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.

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.

Peritoneum and tissues of the female reproductive tract as physiological sources of CA-125.

The origin of physiological CA-125 serum levels, which in normally menstruating women were shown to depend on their actual menstrual cycle phase, has not yet been completely elucidated. It is furthermore conceivable that physiological CA-125 sources may contribute to serum elevations in the various pathologies associated with increased circulating CA-125. The present review deals with menstrual cycle-dependent expression of CA-125 in normal tissues of the female reproductive tract in relation to the actual circulating CA-125 levels together with in vivo data concerning the inductive effect of medroxyprogesterone acetate on circulating CA-125 studied in 24 postmenopausal women. Furthermore, in vitro results on constitutive, steroid hormone- and cytokine-modulated CA-125 shedding from human peritoneal mesothelial and ovarian surface epithelial cells are summarized.

[Endometriosis in tamoxifen therapy]. / Endometriose unter Tamoxifentherapie.

Tamoxifen is widely used in anti-oestrogen treatment of breast cancer. Recent reports show that, due to oestrogen-agonistic effects, tamoxifen is associated with endometrial carcinoma. We report on the case of a patient who developed endometriosis during tamoxifen treatment.

Neopterin, a marker of cell-mediated immune activation in human pregnancy.

High neopterin excretion is closely associated with activation of cell-mediated immunity. We studied urine and serum neopterin concentrations and serum interferon-gamma concentrations in normal pregnant women. In our study population, neopterin concentrations exceeded the normal range in 663 of 840 samples (79%). Neopterin levels increased with the time of pregnancy. Serum samples drawn from women in the third trimester of pregnancy also showed high neopterin concentrations in almost all cases; however, no circulating interferon-gamma was detected. Whereas neopterin is able to penetrate into the blood stream because of its small size (M = 253 D), diffusion of interferon-gamma is limited. Raised neopterin levels provide evidence for activated cell-mediated immunity during pregnancy.

Neopterin as a marker for activated cell-mediated immunity: application in malignant disease.

A review is presented on studies concerning neopterin determination in patients with malignant neoplastic diseases. Neopterin is produced chiefly by human macrophages through their activation by T-cell-derived interferon gamma. In vivo, determinationof neopterin in various body fluids provides a convenient way to monitor early events that are involved in cell-mediated immune responses. In malignant neoplasia, elevation of neopterin concentrations in body fluids depends on tumor type. Within a given type of tumor, more advanced stages are generally associated with higher levels than early disease. In a variety of different tumor types and sites, a significantly poorer prognosis was associated with high pretherapeutic neopterin concentrations. This predictive value is independent of several possible confounders such as stage or therapy. During follow-up malignant disease, neopterin elevations may predict deterioration of the clinical status of the patients and thereby provide a valuable additional marker for monitoring such patients. Possible immunobiological implications of the results are discussed.

[Prognostically relevant factors in malignant mixed Müllerian tumor]. / Prognostisch relevante Faktoren beim malignen Müllerschen Mischtumor.

In a retrospective analysis of 429 endometrial carcinoma and 29 malignant mixed Müllerian tumour (MMMT) patients, the prognostic factors were evaluated. More than 80% of endometrial carcinomata were staged as I or II, whereas about 30% of MMMT's already in stage III or IV (p less than 0.05). MMMT patients were 10 years older than the carcinoma group (73a vs 63a; p less than 0.001). The risk factors parity, adipositas, and diabetes were equally distributed in the two groups, the survival was worse in MMMT (p less than 0.0001). Applying univariate analysis stage, grading, myometrial invasion and type of therapy significantly affected the survival of endometrial carcinoma patients. After a Cox regression, only stage and grading remained significantly associated with the prognosis. For MMMT's, the survival was also influenced by stage, myometrial invasion, and kind of therapy. Moreover, the parity was found to affect markedly the course of disease. Cox regression of our data excluded all but stage and parity. The beneficial influence of parity on the prognosis of MMMTs, despite a latency of more than 20 years from the last birth to tumour appearance, is unique in oncology.