Search

Background: High mobility group A proteins are involved in chromatin remodeling, thereby influencing multiple fundamental biological processes. HMGA2 has been linked to oncogenic traits among a variety of malignancies. Objective: To determine the prognostic implications of subcellular distribution patterns of HMGA2 in breast cancer. Methods: Nuclear and cytoplasmic HMGA2 was evaluated in 342 breast cancer specimens and matched with clinico-pathological parameters. Results: Overall and cytoplasmic, but not nuclear, levels of HMGA2 correlated with better survival prognoses in our collective (hazard ratio (HR) 0.34, P = 0.001 and HR 0.34, P < 0.001, respectively). The protective effect of cytoplasmic HMGA2 persisted in the Luminal A and triple negative breast cancer subgroups. Evaluating Luminal A and B subgroups jointly, only cytoplasmic, but not overall or nuclear HMGA2 levels were associated with better survival (HR 0.42, 95% confidence interval 0.21, 0.86, P = 0.017), irrespective of tumor size and node status. The addition of HMGA2 overall and cytoplasmic scores strengthened the prognostic selectivity in a model of conventional breast cancer risk factors. No predictive significance with regard to endocrine or chemoendocrine therapies was observed. Conclusion: Unexpectedly, we found a favorable survival probability upon overall levels of HMGA2 in our breast cancer collective, which was predominantly determined by the presence of HMGA2 in the cytoplasm.

Pulmonary arterial hypertension is a rare disease that predominantly affects women. The pathophysiology of the disease is complex, with both genetic and hormonal influences. Pregnancy causes significant physiologic changes that may not be well tolerated with underlying pulmonary arterial hypertension, in particular leading to volume overload and increased pulmonary pressures. A multidisciplinary approach and careful monitoring are essential for appropriate management of pulmonary arterial hypertension during pregnancy. Nonetheless, outcomes are still poor, and pregnancy is considered a contraindication in patients with pulmonary arterial hypertension.

Upon ligand binding, plasma membrane-located TNF-related apoptosis-inducing ligand (TRAIL)-receptors 1 and 2 induce apoptosis as well as cancer-promoting signaling in cancer cells. TRAIL-R3 and TRAIL-R4 are believed to negatively regulate TRAIL-mediated apoptosis. Intracellular localization of TRAIL-receptors, as observed in many tumor cells, has been associated with oncogenic features, which are distinct from membrane-associated TRAIL-R signaling. Here, analyzing a panel of 354 breast cancer specimens, we found that an unfavorable outcome correlating with cancer-promoting properties of TRAIL-R1, TRAIL-R2, and TRAIL-R4 was most significantly defined by their intracellular distribution and mutual co-expression. A nuclear or cytoplasmic heterogeneous expression pattern correlated with markedly decreased overall survival and discriminated high-risk breast cancer patients from low-risk patients with a homogeneous distribution of expression, i.e., nuclear and cytoplasmic expression. The homogeneous TRAIL-R expression was associated with favorable breast cancer surrogate markers corresponding with excellent survival prognoses at 5 years after diagnosis (hazard ratio, 0.043) and over the complete course of follow-up (hazard ratio, 0.098; both p 0.001). No associations with specific intrinsic breast cancer subtypes were found. Our data suggest that the determination of intracellular co-expression patterns of TRAIL-R1, TRAIL-R2, and TRAIL-R4 provides an innovative and robust method for risk stratification in breast cancer patients beyond conventional prognostic markers. KEY MESSAGES: A total of 70% of breast cancer specimens show comparably high levels of intracellular TRAIL-Rs. Nuclear or cytoplasmic TRAIL-R co-expression occurs in the majority of tumors. A total of 25% of tumors show a heterogeneous expression of cytoplasmic or nuclear TRAIL-Rs. Patients with a heterogeneous TRAIL-R expression present with poor prognoses. Additive TRAIL-R-based risk stratification comprises different breast cancer subtypes.

Mdm2 (Human mouse double minute 2) is an important opponent of the tumor suppressor p53. The G/G variant of SNP309 in the MDM2 promoter can increase Mdm2 mRNA/protein expression and is associated with an increased risk and earlier onset of different cancers especially in Asian populations. But the frequency and impact of the G/G variant has not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). Next, when separating all females into two groups at their median age (68 years), 7 patients and 1 patient with the G/G variant and 9 patients and 13 patients with the T/T variant were noted in these age groups (P = 0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was analyzed, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P = 0.039 and P = 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs. 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP 309 G/G variant showed a significantly earlier tumor onset than patients with the wildtype T/T genotype. Citation Format: Christine G. Stoehr, Robert Stoehr, Antonia Wenners, Arndt Hartmann, Simone Bertz, Verena Spath, Bernhard Walter, Kerstin Junker, Holger Moch, Raoul Hintze, Stefan Denzinger, Elisabeth E. Bond, Gareth L. Bond, Karen Bluemke, Katrin Weigelt, Verena Lieb, Elke Nolte, Paolo Fornara, Bernd Wullich, Sven Wach, Helge W. Taubert. Association of the G/G-SNP309 variant in the mdm2 gene with earlier tumor onset in female renal cell carcinoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3700.

Background: Sideeffects of adjuvant chemotherapy on ovarian function are inadequately studied by now. Premenopausal women undergoing chemotherapy are at risk for sexual hormone deficiency and impaired fertility. This prospective cohort study searches for predictive parameters of ovarian reserve after chemotherapy. Methods: 51 premenopausal patients (average 38 years; 28-46 years) with primary breast cancer have been included. They all received neo- or adjuvant chemotherapy: anthracycline based "A"(FEC)(n= 18); anthracycline/taxane based "T"( TAC or FEC/Doc or EC/Pac)(n=30) or anthracycline- free "AF"(n=3). After chemotherapy patients received endocrine therapy (ET) for hormone receptor (HR) positive disease (tamoxifen (n=34) or goserelin/tamoxifen (n=7)). For HR negative disease (n=20) no ET was given. Before (visit 1) and 6, 12 and 24 months after initiation of chemotherapy (visit 2-4) age and chemotherapy related changes in hormone (LH, FSH, E2 and Anti-Muellerian hormone (AMH)) levels, antral follicle count and amenorrhea as parameters of endocrine function and fertility were assessed. Also quality of life (QL) and additional impact of parity, BMI and nicotine use on ovarian reserve were evaluated. Results: Antral follicle count is decreasing dramatically after chemotherapy and is not fully recovering after 2 years. Antral follicle count before and 1 year after chemotherapy are significantly correlated (p=0.012). Follicle count and age before chemotherapy are negatively correlated (p=0.004). At visit 4 the type of chemotherapy (A, T, AF) has no influence on antral follicle count or AMH levels. Tamoxifen is correlated with a significant decrease in follicle count (vs. no endocrine therapy) (p=0.039). Smoking is significantly detrimental on antral follicle count after 24 months (p=0.001). AMH levels at visits 2-4 are significantly correlated with levels at the 1 visit and are negatively correlated with age (p=0.032). Tamoxifen therapy has no impact on AMH levels. LH and FSH are increasing between visit 1 and 2 and decreasing at visits 3 and 4 (but stay above basic levels). At visit 4 LH is not and FSH is correlated with visit 1 levels (p=0.005). LH and FSH are correlated with age (p=0.0001) and are not influenced by type of chemotherapy or tamoxifen .E2 levels at visit 4 are not influenced by type of chemotherapy, but significantly decreased (p=0.003) by continued smoking. At visit 4 31/51 patients have stayed amenorrheic, 19 resumed their menstruation. This was not influenced by type of chemotherapy or age. Non- smokers are 13 times more likely to resume their menstruation (vs. smokers). Tamoxifen is correlated with a higher probability of permanent amenorrhea (p=0.058, n.s.). BMI, nicotine abuse, age, type of chemotherapy and tamoxifen have no influence on duration of amenorrhea. QL is significantly lower at visit 2, but recovers to basic values at visits 3 and 4. Conclusions: Our study contributes to a better prediction of ovarian reserve before chemotherapy. We suggest personalized counselling on fertility preserving measures before chemotherapy especially at higher age, with low AMH levels or low antral follicle counts. To stop smoking could enhance chances for ovarian preservation. Citation Format: Christoph Mundhenke, Antonia S Wenners, Jana Grambach, Juliane Koss, Ulrike von Hehn, Walter Jonat, Andreas G Schmutzler. Reduction of ovarian reserve in young early breast cancer patients: 24 months follow up of a prospective cohort trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-05.

This review discusses the current understanding of cardiotoxicities and prevention strategies for several agents including anthracyclines, HER2 monoclonal antibodies, tyrosine kinase inhibitors, and fluoropyrimidines. Heart disease and cancer are by far the most common causes of death in the USA and may coincide in a given individual. Life-prolonging therapies for heart disease and cancer continue to evolve, with a particular proliferation of new agents to treat cancer. These advances in the treatment of cancer have led to an expanding population of cancer survivors. Due to the natural coincidence of heart disease and cancer and due to the cardiotoxicities of certain chemotherapies, it is increasingly important for cardiologists and oncologists to understand and anticipate cardiovascular events in the setting of cancer treatment. A growing body of literature on the incidence of, prediction of, and prevention of cardiotoxicity in the cancer patient is now available.

Background The numerous side effects of chemotherapy in patients with breast cancer are well known. However, the precise effects of chemotherapy on ovarian function in premenopausal women are poorly investigated. The patients are at risk of developing sexual hormone deficiency and impaired fertility. This prospective cohort study addresses predictive parameters of ovarian reserve after chemotherapy. Methods Fifty-one premenopausal women (28–46 years) with primary breast cancer were included in the trial. All of them received anthracycline-based chemotherapy (n = 18), or combinations with taxanes (n = 30), or anthracycline-free chemotherapy (n = 3). Changes in hormone levels (LH, FSH, E2 and Anti-Müllerian hormone (AMH)), antral follicle count (AFC), and amenorrhea were determined before (V1), and 6, 12 and 24 months after the initiation of chemotherapy (V2-V4). Quality of life parameters were evaluated. The additional impact of parity, BMI, and smoking on ovarian reserve was also assessed. Results AFC and AMH fell very markedly after chemotherapy and did not return to pre-treatment levels until V4. A significant positive correlation was noted in AFC before and 1 year after chemotherapy. AMH levels at V2-V4 were significantly correlated with those registered at V1. AFC and AMH were negatively correlated with age. Continued smoking had a significant detrimental effect on AFC after 24 months. LH and FSH levels increased between V1 and V2 and fell at V3 and V4, but stayed above pre-chemotherapy values. Two years after the start of chemotherapy 31/51 patients were amenorrhoic while 17 resumed their menstrual cycle; this was not influenced by the type of chemotherapy or age. Non-smokers were 13 times more likely to resume their menstruation than smokers. Quality of life (QL) was significantly lower 6 months after the initiation of chemotherapy. QL at one and 2 years after chemotherapy did not differ significantly from pre-chemotherapy scores. Conclusions Our study contributes to a better understanding and prediction of ovarian reserve in young early breast cancer patients undergoing chemotherapy. The data suggest that personal counseling in regard of the preservation of fertility should be offered especially to patients of a higher age, with low AMH levels or low follicle counts. Patients should be advised to stop smoking in order to enhance the likelihood of preserving their fertility. Electronic supplementary material The online version of this article (10.1186/s12885-017-3593-x) contains supplementary material, which is available to authorized users.

e19516 Background: Autologous stem cell transplantation (ASCT) followed by maintenance therapy is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. Maintenance typically consists of lenalidomide (LEN), however, bortezomib (BOR) and bortezomib-lenalidomide combination are other options. The respective toxicity of these regimens has not been well studied. We performed secondary data analysis to compare incidence of serious adverse events associated with each maintenance therapy group during post-ASCT maintenance treatment period. Methods: Data was extracted from the open-access MMRF Researcher Gateway corresponding with interim analysis from the CoMMpass study. We extracted data of first-time autologous stem cell transplant patients who completed maintenance therapy post-ASCT. We categorized patients into three sub groups bortezomib, lenalidomide or combination (bortezomib and lenalidomide) maintenance therapy. Incidence rate for serious adverse events (grade 3 or higher) was calculated by number of events per 100 person-months for each maintenance therapy. Results: 231 patients were eligible for our analysis. 169 patients received lenalidomide, 27 bortezomib and 35 combination. The most common adverse event was neutropenia and second most common is pneumonia. Neutropenia incidence was 1.1,0.7 and 0.9 per 100 person-months in lenalidomide, bortezomib and combination regimens respectively. Incidence of deep vein thrombosis, GI intolerance and peripheral neuropathy 0.1 per 100 person-months respectively was observed in lenalidomide group only. Combination maintenance had the highest total adverse event incidence rate of 5.4 per 100 person-months. Incidence of 1.7 and 3.8 per 100 person-months is observed in bortezomib and lenalidomide cohorts respectively. Conclusions: Lenalidomide and bortezomib maintenance had similar incidence of serious adverse events. A higher incidence of serious adverse events was noted in the combination lenalidomide/bortezomib regimens. Interestingly, we observed lower incidence of adverse events in all groups in CoMMpass study compared to respective clinical trials involving maintenance regimens. This may be due to under reporting of adverse events in CoMMpass study. The incidence of adverse events mentioned above should be interpreted in the context of drugs and other factors involved in the disease.

Background: Imatinib is a tyrosine kinase inhibitor of BCR-ABL, ABL, PDGFR-α and -β, KIT, and DDR. In solid tumors, it inhibits proliferation and invasiveness and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in metastatic breast cancer (MBC). This study evaluates the safety and efficacy of imatinib and vinorelbine in combination. Methods: In a prospective, open-label, phase I/II trial, 400 mg imatinib p.o. daily (corrected from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels of 10, 15, 20, and 25 mg/m2 (each n ≥ 5) to treat patients with MBC (expressing PDGFR-α and/or -β, and/or KIT). The last patient of each level was treated for >28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and nonhematological toxicity, and clinical efficacy (data cutoff: November 18, 2011). A total of 33 patients have been enrolled, and all dose levels have been fully recruited. One patient is still on study medication. A translational subprotocol is ongoing. Results: All 33 included patients are evaluable for safety (32 within the ITT population). Eleven patients were excluded early from the study (progressive disease, toxicity, and withdrawal of consent). Twenty-two patients participated in the study for >28 days (‘ITT >28'). Within the ITT population, the response rate [complete response (CR) and partial response (PR)] was 9.4% (n = 3), the clinical benefit rate (CBR; CR+PR+stable disease) 50% (n = 16), and the median time to progression (TTP) 155 days. A total of 21.3% of the patients were on study medication for >6 months, and 15.2% for >12 months (mean 140 days, range 15-643). Within ‘ITT >28', the response rate was 13.6%, CBR 72.7%, and median TTP 176 days. The response was independent of the receptor status (PDGFR-α, -β, and KIT). Toxicities were as follows (safety population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% peripheral neuropathy (severe 9.1%), and 36.4% dyspnea (3% severe). Four patients on trial died (nondrug-related). Conclusion: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pretreated patients suggests that this combination may be active. Although toxicities were frequent, they appeared to be manageable.

Studies that use direct observation to investigate drivers’ cell phone use have been conducted by NHTSA since 2002. The limitations of these studies were identified in a naturalistic driving study conducted at the University of Michigan. In direct observation studies of drivers’ cell phone use, observations are typically conducted at intersections, providing the observer with enough time to accurately observe the behavior but limiting data to one location along the roadway. This may be a limitation of large-scale observation usage studies, which, in turn, translates into a research hypothesis that when stopped at intersections, drivers use their cell phones more frequently. Through a combination of in-field observers and video data collection, more than 3,500 vehicles were observed to determine the difference in cell phone use between drivers upstream and those at the intersection. Signalized intersections were found to have a higher rate of text messaging cell phone use, with the highest percentage observed at red lights. Drivers’ text messaging rates increase with the amount of time spent in stopped conditions, such as red lights. The presence of an observer was also found to have an insignificant impact on drivers’ cell phone use. Effective observation of drivers’ cell phone use is essential for understanding the magnitude of the problem and measuring the effectiveness of campaigns. This study confirms the current methods used while providing recommendations on ways to improve the data quality of future observations.

Die individualisierte Therapie des Mammakarzinoms hat in den vergangenen Jahren grose Fortschritte gemacht. Neben der Chemotherapie sind zielgerichtete Therapien, beispielsweise die Blockade des HER2-Rezeptor-Signaltransduktionsweges, wesentliche Bestandteile einer erfolgreichen Therapie. Dennoch werden immer noch viele Patientinnen einer Chemotherapie unterzogen, von der sie vielleicht gar nicht profitieren. Die Abgrenzung zwischen einem hohen und niedrigen Rezidivrisiko ist mit den klassischen histologischen Parametern zwar moglich, doch die Gruppe der Patientinnen mit intermediarem Risiko ist unakzeptabel gros. Fur dieses Kollektiv ist der Nutzen einer Chemotherapie nicht immer eindeutig erkennbar. Im Einzelfall muss auch hier immer die Frage gestellt werden, wann das individuelle Rezidivrisiko so gros ist, das eine Chemotherapie gerechtfertigt ist. In dieser Ubersichtsarbeit stellen wir die Klassifikation der intrinsischen Subtypen des Mammakarzinoms vor und beschreiben die Einsatzgebiete der zurzeit kommerziell verfugbaren molekularen Tests zur Pradiktion eines Therapieansprechens und Prognose des Mammakarzinoms.

This report details the 2012 observational study used to determine drivers’ cell phone use in Massachusetts; the study was completed as a component of the annual seat belt observation study by the University of Massachusetts Traffic Safety Research Program. This study identified the magnitude of risky driving behavior throughout Massachusetts. The location, the time of day, and the direction of travel for each observation were determined by random selection with consideration given to the region's fatality rate and length of roadway. Throughout the state, the drivers’ cell phone use at any given daylight hour was determined; the timing allowed for comparisons between different populations. The apparent cell phone use of 17,677 drivers was observed at 145 locations, with a finding of an average cell phone use of 7.0%, a handheld use of 5.6%, and a text messaging use of 1.4%. Females were observed having handheld conversations at a greater rate than males, but there was little difference in text messaging use. Teens were observed text messaging more often than adults and elders, while the handheld conversation rate was similar for teens and adults. Drivers observed wearing seat belts had a lower cell phone use than those who were not wearing seat belts, for text messaging and handheld conversations. Notable variations in cell phone use were identified across various driver demographics, road types, and times of observation and furthered the understanding of drivers’ cell phone use and providing an opportunity for targeted countermeasures.

Background and Objective Progress in endoscopic surgery in the past few decades has led to the application of 3-dimensional (3D) procedures in operating rooms. This permits patient- and surgeon-friendly operations and also maximizes the superiority of laparoscopy over laparotomy. In this study, we compare 2-dimensional (2D) and 3D endoscopy techniques with regard to time, efficiency, optics, and handling by users with different degrees of experience at 4 difficulty levels. Design A randomized controlled trial on a pelvitrainer in objectively graded surgical steps for students and postgraduates. Setting The trials took place at the Kiel School of Gynaecological Endoscopy, a training unit of the Kiel University Department of Obstetrics and Gynecology, a tertiary academic medical center. Participants The 277 study participants, divided into students, residents, and specialists, worked on pelvitrainers with 2 different optical systems, the 2D full HD and the 3D mode. The following 4 exercises were performed with each optical system: (1) grasping and transferring of pins, (2) cutting predetermined marks, (3) vaginal closure with prevention of prolapse, and (4) sacrocolpopexy. The duration and success of the tasks were measured and compared. A self-assessment questionnaire was completed by the participants. Results Overall, the 3D-system permitted a greater improvement in working speed, superior optical visualization, and better endoscopic handling in all groups, independent of surgical experience. All students improved in speed (exercises: 1-3) and made significantly fewer mistakes (exercise 2) on 3D compared with 2D. Residents made progress in time (exercises: 1-4) and task performance (exercise 3). Specialists improved significantly in the more challenging tasks 3 and 4. Subjectively, 68.8% of participants preferred 3D for performing laparoscopy. Conclusion Systematic training programs on pelvitrainers can improve endoscopic skills not only in beginners but also in experienced surgeons. The 3D system offered distinct advantages over 2D imaging and was well accepted by surgeons.

et al., The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis. Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to G heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3. Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype., This work was supported by grants from Spanish Ministry of Economy and Competitiveness [PI11/00295 to CS, PI14/01101 to CS and EP-G, SAF2013-46183-R to MQ, and SAF2014-54705-R to MV-M, supported with European Regional Development (FEDER) funds] and Madrid Regional Government (S2010/BMD-2308 to MG, and 2010/ BMD-2359 to MQ). EPG was a recipient of a Postdoctoral Research Contract from Fundación Científica Asociación Española Contra el Cáncer and a Federation of the Societies of Biochemistry and Molecular Biology (FEBS) Short-term Fellowship. SB-B and SC-L are recipients of a Formación de Profesorado Universitario (FPU) fellowship and a Ramón y Cajal research contract, respectively, from the Spanish Ministry of Economy and Competitiveness.

Borderline Tumoren des Ovars (BOT) stehen klinisch wie morphologisch zwischen den zelltypspezifischen benignen und malignen Ovartumoren. Die Hypothese einer kontinuierlichen Karzinogenese wurde anhand eines Modells zur Genese maligner Ovarialtumoren theoretisch unterstutzt. Seine Ubertragbarkeit auf die verschiedenen Ovarialmalignomentitaten ist noch nicht abschliesend geklart, dennoch hat das Modell auch relevante Implikationen fur das Management von BOT. Betroffen von BOT sind uberproportional haufig Frauen im reproduktiven Alter, sodass sich bei der Therapie grundsatzlich die Frage nach einem Fertilitatserhalt stellt. Neben Alter und FIGO-Stadium scheint die Zytoreduktion durch die Primaroperation das entscheidende prognostische Kriterium zu sein, der postoperativ verbliebene Tumorrest ist ein unabhangiger Prognosefaktor. Neben diesen Aspekten wird der Stand in den Bereichen Therapie der BOT und Prognose referiert.

Patients with end-stage heart failure may be treated with home inotropes, “palliatively” or as bridge to left ventricular assist device (LVAD) or transplant (“bridge”). Prior studies showed that home inotropes increased mortality, but were done prior to current medical or device therapy. We

Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo–keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism. Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival. AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker. It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status.

Purpose: Nilotinib is a selective tyrosine kinase inhibitor of c-Kit, Abl and platelet-derived growth factor receptor-α/β. To evaluate nilotinib's potential use as a treatment of human ovarian cancer, we tested nilotinib's preclinical activity in ovarian cancer cell lines with different tyrosine kinase expression patterns. Methods: The effects of nilotinib on ovarian cancer cell growth were studied alone and in combination with carboplatin and paclitaxel. Proapoptotic and antimigratory effects were examined using TUNEL and migration assays. Results: Nilotinib alone and in combination with carboplatin and paclitaxel significantly inhibited cell growth in PDGFR-α-positive ovarian cancer cell lines. The combination of nilotinib with carboplatin and paclitaxel showed synergistic effects on cell proliferation. Nilotinib treatment led to the inhibition of cell migration alone and in combination with carboplatin and paclitaxel. Apoptosis induction occurred in response to nilotinib that increased in combination with carboplatin. Conclusions: Nilotinib may be a feasible targeted therapy option for the treatment of ovarian cancer.

Often breast cancer can be treated by breast-conserving surgery (BCS), after which 10 % locoregional recurrences (LRR) occur within 10 years. After BCS mastectomy is recommended at first LRR, although another BCS could be possible. Changes in clinical parameters and in tumor biology from primary breast cancer to first and multiple LRR are described and correlated with further LRR and overall survival (OS).380 patients with ≥1 ≤3 LRR (1997-2007) were evaluated retrospectively and followed until 5/2009. Patients' age, tumor size, nodal involvement, distant metastases, histological subtype, hormone receptor (HR) and Her-2/neu status were assessed. LRR therapy options were evaluated.247 patients had one LRR (94 two and 39 three). Mean OS was 10.1 years. Number of LRR was not correlated with OS. Positive HR status was significantly correlated with longer OS. Patients, who changed from primarily ER negative to positive at first LRR had a significantly longer OS compared to those, who remained or changed to ER negative (p0.01). Tumor size and grading correlated inversely with OS (both: p0.001). BCS at first LRR correlated with a significantly better OS than mastectomy (p0.001). LRR cases with chemotherapy had a shorter OS. Irradiation and/or endocrine therapy after LRR were not correlated with OS.Patients with positive HR status had the best survival data. HR should always be determined. In positive cases, endocrine therapy is recommended. As clinical data are good, BCS at first LRR can be suggested for more patients.

Introduction Liver transplantation currently represents the only curative treatment for Wilson’s disease. A lifelong immunosuppressive therapy is mandatory. In spite of increased maternal and fetal risks, pregnancies after liver transplantation have been reported with favorable perinatal outcomes. Hypoplastic left heart syndrome is a spectrum of congenital heart defects that results in the inability to support the systemic circulation. Although its etiology remains elusive, the prognosis of this previously fatal condition has dramatically improved over the last 2 decades mainly due to advances in prenatal diagnosis, surgical technique and perioperative care. Case presentation We present a case of a Caucasian 26-year-old woman, gravida 2, para 1 at 36+0 weeks of gestation who had received a liver transplantation due to Wilson’s disease and subsequently delivered a child with hypoplastic left heart syndrome. Conclusions This coincidence of medical conditions has not been described in the literature so far and its implications for mother and child as well as the pathophysiological mechanisms are discussed on the basis of a literature review.

The purpose of this single-center study was to determine the practicability of the intra-operative use of one-step nucleic acid amplification (OSNA) as the only method for detection of SLN. The OSNA system has been well described and is supposed to be as accurate as conventional histology. Three hundred and thirty SLNs from 143 breast cancer patients were analyzed in an intra-operative setting. The CK19-copy number was determined by OSNA and divided into 3 results (“−” no metastasis; “+” micrometastasis; “++” marcometastasis). If OSNA gave a positive result, an axillary lymph node dissection was carried out during the same session. The central 1-mm slice of each node was obtained for permanent histology. Additionally, the results were correlated to clinicopathological factors, and the time for the intra-operative use was evaluated. Thirty-nine of the 143 patients were OSNA positive, 22 with macrometastatic and 17 with micrometastatic spread. The mean time for the OSNA run with one SLN was 34.4 min. We could show a correlation between the tumor size and OSNA positivity as well as between the numbers of OSNA positive SLNs with the tumor load of associated non-SLNs. Furthermore, we found that a cutoff CK19 copy number of 7,900/μL indicates a positive non-SLN result with the highest sensitivity (91 %) and specificity (61 %). We found OSNA to be very helpful for the intra-operative determination of the tumor load of a SLN as a basis for decision-making concerning further surgical axillary intervention. OSNA allows precise differentiation of micro- from macrometastasis, and the CK19 copy number predicts the probability of tumor load in other axillary lymph nodes and might help to find adequate adjuvant treatment options. This objective method is well suitable for everyday use and may reduce the pathologic workload and the risk of secondary operative interventions with all associated costs and stress for the patients.

Primary care must be reengineered to improve outcomes and affordability. To achieve those goals, WellPoint invested in ten patient-centered medical home pilots that encourage care coordination, preventive care, and shared decision making. Two of the three pilots described in this article—in Colorado and New Hampshire—layer incentive payments for care coordination and quality improvement on top of a traditional fee-for-service payment. The third—in New York—pays doctors an enhanced fee that is tied to achievement of quality levels. Preliminary evaluations show encouraging signs that the Colorado and New Hampshire pilots are meeting some cost, utilization, and quality objectives. A full evaluation in all three states is ongoing. To help enable systemwide transformation, WellPoint is now applying similar payment strategies to primary care practices that may not have the resources to become full-fledged medical homes.

Objectives Endometriosis is a common gynaecological disease with clinical symptoms such as chronic pain, infertility and intra-abdominal adhesions. Different theories on the pathogenesis of endometriosis and especially its aggressive subtype with infiltrative growth have been discussed. The objective of this study is to evaluate differences in proliferation and invasive properties of invasive colorectal endometriosis, superficial peritoneal endometriosis and endometrial carcinoma (G1 and G2). Study design Paraffin embedded tissues of peritoneal endometriosis, endometriosis of the intestine and endometrial carcinoma from 97 patients were stained immunohistochemically to assess differences in expression patterns of matrix metalloproteinases (MMP-2, MMP-9) as markers of invasion and the marker of proliferation PCNA. MMP expression was evaluated using the Immuno Reactive Score (IRS) (combining positive cell ratio and staining intensity) and PCNA expression was assessed as the percentage of positively stained cells in representative areas. Results MMP-2, MMP-9 and PCNA showed differential expression patterns in the different tissues examined. MMP-2 and PCNA expression was stronger in invasive colorectal endometriosis than in superficial peritoneal endometriosis ( p =0.0394). MMP-9, however, was more frequently expressed in peritoneal endometriosis (59.1%) than in colorectal endometriosis (44.4%). This result did not reach statistical significance. When colorectal endometriosis was compared to low grade endometrial carcinoma, proliferation detected by PCNA was significantly higher in endometriosis ( p =0.0008). MMP-2 and MMP-9 showed higher expression in endometrial carcinoma than in endometriosis. Conclusions There are obvious differences in expression patterns of MMP-2, MMP-9 and PCNA in different stages of endometriosis and in endometrial cancer. These markers can be helpful to evaluate aggressiveness and invasiveness of endometriosis in different localizations. The results obtained could be of relevance for a better understanding of the pathogenesis of endometriosis and the development of an individual therapy concept.

We have developed a focused ion beam (FIB) system for automated MEMS processing. This product, the Micrion MicroMill, has been successfully used in production and prototype milling of over three million thin film heads (TFH) used in hard disk drives. The FIB column consists of a liquid gallium (Ga+) ion source, running at 50 kV, producing beam currents up to 50 nA. The milling rates achieved in the TFH application have been 0.5 - 4 micrometer3/sec with spot sizes ranging from 150 - 800 nm. This tool is designed to easily integrate into current FAB facilities and supports a wide range of navigational requirements. Different milling scenarios can be easily created or modified using the integrate CAD-like design tools, allowing for quick production line design modifications or rapid prototyping of new designs. The milling strategy can 'adapt' to dimensional changes caused by upstream process variations. On a real-time basis, the FIB system's pattern recognition/inspection software measures the individual part and precisely places the desired milling pattern. The flexible vector scan beam control can position the FIB, within sub-tenth micron dimensional control, to generate an endless variety of geometric milling patterns. This presentation will discuss the work currently done on inductive and magnetoresistive TFH devices as well as other potential MEMS processing applications.© (1997) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

1084 Background: Breast cancer is the most common malignancy in premenopausal women. Sideeffects of chemotherapy are well known nevertheless the precise effects on ovarian function are inadequately studied by now. Premenopausal women undergoing chemotherapy are at risk for symptoms of sexual hormone deficiency and impaired fertility. Searching for predictive parameters of ovarian reserve after chemotherapy this prospective cohort study has been set up. Methods: 36 young patients with primary breast cancer have been included in this trial after written consent (April 2010 to November 2011) and after the study was approved by the local review board. All women were premenopausal (< 46 years). They all received anthracycline based “A” neo- or adjuvant chemotherapy (as FEC) or combinations with taxanes “T” ( as TAC or FEC/Doc). Before and 6 and 12 months after initiation of chemotherapy age and chemotherapy related changes in hormone (LH, FSH, E2 and Anti-Müllerian hormone) levels, antral follicel count and amenorrhea as parameters of endocrine function and fertility were assessed.The additional impact of parity, BMI and nicotine use on ovarian reserve was also evaluated. Results: There is a correlation of antral follicle count before and 1 year after chemotherapy and a negative correlation of age and follicle count before and after chemotherapy (n.s.). This analysis shows that patients receiving “T” compared to those with “A” have a significant increase of LH (p=0.025) and FSH (mean:24 vs.59 IU/l, p=0.021) between visit 1 and 3. The type of chemotherapy has no influence on antral follicle count and AMH levels within the first 3 visits. BMI is negatively correlated with AMH at all time points (n.s.). BMI, nicotine abuse and age have no influence on the duration of amenorrhea, whereas patients with "T" showed 12 months of amenorrhea instead of 9 months in patients with "A" (n.s.). Conclusions: Our study will contribute to a better understanding and prediction of ovarian reserve of young early breast cancer patients undergoing chemotherapy. The 12 months follow up data suggest to offer fertility preserving measures before chemotherapy especially to patients planned for taxane containing chemotherapy.

e13503 Background: Imatinib is a tyrosine kinase inhibitor of bcr-abl, PDGF-R, SCF, c-Kit and abl. In solid tumors it inhibits proliferation and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in MBC. This study evaluates the combination of imatinib and vinorelbine. Methods: In aprospective open-label, phase I/II trial 400 mg imatinib p.o. daily (amended from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels with 10, 15, 20, 25 mg/m² (each n ≥ 5) for pats. with MBC (which express PDGF-R-α and/or -β and/or c-kit). The last pat. of a level was treated > 28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and non-hematological toxicity and clinical efficacy (data cut: 18/11/2011). A translational subprotocol is ongoing. 33 pats. have been enrolled; all dose levels have been fully recruited. 1 patient is still on study medication. Results: 32 pats. are evaluable (ITT population). 11 pats. went off study early (progressive disease, toxicity and withdrawal of consent). 22 pats. were on study >28 days (“ITT>28”). Within the ITT population the response rate (complete (CR) and partial response (PR)) was 9.4% (n=3), the clinical benefit rate CBR (CR+PR+stable disease) 50% (n=16), median time to progression (TTP) 155 days. 21.3% were on study medication >6 months, 15.2% > 12 months (mean 133 days, 15-617 days). Within “ITT>28,” the response rate was 13.6%, CBR 72.7% and median TTP 176 days. Toxicities (ITT population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% periph. neuropathy (severe 9.1%) and 36.4% dyspnea (3% severe). 1 patient on study medication died (non drug related). Conclusions: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pre-treated pats. proves the efficacy of this combination. Although toxicities were frequent, they appeared to be manageable.

595 Background: In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor p...