Despite improvements in detection, surgical approaches and systemic therapies, breast cancer remains typically incurable once distant metastases occur. High expression of TRAIL-R2 was found to be associated with poor prognostic parameters in breast cancer patients, suggesting an oncogenic function of this receptor. In the present study, we aimed to determine the impact of TRAIL-R2 on breast cancer metastasis. Using an osteotropic variant of MDA-MB-231 breast cancer cells, we examine the effects of TRAIL-R2 knockdown in vitro and in vivo. Strikingly, in addition to the reduced levels of the proliferation-promoting factor HMGA2 and corresponding inhibition of cell proliferation, knockdown of TRAIL-R2 increased the levels of E-Cadherin and decreased migration. In vivo, these cells were strongly impaired in their ability to form bone metastases after intracardiac injection. Evaluating possible underlying mechanisms revealed a strong downregulation of CXCR4, the receptor for the chemokine SDF-1 important for homing of cancers cells to the bone. In accordance, cell migration towards SDF-1 was significantly impaired by TRAIL-R2 knockdown. Conversely, overexpression of TRAIL-R2 upregulated CXCR4 levels and enhanced SDF-1-directed migration. We therefore postulate that inhibition of TRAIL-R2 expression could represent a promising therapeutic strategy leading to an effective impairment of breast cancer cell capability to form skeletal metastases.

ABSTR AC TIntroduction There is sufficient evidence showing the positive effects of physical exercise on various aspects of pregnancy. This study evaluates knowledge and status of physical exercise among pregnant women. MethodsThe standardised paper-pencil questionnaire "Pregnancy Physical Activity Questionnaire" (PPAQ) as well as general demographic questions were used to assess the exercise behaviour of study participants. 83 questionnaires completed by women presenting to the Kiel University Hospital for antenatal assessment were included in the analysis.Results At the time of questionnaire completion 10 women were in the first trimester of pregnancy, 64 in the second, and 9 in the third. Just less than 90 % of participants felt they had been informed "sufficiently" on the topic physical exercise during pregnancy, over 50 % felt they were "well" or "very well" informed. Just less than half of participants received their information from a doctor (either their gynaecologist or general practitioner) and none of these felt "insufficiently" informed. Almost 80 % of participants reported still doing no sport or less exercise than before falling pregnant. The maximum proportional energy expenditure for recreational activity -just under 20 % -was in the third trimester. Women who felt they had been well counselled tended to have higher activity levels.Conclusion Study participants demonstrated a clear decline in physical exercise during pregnancy despite clear evidence of the benefits of regular exercise for pregnant women, and despite participants feeling they were well informed. Detailed information on the recommendations for physical exertion in pregnancy should form an integral part of antenatal counselling. ZUSAMMENFASSUNGEinleitung Die positiven Effekte einer körperlichen Aktivität

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.

We present a rare case of giant fibroadenoma in pregnant young women. Because of the progressive structural damage of the breast immediate surgical enucleation was indicated. Safety of the fetus was provided by perioperative monitoring. The pre-operative differentiation from phyllodes tumor is still challenging.

Background and objectives: The primary objective was to evaluate the benefit of training with virtual reality simulation. The secondary objective was to describe the short-term skill acquisition obtained by simulation training and to determine the factors affecting its magnitude. Materials and Methods: We prospectively performed a three-stage evaluation: face, constructive, and predictive to evaluate the training with a laparoscopic simulator with haptic feedback. The participants (n = 63) were divided according to their level of experience into three groups: 16% residents; 46% specialists and 38% were consultants. Results: Face evaluation demonstrates the acceptance of the design and realism of the tasks; it showed a median score of eight (IQR 3) on a Likert scale and 54% of participants (n = 34) gave the tissue feedback a moderate rating. Constructive evaluation demonstrates the improvement of the participants in the training session and the ability of the designed task to distinguish the experienced from the inexperienced surgeon based on the performance score, at task I (transfer of pegs) and II (laparoscopic salpingectomy). There was an improvement in both tasks with a significant increase in score and reduction in time. The study showed that those with a high score at the pre-test recorded a high score post-test, showing a significant pair-wise comparison (Z) and correlation (p) showing a significant statistical significance (p < 0.001). The predictive evaluation demonstrates the beneficiary effect of training four weeks afterward on the practice of surgeons addressed with five questions. It showed an improvement regarding implementation into daily routine, performance of procedure, suturing, shortening of the operative time, and complication management. Conclusions: Virtual reality simulation established high ratings for both realism and training capacity, including clinical relevance, critical relevance, and maintaining training enthusiasm.

No abstract

Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolitebisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p < 0.001). This finding is supported by time-lapse micro-computed tomography analyses, which revealed bone formation volume to be on average 1.6-fold higher with 5-FdU-ale treatment compared with alendronate (p < 0.001). We conclude that 5-FdU-ale, which is a poor prenylation inhibitor but maintains potent antiresorptive activity, does not reduce bone formation and has cytostatic antitumor efficacy. These results document that conjugation of an antimetabolite with bisphosphonates offers flexibility in creating potent bone-targeting drugs with cytostatic, bone protection properties that show limited nephrotoxicity. This unique class of drugs may offer distinct advantages in the setting of targeted adjuvant therapy and chemoprevention of bone diseases.

No abstract