Lothar C. Fuith

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.

Correlation between Steroid Hormone Receptors, Histological and Clinical Parameters in Ovarian Carcinoma

Estrogen (ER) and progesterone (PR) receptors in ovarian tumors of 62 patients (51 carcinomas, 11 benign tumors) were estimated by the dextran-coated charcoal method using Scatchard plot analyses. 63% of carcinomas were ER-positive (greater than 10 fmol/mg cytosol), 38% were PR-positive (greater than 25 fmol/mg cytosol), whereas in benign tumors only 45% were ER-positive and 36% were PR-positive. We found no statistically significant correlation between receptor content and stage of disease, menopausal status or age of the patient. The highest concentration of ER and PR was observed in patients between 61 and 70 years of age. Life table analysis for patients with advanced ovarian carcinomas showed no significant difference in survival time in the group with higher ER and PR content. This study also reports the results obtained in a group of patients with receptor-positive ovarian carcinomas treated with a combination of chemotherapy and antiestrogen therapy. In comparison to treatment with cytotoxic chemotherapy alone, no significant difference in the time of survival or duration of remission could be found.

CA 125 in the Serum and Tissue of Patients with Gynecological Disease

SummarySerum levels of CA 125 were determined in 239 patients suffering from gynecological malignancies. The upper limit for normal was 35 U/ml. Raised levels were found in 82% of patients with primary ovarian carcinoma, and in 29% of those with benign ovarian tumors. The values from patients with ovarian carcinomas in partial or complete remission were compared with those from patients with progressive disease. The former group had elevated levels in 19% compared to 89% in the latter group. Fifty-four percent of the values in progressive cervical carcinoma and 41% of the levels in progressive endometrial carcinoma were greater than 35 U/ml. High CA 125 levels were found in the cytosol of placenta, ovarian carcinoma, cervical carcinoma, and in ascitic fluid; correlation with serum levels was satisfactory. Even though CA 125 is of limited specificity for ovarian cancer, serum levels are important for follow up care and for the early detection of recurrences.

Squamous Cell Carcinoma Antigen in Patients with Cancer of the Uterine Cervix

The serum concentrations of the tumor-associated antigen SCC were determined in 62 patients with invasive carcinoma of the uterine cervix. Antigen values above 2.0 ng/ml were considered as slightly positive, and those above 4.0 ng/ml as highly positive. Pretherapeutic levels were elevated (greater than 2.0 ng/ml) in 68% of the patients with cervical carcinoma. In 49 patients with carcinoma in situ, 18% of the SCC values were above the normal range. The greatest incidence of positive SCC titers (84%) was observed in women with recurrent cervical carcinoma. Only 6.7% of women in remission had elevated titers. Five of 24 cases (21%) with invasive endometrial carcinoma had SCC values exceeding 2.0 ng/ml. Slightly positive levels of tumor antigen were seen in 1.8% (1/56) of the control subjects. Serial SCC determinations revealed a correlation with the clinical course of disease in 84%. The determination of SCC is useful for the surveillance of patients with cervical squamous cell carcinoma.

Neopterin to Monitor Clinical Pathologies Involving Interferon-γ Production

Abstract Upon stimulation with the cytokine interferon-γ human monocytes/macrophages produce neopterin. Accordingly, measurement of neopterin concentrations in body fluids like blood, urine or cerebrospinal fluid provides information about activation of immune response involving type 1 Τ helper cells. Increased neopterin production is found in infections by viruses including human immunodeficiency virus (HIV), infections by intracellular living bacteria and parasites, autoimmune diseases, malignant tumor diseases and in allograft rejection episodes, but also in some neurodegenerative and in cardiovascular diseases. Major diagnostic applications of neopterin measurements are monitoring of the immune status of allograft recipients, detection of infectious diseases in blood donations and monitoring of therapy in HIV-infected individuals. Neopterin concentrations also provide prognostic information in HIV-infected individuals and in several malignant tumor diseases, high neopterin production at the moment of diagnosis is associated with poorer survival expectations. As high neopterin production is associated with increased production of reactive oxygen species and with low serum concentrations of antioxidants like α-tocopherol, neopterin can be regarded as a marker of oxidative stress caused by an activated immune system. Therefore, by neopterin measurements not only the extent of cellular immune activation, but also the extent of tissue damage caused by reactive oxygen specics may be estimated.

Urinary neopterin excretion in patients with uterine sarcomas.

Neopterin, a pyrazinopyrimidine compound, is a marker of activation of cell‐mediated immunity. Urinary neopterin concentrations were measured in a total of 44 patients with uterine sarcomas. Pretherapeutic neopterin excretions were elevated in 78% (14/18). The mean neopterin concentration of patients with sarcomas was significantly higher (P < 0.0001) than that obtained in women with benign myomas and healthy controls. Furthermore, a significant correlation of normal or raised neopterin concentrations with the clinical course of disease was found. These data suggest that urinary neopterin measurement might be a useful immunologic marker for women with uterine sarcomas.

CA 125 in human milk and serum

CA 125 serum concentrations drawn immediately following delivery exceeded 35 U/ml in all cases (median 276 U/ml). One week post partum elevations of CA 125 were still found, but the median level decreased to 45 U/ml. Six weeks after parturition no positivity was detected in the serum (median 12 U/ml). Considerable CA 125 levels were present in the human milk 1 week after delivery (median 208 U/ml). CA 125 was still found in the milk after 6 weeks (median 153 U/ml). We conclude that positive CA 125 concentrations in the serum after parturition derive from an antigen transfer to the maternal circulation during the placental separation. Furthermore, CA 125 seems to be synthesized by the lactating breast.

Allogeneic activation is increased during pregnancy. A risk factor in HIV infection

Increased allogeneic activation may account for the observation that pregnancy induces worsening of HIV infection. Urinary neopterin levels were investigated in a 26-year-old woman who had a 10-year history of parenteral drug abuse and anti-HIV seropositivity. First seen at 16 weeks gestation, the patient presented without any AIDS-related signs or symptoms, but her urinary neopterin levels were highly elevated. The pregnancy was normal until week 31, when intrauterine death was diagnosed and delivery was induced. Urinary neopterin levels, elevated in almost all persons with HIV infection, were high throughout the pregnancy, with a mean value of 752 umol neopterin/mol creatinine. This level was almost double that of the 425 umol neopterin/mol creatinine level present before pregnancy. The neopterin level decreased to 500 umol following the delivery, and the patient remained free from AIDS-related symptoms for a further 10 months. The increased neopterin level is indicative of additional activation of the T cell/macrophage axis during pregnancy. Activation of the T cell axis represents the crucial event triggering progressive HIV expression. The neopterin levels found in this HIV-seropositive patient, in the range usually found in acute pulmonary tuberculosis, exemplify the higher degree of T cell activation in HIV seropositives during pregnancy. This could account for the worsening of HIV infection during pregnancy.

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.

Pregnancy Increases Urinary Neopterin Levels in Human Immunodeficiency Virus Type 1 Infection

Summary Eleven mothers of 12 infants with human immunodeficiency virus type 1 (HIV-1) infection (all intravenous drug users) were followed throughout their pregnancies for evidence of clinical and immunological abnormalities. Intrauterine death occurred in one, growth retardation in 7/12 pregnancies. Moderate progression of HIV-l infection according to the Walter Reed Staging Classification was observed in 5/ 11 women during pregnancy. Two of them developed AIDS during follow up after delivery. Mean neopterin levels in the first, second and third trimester were significantly higher as compared to HIV-l seronegative pregnant women. Furthermore, concentrations of urinary neopterin increased significantly with the time of pregnancy in all HIV-1 seropositive women. Since higher urinary neopterin concentrations are predictive for more rapid disease progression in HIV infected patients the data may indicate that pregnancy increases the risk for developing AIDS. However, a possible influence of continuous drug use has to be considered.