Prognostic value of cathepsin D in breast cancer: comparison of immunohistochemical and immunoradiometric detection methods.

AIM: To test whether immunoradiometric or immunohistochemical detection of lysosomal protease cathepsin D in breast cancer is more predictive of outcome. METHODS: Tumour tissues from 270 primary breast cancer patients were evaluated for the expression of cathepsin D using immunohistochemistry (IH; paraffin embedded tissues) and an immunoradiometric assay (IRMA; cytosol from frozen tissues). Immunohistochemical scores were based on immunoreaction in tumour cells and tumour associated macrophages. RESULTS: IRMA values (cut off 40 fmol/mg cell protein) correlated significantly with IH values. Recorded incidences of positive immunoreaction in tumour cells using two different cut off values were 52% and 35%, respectively. Macrophages stained positive in 31% of tissues. Combined evaluation of tumour cells and macrophages resulted in positivity rates of 59% and 48%, respectively. Node status was the only variable found to correlate with cathepsin D expression. IH results correlated significantly with clinical outcome (median observation time 68 months) in node negative patients (n = 120) but not in node positive patients (n = 145). Cathepsin D positivity as measured by IRMA was not related to clinical outcome in either group. On multivariate analysis in the node negative group, IH detection of cathepsin D appeared to be the only independent factor indicating prognosis. For node positive patients, tumour grade, size, and receptor status were of prognostic relevance. CONCLUSIONS: Because of the simple methodology and the minimal amount of tissue used for analysis, immunohistochemistry was preferred to immunoradiometry for cathepsin D measurement; it also provided more predictive data with respect to prognosis.

Antigen CA 19-9: presence in mucosa of nondiseased müllerian duct derivatives and marker for differentiation in their carcinomas.

CA 19-9, a side branch of the Lewis blood group system, is a sialylated Lewis A antigen that is highly expressed by many adenocarcinomas of the digestive tract. The müllerian duct-derived mucosa of the uterus and fallopian tubes also synthesizes Lewis blood group antigens. To test whether the expression of CA 19-9 is enhanced in carcinomas of müllerian duct origin, we performed immunohistochemical staining for CA 19-9 in normal tissues from 33 women and in adenocarcinomas from 88 patients. In the normal uterine cervix, CA 19-9 was expressed in the cytoplasm of scattered glandular cells in 26 of 29 specimens. It was observed in the apical regions of mucosal cells in six of 26 normal endometrial samples and two of 13 normal fallopian tube specimens. These results are consistent with the presence of antigen CA 19-9 on a secretory product of the nondiseased mucosa of the müllerian duct. In adenocarcinomas of the endocervix, endometrium, and fallopian tubes, CA 19-9 was found in seven of 11, 57 of 71, and five of six samples, respectively. Progressive loss of differentiation was accompanied by disruption of subcellular localization of CA 19-9 and its secretion toward the glandular lumina. In well-differentiated regions of tumors, the antigen was detected mainly at the luminal surface of cancerous glands, whereas the staining was mostly cytoplasmic or vacuolar in less differentiated areas. The degree of CA 19-9 expression was inversely related to tumor differentiation (P less than .001).

Early cancer detection programmes for women at high risk for breast and ovarian cancer: a proposal of practical guidelines.

Women from families with multiple breast and/or ovarian cancers may be at increased risk to develop breast/ovarian cancer themselves. Due to personal experience with family members having these diseases they are anxious and ask for specific prophylactic measurements or treatment. The detection of two susceptibility genes, BRCA1 and BRCA2, has given insight into the genetic background of part of the familial breast/ovarian cancer syndromes. This has led to an increased demand in genetic counselling, testing, and early cancer detection programmes. Prospective data from early cancer detection programmes in this high risk population are yet not available. Based on data from epidemiological risk studies, breast and ovarian screening programmes and follow up data from breast cancer trials recommendations for an early cancer detection programme have been summarized. At the present these recommendations are tested in a prospective trial.

Immunohistochemical detection of epidermal growth factor receptor lacks prognostic significance for breast carcinoma.

OBJECTIVE: We sought to determine whether the immunohistochemical detection of epidermal growth factor receptor (EGF-R) in primary cancer tissues is of prognostic significance in patients with breast carcinoma. METHODS: Paraffin-embedded tissues from 244 study subjects with primary breast carcinomas were tested immunohistochemically for the presence of EGF-R and were compared in a retrospective study with clinical outcome. RESULTS: Epidermal growth factor receptor was detected in the tumors of 49 (20.1%) of the 244 study subjects. The incidence of EGF-R detection was comparable in subjects with disease-free lymph nodes (T1-4, N0, M0, n = 111; EGF-R present 22.5%) or those whose nodes contained carcinoma (T1-4, N+, M0, n = 133; EGF-R present 18.9%). No reliable correlation was found in either group between EGF-R detection and clinical, functional, or morphologic prognostic indicators that included age, menopausal status, tumor size, tumor grade, nodal status, and hormone receptor status. Relapse-free survival and overall survival (median observation time 62.5 months) did not differ between patients with EGF-R-positive or EGF-R-negative breast carcinoma specimens. CONCLUSIONS: In our experience, the immunohistochemical determination of EGF-R in routine formalin-fixed, paraffin-embedded tumor specimens fails to provide useful information concerning the prognosis of patients with primary breast carcinoma.

Comparative prognostic value of Cathepsin D and urokinase plasminogen activator, detected by immunohistochemistry, in primary breast carcinoma.

The lysosomal protease Cathepsin D and the serine protease urokinase plasminogen activator (uPA) are suspected to indicate poor prognosis in primary breast carcinoma. We tested Cathepsin D and uPA immunohistochemically in 281 surgical specimens of primary ductal infiltrating breast carcinomas. Staining was evaluated, taking intracytoplasmic immunoreactions into account, in tumour cells and tumour infiltrating macrophages. Positivity was established in 48.4% and 58.0% of tissue samples for cathepsin D and uPA respectively (co-expression: 67.6%). In patients with cathepsin D- or uPA-positive tumours, relapses were more frequent and disease-free survival was shorter irrespective of nodal status, receptor status or menopausal status, (median observation time 74 months). However, this trend was statistically significant only for cathepsin D. With stepwise cox regression analysis, borderline significance (p = 0.07) was calculated for cathepsin D only in node-negative patients. The combination of cathepsin D with uPA measurements did not enhance its prognostic value. Immunohistochemical detection of Cathepsin D could potentially be used to identify patients with poor prognosis in the group of node negative breast cancer patients.

[Considerations in rational use of tumor markers in breast carcinoma]. / Uberlegungen zum rationellen Einsatz von Tumormarkern beim Mammakarzinom.

The objective of this review is to determine clinical practical guidelines for the use of serum tumor markers in the care of breast cancer patients outside of clinical trials. Mucin antigens (CA 15-3, MCA, CA 549) and CEA are established markers in breast cancer. Owing to their low sensitivity, none of these markers can be recommended for screening, diagnosis or staging. During follow-up, increasing marker levels may indicate recurrence 3-6 months earlier than clinical and radiological examinations in about 40-50% of patients. However, the clinical benefit of this lead-time is not established. Tumor markers are able to monitor response to treatment in 70-80% of patients with metastatic breast cancer. However, paradoxical changes of the markers especially in the beginning of treatment, the insufficient concordance with tumor activity in 20-30% of the women, and the lack of curative therapy regimens limit the prospective clinical use of the markers in the individual patient. Therefore, marker changes require confirmation by radiological methods in most cases. The present data are insufficient to recommend routine use of tumor markers alone for monitoring breast cancer patients after primary treatment or during palliative therapy. However, in the absence of readily measurable disease (e. g. bone metastases) continuously increasing marker levels may be used to indicate treatment failure. If high-dose chemotherapy in metastatic breast cancer renders to be effective, the clinical impact of tumor markers will increase considerably. Until that time, the analytical performance and the sensitivity of the established marker assays should be improved, and the clinical role of newer marker tests (TPS, CA 27.29) should be evaluated.

Radioimmunoassay of laminin P1 in body fluids of pregnant women, patients with gynaecological cancer and controls.

Laminin P1, a pepsin-resistant fragment of the glycoprotein laminin, was determined in body fluids using a double-antibody radioimmunoassay. The median serum concentrations found were: men 1.32, premenopausal women 1.22, postmenopausal women 1.38 and pregnant women (35th gestational week) 2.18 U/ml. The median concentration in amniotic fluid was 1.90, in urine 0.28 and in follicle cyst fluid 1.74 U/ml. During gestation, rising serum levels of up to 5 U/ml were observed which decreased within a few days after delivery. The cut-off value of laminin P1 for 95% specificity of the normal female control group was found to be 1.8 U/ml. The frequencies of elevated serum concentrations were 11, 18, 23 and 33% in patients with primary malignant lesions of the breast, endometrium, cervix and ovary, respectively, and rose up to 50-51% in patients with recurrent or metastatic gynaecological cancer. Laminin P1 was found in high concentrations in the cytosol fractions of breast cancer biopsies. Long-term sequential determinations of serum levels in 10 individual patients with progressive cancer reflected the course of the disease in 8 cases. Although laminin P1 can be considered as a tumour-associated protein, low sensitivity to primary cancer and insufficient specificity limit its application as a tumour marker and its usefulness in monitoring of patients with gynaecological cancer.

[The behaviour therapy and sociopsychiatric model used in Salzburg (author's transl)]. / Das verhaltenstherapeutisch-sozialpsychiatrische Modell Salzburgs.

The article reports on a behaviour therapy ward of the psychiatric hospital department, its origin, difficulties in the initial stages, and current mode of function. The transitory residential quarters and pertaining recreation centre are also described. In the Salzburg model, the behaviour therapy ward and the transitory residential quarters are a functional unit.

CA 125 in normal tissues and carcinomas of the uterine cervix, endometrium and Fallopian tube. II. Immunoradiometric determination in secretions, tissue extracts and serum.

The study deals with the occurrence of cancer antigen 125 (CA 125) in the normal and neoplastic uterine cervix, endometrium and fallopian tube and its applicability as a tumour marker. CA 125 concentrations were measured in 52 secretion specimens, in cytosol fractions of 97 tissue biopsies and in serum from 47 women with nonmalignant disorders and from 334 patients with carcinomas. High quantities of CA 125 (780-454860 U/ml) were detected in cervical mucus, intra-uterine and tubal fluid, exceeding those in the corresponding serum samples by factors of up to 2000. CA 125 concentrations were 9-53 fold higher in cytosol fractions of normal and neoplastic glandular epithelia of the endocervix and endometrium than in those of cervical squamous epithelia and the cervical wall. Despite similarly high antigen concentrations in normal glandular epithelia and adenocarcinomas serum levels elevated to above 65 U/ml were only found in patients with malignant tumours. The positivity rates in serum increased with tumour extent and were 0-43% for primary and 63-79% for recurrent cervical, endometrial and tubal adenocarcinomas. During long-term follow-up, CA 125 serum concentrations were concordant with the clinical course in 10 out of 11 patients with progressive carcinomas. According to these results, the release of CA 125 into the peripheral blood is apparently dependent on the infiltrative growth and the mass of the tumour rather than on the local tissue concentrations. The clinical use of CA 125 is limited to the detection of advanced adenocarcinomas of the Müllerian duct.

[Determination of the SCC antigen in the serum of patients with cervical cancer]. / Bestimmung des SCC-Antigens im Serum von Patientinnen mit Zervixkarzinom.

SCC (Squamous Cell Carcinoma) antigen is a fraction of the tumor antigen TA-4, obtained from squamous cell carcinomas of the cervix uteri. In a retrospective study the clinical significance of SCC antigen was investigated in sera of 119 controls, 30 patients with cervical intraepithelial neoplasia (CIN I-III), 170 women with cervical carcinoma, and 82 patients with other malignant gynecological tumors. Radioimmunoassay was performed with a kit manufactured by Abbott Diagnostics. The limit of the normal range was 2.5 ng/ml. Elevated serum concentrations of SCC antigen were measured in 5% of blood donors, 3% of patients with uterus myomatosus, and 13% of women with CIN I-III. Pathologic SCC antigen concentrations were found in 62% of patients with primary and 73% of women with recurrent cervical squamous cell carcinomas. Only one out of eleven patients with a primary or recurrent adenocarcinoma of the cervix had a slightly elevated antigen level. The positivity rates depended on the spread of the cervical squamous cell carcinomas of the cervix and rose from 32% at FIGO stage I to 83% at stages III/IV. Only 2% of the patients with no evidence of recurrent disease after successful primary treatment of a cervical carcinoma had SCC antigen concentrations exceeding 2.5 ng/ml. The positivity rates were 33% in cases of primary vulval and vaginal carcinomas, 8% in primary endometrial carcinoma, and 15% in primary ovarian carcinoma. None of the women with primary breast cancer had a serum level above 2.5 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical significance of cancer antigen 125 (CA 125) in ovarian cancer.

Cancer antigen 125 (CA 125), a new ovarian cancer-associated antigen, was studied by radioimmunological determination of serum concentrations in 58 healthy blood donors, in 31 women with benign tumors, and 100 patients with malignant tumors of the ovary. Elevated CA 125 levels were found in 5% of normal controls, in 13% of women with benign tumors, and in 78% of patients with ovarian cancer. After successful antineoplastic treatment, false positive CA 125 values were observed in 4% of tumor-free patients. The incidence of pathological CA 125 serum levels was found to depend on the histogenetic origin of the ovarian tumors and was highest in patients with epithelial serous cystadenocarcinomas (85%). Sequential determinations of CA 125 in 27 patients with ovarian cancer under therapy showed a concordance in 89% of cases between serum concentrations and clinical courses. Elevations of CA 125 were already observed 1-6 months before objective evidence of recurrence. Therefore, the determination of serum CA 125 is recommended in the surveillance of patients with ovarian cancer.

[Experiences with CA 125, a tumor marker for malignant epithelial ovarian tumors]. / Erfahrungen mit CA 125, einem Tumormarker für maligne epitheliale Ovarialtumoren.

CA 125 (Cancer Antigen 125) is an antigen identified by means of a monoclonal antibody on the surface of epithelial ovarian carcinoma cells. The serum concentration levels of CA 125 were measured in 41 women with benign and 95 patients with malignant tumours of the ovary. Immunoradiometric determination was effected by means of a kit supplied by Centocor. 35 U/ml was assumed as limit values of the standard range. Enhanced serum concentrations of CA 125 were seen in 5 per cent of the healthy volunteers of a standard group of persons, in 17 per cent of women with benign and in 78 per cent of women with malignant ovarian tumours. Patients without recurrence of tumour after successful primary treatment showed values above 35 U/ml in only 3 per cent of the cases. The incidence of pathological CA 125 serum concentration levels depended upon the histological type of the ovarian tumour and was highest in women with epithelial carcinomas, especially those with serous cystadenocarcinomas (87 per cent). In follow-up examinations of 30 patients with ovarian carcinoma over a period of one to 60 months, CA 125 concentrations correlated with the disease pattern in 90 per cent of the cases. The increases in CA 125 values preceded clinical diagnosis of the relapse by 1-8 months in seven out of twelve women. Routine determination of CA 125 appears advisable in the control of patients with ovarian carcinoma on account of the high sensitivity and specificity during follow-up.

[Symptom of "urinary incontinence" as an indication of tubal cancer]. / Symptom "Harninkontinenz" als Hinweis auf ein Tubenkarzinom.

Discontinuous vaginal discharge in two patients, caused by a carcinoma of the fallopian tube, was misinterpreted as urinary incontinence for months. Complexes of atypical glandular epithelia in the cervico-vaginal smears and detection of adnexal tumors indicated the correct diagnosis.

[Results of transabdominal placental biopsy in the 2nd and 3d trimester]. / Ergebnisse der transabdominalen Plazentabiopsie im II. und III. Trimenon.

From August 1988 to October 1990, 115 transabdominal placental biopsies were performed in the second (68%) and third trimenon (32%). The main indication (80%) was the detection of pathological ultrasonographic findings (foetal malformation, growth retardation, oligohydramnios and polyhydramnios). The success rate of chorionic villus sampling (89%) was independent of the localisation of the placenta. A definite cytogenetic result was found in 83% of patients. By combination of placental biopsy and amniocentesis (n = 77) karyotyping was successful in 97% of pregnancies. Chromosomal abnormalities were observed in 15 (13%) cases (7 autosomal and 2 gonosomal aneuploidies, 1 unbalanced translocation, 1 autosomal deletion, 4 structural variants). The outcome of the pregnancies was substantially influenced by the indication for the procedure and by the cytogenetic result. Foetal and peri-/neonatal losses were found in 53% (3% spontaneous abortions) of patients with sonographic abnormalities (n = 92) and in 9% (abortion rate 4%) of pregnancies with regular findings (n = 23). The pregnancy loss rates were 37.7% and 5.9%, respectively. The results confirm the clinical significance of placental biopsy in the management of pregnancies with pathological ultrasonographic findings.

Constriction of an extremity after amnioreduction in a TRAP-like sequence.

We present an unusual case of TRAP sequence (twin reversed arterial perfusion) with persistent polyhydramnios despite spontaneous thrombosis of the vena umbilicalis of the acardius. Serial amnioreduction was performed owing to considerable maternal discomfort and preterm labor. After three procedures, spontaneous abortion occurred. Unexpectedly, the normal twin had an apparently recent constriction of the right forearm. We hypothesize that limb constriction could be a rare but specific complication of aggressive amnioreduction.

A case of HELLP syndrome at 23 weeks' gestation.

We report a case of the HELLP syndrome at 23 weeks' gestation. Prolongation of pregnancy until the fetus was viable was not possible.

Two fetuses with Fryns syndrome without diaphragmatic defects.

We report two fetuses with Fryns syndrome including the typical facial appearance and distal limb and lung hypoplasia, but no diaphragmatic hernias. The parents were consanguineous. Characteristic in both cases were the distal limb defects with brachytelephalangism and aplasia of the distal phalanges of the first toe. Since one of the two sibs had severe lung hypoplasia without macroscopic or microscopic defects of the diaphragm, we show that lung hypoplasia can occur independently from diaphragmatic defects in Fryns syndrome.