HER-2 amplification, steroid receptors and epidermal growth factor receptor in primary breast cancer.

Amplification of HER-2 oncogene was analysed in DNAs obtained from 291 primary human mammary carcinomas. 52/291 (18%) were found to contain amplified HER-2 oncogene. Moderate amplification (2- to 5-fold) was noted in 36/291 (12%). Thirteen tumors (4.5%) had a copy number of 5 to 10. A 10- to 20-fold and greater than 20-fold amplification was observed in 2 and 1 patient, respectively. Sample sizes allowed the determination of estrogen receptor (ER) and progesterone receptor (PgR) levels in 253/291 primary breast cancers. HER-2 gene amplification was noted in 14% of ER+ patients and in 28% of ER- patients, respectively (P = 0.02). Similarly a significantly greater number of PgR- primary mammary carcinoma exhibited an amplification of the HER-2 gene compared to PgR+ cases (22% vs. 16%, P = 0.01). Although statistically not significant, tumors with HER-2 gene amplification were found to have lower levels of ER and PgR. No association of HER-2 amplification with the androgen receptor and EGF receptor was observed. Present data combine to suggest that tumor progression is more stringently controlled by the oncogene upon loss of hormone dependency. Differences found in HER-2 amplification between steroid receptor positive and negative tumors could be helpful to define a specific subset of women to whom adjuvant therapy should be directed.

HER-2 oncogene amplification and overall survival of breast carcinoma patients.

DNA was extracted from tumour samples of 77 patients with primary breast carcinoma and HER-2 proto-oncogene amplification was assessed. Prognostic indices such as number of positive lymph nodes, tumour size and histological grading were strongly associated with overall survival. No statistically significant correlation between amplification of HER-2 and overall survival was observed. In addition, prognostic indices, HER-2 amplification and disease-free interval was not correlated. Analysis of HER-2 amplification alone is not a useful guide in the management of patients with mammary carcinoma.

Expression of cathepsin D in head and neck cancer.

To determine overexpression of cathepsin D in head and neck tumours we examined cytosols from 53 primary tumours, nine cytosols of lymph node metastases and 12 cytosols from adjacent normal tissue. We found a significantly lower concentration in normal tissue compared with tumour cytosol as well as with metastases, even when we compared tumours and corresponding metastases pairwise. In addition, we found a significantly higher concentration of cathepsin D in five lymph node metastases than in the corresponding tumours. We conclude that the reported role of cathepsin D is not restricted to breast cancer but could also be important in head and neck cancer.

Structural chromosomal abnormalities in gynecologic malignancies.

Surgical specimens taken from four patients with gynecologic malignancies were cultured, and metaphase chromosomes were prepared after staining with chromamycin-A, distamycin, and DAPI. Four specially selected karyotypes and their structural aberrations are discussed in this study and compared with those (also from carcinomas) previously described in the literature.

Body composition characteristics are associated with the bone density of the proximal femur end in middle- and old-aged women and men.

OBJECTIVES: In the present study the associations between bone density of the proximal femur end and weight status, fat distribution patterns (FDI) and body composition parameters i.e. amount of body fat and lean body mass were tested in a sample of old aged women and men. METHODS: In 77 healthy women ranging in age from 60 to 92 years (x=71.8 years) and 62 healthy men ranging in age from 60 to 86 years (x=71.5 years) the bone mineral density (BMD of the proximal femur end and the body composition parameters absolute fat mass, relative fat mass, lean body mass and bone mineral content were estimated by dual energy X-ray absorptiometry. Additionally, the weight status (body mass index, BMI) and the FDI were calculated. The bone density of the proximal femur end was correlated with the absolute fat mass and the lean body mass as well as with the BMI and the FDI. RESULTS: BMD correlated in females significantly positively with parameters of body composition, in males no significant correlations between fat mass (absolute and relative) and BMD as well as BMD/stature was found. Furthermore, it was shown that the weight status (BMI; r(2)=0.13, P<0.0003 in males and r(2)=0.27, P<0.000 in females), and the lean body mass (r(2)=0.21, P<0.001 in males, r(2)=0.36, P<0.004 in females) were associated significantly positively with the BMD of the proximal femur end in both sexes. The absolute fat mass had a significant impact on BMD in the female subsample only (r(2)=0.24, P<0.000). CONCLUSIONS: A lower weight status and a low amount of lean body mass, indicating not only lack of biomechanical forces of the proximal femur end, but also a lack of physical activity can be assumed to be associated increased bone loss and the development of osteoporosis in both sexes. An association between low amount of fat tissue and decreased BMD was especially found in women and may be due to the reduced conversion rates from androgens to estrogens in a low amount of fat tissue.

Ophthalmic complaints as a climacteric symptom.

The menopausal syndrome is characterized by a variety of emotional and physical symptoms of varying intensity. A total of 1287 women who attended the Outpatient Department for Climacteric Symptoms and Osteoporosis Prophylaxis (1st Department of Gynaecology and Obstetrics, University of Vienna Medical School) constituted the study population. These women, who were seeking relief from various complaints or for prophylactic assessment and treatment, visited the clinic over the period 1988-1989. We placed special emphasis on ophthalmic complaints as evidence of the incipient climacteric period. Of the 430 patients with eye complaints, 98 underwent ophthalmological investigation. Within our patient group, we analyzed the incidence and severity of menopausal eye complaints as well as therapeutic responses to hormone replacement therapy on an epidemiological scale. Potential endocrinological factors are discussed.

Beta-endorphin levels during the climacteric period.

Hot flushes are not caused by hypergonadotrophinaemia. This is apparent because peaks of gonadotrophin in the serum do not coincide with cutaneously measured hot flushes while such flushes still occur in hypophysectomized women. Gonadotrophin-releasing hormone and other neurotransmitters (possibly beta-endorphin) affect thermoregulation. The following hypothesis is advanced. During the climacteric period neurotransmitter changes, a decrease in catechol oestrogens, a decrease in alpha-2-adrenoceptor activity and cessation of ovarian steroid production may lead to alterations in endogenous opiate activity and thus to disturbances of thermoregulation, resulting in the occurrence of hot flushes. Low beta-endorphin levels in the peripheral plasma, which rise again following oestrogen treatment, are observed during the climacteric. On the other hand, women with severe hot flushes caused by a stress event show enormously increased beta-endorphin values, which are normalized by hormone substitution therapy acting via still unknown neuroendocrinological feedback mechanisms.

Hormonal, syndromal and EEG mapping studies in menopausal syndrome patients with and without depression as compared with controls.

UNLABELLED: The aim of the study was to investigate brain function in menopausal depression by EEG mapping, as compared with menopausal syndrome patients without depression and normal controls, and to correlate neurophysiological with clinical and hormonal findings in order to elucidate the pathogenesis of depression in the menopause. METHODS: One hundred and twenty-nine menopausal women, aged 45-60 years, with no previous hormonal replacement therapy were investigated in regard to hormones (estradiol [E2], follicle stimulating hormone [FSH]), clinical symptomatology (Kupperman Index [KI], Hamilton depression score [HAMD]) and brain function (EEG mapping). Based on KI and DSM-III-R research criteria for major depression, 3 groups were available for statistics (after removal of protocol violators): group A had a KI of <15 and no depression (n = 29); group B had a KI of > or = 15 and no depression (n = 29) and group C had a KI of > or = 15 and fulfilled the criteria for major depression (n = 60). RESULTS: EEG maps of depressed patients demonstrated less total power and absolute power in the delta, theta and beta band, more relative delta and less alpha power as well as a slower delta/theta and faster alpha and beta centroid than controls, suggesting a vigilance decrement. Group B did not differ from group A. Correlation maps showed significant relationships between estradiol levels and EEG measures (the lower the E2, the worse the vigilance) and between the EEG measures and the Hamilton depression (HAMD) score (the worse the vigilance, the higher the depression score). There were no correlations between the hormones E2 and FSH and the syndromes KI and HAMD. In the target variable, the asymmetry index, depressed patients showed less alpha power over the right than left frontal lobe, whereas normal controls exhibited the opposite. Group B did not differ from group A. The frontal asymmetry index was significantly correlated with the Hamilton depression score and suggests right frontal hyper- and left frontal hypoactivation in depression. CONCLUSIONS: Although hormonal findings are not directly linked to psychic changes, low estradiol levels do contribute to a decreased vigilance at the neurophysiological level , which is in turn correlated with higher depressive and menopausal symptomatology at the behavioural level. Depression is further correlated to a right frontal hyper- and left frontal hypoactivation.

Beta-endorphin, steroids, and prolactin. Immunoassay in breast cysts and blood.

Circulating levels and cyst fluid concentrations of beta-endorphin (beta-EP), estradiol, progesterone, and prolactin were measured by radioimmunoassays in 10 premenopausal women with gross breast cysts. In addition, aspirates and frozen tissue sections from cystic lesions were investigated immunocytochemically for a possible beta-EP production. Epithelia of dilated ducts, smaller cysts, and hyperplastic lesions without atypia showed a strong positive reaction in the cytoplasm. In apocrine metaplasia, this staining was concentrated in the apical region. The staining intensity in atypical hyperplasia was diminished. Occasionally, normal duct and lobular epithelia exhibited positive beta-EP immunostaining. Levels of beta-EP, estradiol, and progesterone in the cyst fluid were significantly higher than in blood, but no significant differences were observed for prolactin. The ratios of progesterone to estradiol, estradiol to prolactin, and progesterone to prolactin in the cyst fluid were considerably higher than in blood. This suggests that beta-EP and steroid hormones are secreted from the lining epithelia into the breast cysts.

[Correlation of skinfold thickness with bone density and estradiol, FSH and prolactin level in a sample of 231 women]. / Korrelation der Hautdicke mit der Knochendichte sowie Ostradiol-, FSH- und Prolaktinspiegel in einem Kollektiv von 231 postmenopausalen Frauen.

Skin thickness was measured by means of ultrasound and correlated with the results of bone densitometry and hormonal parameters. Skin thickness and bone density were significantly correlated (p < 0.0001). These results indicated that not only bone, but also skin is a hormone-dependent organ, which responds to the menopausal decrease in sexual steroids. Hence, skin ultrasound, just like bone densitometry, can be useful implemented in the differential diagnostic procedure, as well as the therapy of the menopausal syndrome. Additionally, the estrogen-dependent postmenopausal decrease in collagen tissue can be assessed by ultrasound and a successful therapeutic outcome achieved by optimizing the dosage of estrogen substitution.

Biotin and phosphorus-isotopic labelled DNA/RNA probes for the detection of human papilloma virus sequences.

In this study, the diagnostic accuracy and practicability of different hybridization techniques for the detection of human papilloma virus (HPV) DNA were tested. Cervical cell scrapes (n = 67) were analysed for HPV-DNAs 6/11 and 16, in order to compare a commercially available in situ DNA hybridization-assay with the conventional Southern-blot analysis. The in situ DNA hybridization-assay gave a sensitivity of 81.5%, a specificity of 97.5% and a diagnostic efficiency of 91.0% for HPV-DNAs 6/11. Using the same assay, we observed a sensitivity of 100%, a specificity of 96.3% and a diagnostic efficiency of 97.0% for HPV-DNA 16. The practicability of dot-blot DNA hybridization technique was tested on 176 cervical cell scrapes, in order to determine the prevalence rate of HPV-genotypes 6/11, 16/18 and 31/33/35. In the random control group (n = 106), 1.9% of the cases were HPV-DNA positive. In the cancer prevention group (n = 70), patients with reactive and reparative cell changes showed a HPV-DNA positivity of 55.0%, with mild (slight) dysplasia/CIN 1 of 73.7%, and with moderate to severe dysplasia/CIN 2 to CIN 3, including the carcinoma in situ/CIN 3 of 80.0%. Patients with squamous cell carcinoma of the cervix uteri gave HPV-DNA positive results in 96.2% of the cases. The suitability of in situ DNA hybridization for morphological studies was tested on tissue biopsies (n = 68). The HPV-DNAs 6/11 were found predominantly to 72.7% of the examined condylomas. The HPV-DNA positive cervices increased with the severity of the cytological dysplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

[Latent cervical virus infection as a possible cause of early abortion]. / Latente zervikale Virusinfektion als mögliche Ursache des Frühaborts.

Cervical smears of 50 women who had an abortion were examined by dot-blot hybridization for human papillomavirus (HPV), herpes simplex virus (HSV) types 1 and 2, and cytomegalovirus (CMV) DNA. HPV DNA type 16 or 18 positivity was shown in 17.6% of the cases; in the aborted material, however, it amounted to 30.8%. IgM-positive titres were present in a few cases. In cervical smears of intact pregnancies, positivity for HPV DNA types 6 and 11 was detected in 9.5% and for the HSV DNA types 1 and 2 and CMV DNA in 48.0% of the cases. In this group of patients mostly positive IgM and IgG titers were present.

[Naloxone-induced gonadotropin changes in females with amenorrhea]. / Naloxoninduzierte Gonadotropinveränderungen bei amenorrhoischen Frauen.

Along with 51 amenorrheic patients the pituitary reactional situation was checked by means of an Gn-RH-stimulation test. Simultaneously to all these women the opiate antagonist Naloxone was infused in a further test series. In 7 from 51 women a significant increase of the LH was demonstrated in comparison to the basic values. Comparing the kinetics of the pituitary gland it was evident, that in all cases the gonadotropin emanation was detective respectively missing after the second Gn-RH-bolus, which followed immediately after the first one. The findings seem to proof the thesis that the endorphins mainly influence the gonadotropin reserve capacity. In cases, where it was possible to objectify the influence--the second pool was missing as well.

[Significance of body weight status for bone density in the elderly and very old]. / Zur Bedeutung des Gewichtsstatus für die Knochendichte bei Betagten und Hochbetagten.

Reduced bone density and osteoporosis are significant health problems and contributors to disability and mortality among older women and men. Therefore the decline of bone mineral content (BMC) and bone mineral density (BMD) are aspects of ageing with great medical and social significance. In recent years a low body weight was declared to be an important risk factor for the development of osteoporosis. In the present study the impact of weight status, defined by the categories of the WHO, on BMC of the whole body and BMD of the proximal femur end, determined by dual energy x-ray absorptiometry (DEXA), were studied in 77 female and 62 male probands aged between 60 and 92 years (x = 71.7 yrs). With increasing weight status (BMI categories), BMC and BMD increased significantly (p < 0.001). This was true of both sexes. Even moderate overweight women and men (BMI 25.0-29.99) showed a significantly higher bone density than their normal weight counterparts (BMI < 25.0). In the present study a marked positive impact of body weight on bone density of old-aged women and men could be shown.

Fever, cancer incidence and spontaneous remissions.

OBJECTIVE: Accumulating evidence exists for (1) an inverse correlation between the incidence of infectious diseases and cancer risk and (2) an inverse correlation between febrile infections and remissions of malignancies. This review is part of an effort of the Office of Alternative Medicine at the National Institutes of Health to examine this evidence. METHODS: A review of the literature to a key word search was undertaken, using the following key words: fever, infectious diseases, neoplasm, cancer incidence and spontaneous remission. RESULTS: The data reviewed in this article support earlier observations on the topic, i.e. that the occurrence of fever in childhood or adulthood may protect against the later onset of malignant disease and that spontaneous remissions are often preceded by feverish infections. CONCLUSION: Pyrogenic substances and the more recent use of whole-body hyperthermia to mimic the physiologic response to fever have successfully been administered in palliative and curative treatment protocols for metastatic cancer. Further research in this area is warranted.

[Cytologic endometrial changes following high-dose iridium-192 radiation]. / Zytologische Veränderungen am Endometrium nach High-dose-Iridium-192-Bestrahlung.

By intrauterine exfoliative smear performed twice in each of seventeen patients, the cytomorphologic effect of an iridium-192 after-loading irradiation was demonstrated. The examinations showed that the cytologic findings were characteristic of the effect of ionizing radiation even in case of the histologically unchanged, not radiosensitive cylindrical epithelium. After the iridium irradiation of malignantly transformed cells of the cylindrical epithelium with 1000 rd, vacuolation and pseudoeosinophilia were the predominant lesions, while after 2000 rd this was above all the presence of macronucleoli. A marked cellular diathesis is a characteristic result of the irradiation with iridium-192. Although hyperchromasia is not an absolute sign of malignancy in case of the adenocarcinoma, it should be mentioned that chromatin concentrations are scarcely found after irradiation.

[Significance and incidence of risk factors in pre- and dysmaturity]. / Bedeutung und Häufigkeit von Risikofaktoren bei Prä- und Dysmaturität.

Anamnestic and clinical data of 10 654 deliveries were related to premature and dysmature pregnancies. The aim of the study was to get a correlation between special data on the one hand and pre- and dysmaturity on the other hand. The risk of dysmaturity is the highest in gravidae with a gestosisscore of more than 4. The risk of prematurity is the highest in gravidae with bleedings during pregnancy. The most frequent symptom in prematurity was a high cervix-score. It occurred in the prematurity collective in 40.7%. In the dysmaturity collective occurred the abuse of nicotine in 32.9%. Some symptoms have a high prognostic value for a pathological pregnancy, but it was impossible to develop a high risk score following these data. An high specificity was connected with a low sensitivity and vice versa.

[A main symptom of the climacteric manifestation complex: arthropathia climacteria]. / Ein Hauptsymptom des klimakterischen Beschwerdenkomplexes: Arthropathia climacteria.

In the last few years several studies have been published raising the question whether hormonal factors are co-responsible for the female prevalence of certain joint diseases. From our own clinical experience we know that more than half of the women seen at our outpatients department because of disorders of the post menopausal syndrome complain about arthralgies (especially of the PIP-joints). We have introduced the term "arthropathia climacterica" for it. Moreover the positive results of two clinical studies on which effects hormone replacement therapy had on these complaints indicate a relation between estrogens and joints.

Screening for Epstein-Barr and human cytomegalovirus in normal and abnormal cervical smears by fluorescent in situ cytohybridization.

Using the routine Papanicolaou test for grouping, 35 normal and 148 abnormal cervical smears were screened by fluorescent in situ cytohybridization for Epstein-Barr (EBV) and human cytomegalovirus (HCMV). Viral presence was detected in 55% of all hybridized smears while routine Papanicolaou tests exposed no morphological evidence for HCMV or EBV. Thus in situ cytohybridization is necessary and suitable for direct identification of EBV and HCMV. The prevalence of viral infection for women with normal cervical smears was 29% for HCMV and 34% for EBV. Even smears of three of the four virgins were positive for HCMV and two had a mixed infection with EBV. The infection rate with at least one of these two herpesviruses was 51% in the control group, 56% in smears with reactive and reparative cell changes, 54% in mild (slight) dysplasias and 56% in moderate or severe dysplasias. Thus infection with HCMV and EBV did not differ significantly in controls and prevention groups. Both viruses were most frequently found in the age group 20 to 29 years. These data suggest that HCMV and EBV are not involved in the etiology of intraepithelial neoplasias and carcinomas of the uterine cervix.

[Bone density before and after the hormonal therapy of young women with hypergonadotropic hypogonadal amenorrhea]. / Knochendichte vor und nach Hormontherapie bei jungen Frauen mit hypergonadotroper hypogonader Amenorrhoe.

Dual energy X-ray absorptiometry of bone density in the lumbar vertebral column was performed in 32 young women (mean age 24.6 [19-34] years) with hypergonadotropic hypogonadal amenorrhoea. There was a significantly lower bone density (0.74 +/- 0.27 g/cm2) than in a control group of 27 women of similar age (1.17 +/- 0.081 g/cm2; P less than 0.001). Subsequently 21 of the 32 women received cyclical hormone substitution therapy for 24 months (day 1-30: 0.625 mg conjugated oestrogens; additionally, on days 20-30: 5 mg medrogestone; followed by a seven-day pause). After 6 months bone density, compared with that of the 11 untreated women, had increased significantly (P less than 0.001). It is therefore recommended that young hypoestrogenemic women should receive early and continuous hormone substitution treatment.