Long-term significance of urinary neopterin in ovarian cancer: a study by the Austrian Association for Gynecologic Oncology (AGO).

BACKGROUND: Neopterin is produced by activated macrophages upon stimulation with interferon-γ (IFN-γ) and thus, elevated neopterin concentrations in patients indicate cellular inate immune response. Most studies in patients with malignant diseases found an association between higher neopterin concentrations and reduced survival and impaired prognosis. Nevertheless, neopterin is not a classical tumor marker since it is not produced by the cancer cells themselves. PATIENTS AND METHODS: In a study conducted by the Austrian Gynecologic Oncology Group (AGO) in 114 patients with ovarian cystadenomas and 223 patients with invasive ovarian cancer, patients' urinary neopterin was determined before and after primary therapy. The relevance of neopterin in long-term median follow-up was assessed. RESULTS: Elevated levels (cut-off 250 µmol/mol creatinine) were found less frequently in women with benign ovarian cystadenomas (24%) than in patients with malignant disease (58%). After 10 years, only 57% of ovarian cancer patients with elevated urinary neopterin levels survived without disease progression following primary therapy when compared with 86% of women with normal levels (P < 0.001). Along with residual tumor, FIGO stage, age and histological type, neopterin was significantly associated with overall survival (OS) and progression-free survival (PFS). The median PFS was 52 and 12 months and the median OS was 81 and 24 months for patients with normal and elevated neopterin, respectively, P < 0.001. In a multivariate Cox regression analysis, only residual tumor, neopterin and age were independently associated with OS, while only residual tumor was predictive for PFS. Thirty patients with early-stage invasive ovarian cancer (FIGO I and II) were analyzed separately. Of 3 patients with elevated neopterin, 2 died of disease in contrast to 2 out of 27 patients with normal neopterin (P = 0.004). CONCLUSION: In ovarian cancer, the negative impact of elevated urinary neopterin levels indicates a detrimental effect of cancer-associated inflammatory reaction.

Modulation of ovarian carcinoma tumor marker CA-125 by gamma-interferon.

Interferons are known to modulate several cellular functions by the induction of different proteins. In our study a gamma-interferon-mediated presentation of one of the most important ovarian tumor markers (CA-125) on the cell surface was demonstrated using two ovarian carcinoma cell lines in vitro (HTB-77 and SKOV-3). This induction was found to be dependent on an intact protein biosynthesis. The gamma-interferon effect reached a maximum on the third day of treatment. Under such conditions the CA-125 concentration was increased intracellularly, on the cell surface, and in the supernatant culture medium. The surface antigen was shed rapidly with a half-life of 1 day. The addition of dexamethasone to gamma-interferon treated HTB-77 cells improved CA-125 expression synergistically. HLA-DR and CA-125 expression was found to be regulated by interferons in different ways. The demonstration of CA-125 expression provides an important insight into the potential regulatory mechanism governing this tumor marker. Since interferons are naturally occurring substances as well as therapeutically administered agents, it seems necessary to pay attention to possible tumor marker modulation.

Clinical significance of neopterin for prognosis and follow-up in ovarian cancer.

Neopterin, a pyrazinopyrimidine compound, is a marker of activation of cell-mediated immunity. The prognostic value of pretherapeutically and of serially measured urinary neopterin levels in patients with ovarian cancer was assessed, in a blinded manner, by analysis of 658 urine specimens from 74 women. The specimens were collected during a 5-year period (January 1981 to January 1986). Thirty-one deaths due to cancer were observed during the study period. By statistical analysis, a significant predictive value of pretherapeutic neopterin levels was found and compared with that of other possible prognostic clinical and laboratory findings. Multivariate analysis, using stratification by tumor stage, demonstrated that this predictive information was independent of other variables. A significant association was found between serial neopterin measurements and the current risk of death during follow-up (P less than 0.0001). In addition, current death risk was correlated with neopterin levels measured 6 months previously (P = 0.026). The histological outcome at surgical reexamination was correlated with the current neopterin levels (P = 0.016). Further, normal neopterin levels in women with evidence of tumor at surgical reexamination were shown to be a sign of better prognosis than elevated levels. Measurement of urinary neopterin levels during follow-up of women with ovarian cancer appears to be a valuable adjunct to conventional techniques, particularly in patients refusing explorative surgery.

Depression of histone acetylation by alkylating antitumor agents in murine cells.

Treatment of Ehrlich ascites tumor cells with the alkylating agent triaziquone [2,3,5-tris(ethyleneimino)benzoquinone-1,4] and nitrogen mustard leads to a reduction of the posttranslational acetylation of histones. Acetylation of all core histones is affected. The reduction of labeling of acetylated sites is accompanied by a dose-dependent decrease in the extent of acetylation as indicated by the level of acetylation of H4. The depression of histone acetylation is expressed at all concentrations of the alkylating agents which cause significant inhibition of tumor cell proliferation. It could be excluded that the observed effects are caused by an impairment of acetyl coenzyme A synthesis.

Neopterin as a prognostic indicator in patients with carcinoma of the uterine cervix.

In vitro, neopterin, a pyrazinopyrimidine compound, is excreted by human monocytes-macrophages after induction by supernatants from activated T-lymphocytes or by recombinant gamma-interferon. In vivo, it represents a noninvasive test for activation of cellular immune reactions. To evaluate the prognostic value of pretherapeutic urinary neopterin levels and of serial neopterin measurements during follow-up in women with cervical cancer, 1088 urine specimens from 186 consecutive patients were analyzed. Clinical assessments were made without knowledge of the results of neopterin assays (a "blinded" assessment). During the observation period (June 1980 to March 1984), 27 relapses, 18 metastases, and 26 deaths were seen. The prognostic significance of pretherapeutic neopterin and other possible prognostic clinical and laboratory parameters was tested by the univariate and multivariate Cox proportional hazards model using a stratification according to stage and surgical treatment. The combination of age at diagnosis, pretherapeutical hemoglobin, leukocyte count, and neopterin was found to predict survival best. On the basis of this result, risk groups were identified exhibiting markedly different survival behavior. A highly significant association was found between serial neopterin measurements and the risk for a relapse, metastasis, or death. The data suggest that urinary neopterin levels might be a useful adjuvant parameter in monitoring women with cervical cancer.

Effects of biological response modifiers on ovarian carcinoma cell lines.

Interferons have a mechanism of action different from chemotherapeutic agents. They modulate many physiologically important cellular functions and are a major building block in the network constructed by the biological response modifiers. Moreover, interferons are known to interact also with anticancer drugs to increase their therapeutic benefit. The aim of the present study was to evaluate the effects of interferon-gamma on cultured ovarian carcinoma cell lines. The growth of 3 out of 4 carcinoma cell lines (OVCAR-3, HTB-77, 2780 vs CRL-1572) was inhibited by interferon-gamma. The same cell lines which were growth inhibited also showed an induction of HLA-DR on their surface. CA-125 was found to be increased in 2 of them (OVCAR-3 and HTB-77) by interferon-gamma, whereas CEA was not detectable even after treatment. For HMFG-I, a shightly increased surface expression was induced on OVCAR-3 cells. HMFG-II expression was not significantly affected by interferon-gamma. The combined treatment with interferon-gamma and cisplatin, retinoic acid, or tumor necrosis factor alpha was studied on the ovarian carcinoma cells. For the combination with cisplatin we observed an additive or synergistic amplification of the antiproliferative activity, whereas tumor necrosis factor alpha resulted in a marked synergism in each case. In contrast to breast cancer cells retinoic acid and interferon-gamma acted synergistically only in one ovarian carcinoma cell line.

Increased neopterin concentrations in patients with cancer: indicator of oxidative stress?

In vitro, large amounts of neopterin are produced by human monocytes/macrophages upon stimulation with interferon-gamma. In vivo increased neopterin concentrations in human serum and urine indicate activation of cell-mediated (Th1-type) immune response, e.g., during virus infections, autoimmune diseases, allograft rejection and in certain types of malignancy. In various groups of patients with malignant diseases neopterin concentrations correlate to the stage of disease, and higher neopterin concentrations in serum, urine or ascitic fluid were shown to significantly predict worse prognosis regarding relapse and survival. The amounts of neopterin produced by activated monocytes/macrophages correlate with their capacity to release reactive oxygen species (ROS). With this background, neopterin concentrations in body fluids can be regarded as an indirect estimate of the degree of oxidative stress emerging during cell-mediated immune response. Moreover, recently neopterin was found itself to be capable of enhancing toxic effects induced by ROS. In vitro, neopterin derivatives were able to interfere with intracellular signal transduction pathways involved in, e.g., programmed cell death and the induction of proto-oncogene c-fos or nuclear factor-chi B. The data support the view that increased production of ROS--indicated by increased neopterin concentrations--could modulate the development, the proliferation and the survival of malignant cells.

Distribution of CA 125 in placental tissues.

The presence of the tumor marker CA 125 was studied in different compartments of the human placenta. Levels of CA 125 in the cytosol of chorionic villi ranged from 27-17100 U/g (median 560 U/g). In the placental amnion and chorion concentrations ranged from 175-29000 U/g, median 1060 U/g and were not statistically different. In the umbilical cord values were significantly lower (range 44-7600 U/g; median 180 U/g). Maternal serum probes were above the upper limit of normal in all cases (range 48-500 U/ml; median 131 U/ml). Immunohistochemistry detected CA 125 exclusively within the amniotic cells of the placenta and the umbilical cord. This might be because CA 125 fixes more to insoluble structures in the amnion or because of contamination of chorionic villi with the underlying decidua.

Rapid development of resistance to tumor necrosis factor alpha on Ishikawa human endometrial carcinoma cells.

The human endometrial adenocarcinoma cells IK were found to be highly susceptible for TNF but rapidly developed a resistance to this cytokine. Inhibitors of RNA transcription or protein biosynthesis could not overcome this resistance. Moreover TNF resistance was not associated with increased resistance to hydrogen peroxide. The resistant phenotype remained stable and was not communicated to neighbouring cells in a paracrine manner. The TNF treatment did not induce a multidrug resistance on IK cells. Nude mice bearing xenotransplanted endometrial carcinoma cells did not benefit from TNF treatment.

[Tumor markers in gynecology]. / Tumormarker in der Gynäkologie.

The employment of tumour markers in gynaecology has gained increasing importance in recent times. Beta HCG for chorionic carcinoma and alpha 1 fetoprotein for germ cell tumours are an essential part of postoperative surveillance. Initial analyses of the amylase isoenzymes are available. CEA, TPA, and CA 125 are recognized as established tumour markers. Very promising results have been obtained using SCC in patients with cervical carcinoma. Neopterin, a marker for cell-mediated immunity, provides good prognostic information.

[Severe bacterial infections in gynecology and obstetrics]. / Schwere bakterielle Infektionen in Gynäkologie und Geburtshilfe.

Within a 3-years period the presence of nosocomial bacteriaemias was analyzed retrospectively among 13.878 hospitalized patients. The incidence was 0.050%. Antibiotic prophylaxis and the operative technique play an important role in achieving a low incidence of morbidity due to infection. The management of a severe infection includes antibiotic therapy according to culture sensitivity and intensive care.