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Abstract: The eLEcTRA trial compared efficacy and safety of letrozole combined with trastuzumab to letrozole alone in patients with HER2 and hormone receptor (HR) positive metastatic breast cancer (MBC). Patients were randomized to either letrozole alone (arm A, n = 31) or letrozole plus trastuzumab (arm B, n = 26) as first-line treatment. Additional 35 patients with HER2 negative and HR positive tumors received letrozole alone (arm C). Median time to progression in arm A was 3.3 months compared to 14.1 months in arm B (hazard ratio 0.67; p = 0.23) and 15.2 months in arm C (hazard ratio 0.71; p = 0.03). Clinical benefit rate was 39% for arm A compared to 65% in arm B (odds ratio 2.99, 95% CI 1.01–8.84) and 77% in arm C (odds ratio 5.34, 95% CI 1.83–15.58). The eLEcTRA trial showed that the combination of letrozole and trastuzumab is a safe and effective treatment option for patients with HER2 positive and HR positive MBC. [Copyright &y& Elsevier]

Abstract: Osteonecrosis of the jaw (ONJ) is a rare but severe disease which has been diagnosed in women with breast cancer on a bisphosphonate (BP) therapy. Thus, the German society of senology appointed a multidisciplinary task force to establish a consensus on the use of bisphosphonates in breast cancer patients with bone metastases, considering in particular the possible risk of ONJ. This report summarizes the results and recommendations for the prevention and treatment of ONJ in breast cancer patients receiving BP. [Copyright &y& Elsevier]

Abstract: We compared the efficiency and safety of a newly developed morcellator with a conventional device for minimally invasive supracervical hysterectomy. The prospective, randomized parallel-group study was set in a department of obstetrics and gynecology within an Academic Teaching Hospital. Patients included 48 women; 20 treated with an existing laparoscopic morcellator (Group 1); 28 treated with newly developed laparoscopic morcellator (Group 2). The weight-adjusted dissection time was reduced significantly by more than half with the new morcellator (p <.01). Significantly fewer (p <.05) and longer pieces of tissue were removed with the new morcellator. The median weight of morcellated tissue in Group 1 was 120 g (range 35–450 g), and the median operating time to remove the morcellated tissue was 10 minutes (range 2–45 minutes). The corresponding figures in Group 2 were 110 g (range 50–320 g) and 4 minutes (range 0.5–12 minutes). No bladder or intestinal lesions or other iatrogenic organ damage was seen with either morcellator. None of the patients in either group had postoperative complications. All interventions were completed as planned in both groups, and none of the procedures had to be converted to an open operation. Adequate tissue for histologic analysis was obtained from all patients. We concluded that the newly developed morcellator is a safe and effective instrument for laparoscopic supracervical hysterectomy, offering a much shorter operation time for the removal of morcellated tissue than a conventional device and a low risk of injury to surrounding organs and tissue. [Copyright &y& Elsevier]

Abstract: In the field of estrogen therapy breast cancer risk is one of the most controversially discussed topic. Actually, the as yet largest placebo-controlled study, the Women''s Health Initiative, rather showed a risk reduction, in contrast to observational studies. In the present study we have investigated the effect of estradiol on TNF-α-induced changes of various markers in human breast cancer cells and compare it with the effect of the antiestrogens tamoxifen and 2-methoxyestradiol. MCF-7 cells were used for the experiments, the incubation time was 96 h. TNF-α elicited a 3–4-fold increase of monocyte-attracting protein-1 (MCP-1) and interleukin-8 (IL-8) as compared to the control value, matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) were enhanced by 30 to 40%. E2 alone had no effect on MCP-1, slightly reduced the synthesis of MMP-9 and increased VEGF concentrations by about 20%. In combination with TNF, E2 induced a further stimulation of MCP-1, IL-8 and VEGF, whereby the MMP-9 synthesis was not changed. Tamoxifen and the endogenous estradiol metabolite 2-methoxyestradiol seem to be able to partly inhibit the action of TNF-α and estradiol. Our results suggest that estrogens may slightly increase tumor growth and spreading beyond the effect of chemokines such as TNF-α. However, the magnitude of this E2 effect seems to be marginal as compared to the effect of TNF-α alone. The risk of recurrence of breast cancer in patients taking hormone therapy after breast cancer may be slightly enhanced by estrogens, but seems mainly to be driven by the potency of still existing tumor cells to secrete chemokines which can stimulate tumor growth and spreading. [Copyright &y& Elsevier]

Progestogens are added to oestrogen in hormone replacement therapy regimens to reduce the risk of endometrial cancer. We have performed in vitro studies analysing gene expression of isolated normal endometrial epithelia cells (NEE) treated with estradiol and the progestogen norethisterone acetate (NETA). We report here for the first time upregulation of the Wnt-7a gene by NETA in estrogen treated NEE. Wnt genes are a large family of developmental genes associated with cellular responses such as oncogenesis. We therefore suggest that upregulation of Wnt-7a may be associated with the antineoplastic effects of progestogens on the endometrium. [Copyright &y& Elsevier]

The human fetal auditory system is functional around the 25th week of gestational age when the thalamocortical connections are established. Fetal magnetoencephalography (fMEG) provides evidence for fetal auditory brain responses to pure tones and syllables. Fifty-five pregnant women between 31 and 40 weeks of gestation were included in the study. Fetal MEG was recorded during the presentation of an amplitude modulated tone (AM) with a carrier frequency of 500 Hz to the maternal abdomen modulated by low modulation rates (MRs) - 2/s and 4/s, middle MR - 8/s and high MRs - 27/s, 42/s, 78/s and 91/s. The aim was to determine whether the fetal brain responds differently to envelope slopes and intensity change at the onset of the AM sounds. A significant decrease of the response latencies of transient event-related responses (ERR) to high and middle MRs in comparison to the low MRs was observed. The highest fetal response rate was achieved by modulation rates of 2/s, 4/s and 27/s (70%, 57%, and 86%, respectively). Additionally, a maturation effect of the ERR (response latency vs. gestational age) was observed only for 4/s MR. The significant difference between the response latencies to low, middle, and high MRs suggests that still before birth the fetal brain processes the sound slopes at the onset in different integration time-windows, depending on the time for the intensity increase or stimulus power density at the onset, which is a prerequisite for language acquisition. [ABSTRACT FROM AUTHOR]

Introduction: Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/ predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide- docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC). Methods: In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459). Results: Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors. In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor. In multivariate interaction analysis (including central and genomic grade), luminal-Blike subtype [HR+ and (Ki-67 =20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients. Conclusion: In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone. [ABSTRACT FROM AUTHOR]

COMPACT was an open-label, multicenter, noninterventional study (NCT00857012) conducted in Germany. This study provided the first prospective data from routine clinical practice on the relationship between arthralgia and patient compliance during the first year of adjuvant anastrozole therapy in postmenopausal women with hormone receptor-positive early breast cancer. Arthralgia may contribute to noncompliance and clinical outcomes in these patients.Background This prospective study evaluated the relationship between arthralgia and compliance during the first year of adjuvant anastrozole therapy in postmenopausal women with hormone receptor-positive early breast cancer. Patients and methods COMPliance and Arthralgia in Clinical Therapy (COMPACT) was an open-label, multicenter, noninterventional study conducted in Germany. Patients had started adjuvant anastrozole 3–6 months before the study start. The primary end points were arthralgia, compliance, and the relationship between compliance and arthralgia, assessed at specific time points. Results Overall, 1916 patients received upfront anastrozole. Mean arthralgia scores were increased from baseline at each visit up to 9 months. Compliance with anastrozole therapy gradually decreased over time from baseline to 9 months (P < 0.001). At 9 months, investigators estimated that >95% of patients were compliant versus patient reports of <70%. There was a significant association between arthralgia mean scores and noncompliance at 6 months (P < 0.0001), 9 months (P < 0.0001), and overall (P < 0.0001). Over time, new events or impairment of existing arthralgias were reported in 14% (3 months), 11% (6 months), and 9% (9 months) of patients. Conclusion Arthralgia is important in the clinical management of women with early breast cancer and may contribute to noncompliance and clinical outcomes. ClinicalTrials.gov identifier NCT00857012. [ABSTRACT FROM AUTHOR]

Background The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. Patients and methods Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. Results DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. Conclusions Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit. [ABSTRACT FROM PUBLISHER]

Abstract: The aim of this study was to evaluate whether prenatal Doppler ultrasound plays a role in the risk assessment of neonatal abnormal cranial ultrasound findings (NACU). Doppler examinations of blood flow velocities in the umbilical artery (n = 132), the fetal middle cerebral artery (n = 96) and the ductus venosus (n = 46) were conducted in 132 consecutive high-risk cases. The cases were divided into three groups: normal (I), pathological (II) and highly pathological Doppler (III) results, according to the resistance index calculated and were assessed for any association between the Doppler groups and the short-term outcome of the neonate, especially NACU. A significant association was found between Doppler groups and gestational age at delivery, birth weight, length and head circumference, growth restriction, cesarean section rate, Apgar score and pH values. NACU was diagnosed significantly more often in the pathological (12.1%) and highly pathological (38.5%) Doppler groups than in the group with normal Doppler (1.7%; p < 0.001). Multivariate analysis showed that the Doppler groups (odds ratio 1.67, 95% confidence interval [CI] 1.14–2.84, p < 0.001) and gestational age at delivery (odds ratio 1.37, 95% CI 1.08–2.74; p < 0.001) were independent variables that could be used to predict NACU. The present study showed that a pathological prenatal Doppler result is highly predictive for NACU in addition to gestational age and can therefore be used for risk assessment. (E-mail: gabriele.meyberg-solomayer@med.uni-tuebingen.de) [Copyright &y& Elsevier]

Abstract: Objectives: Tibolone is a tissue selective compound with estrogenic, androgenic and progestogenic properties in classical bioassays. It is used for alleviation of menopausal symptoms and for osteoporosis prophylaxis in postmenopausal women. Only few data are available regarding the effects of tibolone on the cardiovascular system. We investigated therefore the in vitro effects of tibolone and its metabolites on the vasculature under special controlled conditions, using human female coronary endothelial and smooth muscle cells. Methods: The effect on the production of the following markers in endothelial cells from human female coronary arteries was evaluated: nitric oxide synthase, prostacyclin, endothelin, plasminogen-activator-inhibitor-1 (PAI-1), E-Selectin, Intercellular adhesion molecule (ICAM-1), monocyte attracting protein-1 (MCP-1) and the precursor of matrix metalloproteinase-1 (pro-MMP-1). Tibolone, its metabolites, estradiol (E2), E2/norethisterone (NET) and E2/medroxyprogesterone acetate (MPA) were tested at 0.1μM and 1μM. The markers were determined by enzyme immunoassays in the cell supernatant. Cell proliferation of smooth muscle cells from female coronary artery was measured by an adenosine triphosphate-assay. Results: Tibolone, its 3-hydroxy metabolites, E2/NET, E2/MPA and estradiol alone had significant effects on the synthesis of all markers tested. The magnitude of the tibolone effects, however, was mostly smaller than that of E2/NET and E2/MPA. Concerning smooth muscle cells tibolone and its 3-hydroxy metabolites also elicited an inhibition of the proliferation compared to control values. The strongest effect here was found for E2/NET and E2 alone, whereas E2/MPA had no effect. Conclusion: The results of this in vitro study conducted with cells of the most important vascular bed with respect to the problem of cardiovascular risk suggest that tibolone can positively influence the vasculature. However, these tibolone effects may depend on intact vascular cells and may vary due to the different atherosclerotic stages of the vessels. Thus, experimental studies are useful to explore mechanisms, but clearly cannot replace clinical studies. [Copyright &y& Elsevier]

Abstract: The regulation of human implantation is not fully understood. hCG as one of the earliest embryonal signals may be a major regulator in the parakrine embryo-endometrial communication. The expression of full-length hCG/LH-receptor mRNA could be demonstrated in human endometrium throughout the follicular and secretory phase of the menstrual cycle. In contrast, in early pregnancy decidua only truncated variants could be detected. To investigate direct effects of hCG on the human endometrium, an intrauterine microdialysis device was developed to measure parakrine mediators within the uterine cavity in vivo. Using this system, hCG was applied in the secretory phase and the endometrial response was evaluated. The administration of hCG (500IU/ml) provoked a significant inhibition of intrauterine IGFBP-1 and M-CSF, while LIF, VEGF and MMP-9 were significantly stimulated. Taken together there appear to be multiple direct effects of hCG on the endometrium that precede the classical endocrine role of the hormone. [Copyright &y& Elsevier]

Developing primary systemic chemotherapy (PST) regimens that induce higher pathological complete response (pCR) rates remains a challenge in operable breast cancer. We recruited 77 eligible patients into a multicentre phase I/II study to evaluate the maximum tolerated dose (MTD), toxicity and efficacy of preoperative gemcitabine day 1 and 8 (800 mg/m2 fixed dose), epirubicin and docetaxel on day 1 (doses escalated from 60 mg/m2) (GEDoc), repeated 3-weekly for 6 cycles with filgrastim support. MTD for epirubicin was 90 mg/m2 and for docetaxel 75 mg/m2. Dose-limiting toxicities (DLTs) included febrile neutropenia and grade 3 diarrhoea. Clinical response rate was 92%, pCR rate was 26%. 79% of patients had breast-conserving surgery. Grade 3/4 leucopenia was the main toxicity, occurring in 55 (87%) of 63 patients treated at the MTD. Non-haematological toxicity caused no serious clinical problems. In conclusion, GEDoc is highly active as PST. Efficacy and toxicity compare favourably with other effective combinations. [Copyright &y& Elsevier]

The aim of this prospective trial was to evaluate if 3-D ultrasound (US) brings any advantage to breast diagnostics. A total of 65 women with breast lesions (42 malignant, 23 benign) were examined preoperatively with 2-D and 3-D US. The impact of the use of the 3-D coronal plane for the visualization of the infiltrative zone in comparison to 2-D US was evaluated. Additionally, 3-D surface imaging and volumetry were performed. The coronal plane was of benefit when the infiltrative zone was unclear (6 of 8 cases) or not visible (17 of 39 cases; 43.6%) using 2-D imaging. The surface mode was advantageous for imaging complex structures (e.g., a multinodular fibroadenoma). Volumetry yielded a highly significant correlation between 2-D and 3-D US. 3-D US of breast lesions as adjunct to 2-D sonography can offer a better assessment of the infiltrative zone. Moreover, it enables accurate documentation of data. (E-mail: ) [Copyright &y& Elsevier]

This prospective, parallel-group, dose-escalation study evaluated the cardiac safety of trastuzumab (Herceptin®) plus epirubicin/cyclophosphamide (EC) in women with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) and determined an epirubicin dose for further evaluation. HER2-positive patients received standard-dose trastuzumab plus epirubicin (60 or 90 mg/m2)/cyclophosphamide (600 mg/m2) 3-weekly (EC60+H, n=26; EC90+H, n=25), for four to six cycles; 23 HER2-negative patients received EC alone (90/600 mg/m2) 3-weekly for six cycles (EC90). All patients underwent thorough cardiac evaluation. Two EC90+H-treated patients experienced symptomatic congestive heart failure 4.5 and 6 months after the end of chemotherapy. One EC60+H-treated patient experienced an asymptomatic decrease in left ventricular ejection fraction (LVEF) to <50% 6 months after the end of chemotherapy. No such events occurred in control patients. Asymptomatic LVEF decreases of >10% points were detected in 12 (48%), 14 (56%) and 5 (24%) patients treated with EC60+H, EC90+H, and EC90. Objective response rates with EC60+H and EC90+H were >60%, and 26% for EC90 alone. These results indicate that trastuzumab may be combined with EC with manageable cardiotoxicity and promising efficacy. [Copyright &y& Elsevier]

An open-label, randomised, parallel-group, study was conducted in three study centres in women with premature labor and indication for a single agent intravenous tocolysis therapy with magnesium sulphate. The aim of this study was to examine the local and general tolerability and side-effects of magnesium sulphate for tocolysis. Furthermore, we tested the tolerability of a ready-for-use magnesium solution. No measurements of efficacy were performed during this study. Initially, patients received a loading dose of 4.0 g magnesium sulphate administered over 30 min. Thereafter, a continuous intravenous infusion of 1–2 g magnesium sulphate per hour up to 21 days was given. Venous score (Maddox), vital signs, adverse events as well as general tolerability (assessed by investigator and patients) and blood parameters were assessed. We showed good local and systemic tolerability of high dose magnesium sulphate for tocolysis. Only seven patients (15%) were withdrawn from the study prematurely due to minor adverse events. Potential serious complications of MgSO4 such as respiratory arrest or clinically relevant respiratory depression were not observed. The most frequently reported local adverse events were injection site pain, itching, erythema, swelling, induration and palpable venous cord. The most common systemic adverse events considered to be possibly related to the study drugs involved the nervous system (dizziness) followed by the digestive system (nausea, constipation). Systolic and diastolic blood pressure changed only slightly during the treatment. Respiratory rate and body temperature remained stable also. Toxic magnesium levels (>2.5 mmol/l) were not observed. The assessment of the clinical investigators with regard to tolerability was very good or good in 72.5% of the patients. The introduction of the ready-to-use solution has the advantage of eliminating the need to mix the solution prior to administration. This means a lower risk of overdose and contamination. [Copyright &y& Elsevier]

Objective: The following study analyses the hysteroscopic experience of multiple gynecologic centers throughout Germany in regard to the incidence of complications, the therapy of these complications and anesthesiological management during 21 676 hysteroscopic procedures. Methods and material: Under the supervision of the German Society of Gynecology Endoscopy, 92 hysteroscopic centers were evaluated and the following information was collected: hysteroscopic experience in years, number of surgical hysteroscopies per year, total number of operative hysteroscopies, types of hysteroscopic procedures, intra- and post-operative complications. Results and conclusion: The results of the study show that in most German centers, hysteroscopy is just being established. Nevertheless, the rate of complications such as perforation of the uterus, fluid-overload syndrome, infection and perioperative bleeding is small. This may be due to the high proportion of documented procedures performed by the more experienced centers. [Copyright &y& Elsevier]

Endocrine therapy is widely accepted for the treatment of hormone receptor-positive breast cancer. However, in many cases eventually resistance will develop and tumor regrows. Combination therapy may be one way to resolve this problem. In the present study we investigated the effect of a combination of the widely used antiestrogen tamoxifen with the endogenous estradiol metabolite 2-methoxyestradiol (2-ME) on the proliferation of human estrogen receptor-positive and receptor-negative breast cancer cells.The receptor-positive cell line MCF-7 and the receptor-negative cell line BM were treated with 4-hydroxytamoxifen (4-OHTam) and 2-methoxyestradiol in the concentration range of 0.8–25 μM alone and equimolar combinations for 4 days. The proliferation of the cells was determined using the ATP-chemosensitivity test.4-Hydroxytamoxifen inhibited proliferation of MCF-7 and BM cells with IC50 values of 31 and 10 μM, the corresponding figures for 2-methoxyestradiol were 52 and 8 μM. The combination showed IC50 values of 6 μM and 4 μM.These results indicate that a combination of tamoxifen with 2-methoxyestradiol showed an additive inhibitory effect concerning the proliferation of estrogen receptor-positive and receptor-negative breast cancer cell lines. Thus a combination of these substances may allow ameliorating of adverse events of tamoxifen by reducing its concentrations and probably also drug resistance and should be tested in clinical trials. [Copyright &y& Elsevier]