Prognostic relevance of caspase 8 -652 6N InsDel and Asp302His polymorphisms for breast cancer.

BACKGROUND: The minor allele of two caspase 8 polymorphisms, namely CASP8 -652 6N InsDel (rs3834129) and CASP8 Asp302His (rs1045485), were repeatedly associated with reduced breast cancer susceptibility. Contrarily, the presence of the -652 6N Del or the CASP8 302His variant was reported to be an unfavorable prognostic factor in colorectal cancer or neuroblastoma. However, prognostic relevance of these genetic variants for breast cancer is completely unknown and is therefore adressed by the current study. METHODS: Genotyping was performed by pyrosequencing. Caspase 8 mRNA expression was quantified by comparative RT-qPCR. RESULTS: We observed an allele-dose dependent association between CASP8 -652 6N InsDel and caspase 8 mRNA expression in breast cancer tissue, with homozygous deletion carriers showing lowest relative caspase 8 expression (p = 0.0131). Intriguingly, the presence of the -652 6N Del or the 302His variant was shown to be a negative prognostic factor for breast cancer in terms of an allele-dose dependent influence on overall survival (OS, p = 0.0018, p = 0.0150, respectively). Moreover, both polymorphisms were independent predictors of OS after adjusting for co-variats (p = 0.007, p = 0.037, respectively). Prognostic relevance of both polymorphisms were confirmed to be independent from each other and combined analysis of diplotypes revealed an additive influence upon OS (p = 0.0002). CONCLUSION: This is the first report, showing negative and independent prognostic impact of the CASP8 -652 6N Del and the 302His variant for breast cancer. Our data provide rationale to further validate clinical utility of these polymorphisms for breast cancer and to extend this investigation to a broad scope of other malignancies.

[Aquaporin 1 expression in invasive breast carcinomas]. / Aquaporin-1-Expression bei invasiven Mammakarzinomen.

Aquaporin1 (AQP1) is a water channel protein which facilitates water flux across cell membranes. AQP1 is found in epithelial and endothelial cells in various tissues. There is increasing evidence that AQP1 is expressed in malignant tumours and that it may play a role in tumour angiogenesis, cell migration and metastasis. We studied the immunohistochemical expression of AQP1 in a cohort of 203 invasive breast carcinomas with long-term follow up. AQP1 expression was detected in 11 cases (5.4%), and showed a significant correlation with high tumour grade, medullary-like histology, "triple-negativity", as well a cytokeratin 14 and actin expression. In univariate analysis, AQP1 was associated with a significantly poorer prognosis. Multivariate analysis showed that AQP1 expression has an independent predictive value for outcome if stratified by age, tumour size, lymph node status, histological grade and ER status. AQP1 expression in invasive breast carcinomas is associated with a basal-like phenotype and poor prognosis.

Overexpression of cyclo-oxygenase-2 is an independent predictor of unfavourable outcome in node-negative breast cancer, but is not associated with protein kinase B (Akt) and mitogen-activated protein kinase (ERK1/2, p38) activation or with Her-2/neu signalling pathways.

BACKGROUND AND AIM: The production of prostaglandins is regulated by cyclo-oxygenases (COXs), which also have a role in tumour development and progression in various malignancies, including breast cancer. The mechanisms by which COX-2 contributes to unfavourable prognosis are still poorly understood. The association between expression of COX-2 and possible linked signalling pathways-namely, Akt, extracellular regulated kinases (ERK1/2), the stress-activated kinase p38 or Her-2/neu-is assessed in a series of 113 node-negative breast cancers. RESULTS: COX-2 was identified as an independent prognostic factor (p = 0.034) in node-negative breast cancer by survival analysis. The lack of a relationship between COX-2 expression and activated Akt, Erk1/2, p38 and Her-2/neu was indicated by statistical analysis. CONCLUSIONS: The prognostic effect of COX-2 expression on lymph node-negative breast cancer is confirmed-COX-2 is probably not regulated by HER-2, Akt, Erk1/2 or p38. Further studies are necessary for the elucidation of the signalling pathways responsible for the modification of COX-2 expression and the increased aggressiveness of breast cancers overexpressing COX-2.

Relationship and prognostic significance of phospho-(serine 166)-murine double minute 2 and Akt activation in node-negative breast cancer with regard to p53 expression.

The Akt signalling pathway plays a central role in tumourigenesis. Activation of Akt is related to a more aggressive phenotype in various human cancers, including breast cancer. Its activation contributes to cancer progression via pleiotropic effects, including suppression of apoptosis and modulation of cell cycle regulation. Murine double minute 2 (MDM2) is an oncoprotein that inhibits the function of p53 tumour suppressor protein. Cell culture studies show that Akt-related phosphorylation of MDM2 at serine 166 allows MDM2 to gain nuclear entry and fulfil its p53 regulating function. This study was designed to analyse the relationship of phospho-MDM2 (pMDM2) expression with Akt activation to determine a possible prognostic relevance of pMDM2 in node-negative breast cancer with respect to Akt activation and p53 status. pMDM2, phospho-Akt (pAkt) and p53 protein expression status were analysed immunohistochemically in 121 paraffin-embedded breast cancer cases. Expression of pMDM2 correlated with Akt activation (P<0.001). Univariate analysis identified pMDM2 as a prognostic factor (P=0.0458) in node-negative breast cancers. The unfavourable prognostic significance was even more pronounced in tumours with a pMDM2(+)/pAkt(+) immunophenotype (P=0.0205). Stratification into a p53-negative subgroup further strengthened the adverse prognostic influence. These data confirm that MDM2 phosphorylation at serine 166 is mediated by Akt kinase. Besides the prognostic impact of pMDM2, our findings suggest that Akt-mediated modulation of the MDM2/p53 complex contributes to increased tumour aggressiveness especially in p53-negative breast cancers. However, due to the relatively small number of patients in this cohort, the results obtained need to be confirmed by larger cohorts.

Aromatase inhibition with 4-hydroxyandrostenedione in the treatment of postmenopausal patients with advanced breast cancer: a phase II study.

Estrogen deprivation by aromatase inhibition is an effective treatment in breast cancer. Between October 1986 and March 1988, 91 postmenopausal patients with advanced breast cancer entered a phase II study performed jointly in three center to investigate the new aromatase inhibitor 4-hydroxyandrostenedione. Patients received 500 mg 4-hydroxyandrostenedione intramuscularly (IM) every 2 weeks for 6 weeks, and 250 mg every 2 weeks thereafter. There were two complete (CRs) and 19 partial remissions (PRs) (response rate, 23%). Disease stabilization (no change; NC) was seen in 26 patients, and in 44 patients (48%), disease progression occurred. Duration of the CRs is 20+ months, median durations of PR and NC are 13+ and 8 months, respectively. Receptor status, relapse-free interval, and sites of metastatic lesions did not appear to influence treatment results. However, efficacy of previous tamoxifen treatment favorably predicted response to 4-hydroxyandrostenedione. Serum estradiol levels decreased significantly in patients after 2 weeks of treatment. Side effects were mostly nonspecific and of low degree, requiring discontinuation of treatment in only 3% of the patients. We conclude that aromatase inhibition with 4-hydroxyandrostenedione is efficacious in the treatment of postmenopausal breast cancer.

[Pros and cons of early cancer detection in breast carcinoma]. / Das Mammographie-screening ist zur Früherkennung geeignet ... aber die Qualität der Vorsorge muss stimmen.

Mammography is an appropriate method for the detection of early forms of cancer of the breast, and for reducing mortality. Whether this actually succeeds depends upon the quality of the early detection strategies employed. Currently the data on reduction of mortality by mammographic screening remain ambivalent.

Estrogen and progesterone receptor content of GnRH analogue pretreated and untreated uterine leiomyomata.

OBJECTIVES: The steroid receptor concentration and the histological morphology of uterine leiomyomata in premenopausal patients undergoing myomectomy therapy with and without a preoperative GnRH analogue, was analysed to evaluate whether the GnRH analogue therapy leads to important hormonal receptor changes, histomorphological changes and a significant shrinkage of the leiomyomata. STUDY DESIGN: Sixty-one GnRH analogue pretreated leiomyomata and 28 untreated leiomyomata were analysed. To determine the estrogen and progesterone receptor concentrations, immunohistochemical techniques were used and quantified with the immuno-reactive score (IRS-score). The leiomyomata were divided into cellular rich, normal, hyaline or cystic degenerated and necrotic according to their histology. RESULTS: The GnRH analogue pretreated leiomyomata group showed higher levels of estrogen and progesterone receptors than the untreated group (37.7% of the GnRH analogue group had a high positive and 29.5% a moderate positive estrogen receptor status whereas high levels of estrogen receptor could be found in only 14.3% of the untreated group). The leiomyomata of both groups with the exception of the necrotic ones, were estrogen and progesterone receptor positive. CONCLUSIONS: Our study suggests that pretreatment of uterine leiomyomata leads to a significant increase in the hormonal receptor concentration of these benign tumors. If pretreated leiomyomata are not removed surgically immediately after the therapy, a rapid regrowth can occur and again cause clinical symptoms.

Level of c-erbB-2 oncoprotein in the homogenate of malignant and benign breast tumor samples.

The concentration of c-erbB-2 oncoprotein (HER-2/neu) was examined in the membrane fraction of 196 breast cancer and 39 benign breast specimens using a recently introduced ELISA-assay. The results were compared with established clinical and laboratory prognostic factors, 19% of all breast cancer specimens showed a c-erbB-2 protein level above 10 HNU/micrograms extract protein and were so classified as positive. Considering only the samples of primary tumors the rate was 21%. Surprisingly the rate was only 13.5% in the tissue samples of recurrent disease. Significant correlations were found between high c-erbB-2 protein levels and the tumor diameter, the axillary lymph node status and the progesterone receptor status. In contrast no correlation was found with estrogen receptor or menopausal status. All specimens of benign tumors showed levels < 10 HNU/micrograms extract protein and were classified as negative. The measurement of the c-erbB-2 protein using this ELISA assay was simple to perform and revealed reliable results. Nevertheless the prognostic power of the c-erbB-2 protein seems to be of minor relevance in comparison with established clinical and laboratory parameters, as the positive rates are too small in regard to the much higher recurrence rates of breast cancer. Probably the serum levels of this oncoprotein will be of greater clinical interest in the course of breast cancer.

The role of age in the course of breast cancer.

UNLABELLED: BACKGROUND AND QUESTION: A retrospective study was performed. To check the hypothesis whether there is an inverse connection between age and prognosis. PATIENTS AND METHODS: We investigated a total group of 1000 cases with breast cancer primarily and consecutively treated between 1968 and 1986. After grouping the patients by tumor stage and median age various life table analyses were performed to calculate and compare the overall survival. Entry date was the date at diagnosis of a first breast cancer or date at first diagnosis of distant metastasis. RESULTS: Young patients with a tumor size T1 and T2 had a significantly better prognosis than older patients with the same tumor stage. Influence of age became significantly weaker in patients with a T3 and T4 tumor. At least in the patients with a primarily M1 stage hardy any more dependence of age could be demonstrated. Similar results were obtained for the 198 patients which presented a distant recurrence. CONCLUSION: Better general life expectancy of young patients is the cause of substantially better overall survival in curable stages. Advanced breast cancer is a strongly life-threatening factor. The fatal influence of large tumor mass is independent of age.

Detection of p53 auto-antibodies in the sera of breast cancer patients with a new recurrence using an ELISA assay. Does a correlation with the recurrence free interval exist?

INTRODUCTION: Mutations of the tumor suppressor gene p53 are common in multiple cancer forms, including breast cancer. Data are available that suggest, that the loss of the wild type form of p53 and the appearance of the mutant forms of p53 are correlated with a poorer overall survival rate in patients with breast cancer. The accumulation of the mutant forms of p53 in the cytoplasmatic rooms of the tumor cells leads to the production of human auto-antibodies against these mutant p53 proteins. Therefore, the aim of this study was to analyse and quantify the levels of serum auto-antibodies against p53 protein in patients with an intact immunological system having an active and new recurrence of breast cancer and to compare the obtained results with the recurrence free interval and with established prognostic parameters at the time of first diagnosis, to see if patients with a positive p53 auto-antibody status had a poorer prognosis than those who were p53 auto-antibody positive. MATERIALS AND METHODS: The ser of 61 patients with breast cancer, who experienced a new, clinical and biophysically identified local or distant recurrence and that showed an intact immunological system were analysed with an ELISA assay of Dianova to determine the concentration of auto-antibodies against mutant p53. RESULTS: 14.5% of the patients showed a positive p53 auto-antibody serum status. The recurrence free interval between the p53 auto-antibody positive and negative patients was almost the same: 4.12 years for the p53 auto-antibody positive patients versus 3.72 years for the p53 auto-antibody negative patients (independent t-test value = 0.224 and p value = 0.824; statistically not a significant difference). When comparing the p53 auto-antibody status with established prognostic parameters we could only find a statistically significant correlation with tumor size. No correlations were obtained when comparing the p53 auto-antibody status with the N- and M status, the ER- and PR status, the menopausal status and the cathepsin-D status. DISCUSSION: We were able to demonstrate that the expression of serum auto-antibodies against mutant p53 can not be used as a prognostic parameter in patients with breast cancer as the recurrence free interval between the p53 auto-antibody positive and negative patients did not differ. The determination of the auto-antibodies against p53, though easy to perform, is therefore not a test that helps clinicians in their treatment options, but it remains a useful test for the description of the biological mechanisms of breast cancer.

Expression of the cell adhesion molecules ICAM-1 and VCAM-1 in the cytosol of breast cancer tissue, benign breast tissue and corresponding sera.

OBJECTIVE: Cellular adhesion molecules ICAM-1 and VCAM-1 have been implicated in tumor progression and metastasis. As the sequential interaction of neoplastic cells with the endothelium of tumor neovascularisation is believed to be essential for tumor metastasizing processes, we analysed the concentration of ICAM-1 and VCAM-1 in the cytosol of patients with human breast cancers and their corresponding sera. We compared the obtained values with established prognostic parameters for breast cancer. Benign breast tissues were also analyzed. PATIENTS AND METHODS: Levels of ICAM-1 and VCAM-1 of 62 patients with invasive breast cancer and 17 patients with benign breast tissue were measured using commercially available sandwich enzyme-linked immunoassays with monoclonal antibodies. To establish a reference and control group, levels of ICAM-1 and VCAM-1 were measured in the sera of 66 women without breast tumors. RESULTS: The mean cytosol concentration of ICAM-1 and VCAM-1 was significantly higher in the breast cancer specimens than in the tissue of patients with benign breast diseases. This could be found not only in the tumor cytosol but also in the corresponding sera of the patients. No correlations between the ICAM-1 and VCAM-1 expressions and established prognostic parameters could be observed. CONCLUSIONS: Our findings suggest that malignant breast cancer cells could induce neovascularisation with subsequent high expressions of ICAM-1 and VCAM-1. These upregulations of adhesion molecules might contribute to changes in invasive phenotypes by promoting endothelial cell adhesion and angiogenesis, as well as being responsible for the recognition of tumor cells by the human immune system. Prognostic relevance for the development of breast cancer could not be established.

[Detection of endometriosis during cesarean section for HELLP syndrome in the 32nd week of pregnancy]. / Erkennung einer Endometriose bei Sectio caesarea wegen HELLP-Syndrom in der 32. Schwangerschaftswoche.

The rare case of a decidualized endometriosis of the appendix vermiformis is reported in a woman who developed HELLP syndrome during the 32nd week of a twin pregnancy. Cesarean section and simultaneous appendectomy were performed. An inspection of the appendix should always be carried out if an endometriosis-associated anamnesis is known. No pathophysiological correlations between the HELLP syndrome and the endometriosis of the appendix vermiformis could be found.

Measurements of the growth and distribution of mammalian cells in a hollow-fiber bioreactor using nuclear magnetic resonance imaging.

We have used diffusion-weighted 1H NMR micro-imaging and localized spectroscopy techniques to monitor the growth and distribution of mammalian cells in a hollow-fiber bioreactor. Non-invasive NMR measurements of this type should also allow investigation of metabolic heterogeneity and assist in future designs of hollow-fiber systems.

[External cephalic version in cases of breech presentation: renaissance of a well-known procedure?]. / Die äussere Wendung bei Beckenendlage: Renaissance eines altbekannten Verfahrens?

OBJECTIVE: About 3-4% of all pregnant women will have a fetus presenting by the breech at term. External cephalic version offers the opportunity to reduce the rate of caesarean sections caused by breech presentation. We analysed retrospectively 51 cases of external cephalic version at our clinic. METHODS: External cephalic version was performed 51 times between 37 and 41 weeks of pregnancy. RESULTS: External cephalic version was successful in 32/51 cases (62,7%) with a consecutive rate of vaginal delivery of 71,9%. The best results were seen at 37 weeks of pregnancy with 81,25% of successful versions followed by 76,9% of vaginal deliveries. Complications were rare. There was just 1 case of emergency caesarean section due to persisting fetal bradycardia. CONCLUSION: External cephalic version is an effective and safe treatment to enable vaginal delivery of cephalic presentation. For this operation, 37 weeks of pregnancy can be considered the best time.

[Antibiotic prophylaxis in cesarean section -- piperacillin versus piperacillin/tazobactam in 300 cesarean sections]. / Antibiotikaprophylaxe bei Sectio Caesarea -- Piperacillin 4 g versus Piperacillin/Tazobactam 4.5 g.

INTRODUCTION: Antibiotic prophylaxis is a standard procedure in obstetric surgery and has been discussed in various investigations. Use of treatment is judged by high efficacy and good tolerance. METHOD: In 300 patients undergoing cesarean sections we compared results of application of Piperacillin 4 g and Piperacillin/Tazobactam 4.5 g after cut of umbilical cord. Tazobactam/Piperacillin is a combination of a broad-spectrum penicillin and a beta-lactamase inhibitor with increased toxicity against staph. aureus, enterobacter, and other germs responsible for local and systemic infections in obstetric surgery. RESULTS: We did not observe any severe adverse effects. Rate of severe wound infections was 1.3 % (Tazobactam/Piperacillin) and 2 % (Piperacillin alone). The difference showed no statistic significance (p > 0.01). During postoperative course we found a higher increase of CRP (p < 0.01) in the Piperacillin group. CRP proved to be a useful objective parameter to distinguish between patients with or without postoperative infections. No differences were found in the number of leucocytes, time in hospital and other parameters.

[Advances in the physical therapy of pain in rheumatology.]. / Fortschritte der Physikalischen Therapie des Schmerzes in der Rheumatologie.

The analgesic effectiveness of physical therapy in rheumatology is dependent on the differentiated clinical picture (joint, soft parts, spinal column, musculature) and on the differentiated therapeutic remedy (intensity, duration of single treatments, frequency, duration of therapeutic series). Physico- and kinesitherapy can be distinguished with regard to objective and subjective doses; manual therapy is between them. During the last decade, particular advances were achieved in the field of medical gymnastics (muscular stretching technique), patients' schools (back school) and of cryotherapy (cold-air therapy). The pulsed high-frequency therapy and particularly laser therapy, magnetic-field therapy and high-voltage therapy are critically judged. The problem "rheumatism and pain" mainly exists at the level of "chronic"; diagnostics of movement function (articular and muscular functions) on one hand and dosage of therapeutic remedies (drugs and remedies of physiotherapy) on the other are the guidelines. Course (rehabilitation) as well as onset (prevention) of rheumatic clinical pictures determine the further strategy of pain therapy.

[The primary inflamed and primary degeneratively changed joint from the viewpoint of physical therapy]. / Das primär entzündlich und primär degenerativ veränderte Gelenk unter dem Aspekt der Physiotherapie.

The author emphasizes the interdisciplinary approach that is necessary to rheumatic arthropathies. The pain, inflammation and disturbance of movement must be seen as requiring physiotherapy, while a degree of differentiation is necessary in thermotherapy.