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Von Minckwitz G.,German Breast Group | Eidtmann H.,Universitats Frauenklinik | Rezai M.,Luisenkrankenhaus | Fasching P.A.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 19 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer. METHODS: We randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor-negative disease, or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk. RESULTS: Overall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P = 0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P = 0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor-positive tumors (P = 1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand-foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome. (Funded by Sanofi-Aventis and Roche, Germany; ClinicalTrials.gov number, NCT00567554.) Copyright © 2012 Massachusetts Medical Society.


Untch M.,Helios Klinikum | Loibl S.,German Breast Group | Bischoff J.,Universitats Frauenklinik | Eidtmann H.,Universitats Frauenklinik | And 15 more authors.
The Lancet Oncology | Year: 2012

Background: We compared the efficacy and safety of the addition of lapatinib versus trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy. Methods: In the GeparQuinto randomised phase 3 trial, patients with untreated HER2-positive operable or locally advanced breast cancer were enrolled between Nov 7, 2007, and July 9, 2010. Patients were eligible if their tumours were classified as cT3/4a-d, or hormone receptor (HR)-negative, HR-positive with clinically node-positive and cT2 disease (cT2 cN+), or HR-positive and pathologically node-positive in the sentinel lymph node for those with cT1 disease (cT1 pN SLN+). Patients were randomly assigned in a 1:1 ratio to receive neoadjuvant treatment with four cycles of EC (epirubicin [90 mg/m 2 intravenously] plus cyclophosphamide [600 mg/m 2 intravenously], every 3 weeks), and four cycles of docetaxel (100 mg/m 2 intravenously every 3 weeks) with either trastuzumab (6 mg/kg intravenously, with a starting loading dose of 8 mg/kg, for eight cycles, every 3 weeks) or lapatinib (1000-1250 mg per day orally) throughout all cycles before surgery. Randomisation was done by dynamic allocation with the minimisation method of Pocock and patients were stratified by participating site, HR status, and extent of disease (cT1-3 cN0-2 vs T4 or N3). The primary endpoint was pathological complete response (defined as ypT0 and ypN0) and was analysed in all patients who received at least one cycle of EC. Participants and investigators were not masked to treatment assignment. Pathologists in centres assessing surgery outcomes were masked to group assignment. This trial is registered with ClinicalTrials.gov, number NCT00567554. Findings: Of 620 eligible patients, 309 were randomly assigned to chemotherapy with trastuzumab (ECH-TH group) and 311 to chemotherapy with lapatinib (ECL-TL group). Two patients in the ECH-TH group and three patients in the ECL-TL group did not start treatment because of withdrawal of consent or immediate surgery. 93 (30·3%) of 307 patients in the ECH-TH group and 70 (22·7%) of 308 patients in the ECL-TL group had a pathological complete response (odds ratio [OR] 0·68 [95%CI 0·47-0·97]; p=0·04). Chemotherapy with trastuzumab was associated with more oedema (119 [39·1%] vs 88 [28·7%]) and dyspnoea (90 [29·6%] vs 66 [21·4%]), and ECL-TL with more diarrhoea (231 [75·0%] vs 144 [47·4%]) and skin rash (169 [54·9%] vs 97 [31·9%]). 43 (14·0%) patients discontinued in the ECH-TH group and 102 (33·1%) in the ECL-TL group. 70 serious adverse events were reported in the ECH-TH group and 87 in the ECL-TL group. Interpretation: This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy. Funding: GlaxoSmithKline, Roche, and Sanofi-Aventis. © 2012 Elsevier Ltd.


Xu K.,Cornell University | Montag M.,Universitats Frauenklinik
Seminars in Reproductive Medicine | Year: 2012

During the past 2 decades, biopsy for preimplantation genetic diagnosis at three stages, that is, before conception (the first polar body), after fertilization (the second polar body), and early cleavage (D3 blastomeres) or blastocyst stage (D5/D6 trophectoderm biopsy), have been optimized and performed clinically in hundreds of in vitro fertilization centers around the world. Although opening the zona pellucida by mechanical or chemical means is still effectively in use, noncontact laser has become the indispensable instrument. Overall, the invasive nature of biopsy at any given stage is recognized. It is believed that removal of the polar bodies from M-II oocytes and fertilized zygotes may have the least detrimental effects on subsequent embryonic development; hence increasing applications of polar body biopsy are anticipated. Although D3 biopsy is currently the most frequently used method, the effectiveness of D3 cleavage-stage biopsy is unsettling because of the mosaicism in early cleavage human embryos. Controversies exist in several areas; particularly, the efficacy of preimplantation genetic screening based on one cell removed from a D3 embryo remains to be confirmed. With new genetic testing technology, there may be no need to biopsy two cells because accuracy from one cell is high and the risk of misdiagnosis is very low when sufficient markers are used for chromosome copy number assessment or for mutation detection of single-gene disorders. And finally, it appears that limited harm is caused by biopsy at the blastocyst stage and mosaicism seems to be less common as compared with earlier stages. Therefore, use of the blastocyst-stage biopsy combined with cryopreservation protocol can be effectively used for several indications. Furthermore, faster genetic analytical methods that can be completed within several hours will make this strategy more practical and attractive as fresh embryo transfer is possible. Copyright © 2012 by Thieme Medical Publishers, Inc.


Guller S.,Yale University | Tang Z.,Yale University | Ma Y.Y.,Yale University | Di Santo S.,Universitats Frauenklinik | And 2 more authors.
Placenta | Year: 2011

Shedding of syncytiotrophoblast microparticles (MPs) from placenta to maternal blood occurs in normal pregnancy and is enhanced during preeclampsia (PE). The syncytiotrophoblast synthesizes plasminogen activator inhibitors (PAIs) which regulate fibrinolysis, as well as soluble forms of the fms-like tyrosine kinase (sFlt-1) and endoglin, which exert anti-angiogenic actions. An increase in the ratio of PAI-1/PAI-2 and elevated levels of sFlt-1 and sEng in maternal serum are linked to placental damage and maternal endothelial cell dysfunction in PE. The goal of the current study was to determine whether MPs released to maternal perfusate during dual perfusion contain these factors associated with placental pathophysiology in PE. Initially, high levels of alkaline phosphatase activity and Annexin V binding were found in MPs isolated by sequential centrifugation of maternal perfusates at 10,000 and 150,000×g(10 K and 150 K MPs), indicating their plasma membrane origin. ELISA revealed the presence of these factors at the following relative levels: Eng>PAI-2⋙PAI-1>sFlt-1. Based on comparisons of their concentration in perfusates, MPs, and MP-free 150 K supernatants, we determined that MPs constitute a significant portion of Eng released by placenta. Flow cytometric analysis of 10 K MPs supported the levels of expression found by ELISA and indicated that Eng and PAI-2 were almost exclusively localized to the surface of MPs, a site with biological potential. These results indicate that MPs shed from the syncytial surface express factors which may alter the fibrinolytic and angiogenic balance at the maternal-fetal interface and play a role in the pathophysiology of PE. © 2010 Elsevier Ltd. All rights reserved.


Rarely new surgical strategies have been accepted so rapidly in clinical routine worldwide, without available prospective studies proving safety and effectivity. After the success of midurethral slings, having been implanted in millions, alloplastic meshes are available for the treatment of prolapse with new, so far unknown complications in relevant frequency. In the USA with their own medico-legal system there is a flood of litigations (>60,000 in 2014) for singleton cases with compensations of >10 million $. Even though medical strategies and surgical skills might be different in Germany this development should encourage for strict indications and centralization in pelvic floor centers. © 2016 Springer-Verlag Berlin Heidelberg


The three modern Selective Estrogen Receptor Modulators (SERMs) Raloxifene, Lasoxifene and Bazedoxifene registered in Europe reduce in postmenopausal women with a high risk for osteoporosis the incidence of vertebral fractures by 30 - 50 %, depending on the subgroup they belong to. Solid prospective fracture data for risk reduction in non-vertebral fractures, including the hip, are missing for Raloxifene and Bazedoxifene. However, a post hoc analysis suggests that the risk for non-vertebral fractures is significantly reduced by Raloxfene in women with severe osteoporosis. The simultaneous decrease of the incidence of ER-positive invasive breast cancer in Raloxifene users is highly relevant for clinicians. Unfortunately, Raloxifene and Bazedoxifene are, in the EU and in Switzerland, only labelled for the use in the prevention and treatment of postmenopausal osteoporosis. SERMs may induce or augment vasomotor symptoms. Therefore, SERMs are not a first line therapy in early postmenopause. Looking at other hormonal options, Hormone Replacement Therapy (HRT) remains the first line therapy for fracture reduction in the peri- and early postmenopause. SERMs are an appropriate choice for the continuation of fracture prevention after an initial HRT, particularly for the prevention of vertebral fractures. SERMs are safe if (as in oral HRT) the slightly increased risk for venous thrombo-embolism is respected. In conclusion, SERMs have today their well established place in the prevention and treatment of postmenopausal osteoporosis, particularly in women with a simultaneously increased breast cancer risk. © 2012 Verlag Hans Huber, Hogrefe AG, Bern.


Preeclampsia contributes substantially to both maternal and neonatal morbidity and mortality. Novel markers have improved diagnostic and predictive testing for preeclampsia. The identification of pregnant women at risk of subsequent preeclampsia will allow to monitor them closely and to offer them preventive strategies. Innovative preventive approaches, novel diagnostic and predictive methods using biochemical and sonographic markers seem promising ways of reducing the clinical and socio-economic impact of preeclampsia on our society. © 2016 Hogrefe.


Recurrent abortions, typically defined as more than 2 consecutive early abortions, occur in around 1 % of fertile couples. The risk for further abortions in women < 40 years of age after 2 and after > 2 previous abortions is approximately 25 % and 40 % respectively. The recommendations of the “Royal College of Obstetricians and Gynaecologists”, RCOG, 2011, the “American Society for Reproductive Medicine”, ASRM, 2012 und the “German Society of Gynecology and Obstetrics”, DGGG, 2013, are similar but not uniform. They mainly recommend after > 2 consecutive abortions to exclude relevant uterine factors, thyroid abnormalities, antiphospholipid-syndromes, inherited thrombophilia in patients with a history of thrombembolism and peripheral karyotypic analysis of the couple. Therapeutically they mainly recommend surgical correction of uterine factors, treatment of thyroid disorders, treatment of APS with aspirin and low molecular weight heparin as well as genetic counselling. According to the PROMISE-Study, published in 2015, prophylactic use of progesterone does not reduce the risk for further abortions. Immunomodulatory treatments are not recommended anymore. © 2016 Hogrefe.


Von Wolff M.,Universitats Frauenklinik
Gynakologische Endokrinologie | Year: 2014

Spontaneous conception: Infertility treatment for women over 40 years of age has a limited chance of success. The rapidly decreasing fertility requires a treatment with the highest chance of pregnancy per treatment time. If a woman has been trying to become pregnant for less than 0.5-1 year and if infertility factors such as tubal blockage or low sperm count have been excluded, spontaneous conception should be envisaged. Intrauterine insemination and In vitro fertilization: Intrauterine insemination (IUI) should only be performed if an andrological infertility factor has definitely been diagnosed and should be limited to only a few treatment cycles and to a maximum female age of approximately 42 years. Conventional in vitro fertilization (IVF) should be preferred over a natural cycle IVF in cases where there is a high ovarian reserve. A natural cycle IVF can be considered in expectation of a poor response. A conventional IVF should only be performed if the expected chance of fertilization per stimulation cycle is at least 5 %. In this case the female age limit for a conventional IVF is around 43-44 years. © 2013 Springer-Verlag Berlin Heidelberg.


A substantial number of patients with breast cancer develop recurrent carcinoma which is explained by tumor cell dissemination into distant organs, preferentially bone marrow, which often occurs prior to surgery. Overall, the prognostic value of these cells in the bone marrow is being regarded increasingly as a clinically relevant prognostic factor for breast and ovarian cancer. Furthermore, it has been demonstrated that tumor cells frequently survive chemotherapy and that the persistence of these cells in the bone marrow after conventional adjuvant chemotherapy is associated with poor prognosis. Bisphosponates are currently being discussed to successfully eliminate these cells in breast cancer. Presently, a variety of promising methods for the detection and characterization of tumor cells in blood are under evaluation. These methods include immunocytological and molecular approaches. Nevertheless, not all circulating and persisting tumor cells are bad and it is assumed that only a few cells are capable of forming overt metastases, the so called stem cell like tumor cells. Indeed, subsets of tumor cells in the bone marrow and blood of breast cancer patients have recently been shown to be cancer stem cells with the capacity of self-renewal. A big challenge in tumor cell research is to define »targeted therapies« for each individual patient to eliminate minimal residual disease. One approach is the inhibition of the PI3K/Akt/mTOR pathway which has been described as one of the major pathways in the regulation of mammary stem/progenitor cells and to confer resistance to conventional therapies. Combinational therapy of inhibitors of this pathway, together with standard therapy, proved to be capable of selectively eliminating cancer stem cells.

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