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551 Background: Elevated intratumoral levels of uPA and PAI-1 in ELISA-based measurements are associated with a high recurrence risk and allow to select patients who might particularly benefit from...

Laparoscopic adhesiolysis may be a worthwhile procedure in selected patients. If adhesiolysis for acute obstruction is intended, some risk factors such as peritonitis, previous malignant disease, or complex conventional adhesiolysis have been reported frequently in the literature, and suggest that the laparoscopic approach must be considered cautiously. Laparoscopic surgery for chronic bowel obstruction or even pain can be accomplished with low morbidity, but the long-term results are good in at most 50% of all patients, and this evidence comes from nonrandomized studies (level 3b and 4 evidence). Important factors for a favorable outcome are good surgical judgment and proper selection of patients.

The growing range of applications for peptide arrays prepared by SPOT synthesis confirms that they are a powerful proteomics technique to study numerous aspects of molecular interaction events. The most frequent application for peptide arrays prepared by SPOT synthesis is the identification of linear epitopes that are recognized by antibodies. In the conventional format using secondary antibodies for detection unspecific binding and high background have been observed. This leads to difficulties in evaluation of developed membranes. Especially for application with combinatorial libraries false positive results are to be avoided. To circumvent this issue, we directly labeled compounds of interest with biotin and detected binding by incubation with streptavidin-horseradish peroxidase via chemiluminescence. Optimization of method conditions led to a very sensitive detection technique with no or low number of unspecific spots, which is superior to conventional detection with secondary antibodies. As one consequence, evaluation of competitive assays got more reliable.

Summary Background Tamoxifen has been the standard adjuvant treatment for postmenopausal women with hormone-responsive early breast cancer for more than 20 years. However, the third-generation aromatase inhibitor anastrozole has proven efficacy and tolerability benefits compared with tamoxifen when used as initial adjuvant therapy. We investigate whether women who have received a period of adjuvant tamoxifen would benefit from being switched to anastrozole. Methods We present a combined analysis of data from two prospective, multicentre, randomised, open-label trials with nearly identical inclusion criteria. Postmenopausal women with hormone-sensitive early breast cancer who had completed 2 years' adjuvant oral tamoxifen (20 or 30 mg daily) were randomised to receive 1 mg oral anastrozole (n=1618) or 20 or 30 mg tamoxifen (n=1606) daily for the remainder of their adjuvant therapy. The primary endpoint was event-free survival, with an event defined as local or distant metastasis, or contralateral breast cancer. Analysis was by intention to treat. Findings 3224 patients were included in analyses. At a median follow-up of 28 months, we noted a 40% decrease in the risk for an event in the anastrozole group as compared with the tamoxifen group (67 events with anastrozole vs 110 with tamoxifen, hazard ratio 0·60, 95% CI 0·44–0·81, p=0·0009). Both study treatments were well tolerated. There were significantly more fractures (p=0·015) and significantly fewer thromboses (p=0·034) in patients treated with anastrozole than in those on tamoxifen. Interpretation These data lend support to a switch from tamoxifen to anastrozole in patients who have completed 2 years' adjuvant tamoxifen.

In the present study, 25 patients with breast cancer pretreated with one or two anthracycline-based regimens for visceral metastases were enrolled. Patients were treated with gemcitabine 1250 mg/m 2 on days 1, 8 and 15, q28d. Nine patients received gemcitabine as second-line treatment, whereas 16 patients received gemcitabine as third-line cytotoxic treatment, respectively. In the second-line setting, two (22%) patients gained PR (RR 22%) and four (44%) patients experienced SD ( P =0.2), respectively. In the third-line-setting, one (6%) patient gained CR, one patient PR (6%) and four patients (25%) SD, respectively, resulting in a response rate (RR) of 12%. In the second-line-setting, median time to progression was 5.1±4.0 months (range: 1.6–13.9) versus 3.5–2.5 months (range: 1.3–10.4) in the third-line-setting. Median overall survival was 12.6±9.1 months (range: 3.9–30.8) versus 7.5±6.7 months (range: 2.0–26.0), respectively. Overall, no patient experienced treatment limiting toxicities. We conclude from the present study that gemcitabine induced an overall RR of 16% following prior treatment with anthracyclines. However, median time to progression and median overall survival were limited. In the search for efficacious treatment of patients with metastatic breast cancer, gemcitabine constitutes a valid tool in anthracycline-resistant disease and thus might represent a valuable option for combination chemotherapy in controlled trials in this condition.

Zielsetzung: Das Interleukin-1.System spielt eine bedeutsame Rolle bei tumor-assoziierten Gewebeveranderungen und eine Reihe von Hinweisen deuten auf eine Schlusselrolle von IL-1alpha bei der lokalen Tumorinvasion hin. Methodik: Wir haben mithilfe von RT-PCR und Immunhistochemie das Genexpressionsmuster von IL-1alpha und allen anderen Mitgliedern der IL-1-Familie in Brustkrebszelllinien, in Tumorstromafibroblasten und in Brustkrebspraparaten untersucht und diese mit klinischen Parametern wie Rezeptorstatus oder Grading verglichen. Resultate: In Brustkrebszelllinien war die IL-1alpha- und IL-1beta-Genexpression nur in den phanotypisch malignerem Zellen nachweisbar, und nur in der Rezeptor-negativen hochmaligne Zelllinie MDA-MB 231 war IL-1alpha-Protein dedektierbar, wahrend ERalpha und PR ein exakt inverses Expressionsmuster aufwiesen. In Brustgeweben waren mRNA fur IL-1alpha in 84%, IL-1beta in 92% und fur ihren Rezeptor IL-1tIR in 100% nachweisbar. Genexpression des kompetitiven IL-1-Rezeptorantagonisten IL-1RA war in 74% vorhanden. Immunhistochemisch zeigte IL-1alpha Protein Expression in Tumorzellen oder benachbartem Bindegewebe in 88%. Die Menge der epithelialen Proteinexpression war positiv korreliert mit zunehmender De-Differenzierung (p=0.002; r=0.469) und negativ korreliert mit epithelialer ERalpha-Expression (p=0.004; r=-0.387). Stromale IL-1alpha-Proteinexpression war pradominant in Gewebsabschnitten mit geringer oder negativer ERalpha-Expression in benachbarten Tumorzellen (p=0.001; r=-0.457). Zusammenfassung: Wir konnten die Existenz eines funktionellen IL-1-Systems in Tumorzellen und in benachbartem Bindegewebe nachweisen und fanden eine hochsignifikant negative Korrelation zur lokalen Sexsteroid-Rezeptorexpression. Wir postulieren, dass die unphysiologische Expression von IL-1alpha in entdifferenzierten und rezeptornegativen Brusttumoren durch die Freisetzung von proteolytischen Enzymen zu einer verstarkten Aggressivitat und zu einem bosartigeren biologischen Verhalten dieser Tumoren fuhrt.

Breast cancer in younger patients appears to be more aggressive than disease occurring in older patients. Even though large population-based studies suggest poorer survival of patients younger than 35 years, data demonstrating the relationship of age and prognosis within premenopausal cohorts are much more scarce and conflicting. In this retrospective analysis of 885 premenopausal patients, the relationship between age, typical prognostic factors, treatment, and patient outcome was investigated. Eight hundred four patients (90.8%) > 35 years and 81 patients (9.2%) ≤ 35 years who had been treated for stage I/II breast cancer were evaluated. Median follow-up time was 71 months. The prevalence of adverse prognostic features such as tumor size, tumor type, tumor grading, pathologic lymph node status, and hormone receptor status were evenly distributed between the two age groups. Age ≤ 35 years proved to be a powerful independent prognostic factor in multivariate analyses of recurrence-free (P < 0.0001; relative risk [RR] = 2.5) and overall survival (P < 0.0039, RR = 2.2). Thus, in the face of evenly distributed risk factors in this strictly premenopausal, homogeneous population, young age was seen as the second most powerful risk factor after lymph node status. According to these findings, patients diagnosed with breast cancer at ≤ 35 years of age have a worse prognosis compared to premenopausal women above this age. Future studies should focus on unveiling the young age surrogate in order to improve treatment and prognosis.

Glioblastoma (GBM) is the most common and malignant type of brain tumor in adults with an average survival time of less than a year. A hallmark of GBM is its infiltrating growth hampering successful surgical treatment and precluding curative therapy. Multifocal GBMs - multiple synchronous lesions in the same patient - represent approximately 8-10% of all gliomas and generally have a poor prognosis. There are two theories as to the nature of these multifocal GBMs: they could either have originated from one main GBM or they can be independent tumors. Genetic studies of multifocal GBMs are very rare and such studies could elucidate the nature of these tumors. We have analyzed eleven tumor foci of six patients with multifocal GBMs using array comparative genome hybridization (aCGH), spectral karyotyping (SKY), and Sanger sequencing of PTEN, TP53, and IDH1/2. Array CGH analysis of ten of the tumors revealed multiple genetic aberrations. The most frequent were gain of chromosome 7 (9/10), amplification of EGFR (10/10), loss of chromosome 10 (10/10), and partial loss of chromosome 9 (7/10). SKY analysis identified multiple translocations including complex rearrangements. None of the tumors carried a mutation in IDH1/2 and they were genetically similar to primary GBMs although they exhibited unique characteristics; e.g. all carried an EGFR amplification, indicating that it is important for the multifocal phenotype. Tumor foci derived from the same patient always shared identical aberrations, proving monoclonal origin of these tumors but also exhibited additional aberrations, which were specific for each focus and therefore must have occurred later in tumor development. Moreover, our results show that events important for gliomagenesis could occur at different time points in tumor evolution: for example, the region involved in the EGFR amplification was different in both foci from three patients and identical in two foci from one patient. The same can be said of point mutations in TP53 and PTEN; TP53 mutations were identical in the different foci from one patient and different in another patient while PTEN mutations were different in the foci from two patients and similar in those of one. Interestingly, in each patient one focus always contained more aberrations than the other, highlighting the possibility that one derived from the other; this would further support the hypothesis that multifocal GBMs are of monoclonal origin and then develop independently of each other by clonal evolution. Taken together, multifocal GBM provide an excellent model for investigating tumor progression and invasion and might help to distinguish between driver and passenger alterations in GBM. Acknowledgements: This work was partially supported by a grant (MeDDrive program) of the Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden. Citation Format: Khalil Abou-El-Ardat, Dietmar Krex, Michael Seifert, Kerstin Becker, Morten Hillmer, Sophie Eisenreich, Arleta Käßner-Frensel, Petra Freitag, Eva-Maria Gerlach, Karl Hackmann, Andreas Rump, Gabriele Schackert, Evelin Schröck, Barbara Klink. Genetic analysis of multifocal glioblastoma multiforme foci points to their monoclonal evolution and highlights early and late events in their development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3415. doi:10.1158/1538-7445.AM2014-3415

Glioblastoma multiforme (GBM) is the most prevalent malignant primary brain tumor in adults. GBM is classified as primary if it is assumed to have arisen de novo or as secondary if it progressed from lower grade astrocytoma. Previous studies have found that primary and secondary GBMs have distinct molecular and mutational profiles. Both have a grim prognosis with survival times of about a year with therapy. Although much progress in delineating the temporal order of mutations and copy number aberrations in the progression of lower grade gliomas was made in the past years, none of the studies have actively followed individual tumors through their progression. Whereas this method can detect aberrations that are prevalent in gliomas, it can miss events that are important in a subset of gliomas or are necessary for progression. The GlioMath-DD consortium is an interdisciplinary collaboration of several groups at the Technische Universität Dresden (TU-Dresden) aiming to study the progression of gliomas and to come up with a mathematical model for gliomagenesis. The work involves analyzing pairs of gliomas obtained from patients who had presented with a low grade glioma and who later had a recurrence of a higher grade glioma. All tumors were checked by pathologists and then high quality DNA and RNA material extracted and used for analysis. The tumors are analyzed for copy number variations (CNV) by array comparative genome hybridization (aCGH), while gene expression changes and small mutations are analyzed using high-throughput sequencing (RNA- and Exome-seq). The data gleaned from these experiments and from in vitro models of cell growth and spheroid formation will be used by bioinformaticians and mathematicians to infer key signaling networks and formulate a mathematical model of glioma progression. The ultimate aim of this work that spans two and a half years is to create a comprehensive model of glioma promotion and progression. Furthermore, it will pinpoint driver mutations and aberrations that contribute to this progression and eventually isolate biomarkers for diagnosis and therapy. During the conference, we will present preliminary genetic data of our ongoing study. Acknowledgements: The GlioMath-DD project (coordinator: Andreas Deutsch; SAB-Number 100098214) is funded by the European Social Fund (ESF) and the Free State of Saxony Citation Format: Evelin Schröck, Khalil Abou-El-Ardat, Ralf Wiedemuth, Michael Seifert, Alvaro Köhn-Luque, Mirjam Ingargiola, Kristin Stirnnagel, Alexander Krüger, Wolfgang Nagel, Kathrin Geiger, Andreas Beyer, Leoni A. Kunz-Schughart, Gabriele Schackert, Achim Temme, Barbara Klink, Andreas Deutsch. GlioMath-DD: A multidisciplinary approach to study glioma evolution and identify targets for individualized therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5341. doi:10.1158/1538-7445.AM2014-5341

577 Background: Endocrine therapy is an effective, targeted therapy in patients with hormone receptor positive breast cancer (BC). However, in the adjuvant setting no indicator exists visualizing i...

Aus der verwaltungssoziologischen Literatur weis man, Verwaltung beschreibt eher ihre Umwelt als ein Problem fur sich selbst, als dass sie sich als Problemloser fur ihre Umwelt sieht. Diese Umwelt ist das Publikum ob in individualisierter oder organisierter Form, ob als Burger, Klient, Antragsteller, Leistungsbezieher oder wie immer seine Rolle naher ausgestaltet sein mag. Dass Verwaltung ihre Umwelt als Problem wahrnimmt heist aus ihrer Perspektive dann auch, dass ihr diese Umwelt „Stolpersteine“ bei der Aufgabenwahrnehmung in den Weg stellt.

Estrogens are known as potent mammary mitogen substances and are the major stimulus for the growth of hormone-dependent tumors and clearly implicated in the pathogenesis of breast cancer. Therefore it is a general belief that hormone replacement therapy (HRT) after breast cancer will increase the risk of developing recurrences, though there are no clear data available to support this suggestion. No prospective study with a large number of patients and a long treatment period was performed concerning this issue. On the other hand it may not be justifiable to withhold hormone replacement therapy from low-risk patients after menopause, knowing the benefits of this therapy concerning osteoporosis and cardiovascular advantages. Nevertheless, until appropriate clinical trials help to resolve this problem, non hormonal alternatives constitute the standard of care. One possible approach is to treat menopausal women who have had breast cancer symptomatically and avoid ERT unless absolutely necessary. The risk of cardiovascular diseases can be reduced with lifestyle. Tamoxifen has a beneficial effect on serum lipids and the intake for 5 years leads to a 50% reduction in the incidence of fatal myocardial infarction and a decrease in morbidity associated with ischaemic heart disease. Low doses of progestogen is effective for menopausal hot flushes. Tibolone reduces vasomotoric symptoms such as hot flushes and offers benefit on osteoporosis and has shown a significant reduction in high-density lipoprotein cholesterol. Whether replacing of estrogens is safe for patients after breast cancer remains uncertain. There is a need for a large controlled clinical trial to evaluate the safety and advantages of long time estrogen replacement in women treated for breast cancer.

Der Aufsatz analysiert und prognostiziert die konjunkturelle Entwicklung in Deutschland und im Euroraum in ausführlicher Form für das laufende Jahr 1999 und das Folgejahr 2000. Im Frühjahr 1999 haben sich die Perspektiven der Weltwirtschaft wieder aufgehellt. Auch im Euroraum und in Deutschland mehren sich die Anzeichen, dass der Tiefpunkt der konjunkturellen Delle durchschritten ist und die Wirtschaft auf den eingeschlagenen Aufschwungspfad zurückkehrt. Die konjunkturelle Wende in Deutschland kommt von der Auslandsnachfrage. Als Stütze der Konjunktur erweist sich die Konsumnachfrage der privaten Haushalte. Anregungen kommen aus den Einkommenssteigerungen infolge der höheren Lohnabschlüsse, der Entlastungen bei den direkten Steuern und Beiträgen zur Rentenversicherung, dagegen wirkt die Ökosteuer leicht bremsend. Die wichtigsten Daten der Volkswirtschaftlichen Gesamtrechnung für Deutschland sowie eine Chronologie fiskalischer Maßnahmen seit dem Regierungswechsel sind im Anhang enthalten.

Zwischen den Ländern der Europäischen Union wird die realwirtschaftliche Verflechtung immer enger. Eine Analyse der Multiplikatoreffekte der Ausfuhren zeigt hier, dass die time-lags, mit denen konjunkturelle Impulse aus dem Ausland auf die Binnenkonjunktur übertragen werden, tendenziell gesunken sind, was darauf hindeutet, dass sich der Vorlauf des Exports im Konjunkturverlauf verringert hat.

e11601 Background: Adiponectin impacts on breast cancer risk and prognosis. Obesity and insulin resistance are correlated with low adiponectin serum levels, which increase breast cancer risk and lead to a worse outcome regarding breast cancer. Additionally a cross talk between the adiponectin and estrogen signaling system has been suggested. Here we prospectively investigated the impact of estrogen depletion via aromatase inhibitors (AI) on adiponectin serum levels in postmenopausal patients with breast cancer. Methods: 68 postmenopausal ER positive patients with breast cancer, scheduled to receive anastrozole or letrozole as adjuvant endocrine treatment were prospectively included in this study. Serum was taken before (T1) and 3 months after start with aromatase inhibitors (T2). Non-fasting serum levels of adiponectin, FSH, LH, E2, glucose and insulin were analyzed immediately in the clinical routine lab and in a dedicated central lab able to measure E2 in serum at low concentrations with high sensitivity. Results: At baseline, a strong significant negative correlation between adiponectin and body mass index (BMI) as well as a positive correlation between adiponectin and FSH serum levels could be observed (r=-0.43, p=0.01 and r=0.38, p=0.03, respectively). Taking the previously proposed cut off of 15.5μg/ml, patients with low adiponectin serum levels had a significantly higher BMI and significant lower FSH serum levels. No interaction between adiponectin and estradiol serum levels could be detected. As previously shown, AI treatment significantly decreased estradiol serum levels and consequently increased FSH serum levels. However, 3 months of AI treatment did not alter adiponectin, insulin and c-peptide serum levels, respectively. Conclusions: Short term estrogen depletion via aromatase inhibitors does not impact on non-fasting adiponectin, insulin and c-peptide serum levels in postmenopausal patients with breast cancer.

DNA-binding proteins are a main component of gene regulation as they activate or repress gene expression by binding to specific binding sites in target regions of genomic DNA. However, de-novo discovery of these binding sites in target regions obtained by wet-lab experiments is a challenging problem in computational biology, which has not yet been solved satisfactorily. Here, we present a detailed description and analysis of the de-novo motif discovery tool Dispom, which has been developed for finding binding sites of DNA-binding proteins that are differentially abundant in a set of target regions compared to a set of control regions. Two additional features of Dispom are its capability of modeling positional preferences of binding sites and adjusting the length of the motif in the learning process. Dispom yields an increased prediction accuracy compared to existing tools for de-novo motif discovery, suggesting that the combination of searching for differentially abundant motifs, inferring their positional distributions, and adjusting the motif lengths is beneficial for de-novo motif discovery. When applying Dispom to promoters of auxin-responsive genes and those of ABI3 target genes from Arabidopsis thaliana, we identify relevant binding motifs with pronounced positional distributions. These results suggest that learning motifs, their positional distributions, and their lengths by a discriminative learning principle may aid motif discovery from ChIP-chip and gene expression data. We make Dispom freely available as part of Jstacs, an open-source Java library that is tailored to statistical sequence analysis. To facilitate extensions of Dispom, we describe its implementation using Jstacs in this manuscript. In addition, we provide a stand-alone application of Dispom at http://www.jstacs.de/index.php/Dispom for instant use.

514 Background: Zoledronic acid (ZOL) improves disease outcome in premenopausal patients with breast cancer (BC), especially in those with low estrogen environment. Obesity is associated with increased estrogen serum levels, which might influence the efficacy of ZOL. We investigated the impact of BMI on the efficacy of ZOL in premenopausal patients with BC. Methods: ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg q28d SC) in combination with anastrozole (ANA) or tamoxifen (TAM) ± ZOL 4 mg IV q6mo) in premenopausal women with endocrine-responsive BC. BMI was calculated using the prospectively collected data on patients’ height and weight at study entry. BMI definitions of the WHO were used: normal 18.5-24.9 kg/m2, overweight: BMI 25-29.9 kg/m2, obese BMI ≥ 30 kg/m2). Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method and results were compared by using the log-rank test and Cox proportional hazard modeling. Results: Two thirds of the patients were normal weight (1,111) and one third was overweight (391) or obese (182). Normal weight patients treated with ZOL experienced the same benefit as overweight/obese patients treated with ZOL compared to patients without ZOL regarding disease free survival (HR 0.75, 95%CI 0.53 1.05 p = 0.09 and HR 0.71, 95%CI 0.46 1.1, p=0.12, respectively) as well as overall survival (HR 0.67, 95% CI 0.37 1.22, p=0.19 and HR 0.64, 95%CI 0.32 1.28, p=0.19, respectively). No difference regarding DFS and OS could be detected between normal weight and overweight/ obese patients treated with ZOL (HR 1.05, 95%CI 0.69 1.59, p=0.83 and HR 1.27, 95%CI 0.62 2.61, p= 0.51). Comparing normal weight patients with ZOL to obese patients with ZOL, again no difference could be observed. Conclusions: The significant outcome benefit of adjuvant zoledronic acid in ABCSG-12 can be demonstrated both in normal weight and overweight/obese premenopausal patients with early breast cancer, indicating that the bone marrow microenvironment changing impact of adjuvant bisphopshonate treatment does not correlate with patients’ BMI.

Rome Laboratory is determining the reliability and electromagnetic (EM) performance of multichip modules (MCM) using an integrated multi-disciplinary analysis and measurement methodology. Simulations and Measurements of EM Effects are used to evaluate the susceptibility of MCM technologies and to determine their vulnerability in their operational environments. EM effects are simulated using modern computational electromagnetic (CEM) analysis techniques to determine the fields within the package. Thermal effects in the MCM are simulated using the Intelligent MCM Analyzer which uses finite-element analysis within a object-oriented data base architecture to determine thermal heating effects. This paper will discuss the results of EM Effects measurements and simulations performed on MCM's to determine their conducted EM performance characteristics. This paper will also assess the feasibility of performing EM effects evaluations with less complex devices and models prior to full scale development. The MCM's evaluated include a MMIC Transmit/Receive (T/R) Module and a High Speed Random Assess Memory (RAM).

514 Background: Aromatase inhibitors (AIs) are effective as adjuvant endocrine treatment in breast cancer (BC) patients. Recently, it has been argued that BMI at BC diagnosis impacts on the efficac...

Background: Recently, we have demonstrated that BMI significantly impacts on the efficacy of anastrozole but not tamoxifen (TAM) in premenopausal breast cancer patients. As aromatase inhibitors (AIs) are a mainstay in the treatment of endocrine responsive postmenopausal breast cancer patients, it is of certain interest, if this influence of BMI on endocrine therapy is also true for the postmenopausal situation. Methods: For analysis of the ABCSG 6 and 6a trial, patients were classified as normal weight (BMI 18.5-24.9 kg/m2) or as overweight (BMI ≥25kg/m) according to WHO criteria. The underweight population was excluded from the analyses. We retrospectively analysed the ABCSG 6 trial, which examined the efficacy of TAM versus TAM + aminoglutethimide (first generation AI) in endocrine responsive postmenopausal breast cancer patients. All patients have been censored after 60 months since the majority of patients without events have been re-randomized into trial ABCSG 6a after 5 years. Further, we retrospectively analysed the ABCSG 6a trial, which examined 3 additional years of anastrozole versus no further treatment after 5 years of endocrine treatment. Results: 1,566 patients (311 events/214 deaths) and 477 patients (108 events/64 deaths) were included in the analyses of the ABCSG-6 trial and the ABCSG-6a trial, respectively. About two thirds of all patients in both trials were overweight and one third was normal weight. Analysing the ABCSG 6 trial, no difference in disease free survival (DFS) and overall survival (OS) between normal weight and overweight patients treated with TAM versus TAM + aminoglutethimide could be observed. Analysing the ABCSG-6a trial, normal weight patients treated with anastrozole showed a remarkable and significant reduced risk in DFS and OS compared to control (HR 0.464, 95%CI 0.242 0.842 p=0.02 and HR 0.372, 95%CI 0.16 0.863, p=0.02). In contrast, in overweight patients anastrozole compared to control did not improve DFS and OS (HR 0.991, 95%CI 0.611 1.608, p=0.97 and HR 0.871, 95%CI 0.456 1.662, p=0.67). Conclusion: BMI impacts on the efficacy of anastrozole but not tamoxifen in postmenopausal breast cancer patients. It seems that overweight patients in contrast to normal weight patients do not benefit from additional 3 years of anastrozole after 5 years of endocrine therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD09-05.

512 Background: Aromatase inhibitors (AIs) are effective as adjuvant endocrine treatment in breast cancer (BC) patients. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, BMI might have impact on the efficacy of AIs. In this retrospective analysis of ABCSG-12, we investigated the influence of BMI on the effectiveness of adjuvant endocrine therapy (tamoxifen versus anastrozole in combination with goserelin) in premenopausal BC patients. Methods: ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg q28d SC) in combination with anastrozole (ANA) or tamoxifen (TAM) ± zoledronic acid (ZOL, (4 mg IV q6mo) in premenopausal women with endocrine-responsive BC. BMI was calculated using the prospectively collected data on patients's height and weight at study entry. BMI definitions of the WHO were used: normal 18.5-24.9 kg/m2; overweight: BMI ≥ 25 kg/m2, underweight BMI ≤ 18.5 kg/m2). Disease-free survival (DFS) and overall survival (OS...

Endometrial curettage at the time of conisation is often performed as a routine procedure, even when indication for this treatment is rather unclear. 593 conisations including curettages were performed at the I. Department of Obstetrics and Gynaecology, of the University of Vienna and were evaluated retrospectively. Only 3 patients with a mild endometrial hyperplasia were found. Therefore, in our opinion, there is no indication for a curettage at the time of conisation, if a woman is under the age of 35 years and if there is no other specific indication for sampling the endometrium, based on high risk factors, physical examination, history or abnormal glandular cells found on cervical cytology. Such management would result in reducing the costs and the risk of infection in intrauterine operations.

In this phase II study s new high-does regimen was investigated as consolidation after standard-dose adjuvant chemotherapy of primary breast cancer involving 10 or more axillary lymph nodes. Ten patients with a mean age of 45 year and a mean of 14 positive axillary lymph nodes after mastectomy (n = 8) or segmentetomy (n = 2) received two cycles of cyclophosphamide (CY), doxorubicin, and fluorouracil (CAF) within 56 days of surgery. Then, autologous periphera1 blood stem cells (APBSC) were mobilized with CY and granulocyte colony-stimulalting factor (G-CSF) and enriched for CD34+ cells with immunoadsorption. Thereby, 53% of initial CD34+ cells were recovered and a mean purity of 77% was acheived. High-dose chemotherapy consisted of paclitaxel, Carboplatin, and CY followed by infusion of a mean of 5.1 x 106 CD34+/kg h.w.G-CSF was given is continuous infusion starting one day after APBSC transfusion until neutrophil recovery. Main toxicity of the new high-dose regimen consisted of diarrhea WHO grade 1 to 3 (n = 5), peripheral neuropathy WHO grade 1 (n = 4) and transient elevation of liver enzymes (n = 3). All patients experienced rapid and sustained hematologic recovery and are in excellent performance status 1 to 22 (mean 9) months after APBSC transfusion. In conculsion, paciltaxel combination with carboplatin and cyclophosphamiden is a well tolerated high-dose chemotherpy with acceptable toxicity. Evaluation of relapse rates in patients with high-risk primary breast cancer compared with reported high-dose regimens has to await longer observation times and randomized studies.

The extracellular domain of the HER-2/ neu (c-erbB-2) oncogene protein can be found in soluble form in the sera of patients with breast cancer. We have analyzed serum levels of soluble HER-2/ neu in 42 patients prior to any therapy and put it into relation to the overexpression and amplification of HER-2/ neu in the primary tumor after surgical excision and to data obtained by patho histological staging. In addition, we have investigated the sera of 62 patients with stage IV breast cancer. We have further compared the possible prognostic value of serum HER-2/ neu to two other Known serological tumor markers CEA and CA15–3 in both patient groups. We have observed an elevated serum HER-2/ neu level (>20U/I) in 6/42 (14.2%) preoperative patients, out of whom those with HER2/ neu tissue expression/amplification showed elevated serum, levels in 42.8%. In contrast, 8.5% of patients without HER-2/ neu expression/amplification in the primary tumor presented with elevated serum levels. There was a significant difference in soluble HER-2/ neu serum concentrations between patients with tumors of different size (p neu . In patients with stage IV disease, 27 out of 62 (43,5%) had elevated soluble HER-2/ neu serum levels. A highly signiticant correlation of serum concentrations of HER-2/ neu with CA15–3 (p neu levels at diagnosis defines a small subgroup of breast cancer patients with a relatively advanced stage of disease. Its strong correlation with tumor load in patients with stage II disease and the high prevalence in patients with stage IV disease make it a promising tool for the assessment of disease activity and biologic behaviour in breast-cancer.

ATP-binding cassette (ABC) transporters comprise a large family of membrane proteins that transport a variety of organic substrates across cellular membranes. Human ABC transporters are mostly efflux pumps for physiological and xenobiotic substrates related to immune response and cellular detoxification. Nine human ABC transporters play a major role in cellular multi-drug resistance (MDR), thus being called MDR-related proteins (MRPs). So far, the structure of MRPs and human ABC transporters in general is unclear. Sequence analysis and experimental data indicate that functional ABC transporters are composed of two subunits and imply strong positive cooperativity between those entities. To elucidate the transport mechanism and the molecular origin of the cooperativity a solid-supported biosensor system with defined physicochemical properties is needed. One promising approach is the immobilization of MRP-containing proteoliposomes on functionalized surfaces. We report a new system for immobilizing biotin-doped proteoliposomes via the well-known biotin-streptavidin interaction on gold surfaces functionalized with a self assembled monolayer (SAM) of a binary thiol mixture. The SAM composed of a hydroxy-terminated 16-carbon alkanethiol and its biotinylated derivative protects the gold surfaces from unspecific adsorption and allows the immobilization of defined quantities of streptavidin. Proteoliposomes made from natural lipid compositions and doped with a biotinylated anchor lipid can readily be tethered to these surfaces. By thorough biophysical characterization using quartz crystal microbalance (QCM), atomic force microscopy (AFM) and fluorescence techniques all experimental parameters were optimized for application in biosensor systems. We successfully immobilized intact proteoliposomes containing the reconstituted human ABC transporter MRP3 on the described surfaces. Our system allows the investigation of ABC transporters by a variety of surface-enhanced techniques ranging from AFM and QCM to impedance spectroscopy and surface plasmon resonance based methods under well-defined conditions closely mimicking the protein's natural environment.