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Targeting of tumor immune escape mechanisms holds enormous therapeutic potential. Still, most patients progress under immune checkpoint blockade and some even become hyperprogressors. To investigate how cancer cells respond to activated but ineffective T cells, we challenged peptide-loaded MCF-7 breast cancer cells with antigen-specific CD8+ T cells in which lytic granules had been destroyed by pretreatment with Concanamycin A. Gene expression analysis after coculture revealed simultaneous induction of PD-L1, IDO1, CEACAM1, and further immunoregulatory checkpoints in breast cancer cells. Strikingly, we further observed gene signatures characteristic for dedifferentiation and acquisition of pluripotency markers including Yamanaka factors. Cognate interaction with nonlytic CD8+ T cells also increased the proportion of stem cell–like cancer cells in a cell-to-cell contact- or (at least) proximity-dependent manner in various cell lines and in primary breast cancer cell cultures; this induction of stem cell–like properties was confirmed by enhanced tumor-forming capacity in immunodeficient mice. Resulting tumors were characterized by enhanced cell density, higher proliferation rates, and increased propensity for lymphoid metastasis. These findings describe a widely underappreciated pathway for immune escape, namely immune-mediated dedifferentiation of breast cancer cells, which is associated with profound changes in gene expression and cellular behavior. As the enhanced malignant potential of cancer cells after nonlytic cognate interactions with CD8+ T cells enables increased tumor growth and metastasis in BALB/cnu/nu mice, the described mechanism may provide a possible explanation for the clinical phenomenon of hyperprogression in response to unsuccessful immunotherapy. Significance: This study shows that ineffective immune responses not only fail to clear a malignancy, but can also activate pathways in cancer cells that promote stemness and tumor-seeding capacity.

Targeting of tumor immune escape mechanisms holds enormous therapeutic potential. Still, most patients progress under immune checkpoint blockade and some even become hyperprogressors. To investigate how cancer cells respond to activated but ineffective T cells, we challenged peptide-loaded MCF-7 breast cancer cells with antigen-specific CD8

Die ausgepragte Plazentainsuffizienz mit dopplersonografisch nachweisbarem enddiastolischem Null- oder Ruckfluss (absent or reversed enddiastolic velocity, AREDV) in der Art. umbilicalis ist assoziiert mit einer hohen Morbiditat und Mortalitat. Die Analyse der Flusskurve des Ductus venosus soll helfen, intrauterin bedrohte Feten zu selektieren. 58 Hochrisikoschwangerschaften mit umbilikalem AREDV wurden dopplersonografisch seriell untersucht (n=364). Wir pruften die Korrelation des perinatalen Ergebnisses (Normoblastenzahl/100 Leukozyten, pH, BaseExcess, Apgarwerte) inklusive Kurzzeitmorbiditat (Intubationsnotwendigkeit, Beatmungsdauer, Nachweis von RDS (respiratory distress syndrome), BPD (bronchopulmonary dysplasia), NEC (necrotising enterocolitis), IVH III+IV (intraventricular haemorrhage grade III and IV)) mit der Analyse der abgeleiteten Flusskurven (normale oder erhohte Pulsatilitat, enddiastolischer Null-oder Ruckfluss) in Arteria umbilicalis (AU), Arteria cerebri media (ACM) und Ductus venosus (DV) und untersuchten den Einfluss von Geburtsgewicht und Schwangerschaftsalter. Die mittlere Beobachtungzeit betrug 12,8 Tage, 48% der Feten zeigten eine auffallige DV-Flusswelle, 26% einen venosen AREDV. Das mittlere Schwangerschaftsalter bei Geburt betrug 30 Wochen, das mittlere Geburtsgewicht 816 g. 93% der Kinder wurden lebend geboren, 12% verstarben postnatal. Die Normoblastenzahl als chron. Hypoxiemarker, nicht jedoch Parameter der postnatalen Morbiditat (BPD, NEC, IVH III◦+IV◦) oder die postnatale Mortalitat korrelierten in unserem Gesamtkollektiv signifikant mit den beschriebenen Alterationen arterieller oder venoser Dopplerparameter; 10 min Apgar-Wert, Nabelschurarterien-pH und –BE nur mit Veranderungen der DV-Flusskurve. „Gesundes“ Uberleben beginnt, unabhangig von der Alteration arterieller oder venoser Blutflusskurven ab 27+0 Schwangerschaftswochen. Zwischen 27+0 und 30+6 Schwangerschaftswochen uberlebten deutlich mehr Kinder gesund bei entsprechend weniger alterierten Flussmustern. Ein Geburtsgewicht von 590 g (Sensitivitat 62,5%; Spezifitat 93,5%) und ein Gestationsalter von 28+5 SSW (Sensitivitat 87,5%; Spezifitat 90,3%) wurden als optimale Trennschwelle zwischen gesundem Uberleben und Uberleben mit schwerer Erkrankung ermittelt. Unsere Ergebnisse unterstreichen die Bedeutung der Dopplersonografie, bekraftigen aber insbesondere auch die Bedeutung der Berucksichtigung des Schwangerschaftsalters bei der Festlegung des Entbindungszeitpunktes.

Aus der Feder verzweifelter Ehemanner zeigen dramatische Geburtsberichte von prominenten Frauen die Tragodie der voranasthesiologischen Zeit. Wenn englische Royals, Napoleon und Lessing zu Wort kommen, schreiben Geburten und deren nicht selten dramatischer oder gar fataler Ausgang Kultur- und Weltgeschichte.

Significant placental insufficiency with Doppler ultrasound findings of absent or reverse end-diastolic flow velocities (AREDV) is associated with increased morbidity and mortality. An analysis of blood flow in the ductus venosus assists in the early recognition of threatened foetuses. However, the prognostic value of multivessel Doppler assessment for the timing of delivery is being questioned. Four high-risk pregnancies with umbilical AREDV were repeatedly examined prior to intrauterine foetal demise. Our results demonstrate that ductus venosus Doppler flow velocimetry can be normal prior to intrauterine foetal death.

Endometrial carcinoma is the most common gynaecological malignancy. Nevertheless there is a lack of curative therapies, especially for patients diagnosed with late stage, recurrent or aggressive disease, who have a poor prognosis. Cordyceps Sinensis, Ganoderma lucidum and Agaricus Blazi Murill are three fungi widely used in traditional Chinese medicine, and effects as adjuvants in tumour therapy have been demonstrated. However, the function and effects of these fungi in regard to endometrial cancer are not known. Three endometrial cancer cell lines, Ishikawa, Hec-1A and AN3-CA (derived from endometrial cancers grade I, II and III, respectively), were used to determine the effect of the fungi extracts on endometrial cancer cell function and to analyze the molecular mechanism. All fungi extracts had an inhibitory effect on cell viability and proliferation most probably exerted through induction of autophagy. Our data suggest that these fungi extracts may be used as adjuvants in endometrial tumour therapy.

BACKGROUND Gestational diabetes mellitus (GDM) occurs in 3-5% of all pregnancies. GDM increases both maternal and fetal risks, causes fetal macrosomia, and hence increases the rates of caesarean sections and delivery complications such as shoulder dystocia. An early predictive marker and consequent early treatment could be beneficial, so amniotic fluid insulin and C-peptide have been examined in several studies. Increased amniotic fluid insulin in early amniocentesis between the 14th and 20th gestational week predicted a later GDM. A potential direct association with fetal macrosomia remains to be determined. MATERIAL AND METHODS This retrospective study investigated amniotic fluid insulin/C-peptide from amniocenteses between 14 and 20 weeks of gestation in correlation with fetal birth weight, type of delivery, and complications. To focus on effects of fetal hyperinsulinism apart from therapeutic confounders, we included patients who did not participate in GDM screening. Insulin and C-peptide were measured in 144 samples of frozen amniotic fluid. Birth weight, type of delivery, complications, and birth injuries were noted. RESULTS Birth weights ranged from 760 g to 4410 g with a mean weight of 3424 g at an average of 40 weeks gestation. The mean amniotic fluid insulin was 4.36 U/ml and the mean C-peptide concentration was 0.076 ng/ml. There was no correlation between amniotic fluid insulin or C peptide and birth weight, type of delivery, complications, and birth injuries. CONCLUSIONS Amniotic fluid insulin and C-peptide are unsuitable as predictive marker for fetal macrosomia, type of delivery, complications, or birth injuries.

Der Nachweis eines enddiastolischen Null- oder Ruckflusses (absent or reversed enddiastolic velocity, AREDV) in der Art. umbilicalis mittels Dopplersonografie bereits vor extrauteriner Lebensfahigkeit dokumentiert die starkste Auspragung einer Plazentainsuffizienz. Zur Prognose der Feten existieren kaum Erfahrungen oder Literatur. Wir berichten 2 Kasuistiken mit strukturell und chromosomal unauffalligen Feten und schwerer fruher Wachstumsrestriktion, aber positivem Wachstum. Die Schwangerschaften konnten fur 62 bzw. 64 Tage prolongiert werden, das kindliche Langzeitergebnis ist erfreulich.

Osteopontin-1 is a well characterized protein in many tumour entities. Multiple roles in the processes invasion, metastasis and angiogenesis of tumours are attributed to osteopontin-1. The putative role of osteopontin-1 has not been characterized for endometrial cancer. We investigated multiple endometrial cancer cell lines for osteopontin-1 mRNA- and protein-expression. Osteopontin-1 dependent effects were analysed in vitro by siRNA inhibition. All endometrial cell lines expressed osteopontin-1. Expression of osteopontin-1 was successfully inhibited by specific siRNA. Cells with reduced osteopontin-1 expression showed decreased migration in the Boyden chamber assay and invasion was reduced in the wound-healing assay. Osteopontin-1 seems to play a role in apoptotic processes of endometrial cancer cells. Inhibition of osteopontin-1 expression was associated with an increased susceptibility for radiation therapy. Osteopontin-1 seems to play a role in endometrial cancer. Inhibition of osteopontin-1 expression leads to a higher susceptibility for radiation therapy. Our results suggest that a reduced expression of osteopontin-1 in endometrial cancer could inhibit the development of invasion and metastasis in these cells.

Triple negative breast cancers (TNBC) are associated with an adverse outcome, although these tumors are sensitive to chemotherapy. In part, this phenomenon could be caused by tumor immune escape. The current study investigates immunogenicity of TNBC cells in vitro and the presence of immunosuppressive factors in the tumor microenvironment (pAKT and B7H1 expression, infiltration with regulatory T cells, [Tregs]). Natural killer (NK)-cell induced lysis was evaluated in estrogen receptor (ER) positive MCF 7 breast cancers, in MDA-MB231 and MDA-MB468 and in HCC-1937 (BRCA 1 mutated) and HCC-1806 TNBC cells. Expression of pAKT, B7H1 and infiltration with Tregs were determined by immunohistochemistry in human specimens of benign and malignant breast disease. NK-cell induced lysis was significantly increased (p

Platinum-resistance is the most crucial problem for treatment of ovarian cancer. There is a clinical need for new treatment strategies which overcome platinum resistance. As survival is strongly influenced by immunological parameters, immunotherapeutic strategies appear promising. Therefore a better understanding of the interaction between ovarian tumour cells and cells of the immune system is a necessary prerequisite. In the present study we aimed to enlighten the interactions between platinum resistant and platinum sensitive ovarian cancer cells and natural-killer (NK)-cells. Modified FATAL assay was used for determining the killing efficiency of NK-cells for the parental A2780 cells and the cis-platinum resistant A2780cis human ovarian cancer cells. Expression of pro- and anti-apoptotic genes as well as ligands involved in NK-cell receptor recognition were analysed by RT-PCR and flow cytometric analysis. The efficiency of NK mediated cell lysis differs between A2780 cells and the cis-platinum-resistant A2780cis cells. A2780cis cells are less accessible for NK-cell mediated killing. Based on this observation we characterized the molecular basis for resistance mechanisms. Besides an increase in anti-apoptotic genes (especially CIAP-1 and -2) that probably render A2780cis cells more resistant against apoptosis an increased amount of soluble MICA/B seems to be responsible for the lower killing rate of platinum-resistant A2780cis cells compared to their parental A2780 cells.

Of more than one million global cases of breast cancer diagnosed each year, a high percentage are characterized as triple-negative, lacking the oestrogen, progesterone and Her2/neu receptors. The incidence exceeds the incidence of malignancies like CML by far. Lack of effective therapies, younger age at onset and early metastatic spread have contributed to the poor prognosis and outcomes associated with these malignancies. Here, we investigate the ability of the PI3K/AKT inhibitor AEZS 126 to selectively target the triple-negative breast cancer (TNBC) cell proliferation and survival in vitro by MTT-assays and FACS-based analysis. Furthermore, the mechanism of cytotoxicity is analysed by FACS-based assays and Western blots. AEZS 126 showed good anti-tumour activity in in vitro models of TNBC as well as in MCF-7 cells. Main mechanism of cytotoxicity seems to be programmed cell death after an incubation time of 72 h, which could be abrogated by co-incubation with z-VAD-fmk in MCF-7 and MDA-MB468 cells. In HCC1806 cells, addition of necrostatin-1 has only slightly protective effects, but in HCC1937 cells, the addition of necrostatin-1 has the same protective effect as co-incubation with z-VAD-fmk, and this observation argues for cell death caused by apoptosis and necroptosis in this cell line. We demonstrated the highly efficient anti-tumour activity of AEZS 126 in in vitro models of TNBC. Due to the good anti-tumour activity and the expected favourable toxicity profile, AEZS 126 in combination with chemotherapy seems to be a promising candidate for clinical testing in TNBC especially in the basal-like subgroup of TNBC.

During early gestation, a considerable increase in different leukocyte subsets can be observed in the decidualized endometrium concomitantly to the invasion of cytotrophoblast cells (CTB). To date, it is still in question which factors induce this accumulation of immune cells and whether it is evoked by an in situ proliferation or by a migratory process. Studies on hepatoblastoma cells identified thrombopoietin (TPO) as a novel factor, which elicits dose-dependent chemotactic and chemokinetic effects. However, the impact and function of TPO on decidual cells has not been clarified yet. This study analyses the expression and function of TPO and its receptor c-Mpl in decidua during early gestation. Applying western blot analysis, we detected that TPO is expressed by decidual immune cells (uNK cells and CD14+ monocytes) as well as CTB and decidual stromal cells (DSCs). Expression of the different isoforms of c-Mpl was found in uNK cells, CD14+ monocytes and DSC. Studying the signalling pathway proteins in the uNK cells, an activation of STAT3/Tyr by TPO, was detected. The investigation of the proliferative effects of TPO on the decidual cell subsets revealed that TPO enhances the proliferation of uNK cells and CTB. No change of the proliferative activity after TPO incubation was found in DSC and even a decrease in CD14+ monocytes. In addition, TPO was observed to induce significantly the migratory activity of uNK cells, CD14+ monocytes and CTB. Investigating the effects of TPO on the cytokine profile of the isolated decidual cells, we observed a decrease in the secretion of IL-8, IL-10 and IL-1β of isolated uNK cells, CD14+ monocytes and CTB, although these changes did not reach statistical significance. Thus, we here identified TPO as a novel factor modulating the proliferation, migration and possibly cytokine secretion of decidual cell subsets.

Background Ovarian cancer (OvCA) tissues show abundant expression of the ectonucleotidases CD39 and CD73 which generate immunomodulatory adenosine, thereby inhibiting cytotoxic lymphocytes. Little, however, is known about the effect of adenosine on myeloid cells. Considering that tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) constitute up to 20 % of OvCA tissue, we investigated the effect of adenosine on myeloid cells and explored a possible contribution of myeloid cells to adenosine generation in vitro and ex vivo. Methods Monocytes were used as human blood-derived myeloid cells. After co-incubation with SK-OV-3 or OAW-42 OvCA cells, monocyte migration was determined in transwell assays. For conversion into M2-polarized “TAM-like” macrophages, monocytes were co-incubated with OAW-42 cells. Ex vivo TAMs were obtained from OvCA ascites. Macrophage phenotypes were investigated by intracellular staining for IL-10 and IL-12. CD39 and CD73 expression were assessed by FACS analysis both on in vitro-induced TAM-like macrophages and on ascites-derived ex situ-TAMs. Myeloid cells in solid tumor tissue were analyzed by immunohistochemistry. Generation of biologically active adenosine by TAM-like macrophages was measured in luciferase-based reporter assays. Functional effects of adenosine were investigated in proliferation-experiments with CD4+ T cells and specific inhibitors. Results When CD39 or CD73 activity on OvCA cells were blocked, the migration of monocytes towards OvCA cells was significantly decreased. In vivo, myeloid cells in solid ovarian cancer tissue were found to express CD39 whereas CD73 was mainly detected on stromal fibroblasts. Ex situ-TAMs and in vitro differentiated TAM-like cells, however, upregulated the expression of CD39 and CD73 compared to monocytes or M1 macrophages. Expression of ectonucleotidases also translated into increased levels of biologically active adenosine. Accordingly, co-incubation with these TAMs suppressed CD4+ T cell proliferation which could be rescued via blockade of CD39 or CD73. Conclusion Adenosine generated by OvCA cells likely contributes to the recruitment of TAMs which further amplify adenosine-dependent immunosuppression via additional ectonucleotidase activity. In solid ovarian cancer tissue, TAMs express CD39 while CD73 is found on stromal fibroblasts. Accordingly, small molecule inhibitors of CD39 or CD73 could improve immune responses in ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1186/s40425-016-0154-9) contains supplementary material, which is available to authorized users.

Pregnancies that occur after infertility treatment, particularly after assisted reproduction, constitute high-risk pregnancies. Occurrences of conditions such as high blood pressure, preeclampsia, growth retardations and bleeding are higher in comparison with the norm of spontaneously entered pregnancies. The rate of premature births and the frequency of intrauterine deaths are much higher than the average for all pregnancies. Furthermore, pregnancies resulting from in-vitro fertilisation (IVF) have significantly higher rates of requiring induced labour or caesarean section. However, it is to be assumed that these complications and unfortunate developments are not caused by extracorporeal fertilisation itself, but rather are due to the frequency of multiples and to the risk factors of the women involved. These women are, on average, older and there are often more problems with cycle irregularities, uterine anomalies and obesity than in the total collective of all pregnancies. The methods of modern reproductive medicine often bring a higher rate of multiple pregnancies. The clinical problem of multiple pregnancies is, above all, the raised rate of premature births and intrauterine growth retardations that contribute to the significantly higher rate of morbidity and mortality for these children. The slightly higher rate of congenital defects after IVF and intracytoplasmic sperm injection (ICSI) are also attributed more to the risk profile of the parents and less to the techniques themselves. The most important and easy-to-avoid complication is the multiple pregnancy, and it should be our goal to lower this rate even further.

The female reproductive tract represents a great challenge to the residing immune cells: Concomitantly, those immune-competent cells have to provide tolerogenic mechanisms favoring the development of a successful pregnancy while permitting protection against harmful pathogens. The predominant cell population facing this "double edged" regulatory capacity within the reproductive tract is that of dendritic cells (DC). There is evidence that DC represent a highly adaptive cell type, which can either be transformed in an immune-stimulatory phenotype after exposure to inflammatory or infectious signals, or in an immune inhibitory phenotype preventing T cell activation when located in an adequate antiinflammatory microenvironment. Thus, this review highlights this two-faced character of DC focusing on their morphology and function within the human reproductive tract and especially during pregnancy.

The success of artificial reproductive techniques not only depends on the quality of oocytes and spermatozoa but also on the receptivity of the endometrium. The aim of this study was to assess the value of measurement of endometrial volume by three-dimensional (3D) in comparison to 2D-ultrasound in the prediction of implantation in women having transfer of cryopreserved embryos. One hundred and eight couples were included in this prospective study. All patients underwent the IVF or ICSI program and had transfer of cryopreserved embryos. Sixty-eight transfers were done in a spontaneous cycle and 40 in an artificial cycle. Endometrial thickness, pattern and three-dimensional volume were measured immediately before embryo transfer. Twenty clinical pregnancies were achieved (PR 18.5 % per transfer), the PR being similar in spontaneous (22.1 %) and artificial (12.5 %, ns) cycles. Three to five days after ovulation (spontaneous cycles) or after the endometrium reached a thickness of at least 8 mm (artificial cycles), a median of three embryos were replaced. In spontaneous cycles, there were no significant differences in endometrial thickness or volume between pregnant (11.9 mm, 2.9 ml) and non-pregnant women (10.7 mm, 3.4 ml). In artificial cycles, the endometrial volume (3.9 vs. 2.5 ml, p

Lobaplatin as a single agent and in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is investigated in in-vitro models of p53-negative triple-negative breast cancers (TNBCs) and compared with a model of oestrogen receptor-positive p53-positive breast cancer. In addition, the induction of programmed cell death by lobaplatin is further explored. By using cell viability assays and western blotting, the cytotoxic effects of lobaplatin alone and in combination with TRAIL are compared with cisplatin in HCC 1806, HCC 1937, and MCF 7 cells. The multicaspase inhibitor z-VAD-fmk and necrostatin, an inhibitor of necroptosis, are used to demonstrate the mechanism of cell death caused by lobaplatin. Lobaplatin displayed antitumour activity in all three cell lines, which increased time dependently. Cotreatment of lobaplatin and TRAIL induced an increase in cytotoxicity by 30-50% in the different cell lines. The pan-caspase inhibitor z-VAD-fmk as well as necrostatin could weaken but not abolish the cytotoxic effect of lobaplatin and cisplatin. Lobaplatin showed substantial cytotoxic effects in two in-vitro models of p53-mutated TNBC. Cotreatment with TRAIL and platinum agents resulted in increased antitumour activity in the TNBC cell lines investigated. Cell death subsequent to treatment with cisplatin and lobaplatin occurred because of apoptosis. However, caspase-independent mechanisms of programmed cell death were also involved. It was also demonstrated that platinum compounds could induce necroptosis, although to a minor extent.

Malformations of the central nervous system are among the most frequent congenital anomalies. At best, a qualified and standardised screening of the foetal brain is possible between the 18th and the 22nd week. The newly decided modification of the maternity directives envisages an extended screening upon request. This extended screening refers to the central nervous system and the representation of the ventricles, the evaluation of the head shape and the cerebellum and the back. The examination of the foetal brain should be carried out in a structured way. Three axial planes, the transventricular, the transthalamic and the transcerebellar planes, suffice to represent and measure all structures which are of importance for the screening. In case of ventricular anomalies, anomalies of the head shape, anomalies of the cerebellum and irregularities of the dorsal skin outlined in the second screening a further diagnostic procedure should be initiated. This diagnostic work-up should include a detailed neurosonography, a diagnostic evaluation of the organs and eventually further examination in the form of a caryotyping, determination of the infectology or a foetal MRI. The present article offers an overview of possible CNS abnormalities which could be recognised during the second screening according to the extended maternity directives and describes which differential diagnostics should be considered. In detail, anomalies of the head size (microcephaly, macrocephaly), of the head size (brachycephaly, dolichocephaly, cavities of the cranium, banana sign, etc.,), ventricular abnormalities, anomalies of the cerebellum (cerebellum hypoplasia, abnormal cerebellum shape) and abnormalities of the intermediate line and the intracerebral space requirements are discussed.

Der vorliegende Artikel untersucht, ob ein induktives Verfahren der Normengewinnung in der moralisch prekaren Frage des Spatabbruchs einer Schwangerschaft bei fetaler Erkrankung ethisch vertretbar ist. John Rawls stellt eine Gruppe sog. „kompetenter Moralbeurteiler“, die objektiv, tolerant und einfuhlsam sein sollen an den Anfang einer ethischen Normengenerierung. Real existierende Situationen, die von den kompetenten Moralbeurteiler intuitiv und einhellig klar beurteilt werden konnen, werden als Modellfalle herangezogen, um induktiv die dem Urteil zugrundeliegenden ethischen Prinzipien herauszuarbeiten. Diese so gewonnenen Prinzipien konnen Anspruch auf eine gewisse objektive Gultigkeit erheben und dann auf weniger klar liegende Falle ubertragen werden. In unserer Arbeit wurde ein Fall mit fetaler Trisomie 18 und ein Fall mit fetaler Lippen-Kiefer-Gaumenspalte hinsichtlich der Vertretbarkeit des Spatabbruchs gepruft. Im ersten Fall wurde fur im zweiten gegen den Abbruch entschieden. Das zugrundeliegende ethische Prinzip war eine Schadensminimierung im utlitaristischen Sinn fur Mutter und Fetus. Zum Schluss wurde versucht dieses Prinzip auf den Fall einer fetalen Trisomie 21 anzuwenden. In diesem Fall erschien es uns allerdings nicht moglich zu einem klaren Urteil zu kommen, da v. a. das fetale Interesse nicht klar beurteilt werden kann, sodass hier immer nur Einzelfallentscheidungen getroffen werden konnen.

Trastuzumab (Herceptin®) has significantly improved the overall survival of patients with HER2−positive breast cancer. The efficacy of this treatment depends significantly on antibody-dependent cell mediated cytotoxicity (ADCC). However, while trastuzumab can direct NK cells towards tumor cells and thereby promote tumor cell lysis, spheroid-forming tumor-initiating cells are largely spared. Consequently, populations of surviving cells showed greatly enhanced clonogenicity in vitro and tumorigenicity in vivo. Low HER2 levels and reduced expression of activating NK cell ligands provide likely explanations for the escape of these cells from HER2−directed NK cell-dependent therapies. Moreover, recent data show that unproductive interactions between immune cells and cancer cells can induce a process called “epithelial-to-mesenchymal transition” (EMT) which enables previously differentiated cancer cells to acquire stem cell-like properties as evidenced by a CD44highCD24low breast cancer stem cell signature and aldehyde dehydrogenase positivity. We thus investigated whether new HER2−specific antibodies could enhance NK-cell mediated target cell lysis or inhibit the induction of tumor stem cells. The antibody pertuzumab also binds to the HER2−receptor. It inhibits homo- and heterodimerization of the HER2 receptor with other member of the HER family, in particular the dimerization of HER2/HER3 receptors. We were able to show that the combination of trastuzumab and pertuzumab leads to increased antibody-binding on breast cancer cells and breast cancer stem cells, resulting in enhanced ADCC. This correlates with the clinically observed synergy between trastuzumab and pertuzumab as observed for example in the Neosphere trial, a neoadjuvant study for HER2−positive breast cancer. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combines trastuzumab with the tubulin inhibitor maytansine. Interestingly, treatment with T-DM1 largely prevented the NK cell-dependent induction of the EMT markers Twist and Snail and the characteristic downregulation of E-cadherin. Thus, T-DM1 apparently interferes with EMT and may hence prevent the re-induction of the stem cell phenotype. In line with the presumed effect against cancer stem cells, T-DM1 significantly attenuated the clonogenic potential of FACS-sorted trastuzumab-unresponsive cancer stem cells. Accordingly, our data show that these new therapeutics may be more effective against cancer stem cells and thereby promise a more sustained treatment of HER2−positive breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-05.

A case of a papillary squamotransitional cell carcinoma (PSTCC) of the vagina with a follow-up of 3 years is presented here. The characteristics of this case support a squamous rather than urothelial origin of this rare entity. Unlike its counterparts in the cervix uteri, the clinical behavior of vaginal PSTCC is more favorable than squamous cell carcinoma. Histological and clinical features are compared to those of previously described cases of vaginal and cervical PSTCC.

BACKGROUND Gestational diabetes mellitus (GDM) occurs in 3-5% of all pregnant women. As there is no general screening in Germany, many cases remain undetected. Maternal as well as foetal morbidity are increased in GDM. The aim of this study was to investigate whether amniotic fluid insulin or C-peptide levels, collected by genetic amniocentesis in early pregnancy, are predictive for gestational diabetes. Patients at risk for developing GDM might be identified and treated very early. PATIENTS AND METHODS 260 patients having a genetic amniocentesis were included in this prospective trial. Insulin and C-peptide levels were identified in frozen amniotic fluid samples. All patients should undergo an oral glucose tolerance (oGTT) test at 24-28 weeks of gestation. Only cases with normal genetic screening, normal foetal sonomorphology and birth at term were included in this trial. 90 of 260 patients having an amniocentesis underwent the oGTT and fulfilled all inclusion criteria. RESULTS GDM was diagnosed in 8 patients, in another 6 patients only one glucose level was out of the normal range. Neither amniotic fluid insulin nor C-peptide levels showed significant differences between normal and GDM pregnancies. The insulin and C-peptide levels did not correlate with blood glucose levels or with foetal weight. CONCLUSIONS In contrast to literature reports, according to these data no relationship between amniotic fluid insulin or C-peptide levels and gestational diabetes can be assumed. Amniotic fluid insulin or C-peptide levels are not predictive for GDM.

Intrauterine growth restriction (IGUR) can have different etiologies, but placental insufficiency is the clinically most relevant. Fetuses with IUGR have a significantly higher morbidity and mortality than normally grown fetuses of the same gestational age. It is important to distinguish a growth restricted fetus from a normal, small fetus and from a fetus being small because of a disease, e.g., an aneuploidy. This differentiation requires the knowledge of the gestational age and the use of multiple imaging modalities. Serial assessments of fetal growth by ultrasound are necessary to recognize declining growth. Doppler sonography can detect changes in the uteroplacentar and the fetal perfusion. Blood vessels of clinical relevance are the uterine arteries, the umbilical artery, the middle cerebral artery and the ductus venosus. When no fetal anomalies can be detected, fetal growth is parallel to the percentiles and Doppler sonography measurements are normal, IUGR is unlikely. In most IUGR fetuses, a typical sequence of circulatory changes and ultrasound findings can be observed. As there is no evidence-based treatment option for IUGR until now, obstetric management consists in defining the optimal time of delivery. This means weighing the risks of prematurity against the risks of a potentially hostile intrauterine environment.

background: During the process of fertilization, human spermatozoa are confronted with phagocytic cells of the female reproductive tract. Part of this host mucosal barrier are immature dendritic cells (DCs), which play an important role in the defense of invading microbial pathogens. In the present study, we investigated the potential interaction of spermatozoa with DCs and raised the question of whether seminal plasma impacts the interaction of DCs with spermatozoa or pathogenic microbes. methods and results: Flow cytometry and microscopy detected a strong association between spermatozoa and human monocyte-derived DCs, which was partly mediated by the DC-specific adhesion receptor, DC-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN). Coincubation assays also showed that capture of spermatozoa by DCs was blocked in the presence of increasing concentrations of seminal plasma. This inhibitory effect of seminal plasma was accompanied by altered DC maturation, revealed by flow cytometry analysis of maturation-specific DC surface markers. Phalloidin-staining of the DC cytoskeleton further visualized an impact of seminal plasma on DC morphology. To elucidate the molecular nature of the inhibitory activity of seminal plasma on sperm –DC -association, binding assays were performed in the presence of individual seminal plasma components. This approach identified specific prostaglandins—in particular, PGEl, 19-OH-PGEl and PGE2, which are present in seminal plasma at high concentrations—as likely inhibitory factors. In contrast to glass beads, the yeast Candida albicans, a common commensal organism and frequent pathogen of the genital tract, was also found to be protected from capture by DCs in the presence of seminal plasma or the specific prostaglandins. conclusions: The immunomodulatory power of seminal plasma may help spermatozoa to circumvent the attack of DCs of the female reproductive tract, thereby supporting successful fertilization. At the same time, however, such protective effects of seminal plasma may also modulate DC action during host –pathogen interactions.

Die Aktinomykose ist eine seltene, subakut bis chronisch verlaufende, bakterielle Infektionserkrankung, die zu multipler Abszess- und Fistelbildung neigt. Je nach Lokalisation werden zervikofasziale (40–50 %), abdominopelvine (20 %) und thorakale (15 %) Formen unterschieden [3].

Eine 17-jahrige I-Gravida stellte sich mit 20 SSW wegen einer fetalen Anomalie vor. Sonographisch zeigte sich ein extraabdominal gelegenes Darmkonvolut, sodass die Diagnose Gastroschisis gestellt wurde. Bei gleichzeitig vorhandener Dilatation der intraabdominal gelegenen Darmschlingen wurde die Verdachtsdiagnose Darmatresie gestellt. Aufgrund der Zunahme sowohl der extra- als auch der intraabdominal gelegenen Darmschlingen wurde mit 31 SSW eine elektive Sectio durchgefuhrt. Bei der am gleichen Tag durchgefuhrten Operation zeigte sich neben der Gastroschisis eine Duodenalatresie, die primar versorgt werden konnte.

Although trastuzumab (Herceptin) has substantially improved the overall survival of patients with mammary carcinomas, even initially well-responding tumors often become resistant. Considering that clinical efficacy of trastuzumab correlates with the infiltration of natural killer (NK) cells into the tumor site, we established a cell-culture-system to select for ovarian cancer and mammary carcinoma cells that survive a challenge by trastuzumab and NK cells. Under these conditions, NK cells can eliminate tumor cells either via antibody-dependent-cell-mediatedcytotoxicity (ADCC) or by direct recognition of tumor-associated ligands for NKG2D or DNAM-1. The most striking phenotypic alteration observed in immunoselected ovarian cancer cells was a down-regulation of HER2 expression, leading to an ADCC-resistant phenotype. All breast cancer cells tested (MCF7, SK-BR-3, MDA-MB231, BT474), however, failed to develop resistance in vitro. Instead, treatment with trastuzumab and polyclonal NK-cells resulted in the preferential survival of individual sphere-forming cells that displayed a CD44highCD24low ‘'cancer-stem-celllike” phenotype (CSC) and expressed significantly less HER2 compared with non-stem cells. Moreover, the molecular determinants for the direct recognition of transformed cells, most notably the NKG2D ligands MICA, MICB, ULBP1-4 and the DNAM-1 ligands CD112 and CD155, were virtually absent from CSC. When immunoseleced breast cancer cells were then re-expanded, they mostly lost the observed phenotype and regenerated a tumor cell culture that displayed initial HER2 surface expression and ADCC susceptibility, but was enriched in CD44highCD24low CSC. This translated into increased clonogenicity in vitro and tumorigenicity in vivo. We provide evidence that recruition of NK-cells and induction of ADCC by trastuzumab may spare actual tumor-initiating-cells, which could explain clinical relapse. Moreover, our observation that “relapsed” in vitro cultures show identical HER2 surface expression and susceptibility toward ADCC suggests that administration of trastuzumab beyond relapse might be considered, especially when combined with proteasome inhibition which increase the expression of NKG2D ligands. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD02-05.

This article applies the moral sentimentalism founded by David Hume to the moral status of the embryo. It will attempt to explain the paradoxical fact that in Germany abortion is common and socially accepted while preimplantation genetic diagnosis is banned with the aid of an approach based on moral sentimentalism. David Hume established the thesis that the human being is guided by the emotions and not by reason when making moral decisions. Scientific innovations often create a feeling of anxiety. Consequently, the initial moral judgment about it is negative. Due to this habit, the innovation is often accepted after a phase of indifference. This phenomenon has been observed in the case of heart transplantation, as well as for IVF. Consequently, the apparent contradiction in the varying degrees of the embryo's worthiness of protection in the womb and in the Petri dish is due to the simple fact that these are different stages of habituation. Therefore, the ethics of Hume cannot stipulate the embryo's moral status for once and for all; however, they can paradoxically raise the ongoing current debate to a more rational level through the insight that the underlying moral concepts are not based on reason alone.

Citation Ivanisevic M, Segerer S, Rieger L, Kapp M, Dietl J, Kammerer U, Frambach T. Antigen-presenting cells in pregnant and non-pregnant human myometrium. Am J Reprod Immunol 2010; 64: 188–196Problem Inflammatory cells play a crucial role in human parturition. Different populations of leucocytes i

Background: Screening is an unsolved problem for ovarian cancer (OvCA). As late detection is equivalent to poor prognosis, we analysed whether OvCA patients show diagnostically meaningful microRNA (miRNA) patterns in blood cells. Methods: Blood-borne whole miRNome profiles from 24 patients with OvCA and 15 age- and sex-matched healthy controls were biostatistically evaluated. Results: Student's t-test revealed 147 significantly deregulated miRNAs before and 4 after Benjamini–Hochberg adjustment. Although these included miRNAs already linked to OvCA (e.g., miR-16, miR-155), others had never before been connected to specific diseases. A bioinformatically calculated miRNA profile allowed for discrimination between blood samples of OvCA patients and healthy controls with an accuracy of >76%. When only cancers of the serous subtype were considered and compared with an extended control group (n=39), accuracy, specificity and sensitivity all increased to >85%. Conclusion: Our proof-of-principle study strengthens the hypothesis that neoplastic diseases generate characteristic miRNA fingerprints in blood cells. Still, the obtained OvCA-associated miRNA pattern is not yet sensitive and specific enough to permit the monitoring of disease progression or even preventive screening. Microarray-based miRNA profiling from peripheral blood could thus be combined with other markers to improve the notoriously difficult but important screening for OvCA.

We analyzed the anti-tumor effect and the mechanism of action of perifosine, an orally active alkylphospholipid AKT inhibitor using in vitro models of human ovarian cancer.Ovarian cancer cells OAW42, PA-1, SKOV3, and A2780 as well as platinum resistant A2780cis cells were incubated with increasing concentrations of perifosine, with and without multi-caspase inhibitor zVAD-FMK. The effect of a combined treatment with cisplatin and perifosine was investigated in OAW42, SKOV3, A2780 and A2780cis cells. Cytotoxic effects of perifosine were analyzed using crystal violet staining, FACS analysis of DNA content as well as Annexin V/propidium iodide-double staining. The effect of perifosine on AKT phosphorylation was determined by Western blotting.Perifosine displayed anti-tumor activity in all five cell lines, which increased time-dependently. While IC(50) values at 24 h were40 μM, IC(50) values after 72 h decreased to 10 μM in OAW42 and 25 μM in PA-1 and 30 μm in SKOV3 cells. In platinum resistant A2780cis cells perifosine showed good antiproliferative activity (IC(50) = 3 μm). At adequate doses, perifosine increased cytotoxic effects of cisplatin in OAW42, A2780 and A2780cis cell. Anti-tumor activity of perifosine was not confined to a specific phase of the cell cycle and could not be decreased by the pan-caspase inhibitor zVAD-FMK. AnnexinV/propidium iodide-double staining after treatment with perifosine was not indicative of classical apoptosis. AKT phosphorylation was dose-dependently inhibited by perifosine.Perifosine showed substantial cytotoxic effects in various in vitro models of ovarian cancer. Since anti-tumor effects were not confined to platinum-sensitive cells perifosine seems to be a good candidate for clinical studies in patients especially with platinum resistant ovarian cancer.

The current article reviews a novel approach in tumor therapy based on peptide hormon analogs of GnRH, Bombesin/GRP and Somatostatin as carrier substances for cytotoxic agents, thus aiming to achieve a higher concentration of the active compound in the vicinity of the tumor. This therapeutic concept should lead to an increased antitumoral efficacy and minimized side effects. Targeted therapy with cytotoxic analogs of GnRH, Bombesin/GRP and Somatostatin has been highly effective in preclinical tumor models of breast-, endometrial, and ovarian cancer, although associated with only a low haematological toxicity. In the current studies cytotoxic hybrid molecules were significantly more potent than the chemotherapeutic agent alone. However, the expression of the respective target receptor on the tumor cells is a necessary requirement for an effective therapy, as blockade of tumoral receptors significantly decreased the efficacy of the cytotoxic hybrid molecules in vivo. The haematological toxicity of targeted chemotherapy was significantly less pronounced than the corresponding nondirected therapy with a cytotoxic radical alone in all animal experiments. The rapid development of a resistance to targeted chemotherapy is unlikely, as the expression of MDR proteins after targeted therapy was not increased as compared to a corresponding non-targeted approach in all experiments. AN-152, one of the compounds investigated in this article has already entered clinical testing. Thus, AN-152 showed a good tolerability in a clinical phase I study for patients with GnRH-positive breast-, ovarian-, and endometrial cancer and is now tested for efficacy in a clinical phase II study.

Infertility in men and women is frequently associated with genital contamination by various commensal or uropathogenic microbes. Since many microorganisms are known to release quorum-sensing signals in substantial amounts, we raised the question whether such molecules can directly affect human spermatozoa. Here we show that farnesol and 3-oxododecanoyl- l -homoserine lactone, employed by the opportunistic pathogenic yeast Candida albicans and the gram-negative bacterium Pseudomonas aeruginosa , respectively, induce multiple damage in spermatozoa. A reduction in the motility of spermatozoa coincided in a dose-dependent manner with apoptosis and necrosis at concentrations which were nondeleterious for dendritic cell-like immune cells. Moreover, sublethal doses of both signaling molecules induced premature loss of the acrosome, a cap-like structure of the sperm head which is essential for fertilization. Addressing their mechanism of action, we found that the bacterial molecule, but not the fungal molecule, actively induced the acrosome reaction via a calcium-dependent mechanism. This work uncovers a new facet in the interaction of microorganisms with human gametes and suggests a putative link between microbial communication systems and host infertility.

Problem During pregnancy, the immune and the endocrine system cooperate to ensure that the fetal allograft develops without eliciting a maternal immune response. This is presumably in part achieved by dendritic cells (DCs) that play a dominant role in maintaining peripheral tolerance. In this study, we investigated whether female sex hormones, such as human chorionic gonadotropin (hCG), progesterone (Prog), and estradiol (E2), which are highly elevated during pregnancy, induce the differentiation of DCs into a tolerance-inducing phenotype. Methods/Results Immature DCs were generated from blood-derived monocytes and differentiated in the presence of hCG, Prog, E2, or Dexamethasone (Dex) as a control. Unlike Dex, female sex hormones did not prevent the upregulation of surface markers characteristic for mature DCs, such as CD40, CD83, and CD86, except for hCG, which inhibited HLA-DR expression. Similarly, hCG, Prog, and E2 had any impact on neither the rearrangement of the F-actin cytoskeleton nor the enhanced chemokine secretion following DC maturation, both of which were strongly altered by Dex. Nevertheless, the T-cell stimulatory capacity of DCs was significantly reduced after hCG and E2 exposure. Conclusion Our findings suggest that the female sex hormones hCG and E2 inhibit the T-cell stimulatory capacity of DCs, which may help in preventing an allogenic T-cell response against the embryo.

Metabolic dependence on glucose utilisation has been described for different tumours characterised by activation of Akt, upregulation of GLUT1, M2PK and TKTL1. To date, however, little is known about glucose metabolism in breast cancer tissue. We analysed 55 breast cancer specimens, 26 adjacent ductal carcinomas in situ (DCIS) and 23 adjacent normal breast tissues for expression of glycolytic markers by immunohistochemistry. We found expression of pAkt in 49%, GLUT1 in 25%, M2PK in 68% and TKTL1 in 31% of the tumours investigated. Expression of pAkt and Her2neu are positively correlated with borderline significance (P = 0.055). Expression of pAkt, GLUT1 and TKTL1 were higher in breast cancer and DCIS than in normal tissue. Surprisingly, M2PK expression was highest in normal breast tissue. We found a glycolytic phenotype in a high percentage of breast cancer samples. Inhibition of glycolysis might evolve as a future option for breast cancer therapy.

Background: Following implantation, endometrial stroma is transformed into decidual tissue via a complex remodeling process. In parallel with that process, a significant increase in immune cells can be detected. Several studies suggest that chemokines and cytokines orchestrate the transformation of decidual tissue and the infiltration of leukocytes. In this study, we therefore compared chemokine and cytokine expression in the first- and third-trimester nonpregnant endometrium and decidua. Methods: Investigation of the expression patterns of cytokines, chemokines and growth factors in endometrial tissue (after routine hysterectomy) and human decidual tissue (7–8 weeks of gestation and 38–40 weeks of gestation, respectively) was performed by protein array analysis. Results: This analysis revealed a significant increase in monocyte-attracting chemokines (granulocyte-macrophage colony-stimulating factor, growth-related oncogene, growth-related oncogene-α and monocyte chemoattractant protein-2) , granulocyte-attracting chemokines (epithelial neutrophil activating peptide and interleukin 8) and proinflammatory factors (interleukin-1α, leptin) in decidual compared to endometrial tissue. Furthermore, concentrations of angiogenic substances (vascular endothelial growth factor and thrombopoietin) significantly peaked in first-trimester deciduas. Conclusion: This study demonstrates increased expression of chemokines and cytokines in decidual tissue compared to nonpregnant endometrium.

Objective Perifosine is an orally active alkylphospholipid analog, which has shown anti-tumor activity in a variety of cancers by inhibition of AKT phosphorylation. The objective of the current study was to evaluate its efficacy in in vitro models of human endometrial cancer. Study design The effect of 10 μM and 40 μM perifosine on AKT phophorylation in human endometrial cancer cell lines Ishikawa and HEC 1A was determined by Western blotting. To screen for a putative anti-tumor effect, HEC 1A and Ishikawa cells were incubated with increasing concentrations of perifosine for 24 h, 48 h and 72 h and the number of viable cells was determined by crystal violet staining. Also the effect of a combined treatment with cisplatin and perifosine was investigated in Ishikawa cells. Flow cytometric analysis of DNA content was used to determine the effect of perifosine on the cell cycle distribution of HEC 1A and Ishikawa cells and to assess potential toxic side effects of perifosine on peripheral blood lymphocytes (PBL). Results AKT phosphorylation was dose-dependently inhibited by perifosine. Concomitantly, perifosine displayed anti-tumor activity in both cell lines at concentrations that showed no effect on peripheral blood lymphocytes. Growth inhibitory effects became more pronounced with increasing treatment time. While IC 50 values at 24 h were >40 μM, IC 50 values after 48 h were approximately 7 μM in Ishikawa and 25 μM in HEC 1A cells. After 72 h, the IC 50 was below 1.25 μM for Ishikawa and about 6 μM for HEC 1A cells. Perifosine cotreatment substantially increased cytotoxic effects of cisplatin in human Ishikawa endometrial cancer cells. Of note, the anti-tumor activity of perifosine was not confined to a specific phase of the cell cycle. Conclusions The small molecule AKT inhibitor perifosine showed substantial anti-tumor activity in human endometrial cancer cell lines. Since these effects were increased with cisplatin, perifosine seems to be a good candidate for treatment combinations with classical cytostatic compounds. Thus, perifosine should be further evaluated in clinical studies in endometrial cancer.

The proinflammatory cytokine macrophage migration inhibitory factor (MIF) stimulates tumor cell proliferation, migration, and metastasis; promotes tumor angiogenesis; suppresses p53-mediated apoptosis; and inhibits antitumor immunity by largely unknown mechanisms. We here describe an overexpression of MIF in ovarian cancer that correlates with malignancy and the presence of ascites. Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells. Together with the additional tumorigenic properties of MIF, this finding provides a rationale for novel small-molecule inhibitors of MIF to be used for the treatment of MIF-secreting cancers.

BACKGROUND The prevalence of overweight and obesity in pregnant women has increased during the last decades (in our examination period from 10.9 to 29.8 %). Maternal obesity is a risk factor for pregnancy, delivery and the newborn. Does the neonatal outcome of pregnancies with maternal overweight and obesity in 2005 differ from that in 1980? METHODS All patients with a body mass index (BMI) > 25 kg / m (2) who delivered in 1980 (n = 130) and in 2005 (n = 392) at the University Hospital Wurzburg were evaluated retrospectively. The neonatal result of singletons born at term was studied (1980: n = 125; 2005: n = 315). RESULTS The rates of macrosomia > 4500 g (5.6 vs. 1.3 %) and shoulder dystocia (4.8 vs. 0.3 %) declined significantly. No significant differences were found regarding the mean newborn weight (3560 vs. 3508 g), weight percentile (55.5 vs. 56.4 %), length (51 cm), head size (35 cm), fetal distress (3.2 vs. 3.8 %), respiratory insufficiency (3.2 vs. 2.2 %), 5-min-Apgar (9.77 vs. 9.69) and arterial umbilical cord pH (7.27 vs. 7.26). Birth weight was not associated with the degree of obesity in 2005 compared to 1980. CONCLUSION Despite the increasing prevalence and severity of obesity in pregnant women most parameters of neonatal outcome did not change. The observed relative rate of macrosomia and shoulder dystocia declined, but the case number of these complications is still relevant. Obviously obstetricians have responded appropriately to the changing risk profile.

OBJECTIVE: The background for this study is the increasing prevalence of overweight and obesity in industrialized countries. Obstetricians and gynecologists are also confronted with these problems. The prevalence of overweight and obesity among pregnant women in Germany has only rarely been studied. The aim of this study was to examine the increase in overweight and obesity and to compare the perinatal outcomes for obese patients in 1980 and 2005. METHODS: A retrospective analysis was carried out of all deliveries at the University hospital Wurzburg in 1980 (n = 1359) and in 2005 (n = 1351). The perinatal results of patients with a body mass index (BMI) < 25 kg/m 2 were studied in detail (1980: n = 125; 2005: n = 315). RESULTS: During this period, the prevalence of overweight and obesity rose significantly from 10.9 % to 29.8 %. The higher obesity grades increased disproportionately: the incidence of overweight gravida rose from 8.8 to 18.5 %, while obesity grade 1 increased from 1.4 to 6.4 %, grade 2 from 0.7 to 3.5 %, and grade 3 from 0.08 to 1.4 %. In contrast to 1980, there was no longer a positive correlation between BMI and age in 2005. Gestational diabetes (0 vs. 4.5 %) and primary cesarean delivery (1.6 vs. 14 %) had dropped significantly in 2005. The decrease in hypertension (20.8 vs. 8.9 %), macrosomia < 4500 g (5.6 vs. 1.3 %) and shoulder dystokia (4.8 vs. 0.3 %) was also significant. Pre-eclampsia, fetal growth restriction, average birth weight, secondary cesarean delivery, Apgar score and pH-values did not differ. CONCLUSION: The prevalence of overweight and obesity has increased almost threefold from 1980 to 2005 (currently 29.8 %). Some perinatal outcomes have changed significantly, others have not. Preliminary investigations (e.g. screening for gestational diabetes, cesarean section in case of additional risks) can improve perinatal results.

Problem In human decidua, a significant increase of leukocytes including CD56++CD16– uterine natural killer (uNK) cells and CD14+ monocytes has been observed with the onset of pregnancy. The mechanisms required for the recruitment of those cells to the uterus are still under debate. Cytokines and chemokines have been suggested as key factors for the regulation of these complex cellular migration and interaction processes. Method of study Investigation of the expression patterns of cytokines, chemokines and growth factors in human decidual tissue (7–8 weeks of gestation) was performed by protein array analysis. Isolated decidual leukocytes, i.e. CD56++CD16– uNK, CD14+ monocytes as well as cytotrophoblast (CTB) and stromal cells were tested separately. Results This analysis revealed the production of monocyte attracting chemokines (GRO, MCP-1), angiogenetic substances (EGF, VEGF, Angiogenin) as well as granulocyte activating peptides (ENA-78, IL-1β, RANTES, IL-8) by decidual tissue and its cell subsets. Conclusion The observed pattern supports the role of decidua as a tissue which promotes angiogenesis, attracts monocytes and modulates the function of the latter.

Foetal growth retardation (IUGR) occurs in approximately 3-10 % of all pregnancies and may result from foetal, maternal or placenta-related conditions. In IUGR, the placental weight is often reduced and the placental capacity, reflected by the organ's weight, is impaired. Uterine malformations have an incidence of 3-4 % and may be the cause of placental abruptions occurring in 0.4-1.3 % of all pregnancies. We report on a patient in the 26 (th) week of pregnancy who was admitted with vaginal bleeding. A uterus bicornis had been found previously. Sonography showed severe foetal growth retardation and a pathological foetal Doppler signal. A haematoma located cranial of the os uteri was sonographically diagnosed, and a partial placental abruption was suspected. Due to a pathological cardiotocography, a primary Caesarean section was performed. Intraoperative evaluation confirmed the presence of a uterus bicornis. In addition, the placenta showed an insertio velamentosa. The growth retarded foetus - 490 g birth weight - was anaemic. Respiratory therapy and surfactant substitution were performed because of a respiratory distress syndrome. At a corrected age of 8 weeks the boy was sent home without neurological sequelae. In the case reported, a malformation of the uterus was the cause of a pathologically altered placenta. The multiple factors responsible for the described severe intrauterine growth retardation were a low placental weight and thus a reduced placental capacity, an impaired foetal circulation caused by the velamentous insertion, as well as a partial placental abruption. In normotensive pregnancies with IUGR, macroscopic and histopathological examinations of the placenta are therefore strongly recommended. Prior to getting pregnant, the therapeutic options should be explained to women with uterine malformations.

In 1999, the peptidic antagonist of gonadotropin-releasing hormone (GnRH), cetrorelix, was the first compound of this class to be marketed. Cetrorelix is a classic antagonist at the GnRH pituitary receptor. It is used to achieve reversible, dose-dependent suppression of the gonadotropins and the sex steroids. Cetrorelix is approved in over 80 countries including the USA and Japan for the prevention of the premature luteinizing hormone surge in controlled ovarian stimulation (COS) cycles. Using GnRH antagonists instead of GnRH agonists in COS cycles may facilitate infertility treatment. Pregnancy rates after both treatment regimens appear to be similar, while in GnRH-controlled COS cycles a lower rate of side effects such as ovarian hyperstimulation syndrome occur. Cetrorelix may also be useful in minimal stimulation cycles for in vitro fertilization or intrauterine insemination, although further and larger studies are required. Other indications for cetrorelix may be sex steroid-dependent benign and malig...

OBJECTIVE Evaluation of the influence of socio-economic status on the utilization of epidural analgesia during labor. MATERIAL AND METHODS Modes of delivery, insurance, marital status and maternal occupation were retrospectively reviewed between 2000 and 2003 according to the birth documentation of all deliveries at the department of obstetrics and gynaecology, university of Wuerzburg, Germany. Using the maternal occupation groups were formed according to the minimum degree of education required for its practise. Women with epidural analgesia during labor were compared to those without it. RESULTS 30 % of all deliveries during the evaluated four years were aided by employing epidural analgesics. For both collectives there were no changes of percentages concerning insurance, marital status or maternal occupation during this time. With 12-24 %, epidural analgesia was more often performed in patients undergoing operative transvaginal deliveries in comparison to women without epidural analgesics (2-5 %). There are no differences between the two groups concerning maternal occupation, insurance or marital status. However, looking at the collective of women with epidural analgesia during labor, epidural analgesia is more often used among women with private insurance. Concerning the degree of education there is also a marginal significant difference in the utilization of epidural analgesia in favour for women with a higher educational degree. CONCLUSION The use of intrapartum epidural analgesia is associated with insurance and maternal occupation/educational degree.

Endometrial carcinoma is the most common malignant tumor of the female genital tract. The major non-invasive diagnostic method is ultrasound. Endometrial thickness (double layer) is measured by transvaginal sonography. The cut-off value in patients with postmenopausal bleeding is still controversial, although in patients with endometrial thickness below 4 mm (or 5 mm respectively), malignancy can be excluded with high probability. If the endometrium measures more than 4 mm (or more than 5 mm respectively) or the patient presents with continuous bleeding, hysteroscopy and curettage should be performed in order to obtain histologic diagnosis. Sonographic findings like structure and demarcation of the endometrium increase diagnostic specificity only when combined with the measurement of endometrial thickness. Measuring the fluid within the uterine cavity does not seem to be useful in differentiating malignant from benign disorders. The extent of surgery depends on the preoperative estimation of the tumor stage which is particularly important for elder patients with increased morbidity. Transvaginal sonography has not been widely accepted to predict the depth of myometrial invasion or cervical infiltration. Although promising studies exist, additional examinations have to be done in order to determine the role of transvaginal sonography beside other methods (CT, MRT). This article on transvaginal ultrasound reviews current data on the method's capacity to identify endometrial cancer and to diagnose the depth of invasion.

Scientific reports 5, 12319 (2015). doi:10.1038/srep12319, Published by Nature Publishing Group, London