific and saturable binding sites for bradykinin with characteristics of the B2R. Binding of bradykinin to the cells is enhanced by the inflammatory mediator interleukin-1beta. In summary, human decidua-derived cells express the B2R, its expression is upregulated in response to interleukin-1beta, and bradykinin stimulates the secretion of further mediators by these cells. Thus, bradykinin and the B2R could play a central role in decidual activation. If so, B2R antagonists would add to established tocolytic therapies that are applied together with antibiotics in cases of chorioamnionitis at low gestational age.

Evidence for bradykinin B2-receptors on cultured human decidua cells.

Bradykinin is known to be present at sites of acute inflammation and to exert its potent inflammatory effects mainly via the bradykinin B2-receptor. Recently, bradykinin dependent processes have been described in cultured human decidual cells, so that bradykinin may expand the list of paracrine factors involved in labour induction. In this paper we present the results of in vitro studies giving evidence that these cells carry the bradykinin B2-receptor. By immunocytochemical methods the receptor protein was localized on decidual cells. Analysis of cellular extracts of cultured decidual cells by RT-PCR showed the presence of the specific mRNA coding for the bradykinin B2-receptor. Binding studies revealed a single, saturable and specific binding site for bradykinin of high affinity (Kd = 0.85 nM, Bmax = 436 fmol/mg protein). Competitive binding studies showed displacement of [3H]-bradykinin by HOE 140, but not by the ligands for the bradykinin B1-receptor, des-Arg10-kallidin and [Leu8]-des-Arg9-bradykinin. The results are consistent with the presence of the bradykinin B2-receptors.

Bradykinin stimulates interleukin-6 and interleukin-8 secretion of human decidua derived cells.

Cytokines are known to participate in the process of parturition within a paracrine network in fetal membranes. Bradykinin can also contribute to this process, increasing the release of eicosanoids from decidua cells. In this study, we present evidence for a cross-link between bradykinin and the cytokines. Short and long term cultures of human decidua cells were incubated for 4 h and 24 h with and without bradykinin. IL-6 and IL-8 were determined in the supernatants by ELISA. Results show a large interindividual variability in the basal secretion of IL-6 and IL-8 and a clear increase in the secretion of both ILs in response to bradykinin. By this amplifying effect on cytokine secretion, bradykinin can initiate local and systemic effects of amniochorionitis.

Expression and cellular localization of kininogens in the human kidney.

Human high (H) and low (L) molecular weight kininogens are encoded by distinct mRNAs derived by alternative splicing from a single kininogen gene. Previous studies have demonstrated the presence of L-kininogen but not of H-kininogen in the distal nephron structures of the kidney. Using the highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) we have been able to demonstrate the expression of both H-kininogen mRNA and L-kininogen mRNA in kidney and liver. The presence of H- and L-kininogen antigen was shown immunohistochemically by applying specific antibodies that discriminate between the two types of kininogens. Immunoreactive kininogens were localized in the cortical and medullary collecting ducts. Our results indicate that both types of kinin-bearing kallikrein substrates are expressed in the human kidney where they might contribute to the suggested roles of the kallikrein-kinin system in the regulation of renal blood flow and electrolyte excretion.

The B2 receptor on cultured human decidua cells: release of arachidonic acid by bradykinin.

In vitro studies on cultured human decidual cells present evidence for the expression of the bradykinin B2 receptor. This protein was localized by immunocytochemical methods at the cellular plasma membrane and the mRNA was found in cellular extracts by RT-PCR. As a biological effect the release of 14C-AA was observed. Cells that had been incubated for 24 h with 14C-AA showed a bradykinin (BK)-induced release of radioactivity into the culture medium. This response was prevented by the specific bradykinin B2 receptor antagonist HOE 140. Pretreatment with LPS resulted in an increase of the spontaneous release of radioactivity. Adding BK, a further release of about 40-50% was to be shown. We conclude that BK can play a role in the case of bacterial infection of the fetal membranes AND may stimulate labour by an augmented production of prostaglandins.

High and low molecular weight kininogen and plasma prekallikrein/plasma kallikrein in villous capillaries of human term placenta.

This study examined the expression and presence of components of the kallikrein-kinin system in human term placenta. Immunohistochemical studies localized H-kininogen and plasma prekallikrein/plasma kallikrein to endothelial cells of placental villous capillaries. In larger placental blood vessels and umbilical cord, neither kininogens nor kallikreins were detected. High (H) and low (L) molecular weight kininogen, plasma prekallikrein and plasma kallikrein were detected by Western blot analysis in human term placenta and in maternal and fetal blood, whereas tissue kallikrein was not. Furthermore, mRNA of plasma prekallikrein was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in placental homogenates, while mRNA of H-kininogen, L-kininogen and tissue kallikrein was not. Because H-kininogen and plasma prekallikrein circulate in a complexed form, we suggest that endothelial cells bind kininogen and plasma prekallikrein in which they are secreted by the fetal liver from fetal blood. The co-localization of kininogen and plasma prekallikrein/plasma kallikrein suggests that kinins could be generated locally in placental capillaries. When released, they may play a role in regulating placental blood flow and transplacental transport of substrates and metabolites.

T lymphocytes from the normal human peritoneum contain high frequencies of Th2-type CD8+ T cells.

The majority of peritoneal T lymphocytes have been shown to be CD8+ and to co-express CDw60. Expression of CDw60 characterizes CD8 T cells capable of secreting interleukin (IL)-4 and supporting IgG production by B cells. We analyzed at the clonal level the functional cytokine profile of CD8+ T lymphocytes from the normal human peritoneum. While the majority of the clones produced interferon (IFN)-gamma and exhibited high alloantigen-specific cytolytic activity, some clones secreted IL-4 and IL-5 but no detectable IFN-gamma. These Th2-type CD8+ T cell clones provided substantial B cell help for IgG and IgA synthesis and exhibited reduced cytolytic activity. Our results suggest that distinct subsets of CD8+ T cell may occur in different immune compartments.

Visualization of tissue kallikrein in human breast carcinoma by two-dimensional western blotting and immunohistochemistry.

Tissue kallikrein is well known to liberate the vasoactive peptide kallidin from L-kininogen. Recently it was reported to activate matrix degrading metalloproteinases in vitro and to be present in gastric carcinoma cells. By immunohistochemistry we localized tissue kallikrein in the cytoplasm of ductal breast cancer cells. In addition, two-dimensional Western blotting was used to further characterize its biochemical properties. By this method immunoreactive tissue kallikrein was found to have a molecular mass of 25 kDa and an isoelectric point close to pH 6. Furthermore its presence in human milk could be demonstrated.

Identification of immunoreactive tissue kallikrein in human ductal breast carcinomas.

Various proteases have been shown to be present in malignant breast tissue. Although the question of the involvement of tissue kallikrein, a serine protease, in the pathophysiology of tumours has been raised, the presence of this enzyme in human breast carcinoma has so far not been examined. In the present study, both neoplastic and normal human breast are scanned by immunocytochemistry for the presence and cellular localization of tissue kallikrein. In the healthy breast, tissue kallikrein was observed as a deposit of immunoreactive material that localized in the apical portion of duct cells. In the malignant breast tumours surveyed, the enzyme was observed only in ductal carcinomas, whereas lobular carcinomas were devoid of immunostaining. In ductal carcinomas, the immunoreactivity for tissue kallikrein appeared to be associated with gradations of malignancy, being absent in dedifferentiated tumours. The presence of tissue kallikrein in malignant breast tumours poses the question of the role of this enzyme in malignant breast tissue. The enzyme may participate within the tissue either in proteolytic processes (it has been shown to activate procollagenase) or by enhancing vascularity or mitogenicity by the generation of kinins.

Quantification of Ile-Ser-Bradykinin degradation in human serum and ascites.

A leucine aminopeptidase (LAP) and a carboxypeptidase (CP) activity in human serum and malignant ascites degrade Ile-Ser-Bradykinin (ISB = T-Kinin) in two catalytic steps to desArg9Bradykinin. The catalytic activity in serum is always higher than in ascites. In serum the carboxypeptidase activity is higher than the LAP activity whereas in ascites the two activities are not different.

[Destructive bladder mole--follow-up by human chorionic gonadotropin (HCG), ultrasound and digital subtraction angiography (DSA)]. / Destruierende Blasenmole--Verlaufskontrolle mittels humanem Choriogonadotropin (HCG), Ultraschall und digitaler Subtraktionsangiographie (DSA).

A case report of a mola destruens is presented including the clinical monitoring and the therapeutical conclusions. Control parameters were the HCG, ultrasound and DSA. The DSA in a new and improved technique, provided helpful information during a critical phase of the disease, when changing from mono- to polychemotherapy was necessary. Furthermore, the excellent vascular mapping enables planning of radiological interventions. In case of tumour bleeding hysterectomy can be avoided by embolisation. There may thus be more time for conservative treatment by chemotherapy.

PGE2 concentrations in renal venous plasma and renal lymph during basal and stimulated conditions in the dog.

PGE2 concentration (pg/ml + SEM) was measured in canine renal lymph (394 +/- 115), renal venous plasma (276 +/- 55), arterial plasma (172 +/- 34) and urine (1290 +/- 934). Control periods were followed by an infusion of the sodium salt of arachidonic acid (AA) (40 micrograms/kg min) into the renal artery to stimulate prostaglandin synthesis. During infusion of AA PGE2 concentrations increased significantly in renal lymph (672 +/- 155) renal venous plasma (549 +/- 123), and urine (6768 +/- 1420), but not in the arterial plasma (176 +/- 31). Concentrations in renal lymph and renal venous plasma were not significantly different under either condition. These findings indicate that PGE2 concentration in renal venous plasma is, by and large, representative of mean PGE2 concentrations in the cortical renal interstitium, although focal inhomogeneities in PGE2 concentration in the different areas of the renal interstitium cannot be excluded. Since flow rate of renal lymph is insignificant in comparison with renal venous plasma flow rate total renal PGE2 output can be estimated from measurements in renal venous plasma and urine.

A new technique for the cannulation of small lymph vessels.

A method is described which allows rapid cannulation of small lymph vessels using a modified, in-dwelling cannula and a tissue glue. The method was used to cannulate hilar lymph vessels of the kidney but should but appropriate to cannulate small lymph vessels at other locations as well.