Survival chances and psychological aspects of quality of life in patients with localized early stage breast cancer.

BACKGROUND: The present analysis focuses on the long term psychological reactions to early stage breast cancer. Two hypotheses were formulated. The first hypothesis draws a direct link between tumour size/survival chances and Quality of life (QoL): The better the survival chances, the better QoL ('biological danger model'). The second hypothesis assumes that localized early breast cancer has excellent prognosis (> 90% five year survival rate), and that therefore QoL differences between various forms of early breast cancer should be minimal ('medico-pragmatic model'). PATIENTS AND METHODS: In a defined rural area with 252.000 inhabitants (small-area-analysis), a total of n = 389 patients with primary breast cancer were recruited. For the present analysis we selected a subgroup (n = 269) from the cohort by tumour size (pTis, pT1a,b, pT1c, and pT2). QoL scores for global quality of life, emotional functioning and future perspective were computed according to the EORTC manual and compared to age-matched norm data of the German population. RESULTS: A total of 690 QoL questionnaires were obtained from n = 269 patients with comparable completion rates within the four subgroups (pTis, pT1a,b, pT1c, and pT2). For all four groups and in all scores there were improvements over time. Generally, pTis always scored highest, pT2 always lowest, the other two groups in between. After one year pTis patients had higher mean scores in global quality of life than the norm. In contrast, pT1a,b were considerably lower than the norm and the difference between these two was 17.2 score points. It seems that the small difference (3.5%) in five year survival chances between pTis and T1 a,b tumours transforms into marked differences regarding quality of life, thus supporting a biological danger model of the survival/QoL relationship. CONCLUSIONS: Our results show that physicians have to realise although their early breast cancer patients have excellent survival chances, psychological distress is present. From a clinical perspective we would recommend that early stage breast cancer patients, and especially patients with occult, pT1a,b tumours be informed about their excellent prognosis. In addition, cognitive therapy might help patients stop worrying about their cancer.

Short version of the Guideline: Early Detection of Breast Cancer in Germany. An evidence-, consensus-, and outcome-based guideline according to the German Association of the Scientific Medical Societies (AWMF) and the German Agency for Quality in Medicine (AeZQ).

The goal of the Guideline "Early Detection of Breast Cancer in Germany" is to assist physicians, healthy women, and patients in the decision-making process in favour of appropriate health care regarding early detection and diagnosis of breast cancer. The principle of early detection of breast cancer embraces the detection of non-invasive stages of breast cancer (UICC stage 0, carcinoma in situ), reducing the frequency of invasive breast cancer development, as well as the identification of breast cancer at an early stage (UICC stage I) having a chance of cure of more than 90%, as shown by a large number of trials. The Guideline summarized in the following paper is a precondition to establishing a nation-wide, comprehensive, quality-assurance program for the early detection and diagnosis of breast cancer. The resulting consequence should be a timely mortality reduction of breast cancer. The cure of early stage disease will additionally be achieved by less intensive treatment methods while largely maintaining the quality of life of breast cancer patients. Implementing the Guideline offers the possibility of a significant improvement in women's health care.

[Stage 3 recommendations--the early recognition of breast cancer in Germany. Abridged version for medical practitioners]. / Stufe-3-Leitlinie--Brustkrebs-Früherkennung in Deutschland Kurzfassung für Arzte.

The Aim of this level 3 good clinical practice guideline is to help physicians, women and patients in decision making about the appropriate health care for early detection of breast cancer. The principle of early detection of breast cancer comprise the detection and diagnosis of premalignant breast tumors (stage 0, Carcinoma in situ), risk reduction of cancer development as well as the detection and diagnosis of breast cancer at an early stage (stage I), with a 90% chance of cure as shown by a large number of clinical trials. To establish a nation wide, comprehensive quality assuring program for the early detection of breast cancer the guideline summarized in the following paper offers the basis for a timely mortality reduction of breast cancer. The cure of early stage disease will be additionally possible by less invasive treatment allowing patients to maintain quality of life. The guideline leads to a major improvement of women's health care.

The influence of serum leptin concentration on bone mass assessed by quantitative ultrasonometry in pre and postmenopausal women.

OBJECTIVE: the aim of this study was to evaluate the influence of serum leptin concentration on bone mass assessed by quantitative ultrasound (QUS) in a large sample of healthy pre and postmenopausal women. DESIGN: 555 healthy pre and postmenopausal (n=261 and n=294) women (mean age, 49.5+/-17.2 years) not on hormone replacement therapy were recruited on the occasion of a routine gynecological visit. Before entry to the study, all women had answered a detailed questionnaire on important risk factors and gave written informed consent. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI) of the os Calcis were measured using the Achilles ultrasonometer (GE/lunar). We systematically investigated the relation of menopause, BMI and leptin on bone mass by allocating women into the following groups: (a) premenopausal women BMI<25 kg/m(2) (N=178); (b) premenopausal women BMI>25 kg/m(2) (N=83); (c) postmenopausal women BMI<25 kg/m(2) (N=125); and (d) postmenopausal women BMI>25 kg/m(2) (N=169). Additionally we investigated the relation of serum leptin concentrations, age and BMI on ultrasonometry variables by performing a multiple linear regression analyses. RESULTS: in the initial analyses premenopausal women showed a significantly (P<0.001) lower mean age, weight, BMI, follicle stimulating hormone (FSH) and leptin concentration, a higher mean height, serum estradiol and ultrasonometry variables in comparison to postmenopausal women. Irrespective of the menopausal status, women with a BMI>25 kg/m(2) had significantly higher leptin concentrations (P<0.001) and BUA (P<0.05) whereas SOS and SI was not significant different, compared to women with a BMI<25 kg/m(2). The multiple linear regression analyses showed that only BMI but not Leptin was related to higher ultrasonometry variables, whereas increasing age was associated with a decrease in ultrasonometry variables. Furthermore, the multiple linear regression analyses confirmed that age and BMI were the only statistically significant independent predictor for ultrasonometry variables. There was no significant influence of leptin on ultrasonometry variables even after controlling for BMI or age, or BMI and age. CONCLUSIONS: serum leptin concentrations are significantly higher in pre and postmenopausal obese women, compared with normal weight controls. Ultrasonometry variables are influenced by age and BMI but not by serum leptin concentrations.

[A guideline for guidelines--methodological report and use of the guideline women's information]. / Eine Leitlinie für Leitlinien: Die methodische Entwicklung und Anwendung der Leitlinie Fraueninformation.

UNLABELLED: Information and education is needed to empower autonomy and self-determination of patients (informed consent). Furthermore reliable and accurate medical information is necessary for patients who want to take an active part in medical decision-making. The aim of this work is to define the requirements helping to assure the development of good qualified information material relevant for women and female patients as "a guideline on women information". An example of its use is given by embeding this guideline in the guideline for early detection of breast cancer in Germany by defining the specific elements required for developing qualified information on this issue for women. METHODS: A systematic, stepwise methodological process according to a level two guideline of the German Association of the Scientific Medical Societies (AWMF) and the Agency for Quality in Medicine (AZQ) was performed with the following elements: 1. Establishing an expert panel, 2. Generating the guideline statements by a formal, consensus based nominal group process, 3. External review process and finding supportive partners for the guideline on women information, 4. Using the guideline for guidelines: implementing the concept in the guideline of early detection of breast cancer in Germany. RESULTS: The "guideline women information" comprises nine elements of quality assuring requirements for the development of gender-specific information material and eleven specific elements which directly relate to the guideline statements on early detection of breast cancer. After external review 30 organisations gave their written support for future implementation of the guideline. The "guideline women information" was integrated as a tool for quality assurance of lay information into the "guideline for early detection of breast cancer in Germany". CONCLUSION: The "guideline women information" is a systematically developed, consensus-based recommendation to improve the development of qualified lay information at the point of its process by defining gender-specific aspects required for good lay information and its evaluation. As a guideline for guidelines its use is demonstrated by integrating this guideline into the "guideline for early detection of breast cancer in Germany" to ensure the development of qualified guideline compliant information.

Primary breast cancer therapy in six regions of Germany.

Studies from six regions of Germany (Aachen (W1), Dresden (E1), Jena (E2), Marburg (W2), Munich (W3), and Stuttgart (C1)) have been compared to verify and assess the quality of healthcare using breast cancer as an example. All of the data collection was carried out in comprehensive cancer centres and is population-based, with the exception of C1. Classic prognostic factors and the initial treatment of 8661 women with breast cancer, diagnosed between 1996 and 1998, were examined. Primary therapy, breast conserving therapy (BCT), and the use of subsequent local radiation and/or systemic therapy (chemotherapy or hormonal therapy) were analysed. BCT was performed on 39.3-57.7% of patients. By pT-category, the proportion of BCT in the six regions were as follows: for pTis between 37.8 and 64.3%, for pT1 between 51.7 and 71.5%, for pT2 between 25.9 and 51.1%, for pT3 between 0 and 13.1% and for pT4 between 0 and 15.2%. Multivariate analyses, adjusted for age and biological factors, showed a significant influence of the treating hospital on the mastectomy rate. The use of radiotherapy after BCT (80%) was quite homogeneous in the six regions. The application of radiotherapy after mastectomy, however, varied between 10.4 and 32.2%. In all regions, for premenopausal patients, the use of adjuvant systemic therapy almost reflected the St. Gallen-Consensus recommendations. In contrast, post-menopausal women with positive lymph nodes were not always treated according to these standards. In all regions, age had an influence on the administration of treatment: elderly breast cancer patients received less BCT, less radiotherapy and less adjuvant therapy than recommended in the St. Gallen-Consensus. Feedback of the results was made available to each hospital, providing a comparative summary of patient care that could be used by the participating hospitals for self-assessment and quality-control.

Quality of life profile: from measurement to clinical application.

Quality of life (QoL) can be assessed in an accurate, valid and reliable way by means of standardized QoL questionnaires and is an important endpoint in clinical trials today. The aim of this study is to implement quality of life as a diagnostic tool for problem-oriented follow-up care of cancer patients. This is done in the framework of an intervention study in the area of regional health care research using qualitative analysis and the methodological concept of barrier analysis. We developed the diagnostic tool by generating individual, graphic QoL profiles based on patients' responses to the EORTC QLQ-C30 and the corresponding disease-specific modules BR23 for breast cancer and CR38 for rectal cancer. The clinical application is investigated by assessing physicians' responses. The QoL profile is judged as a useful diagnostic tool by all participating physicians. It enables physicians to assess the QoL of the patient and incorporate the knowledge they gain in their daily practice. Especially in breast cancer follow-up care QoL profiles give added value to both patients and doctors. The next implementation steps have to extend the concept of QoL to larger groups of patients and physicians by overcoming the restraining factors as identified in the barrier analysis.

[Validity of the breast imaging reporting and data system BI-RADS(TM) for clinical mammography in men]. / Anwendbarkeit des Breast Imaging Reporting and Data System (BI-RADS(TM)) auf die klinische Mammographie des Mannes.

AIM: The implementation of diagnostic standards enhances quality assurance. The American College of Radiology's Breast Imaging-Reporting and Data System (BI-RADS(TM)) is intended to standardize terminology in the mammography report, the assessment of the findings, and the recommendation af action to be taken. The purpose of this study was to assess the value of the standardized system for clinically apparent male breast tumors. Do the special male anatomy and physiology limit the applicability of an evaluation system designed for female screening mammograms? METHODS: 4 investigators with different degrees of experience retrospectively evaluated 160 male mammograms. Our study was based on the 36 cases which could be correlated to histopathological findings: gynecomastia in the majority of cases, but also 4 invasive ductal carcinoma, 1 leiomyosarcoma and 1 ductal carcinoma in situ. RESULTS: Assessment of the mammograms by BI-RADS(TM) (3(rd) Edition 1998) correctly placed all cases of malignancy into categories 4 and 5 without respect to the investigators's level of experience. CONCLUSION: Therefore, we conclude that the BI-RADS(TM)-classification can successfully be used to classify male mammograms with a high positive predictive value for malignancy. Knowledge of gender-specific imaging characteristics increases the specificity at a constant high level of sensitivity.

[Sonographic variability of lactating adenoma demonstrated by a longitudinal evaluation of 4 cases]. / Sonographische Variabilität laktierender Adenome am Beispiel von 4 langzeitüberwachten Fällen.

AIM: Lactating adenoma are circumscribed benign breast lesions developing during pregnancy or lactation due to overall enhanced proliferation of steroid hormone dependent tissue. Sonography is the method of choice for imaging mainly because of the physiologically dense breast tissue. Which is the predictive value of sonography in the diagnosis of lactating adenoma? Are sonographic characteristics dependent on age of gestation or time of lactation? Which diagnostic procedure should be recommended? METHOD: We report the long time course of four patients with histologically proven (core-needle biopsy, 16 Gauge) lactating adenoma, first diagnosed during pregnancy, which were followed up sonographically (1997-2000) with real-time B-mode, panorama-mode (Siescape) and colour-sonography. RESULTS: Demonstrating a high inter- and intraindividual variability the tumors were biggest around parturitation. Despite ongoing lactation tumors regressed in size, but did not vanish completely even after definite termination of breast feeding. Evaluation of sonographical characteristics did not allow to rule out malignancy. CONCLUSION: Three percent of all breast cancers at childbearing age coincide with pregnancy and lactation, therefore, an early histologic diagnosis is absolutely necessary. Sonographically guided core-needle biopsies allow to exclude malignancy without negative effects on breast feeding.

[Radiation therapy after mastectomy--interdisciplinary consensus puts and end to a controversy. German Society of Senology]. / Strahlentherapie nach Mastektomie--Interdisziplinärer Konsensus beendet Kontroverse. Deutsche Gesellschaft für Senologie]

BACKGROUND: Recent publications of the Danish Breast Cancer Cooperative Group together with data from the British Columbia Trial have stirred major discussions concerning the role of radiation therapy after mastectomy. Different treatment approaches are to be found even within the same cancer center. The German Society of Senology, a cooperative group of all medical disciplines involved in the treatment of breast cancer, has therefore worked out a consensus statement. MATERIAL AND METHOD: The recently published literature and experts opinions, in particular randomized studies since 1997, meta-analyses from the Early Breast Cancer Trialists' Collaborative Group, epidemiological investigations with regard to the time course of distant metastases in breast cancer as well as the current consensus of the American Society for Therapeutic Radiology and Oncology served as the basis for discussion and consulting. RESULTS OF THE CONSENSUS: (1) An optimally performed mastectomy is a major prerequisite for tumor cure. Radical (R0) resection of the tumor as well as dissection of at least 10 lymph nodes from the axillary level I and II should be accomplished. If axillary lymph nodes are involved, the surgical removal of these lymph nodes is not only of diagnostic, but also of therapeutic value, as it reduces the risk for locoregional relapses. (2) Most probably, locoregional relapses do not only indicate, but are also a source for distant metastases. (3) Radiation therapy of the chest wall and the regional lymph nodes increases the overall survival in risk patients and reduces the risk of locoregional relapses. Moreover, radiation therapy improves the prognosis in case of residual tumor or an incomplete axillary dissection. Unequivocal and reasonable indications for radiation therapy after mastectomy include T3/T4-carcinoma, T2-carcinoma > 3 cm, multicentric tumor growth, lymphangiosis carcinomatosa or vessel involvement, involvement of the pectoralis fascia or a safety margin < 5 mm, R1- or R2 resection and more than 3 axillary lymph node metastases. Further reasonable indications, albeit not yet evaluated in clinical trials, include multifocality, extensive intraductal component, negative hormone receptor status, G3-differentiation grade, diffuse micro-calcifications, 1 to 3 axillary lymph node metastases, multiple, non-complete biopsies and age < 35 years. (4) An endocrine therapy with tamoxifen concurrent to radiation therapy is also reasonable--despite some contradictory in-vitro data--as it enhances the apoptotic cell death. The CMF-regimen is usually performed as sandwich procedure, but can also be applied concurrently to radiation therapy, if indicated. Conversely, an anthracycline-containing chemotherapy should be finished prior to postoperative radiation therapy. CONCLUSIONS: Adjuvant radiation therapy after mastectomy improves the 10-year-survival probability up to 10%, at least for risk patients. The hypotheses of Halsted and Fisher do not exclude each other. There are patients, in which the one, and there are patients, in which the other hypothesis applies.

Receptor mediated antiproliferative effects of the cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines.

Eighty percent of human ovarian and endometrial cancers express receptors for luteinizing hormone-releasing hormone (LHRH). These receptors might be used for targeted chemotherapy with cytotoxic LHRH analogs such as AN-152, in which doxorubicin is linked to agonist carrier [D-Lys6]LHRH. The antiproliferative effects of doxorubicin and AN-152 were assessed in LHRH receptor-positive ovarian (EFO-21, EFO-27) and endometrial (HEC-1A, Ishikawa) cancer cell lines as well as in LHRH receptor negative ovarian SKOV-3 and endometrial MFE-296 lines. The mechanism of action of AN-152 was investigated by a blockage of receptors using an excess of the LHRH agonist [D-Trp6]LHRH. In some cases, confocal laser-scanning microscopy was used to visualize the accumulation of AN-152 or doxorubicin within the cells. In 3 of 4 LHRH receptor-positive cell lines (EFO-21, HEC-1A, Ishikawa) AN-152 was more effective than doxorubicin in inhibiting cell proliferation. The effect of AN-152 was shown to be receptor-mediated because it could be reduced by competitive blockade of the LHRH receptors with [D-Trp6]LHRH. In contrast, AN-152 was less active than doxorubicin in LHRH receptor-negative lines. Confocal laser-scanning microscopy showed an intranuclear accumulation of AN-152 and competitive inhibition thereof by [D-Trp6]LHRH in LHRH receptor-positive cell lines, but no intracellular accumulation of AN-152 could be detected in the receptor-negative SKOV-3 line. These results suggest a selective receptor-mediated action of AN-152 in receptor-positive cell lines.

Luteinizing hormone-releasing hormone agonist triptorelin and antagonist cetrorelix inhibit EGF-induced c-fos expression in human gynecological cancers.

OBJECTIVES: Spontaneous and epidermal growth-factor-induced proliferation of human gynecological cancer cell lines is dose- and time-dependently reduced by treatment with the luteinizing hormone-releasing hormone (LHRH) agonist triptorelin and antagonist Cetrorelix. This antiproliferative activity is probably directly mediated through the LHRH receptors expressed by the tumor cells interacting with growth-factor-dependent mitogenic signal transduction. We have examined whether epidermal growth-factor (EGF)-induced expression of the early response gene c-fos is reduced by LHRH analogs. METHODS: Human endometrial (Ishikawa, Hec-1A), ovarian (EFO-21, EFO-27, SK-OV-3), and breast cancer cell lines (MCF-7) were rendered quiescent by incubation (72 h) in the absence of fetal calf serum and phenol red. This was followed by a 15-min incubation in the absence or presence of the LHRH agonist triptorelin (100 nM) or the antagonist Cetrorelix (100 nM) before the cells were stimulated for 10 min with EGF (100 nM). C-fos mRNA expression was determined by semi-quantitative RT-PCR using a synthetic DNA fragment as internal standard. C-Fos protein synthesis was determined by SDS-PAGE and semi-quantitative Western blotting. RESULTS: In cells derived from endometrial and ovarian cancer, maximal c-fos mRNA expression (seven- to ninefold over basal level) was obtained 30 min after EGF stimulation. In the breast cancer cell line MCF-7 this effect was obtained 60 min after EGF treatment. In all of the lines expressing LHRH receptor, EGF-induced c-fos mRNA expression as well as c-Fos protein synthesis was dose-dependently reduced by treatment with LHRH agonists and antagonists. At 100 nM concentrations of the LHRH analogs, c-fos expression was reduced to baseline levels. No effect of LHRH analogs on EGF-induced c-fos expression was observed in the ovarian cancer cell line SK-OV-3, which does not express the LHRH receptor. CONCLUSIONS: These results suggest that the binding of LHRH agonists and antagonists to their receptors inhibits the mitogenic signal transduction pathway of the EGF receptor in endometrial, ovarian, and breast cancer cell lines. The coupling of both signal transduction systems mediates the antiproliferative effect of LHRH analogs.

The influence of menopause and body mass index on serum leptin concentrations.

OBJECTIVE: The aim of this study was to evaluate the influence of menopausal status, serum estradiol and body mass index (BMI) on serum leptin concentration in a large sample of pre- and postmenopausal women. DESIGN: 434 healthy women (mean age +/-s.d., 52.2 +/- 10.3 years) were recruited at the University of Marburg on the occasion of a routine gynecological visit. Two hundred and eighteen (50.2%) women were premenopausal (mean age, 36.5 +/- 10.4 years) and not on oral contraceptives or hormone replacement therapy (HRT) and 216 (49.8%) women were postmenopausal (mean age 61.8 +/- 8.9 years) not on HRT. To evaluate the influence of menopausal status, estradiol level and BMI on serum leptin concentrations, women were allocated to one of the four groups: (a) premenopausal women BMI <25 kg/m(2) (n=137), (b) premenopausal women BMI >25 kg/m(2) (n=81), (c) postmenopausal women BMI <25 kg/m(2) (n=94) and (d) postmenopausal women BMI >25 kg/m(2) (n=122). RESULTS: Irrespective of the menopausal status, women with a BMI >25 kg/m(2) had significantly higher leptin concentrations in all age groups compared with women with a BMI <25 kg/m(2) (P<0.001). The multiple linear regression analyses showed that BMI was the only statistically significant independent predictor for leptin. In comparison to postmenopausal women, premenopausal women showed a significantly lower mean age, weight, BMI and FSH concentration (P<0. 001), a higher mean height and serum estradiol (P<0.01 and P<0.001 respectively) but significantly lower serum leptin concentration (P<0.01). The multiple linear regression model showed no significant influence of menopausal status or serum estradiol on serum leptin concentration, even after controlling for BMI. CONCLUSIONS: Serum leptin concentrations are significantly higher in pre- and postmenopausal obese women, compared with normal weight controls. Serum leptin concentrations are not influenced by menopausal status or serum estradiol level.

LHRH might act as a negative autocrine regulator of proliferation of human ovarian cancer.

OBJECTIVE: More than 80% of human ovarian cancers express LHRH and its receptor. The proliferation of human ovarian cancer cell lines is reduced by both LHRH agonists and antagonists. This study was designed to further clarify the possible biological function of this LHRH system. DESIGN: As LHRH agonists and antagonists uniformly reduce proliferation of human ovarian cancer in a dose-dependent way, the effect of low concentrations of authentic LHRH was studied. In addition, longer periods of treatment (up to 9 days) were analyzed. To assess the physiological role of LHRH produced by ovarian cancer cells it was neutralized by adequate concentrations of a specific LHRH antiserum. METHODS: Human ovarian cancer cells EFO-21 and EFO-27, which express LHRH and its receptor, were incubated for 1-9 days with increasing concentrations (1pmol/l to 10 micromol/l) of authentic LHRH or with concentrations of LHRH antiserum capable of neutralizing at least 1nmol/l LHRH. Proliferation was assessed by counting cells. RESULTS AND CONCLUSIONS: Authentic LHRH reduced time- and dose-dependently proliferation (by maximally mean+/-s.e.m. 32.7 +/- 4.4%, Newman-Keuls, P < 0.001) of both ovarian cancer cell lines. At very low concentrations (1pmol/l) a marginal reduction of proliferation or no effect was observed. A mitogenic effect of authentic LHRH was never detected. Treatment of ovarian cancer cell cultures with antiserum to LHRH significantly increased (up to mean+/-s.e.m. 121.0 +/- 2.8% of controls, Newman-Keuls P <0.001) proliferation of EFO-21 and EFO-27 cells. These findings suggest that LHRH produced by human ovarian cancer cells might act as a negative autocrine regulator of proliferation.

Imprint cytology of core needle biopsy specimens of breast lesions. A rapid approach to detecting malignancies, with comparison of cytologic and histopathologic analyses of 173 cases.

OBJECTIVE: To investigate whether imprint cytology of core needle biopsy (CNB) specimens from breast lesions is a useful method of rapidly obtaining additional diagnostic information and potentially can be used to reduce the number of biopsies needed. STUDY DESIGN: Cytologic analysis was performed on 173 breast lesions and compared with their histopathologic diagnoses (143 malignant and 30 benign). For imprint cytology, one CNB specimen was rolled between two slides and stained with Diff-Quik and Papanicolaou stain. RESULTS: The diagnostic overall accuracy of Diff-Quik stain (Papanicolaou stain) was 95.4% (95.9%), with a sensitivity of 96.5% (97.2%), specificity of 90% (90%), positive predictive value of 97.8% (97.8%) and negative predictive value of 84.3% (87.0%). There was no statistically significant difference between the stains. Histopathologic analysis had an overall accuracy of 97.7%, with a sensitivity of 97.2%, specificity and positive predictive value of 100% and a negative predictive value of 88.2%. CONCLUSION: Imprint cytology of CNBs is a sensitive method of detecting malignancies in breast tumors. Diff-Quik is a rapid and reliable approach that can reduce the number of biopsies. Inadequate and suspicious cases should be evaluated based on complementary diagnostic procedures for breast lesions.

Primary and salvage therapy with LH-RH analogues in ovarian cancer.

The efficacy of modern surgical and chemotherapeutic options for the treatment of ovarian cancer is still unsatisfactory. In spite of the availability of new cytotoxic agents, the majority of ovarian cancer patients will finally die of chemoresistant disease. LH-RH agonists in conventional doses have been shown to induce objective responses in approximately 9% of patients with refractory ovarian cancer and disease stabilization in 26% of these women. As toxicity of LH-RH agonists is low or absent, and since their efficacy is not strikingly inferior to that of experimental chemotherapy, they have a vital indication in the salvage situation. A trial is presently being performed among platinum/taxol-refractory patients, comparing the impact of the LH-RH agonist leuprorelin and that of the cytotoxic agent treosulfane on survival and quality of life. The addition of LH-RH agonists in conventional doses to standard first-line surgical and chemotherapy does not improve relapse-free and overall survival. For many years it has been suggested that LH-RH agonists inhibit proliferation of ovarian cancer by suppressing endogenous gonadotropins, which were considered to be mitogenic in this malignancy. Recent experimental and clinical data have made this hypothesis questionable. In contrast, a large body of experimental evidence has emerged during the past few years indicating that LH-RH agonists and antagonists directly inhibit proliferation of ovarian cancer through LH-RH receptors expressed by 80% of these tumors. To exploit these direct antiproliferative effects of LH-RH analogues, higher tissue concentrations are necessary than those achieved with the conventional doses used today. Alternative routes of administration or higher systemic doses of potent LH-RH antagonists, such as Cetrorelix, might improve the efficacy of this approach. Clinical trials addressing this issue are under way. Finally, the LH-RH receptors expressed by ovarian cancers could be employed for targeted chemotherapy using cytotoxic LH-RH analogues. This approach has been shown to be effective in experimental models and might be tested in clinical trials in the near future.

The influence of hormone replacement therapy (HRT) on serum leptin concentration in postmenopausal women.

OBJECTIVE: This study aimed to evaluate the influence of hormone replacement therapy (HRT), the estradiol concentration and body mass index (BMI, kg/m(2)) on the serum leptin concentration in postmenopausal women. SUBJECTS AND METHODS: 352 healthy postmenopausal women (mean age, 60.9 +/- 8.5 years) participated in this comparative study. 71 (30%) women (mean age 55.9 +/- 8.3 years) had taken HRT, while 281 (70%) women (mean age, 59.1 +/- 10.6 years) had not. Baseline characteristics -age, weight, height, BMI (greater than or = 25 or <25), follicle stimulating hormone, estradiol, and leptin values-were compared in the two groups. In a second analysis to evaluate the influence of HRT, estradiol concentrations, and BMI on leptin concentrations, these data were analysed in women allocated to one of four groups: (a) postmenopausal women not on HRT with a BMI <25 (n = 130); (b) postmenopausal women not on HRT with a BMI greater than or = 25 (n = 151); (c) postmenopausal women on HRT with a BMI<25 (n = 48); and (d) postmenopausal women on HRT with a BMI greater than or = 25 (n = 23). Leptin concentrations were subsequently analysed in relation to BMI and age and BMI and estradiol concentrations to determine any independent effect of these variables. RESULTS: The women taking HRT had a significantly lower mean age, weight, BMI and follicle stimulating hormone concentration than those who were not taking HRT. Furthermore, they had a higher mean height and serum estradiol value, but a significantly lower serum leptin concentration. After controlling for BMI, neither the use of HRT nor the estradiol concentration was found to be related to the leptin value (group (a) versus (c) and group (b) versus (d)), but there were significant differences in leptin concentrations between HRT users with BMI greater than or = 25 and BMI <25 and between women not taking HRT with BMI greater than or = 25 and BMI <25 (groups (a) versus (b) and (c) versus (d)). Furthermore, women with a BMI greater than or = 25 had significantly higher leptin concentrations than women with a BMI<25, irrespective of the HRT use. CONCLUSIONS: Leptin concentrations are significantly higher in obese postmenopausal women than in their non-obese counterparts. Serum leptin concentrations are not influenced by HRT use or estradiol concentrations. Further studies are needed to elucidate the role of HRT and estrogen on serum leptin concentrations.

Regulation of GCDFP-15 expression in human mammary cancer cells.

Gross cystic disease fluid protein 15 (GCDFP-15) is a major protein component of benign breast gross cysts. It is also found in approximately 50% of all breast cancer specimens. Androgen receptor (AR) mediated regulation of GCDFP-15 expression was investigated in the AR-positive human mammary cancer cell lines MFM-223 and ZR-75-1. Proliferation of MFM-223 and ZR-75-1 cells is inhibited by androgens. Ten nM 5alpha-dihydrotestosterone stimulated the expression of GCDFP-15 mRNA in MFM-223 (ca. 3-fold) and ZR-75-1 cancer cells (ca. 30-fold) as well as the secretion of GCDFP-15 into the culture medium. Competition experiments with DHT and the antiandrogens hydroxyflutamide and casodex confirmed the involvement of the AR in the regulation of GCDFP-15. Both antiandrogens inhibited GCDFP-15 mRNA expression even in the absence of DHT. AR mRNA was down-regulated in MFM-223 and ZR-75-1 cells (80 and 20% of the control, respectively) during incubation with DHT. Our data demonstrate the effective inhibition of GCDFP-15 expression by pure antiandrogens.

Interactions of ovarian steroids with pituitary adenylate cyclase-activating polypeptide and GnRH in anterior pituitary cells.

Pituitary adenylate cyclase-activating polypeptide (PACAP) releases LH and FSH from anterior pituitary cells. Although this effect is relatively weak, it has a strong sensitizing action on GnRH-induced gonadotropin secretion. Here we investigated the possibility that ovarian steroids, which are well-known modulators of LH secretion, interact with PACAP and GnRH in pituitary gonadotrophs. Rat pituitary cells were treated for 48 h with vehicle, 1 nmol/l estradiol, 1 nmol/l estradiol + 100 nmol/l progesterone or 48 h with 1 nmol/l estradiol and 4 h with 100 nmol/l progesterone. The cells were stimulated for 3 h with 1 nmol/l GnRH or 100 nmol/l PACAP. Estradiol treatment alone enhanced basal as well as GnRH- or PACAP-stimulated LH secretion. LH release was facilitated by additional short-term progesterone treatment. Long-term treatment with estradiol and progesterone led to reduced LH responses to GnRH and PACAP. Neither treatment paradigms affected cAMP production. However, estradiol treatment led to enhanced cAMP accumulation in quiescent or GnRH-stimulated cells. PACAP-induced increases of cAMP production were inhibited by estradiol treatment. After 7-h preincubation with 10 nmol/l PACAP, cells responded with enhanced LH secretion to GnRH stimulation. When steroid pretreatment was performed the responsiveness of gonadotrophs to low concentrations of GnRH was still increased. In contrast, at high concentrations of GnRH the sensitizing action of PACAP on agonist-induced LH secretion was lost in steroid-treated cells. There were no significant differences between the steroid treatment paradigms. It is concluded that estradiol but not progesterone acts as a modulator of adenylyl cyclase in gonadotrophs. The stimulatory effect of estradiol is thought to be involved in its sensitizing action on agonist-induced LH secretion. The inhibitory effect of estradiol on PACAP-stimulated adenylyl cyclase activities seems to be responsible for the loss of its action to sensitize LH secretory responses to GnRH.

Oesophagitis caused by Candida kefyr.

The unusual case of an oesophagitis caused by Candida kefyr in a patient with squamous cell carcinoma of the oropharynx is reported. The further implementation of C. kefyr in the production of milk products is discussed.