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Background The progesterone-receptor (PR) antagonists onapristone (type I) and mifepristone (type II) showed modest activity in hormone-receptor-positive breast cancer; however, onapristone in particular was associated with hepatotoxicity. Lonaprisan is a novel, type III PR antagonist that was well tolerated in phase I studies. Patients and methods This randomized, open-label, phase II study evaluated the efficacy and tolerability of lonaprisan as second-line endocrine therapy in postmenopausal women with stage IV, PR-positive, HER2-negative, metastatic breast cancer. Results Patients received once-daily lonaprisan 25 mg (n = 34) or 100 mg (n = 34). The primary objective was not met (≥35% clinical benefit rate: complete/partial responses at any time until month 6 or stable disease [SD] for ≥6 months from start of treatment). There were no complete/partial responses. In the 25 mg and 100 mg groups, 6 of 29 patients (21%) and 2 of 29 patients (7%), respectively, had SD ≥6 months. Overall, 61 of 68 patients (90%) had ≥1 adverse event (AE), the most frequent (≥10% overall) being fatigue, hot flush, dyspnoea, nausea, asthenia, headache, constipation, vomiting, and decreased appetite; 33 patients had serious AEs. Conclusion Lonaprisan showed limited efficacy as second-line endocrine therapy in postmenopausal women with PR-positive metastatic breast cancer. [ABSTRACT FROM PUBLISHER]

Background: For more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. However, not only does tamoxifen have potential side-effects such as an increased risk of endometrial cancer and thromboembolic events, but patients can also develop resistance to the drug. We aimed to investigate whether switching treatment of postmenopausal women with such breast cancer to anastrozole after 2-3 years of tamoxifen would be more effective than continuing on tamoxifen for a total of 5 years.Methods: We did a meta-analysis of three clinical trials--the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8), Arimidex-Nolvadex (ARNO 95), and the Italian Tamoxifen Anastrozole (ITA) studies--in which postmenopausal women with histologically confirmed, hormone-sensitive early-stage breast cancer were randomised to 1 mg/day anastrozole (n=2009) after 2-3 years of tamoxifen treatment or to continued 20 or 30 mg/day tamoxifen (n=1997). We analysed the data with a stratified Cox proportional hazards model with the covariates of age, tumour size, nodal status, grade, surgery, and chemotherapy.Findings: Patients who switched to anastrozole had fewer disease recurrences (92 vs 159) and deaths (66 vs 90) than did those who remained on tamoxifen, resulting in significant improvements in disease-free survival (hazard ratio 0.59 [95% CI 0.48-0.74]; p<0.0001), event-free survival (0.55 [0.42-0.71]; p<0.0001), distant recurrence-free survival (0.61 [0.45-0.83]; p=0.002), and overall survival (0.71 [0.52-0.98]; p=0.04).Interpretation: Our results show that the clinical benefits in terms of event-free survival seen in individual trials for those patients who switched to anastrozole translate into a benefit in overall survival. These findings confirm that clinicians should consider switching postmenopausal women who have taken adjuvant tamoxifen for 2-3 years to anastrozole. [ABSTRACT FROM AUTHOR]

Purpose: The majority of breast cancers are diagnosed at an early stage, and treatment is focused on cure and prolonging disease-free survival. Local therapy (surgery and/or radiation treatment) is standard, along with systemic adjuvant therapy that may effectively prevent or delay relapse and death in early-stage disease. In premenopausal women, adjuvant therapeutic approaches include combination cytotoxic chemotherapy and endocrine therapy. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) was the established chemotherapy regimen; however, newer regimens have more recently been introduced that may offer some benefit over CMF including anthracycline-containing regimens [e.g. cyclophosphamide, epirubicin and 5-fluorouracil (CEF)], and taxane-containing regimens. For women with oestrogen receptor (ER)-positive disease, a second option is endocrine therapy that aims to suppress mitogenic oestrogen signalling. Until recently, 5 years of tamoxifen was regarded as the standard adjuvant endocrine treatment in ER-positive disease. Ovarian ablation is also effective in premenopausal women, and can be achieved by surgery, radiotherapy, or via the use of a luteinising hormone-releasing hormone analogue such as goserelin. Combining tamoxifen and goserelin treatment provides more effective oestrogen blockade than either drug alone. However, as the third-generation aromatase inhibitors (AIs) have demonstrated improved efficacy over tamoxifen in postmenopausal women with early and advanced disease, combination treatment with goserelin plus an AI may provide optimal oestrogen blockade in premenopausal patients. Conclusions: This review assesses the relative merits of chemotherapeutic and endocrine approaches for the treatment of early breast cancer, and summarises relevant ongoing clinical trials, with an emphasis on the premenopausal setting. [ABSTRACT FROM AUTHOR]

The Zoladex Early Breast Cancer Research Association (ZEBRA) trial compared the efficacy and tolerability of goserelin (Zoladex™) with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy in pre-/perimenopausal women with node-positive early breast cancer. The results of disease-free survival (DFS) analyses have already been published. Here we present an update including data on overall survival (OS) from the ZEBRA trial at a median follow-up of 7.3 years. In patients with oestrogen receptor (ER)-positive tumours, non-inferiority of goserelin versus CMF for OS was shown; goserelin was again shown to be equivalent to CMF for DFS. This updated analysis has demonstrated that the two treatments are also equivalent for distant disease-free survival (DDFS). In patients with ER-negative disease, goserelin was inferior to CMF for DFS, DDFS and OS. This follow-up analysis confirms the previously reported outcomes from the ZEBRA trial and demonstrates that goserelin offers an effective alternative to CMF chemotherapy for adjuvant therapy of premenopausal patients with ER-positive, node-positive early breast cancer. [Copyright &y& Elsevier]

Current standard adjuvant therapies for premenopausal women with early breast cancer include ovarian ablation by surgery or irradiation, chemotherapy and tamoxifen. The value of ovarian ablation in prolonging the survival of premenopausal patients with early breast cancer was clearly established by the analyses performed by the Early Breast Cancer Trialists' Collaborative Group in 1996. More recently, the value of ovarian suppression using the luteinizing hormone releasing hormone analogue goserelin as adjuvant therapy in pre-/perimenopausal women with early breast cancer has been confirmed in a series of studies involving over 8000 patients. The results from these studies provide evidence that goserelin, alone or in combination with tamoxifen, is at least as effective as cytotoxic chemotherapy in patients with hormone receptor-positive tumours and is effective when used after adjuvant chemotherapy. The use of goserelin in the management of early breast cancer presents an option which can avoid the side-effects experienced with cytotoxic chemotherapy and may offer unique benefits to premenopausal patients. The consolidation of these emerging results should help in defining the optimal role for goserelin in pre-/perimenopausal patients with early breast cancer. [ABSTRACT FROM AUTHOR]

AbstractParvovirus B19 infection during pregnancy causes up to 27% cases of non-immune hydrops in anatomically normal fetuses. The virus is believed to cause arrest of maturation of red blood cell precursors at the late normoblast stage and also causes a decrease in the number of platelets. Fetal anemia is presently thought to be responsible for the development of skin edema and effusions. Myocarditis leading to heart failure may contribute to the development of fetal hydrops. We reviewed the literature regarding prevalence, transmission rates, clinical presentation, diagnostic techniques, current invasive vs. conservative management options, outcome and postmortem findings in a total of 82 studies involving 230 invasively and 435 conservatively managed pregnancies. In this non-selected population, the proportion of seronegative susceptible mothers ranged from 19 to 65%, seroconversion with an incubation time of up to 20 days occurred in 5.7–12.1%, and 188/230 (82%) who were transfused infected fetuses had a normal outcome as opposed to only 239/435 (55%) in the conservatively managed group. The average time from diagnosis to resolution in both groups was 6 weeks (range, 3–12 and 2–12 weeks, respectively). The most promising diagnostic techniques were PCR of amniotic fluid or fetal blood and electron microscopy. There are some reports of fetal abnormalities occurring (probably coincidentally) in cases of parvovirus, but the majority of postmortem findings were infection-related, in particular myocarditis and hepatic abnormalities. Although management guidelines cannot be derived from this study due to the variable degree of hydrops in the analyzed studies, the present data suggest a benefit of transfusion therapy over conservative management in infected fetuses. The only study which was corrected for severity of hydrops using ultrasound criteria showed a clear benefit of intrauterine transfusion. [ABSTRACT FROM AUTHOR]

British Journal of Cancer (2002) 87, 1480–1480. doi:10.1038/sj.bjc.6600652 www.bjcancer.com© 2002 Cancer Research UKCORRECTION TO:: British Journal of Cancer 2001; 85 (Suppl 2): 1–5 [ABSTRACT FROM AUTHOR]

Background: Hormone receptor-positive advanced breast cancer is an increasing health burden. Although endocrine therapies are recognised as the most beneficial treatments for patients with hormone receptor-positive advanced breast cancer, the optimal sequence of these agents is currently undetermined. Methods: We reviewed the available data on randomised controlled trials (RCTs) of endocrine therapies in this treatment setting with particular focus on RCTs reported over the last 15 years that were designed based on power calculations on primary end points. Results: In this paper, data are reviewed in postmenopausal patients for the use of tamoxifen, aromatase inhibitors and fulvestrant. We also consider the available data on endocrine crossover studies and endocrine therapy in combination with chemotherapy or growth factor therapies. Treatment options for premenopausal patients and those with estrogen receptor-/human epidermal growth factor receptor 2-positive tumours are also evaluated. Conclusion: We present the level of evidence available for each endocrine agent based on its efficacy in advanced breast cancer and a diagram of possible treatment pathways. [ABSTRACT FROM PUBLISHER]

Purpose: To determine the value of a breast ultrasound (US) examination in addition to mammography in cases of American College of Radiology (ACR) tissue pattern III and IV in symptomatic women and women at risk.Materials and Methods: A prospective cohort was initiated between 2001 and 2005 with a total of 59,514 patients and 102,744 mammograms. Documentation was available for 102,557 diagnostic procedures. Breast US was indicated in all women with ACR III and IV in addition to a suspicious clinical examination and in cases of masses and focal asymmetries in mammography.Results: In total, 62,006 additional USs were performed, in which 116 mammographically and clinically occult breast cancers were diagnosed (detection rate: 1.9/1,000 examinations), while mammography alone (40,551 examinations) revealed 903 cancers (22.3/1,000). Of all 1,019 breast cancer findings, 12.8% were detected because of the combination of mammography and US. In the group with ACR III/IV, 15.9% of cancers were found by supplemental US compared with mammography alone.Conclusion: The addition of US to mammography vs. mammography alone resulted in a significant (P < 0.01) increase in breast cancer detection rate. [ABSTRACT FROM AUTHOR]

GABG-IV B-93 is a prospective, randomised study comparing goserelin (n=384) with no further treatment (n=392) in hormone receptor (HR)-negative breast cancer patients (n=465) after 3 cycles cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for patients with 0-3 positive lymph nodes (LN) or 4 cycles epirubicin, cyclophosphamide (EC) followed by 3 cycles CMF for patients with 4-9 positive LN. After completion of the ZEBRA trial the study was amended to enrol also HR-positive patients with 1-9+LN (n=311). After a median follow-up of 4.7 years neither HR-negative nor HR-positive patients showed a benefit for goserelin. The adjusted estimated hazard ratio for event-free survival in HR-negative patients was 1.01 (goserelin versus control, 95% confidence interval [CI] 0.72-1.42, P=0.97) and 0.77 in HR-positive patients (95% CI 0.47-1.24, P=0.27). These results do not support the general use of goserelin after adjuvant chemotherapy in this group of premenopausal patients. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Background: An increasing proportion of patients are exposed to anthracyclines and/or taxanes in the adjuvant or neoadjuvant setting. Re-exposure in the metastatic stage is limited by drug resistance, thus evaluation of non-cross-resistant regimens is mandatory.Methods: Anthracycline-pretreated patients were randomly assigned to three gemcitabine-based regimens. Chemotherapy consisted of gemcitabine 1.000 mg m(-2) plus vinorelbin 25 mg m(-2) on days 1+8 (GemVin), or plus cisplatin 30 mg m(-2) on days 1+8 (GemCis), or plus capecitabine 650 mg m(-2) b.i.d. orally days 1-14 (GemCap), q3w. The primary end point was response rate.Results: A total of 141 patients were recruited on the trial. The overall response rates were 39.0% (GemVin), 47.7% (GemCis) and 34.7% (GemCap). Median progression-free survival was estimated with 5.7, 6.9 and 8.3 months, respectively. Corresponding median survival times were 17.5 (GemVin), 13.0 (GemCis) and 19.4 months (GemCap). Neutropenia ≥grade 3 occurred in 16.7% (Gem/Vin), 4.4% (GemCis) and 0% (Gem/Cap), whereas non-haematological toxicities were rarely severe except grade 3 hand-foot syndrome in 2.0% of the GemCap patients (per patient analysis).Conclusions: This randomised phase II trial has revealed comparable results for three gemcitabine-based regimens regarding treatment efficacy and toxicity. Gemcitabine-based chemotherapy appears to be a worthwhile treatment option for pretreated patients with metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate the diagnostic performance of ultrasound elastography in breast masses. Material and methods: 193 lesions (129 benign, 64 malignant) were analyzed with the EUB 8500 Logos-ultrasonic-unit (Hitachi Medical, Japan) and a linear-array-transducer of 7.5–13-MHz. Standard of reference was cytology (FNAfine needle aspiration) or histology (core biopsy). The elastic-score was classified according to a 6-point colour-scale (Ueno classification; 1–3=benign, 4–5=malignant). Conventional B-mode ultrasound (US) findings were classified according to the BI-RADS classification. Statistical analysis included sensitivity, specificity, ROC-analysis and kappa-values for intra-/interobserver reliability. Results: The mean score for elasticity was 4.1±0.9 for malignant lesions, and 2.1±1.0 for benign lesions (p <0.001). With a best cut-off point between elasticity scores 3 and 4, sensitivity was 96.9%, and specificity 76%. Setting a best cut-off point for conventional US between BI-RADS 4 and 5, sensitivity was 57.8%, and specificity 96.1%. Elastography provided higher sensitivity and lower specificity than conventional US, but two lesions with elasticity score 1 were false negative, whereas no lesion scored BI-RADS 1–3 were false negative. ROC-curve was 0.884 for elastography, and 0.820 for conventional US (p <0.001). Weighted kappa-values for intra-/interobserver reliability were 0.784/0.634 for BI-RADS classification, and 0.720/0.561 for elasticity scores. Conclusion: In our study setting, elastography does not have the potential to replace conventional B-mode US for the detection of breast cancer, but may complement conventional US to improve the diagnostic performance. [Copyright &y& Elsevier]

Purpose: To evaluate the diagnostic performance of ultrasound elastography in breast masses. Material and Methods: 193 lesions (129 benign, 64 malignant) were analyzed with the EUB 8500 Logos-ultrasonic-unit (Hitachi Medical, Japan) and a linear-array-transducer of 7.5-13-MHz. Standard of reference was cytology (FNAfine needle aspiration) or histology (core biopsy). The elastic-score was classified according to a 6-point colour-scale (Ueno classification; 1-3 = benign, 4-5 = malignant). Conventional B-mode ultrasound (US) findings were classified according to the BI-RADS classification. Statistical analysis included sensitivity, specificity, ROC-analysis and kappa-values for intra-/interobserver reliability. Results: The mean score for elasticity was 4.1 ± 0.9 for malignant lesions, and 2.1 ± 1.0 for benign lesions (p < 0.001). With a best cut-off point between elasticity scores 3 and 4, sensitivity was 96.9%, and specificity 76%. Setting a best cut-off point for conventional US between BI-RADS 4 and 5, sensitivity was 57.8%, and specificity 96.1%. Elastography provided higher sensitivity and lower specificity than conventional US, but two lesions with elasticity score 1 were false negative, whereas no lesion scored BI-RADS 1-3 were false negative. ROC-curve was 0.884 for elastography, and 0.820 for conventional US (p < 0.001). Weighted kappa-values for intra-/interobserver reliability were 0.784/0.634 for BI-RADS classification, and 0.720/0.561 for elasticity scores. Conclusion: In our study setting, elastography does not have the potential to replace conventional B-mode US for the detection of breast cancer, but may complement conventional US to improve the diagnostic performance. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Imatinib mesylate is a tyrosine kinase receptor inhibitor targeted against PDGFR α and β, c-kit and bcr-abl. These receptors regulate cellular processes such as proliferation, differentiation, and survival. This study was performed to evaluate the effects of imatinib on breast cancer cell lines with respect to the activity of PDGFR β and Akt: a downstream modulator of cell growth and survival. Methods: Expression of imatinib targets was analyzed with reverse transciptase PCR and immunoblotting assays in the breast cell lines MDA MB 231, MCF 7, ZR 75-1, and T 47-D. Changes on receptor expression and phosphorylation status under imatinib were evaluated using drug concentrations of 2 to 10μM. The anti-proliferative and pro-apoptotic effects of imatinib alone and in combination with vinorelbine were investigated with an MTT and TUNEL assay. Results: Imatinib inhibited growth and induced apoptosis of all cell lines examined. This effect was increased when combined with vinorelbine. A dose-dependent inhibitory effect on the phosphorylation of PDGFR β and Akt was detected. Conclusions: The growth inhibitory effect of imatinib on breast cell lines may be caused by inhibiting the activity of the tyrosine kinases PDGFR β and Akt. Imatinib is a promising novel drug for targeted therapy of breast cancer patients. [Copyright &y& Elsevier]

Purpose: To examine factors associated with one step surgery in case of non-palpable breast cancer. Materials and Methods: Clinical data of 152 consecutively diagnosed patients with breast cancer were analyzed retrospectively. Preoperative diagnostic findings were divided in subgroups: mammographically visible mass/microcalcifications/sonographically visible mass/sonographically visible architectural distortion. Correlation between tumor-size, radiologic tumor morphology, quality of localization and number of operation was evulated. For localization exact wire position was defined less than 3mm apart from the lesion. Results: One hundred and thirty-six patients attempted breast conservation and underwent preoperative tumor localization. Fourteen of 16 patients had mastectomy without preoperative localization. Average tumor size was 12mm for one-operation, and 17mm for re-operation. Significant correlation (p<0.001) was found between one operation and masses visible in mammograms (55/62 (89%) patients) or sonography (53/64 (83%) patients). Significant correlation was found (p<0.001) between more re-operation and microcalcifications in mammograms (33/89 (37% patients). In 123/138 (89%) cases wire position was central, in 15/138 (11%) cases distance was maximally 10mm. No significant correlation was found between number of operation and wire position. Re-operation was required in 38 cases. Conclusion: Mammographically or sonographically visible mass, small size of tumors, preoperative percutaneous biopsy and exact preoperative localization are important for a single step procedure for definite surgical treatment, that we found in 74% of the patients. [ABSTRACT FROM AUTHOR]

Problem: As recent studies have suggested abnormalities in the regulation of specific genes in the development of endometriosis, we investigated differentially expressed genes in endometriosis compared to endometrium. Method of study: Gene expression profiles using the Atlas microarray were performed in endometriotic tissue and endometrium. Nine of the 13 genes of endometriotic tissue showed an up-regulation in relation to endometrium and four of the 13 genes a down-regulation. Results: Of the 1176 genes on the Atlas Human 1,2 array, only 13 differentially expressed identical genes were detected after repeating the gene analysis three times. Conclusion: According to our c-DNA analysis some differentially expressed genes may be involved in the pathogenesis of endometriosis. An imbalance in the genes responsible for the reproductive process may lead to a decrease in embryo implantation in patients with endometriosis. [ABSTRACT FROM AUTHOR]

We report on a family in which a daughter is described with mental retardation, as well as malformations of the heart, and of the brain (Dandy-Walker variant). The patient’s phenotype suggests a chromosomal rearrangement. However, her karyotype was unremarkable by conventional cytogenetic analysis. In order to detect chromosome rearrangements overseen by this method, the subtelomere regions of suspicious chromosomes were verified by fluorescence in situ hybridization (FISH). A rearranged derivative chromosome 6 was identified. Further examinations by FISH-microdissection (FISH-MD) revealed a maternal complex balanced translocation. The patient inherited the derivative chromosome 6 from her mother and therefore carries a partial monosomy 6q26→qter and a partial trisomy 11q23.3→qter. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Gonadotrophin-releasing hormone analogues were investigated as adjuvant treatment for patients with node-negative, hormone-sensitive, premenopausal breast cancer. Patients were randomised to either three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy (n=378) or goserelin every 28 d for 2 years (n=393). During a median follow-up of 4.9 years, 123 events were observed. The first-failure event of CMF versus goserelin, respectively, was ipsilateral locoregional recurrence (18 versus 20), contralateral breast cancer (7 versus 6), distant failure (35 versus 24) and death without recurrence (2 versus 2). Forty-two (23 versus 19) deaths of any cause occurred. The estimated adjusted hazard ratio for goserelin versus CMF (intention-to-treat analysis) was 0.79 (95% CI=0.54-1.14; P=0.19). It is concluded that medical ovarian ablation with goserelin represents a valid option for premenopausal patients with node-negative breast cancer. [ABSTRACT FROM AUTHOR]

The use of electrical charge for electroporation or electrofusion is widely applied to customize dendritic cells (DC) and their immunological properties as anticancer vaccines. The aim of this study was to evaluate the influence of various electrical field strengths on the recovery, viability and physiology of DC. Immature DC were transferred into low-conductive medium and electrically charged within a range of 0–1500 V/cm. Viability was assessed by Trypan Blue dye exclusion or staining with impermeant nucleic acid stains and fluorescence-activated cell sorter analysis. Additionally, apoptosis was determined by flow cytometry after staining with Annexin-V, endocytosis by uptake of fluorescein isothiocyanate-dextran and metabolic activity by a standardized fluorescent live/dead assay. There was a strong correlation between the electrical field strength and the viability and physiology of DC. Field strengths ≥1000 V/cm significantly impaired viability, metabolism and endocytotic activity. Dual fluorescence with 7-7-amino-actinomycin D and Annexin-V demonstrated that loss of viability was predominantly due to necrosis rather than apoptosis. Field strengths ≤500 V/cm allowed to maintain good cell viability and recovery of DC and did not cause alterations of metabolism and endocytosis. Therefore, the frequently used amplification of field strengths to improve the efficacy of electroporation and electrofusion requires critical re-evaluation. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective To establish comprehensive transabdominal ultrasonographic reference ranges for viable normal singleton human fetuses at 11–14 weeks’ gestation. Methods Single transabdominal ultrasound measurements were taken once per pregnancy at a gestational age of between 11+0 and 14+0 weeks (crown–rump length, 45–84 mm), in viable singleton fetuses with nuchal translucency ≤ 3 mm and without detectable structural anomalies, using four standard planes: (i) biparietal diameter (BPD) and fronto-occipital diameter (FOD) resulting in head circumference (HC), anterior horn (Va), posterior horn (Vp), and hemisphere (HEM); (ii) transcerebellar diameter (TCD) and cisterna magna (CM); (iii) abdominal anteroposterior (AAP) and abdominal transverse diameter (ATD) resulting in abdominal circumference (AC); and (iv) femur length (FL). The respective ratios Va/HEM, Vp/HEM, HC/AC, BPD/FL, BPD/FOD, FL/CRL, FL/BPD and FL/AC and the estimated weight were derived. Reference ranges were constructed and the mean and 5th and 95th centiles were plotted against gestation. Results There was a general increase in biometric parameters with gestation. The ratios for the ventricles vs. hemisphere and BPD/FL ratio decreased while the BPD/FOD and HC/AC ratios remained constant. Analysis of the reference range for BPD/FL was performed in both 167 and 664 fetuses and the results showed almost the identical type of equation, indicating a high degree of accuracy for the growth charts. Conclusions We have established comprehensive reference ranges for first-trimester fetal biometry by transabdominal sonography. These charts may have a role in the diagnosis of early onset symmetrical or asymmetrical growth restriction and in the interpretation of measurements in chromosomally abnormal fetuses, and they may help in the detection of skeletal dysplasias or acrania/anencephaly. [ABSTRACT FROM AUTHOR]

Background: The PI3K/AKT/mTOR pathway has been reported altered in up to 40% of hormone receptor-positive (HR+) breast cancers (BC). Furthermore, pathway activation has been implicated in resistance to endocrine therapy, including aromatase inhibitors (AI). BKM120 is an oral inhibitor of all 4 isoforms of class I PI3K (α, β, γ, δ). In combination with fulvestrant, BKM120 has demonstrated pro-apoptotic effects in vitro, and achieved near- complete tumor regression in HR+ PIK3CA-mutated estrogen-independent xenografts. Preliminary clinical activity was observed with BKM120 in patients with BC, both as a single agent and in combination with letrozole (Mayer, et al. ASCO 2012: #510) or trastuzumab (Saura, et al. SABCS 2011: #PD09-03). Study design: This is a Phase III randomized, double-blind, placebo-controlled trial of BKM120 or placebo in combination with fulvestrant in postmenopausal women with HR+/HER2- locally advanced or metastatic BC that progressed on or after AI treatment (BELLE-2; CBKM120F2302; NCT01610284 ). After a 14-day fulvestrant run-in phase to allow determination of tumor PI3K pathway activation status, patients are randomized (1:1) to receive continuous BKM120 (100 mg/d) or placebo, and fulvestrant 500 mg at C1D15, and D1 of all cycles thereafter; 1 cycle=28 days. Randomization is stratified according to PI3K pathway activation (PIK3CA mut and/or PTEN mut and/or loss of PTEN protein expression by IHC), and visceral disease status. Study treatment is given until disease progression or until study discontinuation for any reason. Eligibility criteria include: postmenopausal women with HR+/HER2- locally advanced or metastatic BC refractory to AI (progression while on AI, or within 4 wks [metastatic] or 12 mos [adjuvant] of last AI dose); no more than 1 previous line of chemotherapy for advanced disease; and available archival tumor tissue for analysis of PI3K-related biomarkers. Co-primary endpoints: PFS in the full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints: overall survival (OS) in both full and PI3K pathway-activated populations. Other secondary endpoints: PFS and OS (PI3K non-activated/unknown population), overall response rate and clinical benefit rate (both in full, PI3K-activated, PI3K non-activated/unknown populations), safety (CTCAE 4.03), pharmacokinetics of BKM120 and fulvestrant, and patient-reported quality of life (EORTC QLQ- C30 and QLQ-BR23). Statistical methods: PFS and OS will be estimated using the Kaplan-Meier method for both full and PI3K pathway activated populations. Both primary and key secondary endpoints will be tested using a stratified log-rank test at levels a governed by a graphical gate-keeping procedure. A stratified Cox regression will be used to estimate the hazard ratio, along with two- sided 95% confidence interval. Target accrual: Estimated enrollment for BELLE-2 is 842 patients. Recruitment in this Global study is ongoing with planned enrollment of patients in North America, South America, Europe, Asia and Africa. [ABSTRACT FROM AUTHOR]

Introduction: Granulocyte-colony-stimulating factor (G-CSF) is produced by haemopoietic cells and several non-haemopoietic cells, such as stromal cells, fibroblasts, granulosa cells and epithelial cells of the uterine endometrium. Materials and Methods: The level of SCF in serum and in FF was measured in 74 IVF/ICSI patients (group 1) on the day of follicular puncture (FP) by ELISA. In group 2 (n = 30) SCF levels were measured in serum in all cycle phases until gestation. Results: In group 1 there were no significant differences in the median SCF concentration between serum (797.12±162.1 pg/ml) and FF (788.74±161.1 pg/ml) on the day of oocyte retrieval. A significant and positive correlation was found between the levels of SCF related to the number of follicles (SCF/f) and total injected dose (D/f) (P <0.001, r = 0.85). The level of SCF/f in serum and FF in patients who did not become pregnant was significantly higher than in those who became pregnant (P <0.05). Patients with poor response showed the highest SCF/f level in serum (289.8±106 pg/ml) and a pregnancy rate of 11.1%. Patients with moderate response had lower SCF/f levels in serum (177.2±59 pg/ml) and a pregnancy rate of 31.5%. Patients with good response displayed the lowest SCF/f level in serum (78.8±33 pg/ml) and a pregnancy rate of 51.7% (c2, p = 0.001). In group 2 the SCF in serum increased gradually from stimulation day (st.) 6-8 through st. 9-11 and reached a peak on the day of hCG injection (P ≤ 0.04). On the day of oocyte retrieval the SCF levels dropped slightly but not significantly. On post retrieval days, from the day of FP through ET, implantation (FP +1w) to the day of confirmation of pregnancy (ET +2w), the SCF levels increased significantly and reached their highest level (P = 0.02). After implantation the SCF level decreased slightly and reached a plateau during gestation. Conclusions: Our data show that SCF is involved in follicle development and ovulation and plays an important role in the maintenance of pregnancy. It could also be a predictor of embryo implantation for IVF outcome. [ABSTRACT FROM AUTHOR]

An abstract of the conference paper "Intrauterine non-invasive measurement of intracerebral pressure in cases of intracerebral bleeding and dysgenesis," by M. T. Weigel, and colleagues is presented.

Objective: The aim of this study was the analysis of maternal aneuploidy mechanisms. Three origins have been described: (i) non-disjunction of bivalent chromosomes (NDJ) which could be age related: (ii) unbalanced predivision of sister chromatids at meiosis I (22 + 1/2 or 23 + 1/2); and (iii) balanced predivision (22 + 1/2 + 1/2), which could be an artefact caused by prolonged in-vitro culture. Materials/Methods: Metaphase II oocytes which failed to fertilize after IVF or intracytoplasmic sperm injection were fixed at days 1-4 after follicular puncture and stored at -20°C. Chromosomes 13, 16, 18, 21 and 22 were hybridized by fluorescence in-situ hybridization (FISH, Vysis kit and protocol, with modification). Aneuploidy was scored with strict criteria: if it was complemented in the polar body, if an additional chromosome or chromatid was found and the polar body was absent, and if sister chromatids were separated by more than two signal diameters. Results: From 81 patients 258 oocytes were fixed. Fixation efficiency was 52% (135/258). A total of 93 of 135 oocytes have been analysed by FISH, Hybridization efficiency was 90% (84/93). In 32% (27/84) the polar body could be analysed simultaneously. (i) NDJ was found in 26% {22/84}. (ii) Unbalanced predivision was found in 13% (11/84) and both were found in 6%, (5/84). (iii) Balanced predivision was found in 48% (40/84): in 35% (12/34) of day 1 oocytes, in 54% (22/41) of day 2 oocytes, and in 67% (6/9) of day 3 and 4 oocytes combined (P < 0.05). There was no significant difference for NDJ and unbalanced predivision between day 1 (24% and 18%), day 2 (29% and 13%) and days 3 and 4 combined (22% and 0%), Aneuploidies were found in all five chromosomes with a range of 6% (chromosome 21) to 26% (chromosome 13). Conclusions: Every second unfertilized oocyte can be successfully checked for chromosomal abnormalities by FISH. Every third oocyte was aneuploid for NDJ and unbalanced predivision. These aneuploidies are not related to in-vitro ageing, Balanced predivisions are linked to in-vitro ageing. Chromosome 13 is the one most frequently abnormal. [ABSTRACT FROM AUTHOR]

Background: Reduced quality of life, limited performance and fatigue are commonly observed side effects of breast cancer systemic treatment. In previous studies sport therapy could improve these symptoms. Sport has also been reported to positively impact the clinical course of the disease. So far it has remained unclear if these influences on clinical outcome are caused by alterations in the immune system or in tumor biology or in glucose or fat metabolism. The aim of this study is to analyse the implications of individual interventions in exercise therapy on endurance, muscle strength, fatigue and quality of life, alterations in the immune system or in tumor biology or in glucose or fat metabolism for breast cancer patients during chemo therapy. Method: The trial is prospectively randomised and controlled and will involve 60 breast cancer patients receiving adjuvant chemotherapy. 20 patients each are randomized into a strength training group, an endurance training group or a control group (with standard care). At the beginning and after 12 weeks the following tests are undertaken: isometric maximum strength test, a PWC 150 test to determine the endurance of patients. The standardised questionnaire EORTC QLQ C30 including module BR23 to measure quality of life and the questionnaire MFI-20 to determine symptoms of fatigue are filled in. Questionnair D2 measures ability to concentrate. Immunologic parameters as CD4, CD8 and T-REG-cells (FACS-Analysis), the number of the circulating tumour cells (measured by density gradient centrifugation) and also the concentration of glucose, insulin, leptin and adiponectin are being measured at study entry and after 12 weeks. Momentarily patients are being screened, recruited and randomised into the trial. The final evaluation of the results is planned II/ 2013. Discussion: The purpose of this study is to show if additional value can be added by individualized strength- or endurance training. Stabilisation or improvement of maximum [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate prospectively the correlation of scar-formations after vacuum-assisted biopsy with different systems and needle-sizes and interventional bleeding/post-interventional hematoma. Methods and materials: Between 01/2008 and 12/2009, 479 patients underwent vacuum-assisted biopsy under stereotactic-guidance, using the Mammotome®-system with 11/8-gauge and ATEC®-system with 12/9-gauge, whereas in 178 cases with representative benign histology no surgical-biopsy after vacuum-assisted biopsy was performed and at least a 2-plane-follow-up-mammogram after 6 month post-vacuum-assisted biopsy was available. Bleeding during intervention, hematoma post-intervention and scar-tissue was scored as minimal and moderate/severe. Statistical analysis included Chi-Square-trend-test, p-value <0.05 was considered to be significant. Results: Significantly more bleedings and post-interventional hematomas for 8-gauge-Mammotome®-system vs. 11-gauge-Mammotome®-system (41.9% vs. 8.4%, p <0.001/35.5% vs. 16.7%, p =0.029), no significant-differences for the ATEC®-systems 9-gauge vs. 12-gauge (26.9% vs. 29.7%, p =0.799/42.3% vs. 43.2%, p =0.596). 11-gauge-Mammotome®-system vs. ATEC®-12-gauge-system revealed significantly less bleedings/hematomas (8.4% vs. 29.7%, p =0.015/16.7% vs. 43.2%, p =0.001), no significant differences for the large-systems (p =0.135/p =0.352). Follow-up of Mammotome®-11/8-gauge-system system has shown 13.1/16.1% minimal scar-formation and 1.2/3.2% moderate/severe scars, whereas ATEC®-12/9-gauge-system has shown 10.8/3.8% minimal scar-formation and 0/11.5% moderate/severe scars, no significant differences. No significant difference was found when comparing Mammotome®-11/8-g-systems vs. ATEC®-12/9-g-systems (p =0.609/p =0.823). There was also no correlation between risk of scar-formation after occurrence of bleeding or hematoma with any examined VAB-system or any needle size in this study (p =0.800). Conclusion: Using larger needle-sizes significantly (Mammotome®)/not significant for ATEC®) more interventional bleedings and post-interventional hematomas were detected, only a tendency concerning scar-formation. [Copyright &y& Elsevier]

Introduction: Preimplantation genetic screening (PGS) gives new insights into the biology of reproduction. Implantation and intrauterine growth biases to the analysis of aneuploidies are overcome by blastomere biopsy of embryos in vitro for PGS -- but not the bias of this investigation taking place after fertilisation. This can only be overcome by diagnosis of oocytes. As aneuploidies can result from first or second meiosis, results from first and second polar bodies must be analysed separately in order to understand possible reasons for intracellular malfunctions, e.g. of the spindles. Finally biases of origin for those malfunctions, i.e. especially age, should be excluded. Material and Methods: After approval of the local ethics committee, we performed 104 PGS cycles between 2004 and 2008. PGS was offered to all patients with 8 or more oocytes, independent of age or other indications. It was performed by laser biopsy of the first polar body on day 0, fixation for FISH and hybridisation with chromosomes 13, 16, 18, 21, 22 (Vysis). For each chromosome the number of chromatids present in the first polar body was noted: 0 (lack of 1 chromosome), 1 (lack of one chromatid), 2 (normal), 3 (surplus of one chromatid), 4 (surplus of one chromosome). Results: The average age of the women was 34 years (range 23-43 years). 1285 oocytes were retrieved, i.e. in average 12 per patient. Of these 1150 were mature (89%), of these 893 (78%) were biopsied, of these 833 (93%) survived. Of the 893 biopsied oocytes 778 (87%) polar bodies could be fixed, of these we obtained genetic results for 621 (80%) oocytes: 227 (37%) were euploid, 394 (63%) aneuploid. For the 5 chromosomes investigated we got 2495 single results. (I) Aneuploidy rates for chromosomes 13, 16, 18, 21, 22 were 26%, 17%, 16%, 30%, 31%, respectively. These differences were statistically significant (p < 0.01). (II) Malsegregation of chromatids was responsible for 33, 56, 68, 31, 37% of the aneuploidies, respectively (p < 0.01). Conclusions: (I) Chromosomes 21 (50MB) and 22 (56MB) show an aneuploidy rate (30-31%) about double the size than chromosomes 16 (98MB) and 18 (85MB) (16-17%). Aneuploidy correlates negatively and proportionally with the length of the chromosome. (II) Single chromatid maldistribution correlates positively and proportionally with the length of the chromosome. (III) Chromosome 13 (114MB) for both seems to be an exception. (IV) In sum spindles seem to have a tendency to missort chromosomes in first meiosis the smaller they are and chromatids the bigger they are! [ABSTRACT FROM AUTHOR]