[Severe maternal hepatopathies in the peripartum period--a case series with review of the literature focusing on pathogenesis and differential diagnosis]. / Lebensbedrohliche, maternale Leberaffektionen in der späten Schwangerschaft und im Wochenbett--eine Fallserie mit Überblick über Pathogenese und differenzialdiagnostische Abgrenzung.

BACKGROUND: A severe hepatopathy constitutes a serious threat during pregnancy and poses considerable challenges to the treating physicians. A broad spectrum of pregnancy-dependent or independent diseases like HELLP-syndrome, liver infection or acute fatty liver of pregnancy (AFLP) is characterized by these affections of the liver. In this study, we present a series of 3 cases with life-threatening hepatopathies and discuss the current state of the literature. A special focus is placed on pathogenesis and differential diagnosis. METHODOLOGY: Pathological, radiological and gynaecological/surgical procedures were performed according to the current German guidelines. Laboratory tests were conducted in the clinics' routine diagnostics section. The existing literature was reviewed via the US National Library of Medicine database "PubMed.gov". RESULTS: The first patient had been afflicted by a fulminant HELLP syndrome causing delivery after 32 weeks of pregnancy. Consecutively, she suffered a sub-total liver infarction followed by a severe coagulopathy and septic peritonitis. The second patient was diagnosed with HELLP syndrome at 36 weeks of pregnancy. The initially mild syndrome exacerbated after delivery leading to haemorrhagic shock and acute renal failure. In the third case, a woman with asymptomatic hepatitis B delivered in the 36th week of pregnancy. Post partum, her pre-existing condition worsened fulminantly resulting in sub-acute liver dystrophy and massive coagulopathy. DISCUSSION AND CONCLUSION: Whenever a hepatopathy occurs during pregnancy, several divergent diagnoses with severe implications and different aetiopathologies have to be considered. Diagnostic and therapeutic strategies have to be weighed quickly to enable a fast, interdisciplinary cooperation in order to prevent fatal outcomes.

The post-reproductive Fallopian tube: better removed?

Recently, the distal Fallopian tube has attracted considerable attention not only as site of origin for serous cancer in women with BRCA mutations, but also as the anatomical location where the majority of serous ovarian cancers apparently develop. Consequently, the Fallopian tube may be the unique location where early 'ovarian' cancers can be found--which would contradict the long-standing impression that the ovaries and the Fallopian tubes are always simultaneously involved. Based on the dismal prognosis associated with ovarian cancer and our inability to screen for early-stage disease, we discuss the rationale for introducing salpinges-hysterectomy as new clinical standard for women in need of hysterectomy and further weigh the arguments for and against bilateral salpingectomy as a sterilization method. There is no known physiological benefit of retaining the post-reproductive Fallopian tube during hysterectomy or sterilization, especially as this does not affect ovarian hormone production. On the other hand, the consequences associated with a surgical menopause provide a rationale for preserving the ovaries in premenopausal women. Prophylactic removal of the Fallopian tubes during hysterectomy or sterilization would rule out any subsequent tubal pathology, such as hydrosalpinx, which is observed in up to 30% of women after hysterectomy. Moreover, this intervention is likely to offer considerable protection against later tumour development, even if the ovaries are retained. Thus, we recommend that any hysterectomy should be combined with salpingectomy. In addition, women over 35 years of age could also be offered bilateral salpingectomy as means of sterilization.

[Late interruption of pregnancy due to foetal disease: is an inductive method for the generation of ethical principles applicable?]. / Spätabbruch von Schwangerschaften bei fetalen Erkrankungen: Führt ein induktives Verfahren der Normgewinnung zu ethischer Klarheit?

BACKGROUND: The current study investigates if an inductive method for the generation of ethical principles can be applied to the crucial moral question if late interruption of pregnancy due to fetal disease is ethically adequate. METHODS: This method originates from the US American philosopher John Rawls and puts a group of so-called competent moral investigators in the beginning of the decision process. These competent moral investigators should be objective, tolerant and sensitive. Thus, real cases which lead to an intuitive, unanimous and clear decision of the competent moral investigators are analysed for the underlying ethical principles. The ethical principles thus detected are then applied to more complicated cases which could not be assessed clearly. RESULTS: In the current study, the case of foetal trisomy 18 and foetal palate cleft could be clearly judged with a yes and a no, respectively, with regard to an approval of late interruption of pregnancy. The underlying ethical principle leading to these decisions is the utilitaristic principle of minimising harm for mother and fetus. DISCUSSION: We then tried to apply this principle to a case of foetal trisomy 21, however, no clear decision for an approval or a disapproval of the interruption of pregnancy could be found as it was not possible to assess foetal interests.

Whole blood-derived miRNA profiles as potential new tools for ovarian cancer screening.

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.

The moral status of the embryo: an attempt at an analysis with the aid of David Hume's ethics.

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.

Prolonged clinical benefit from platinum-based chemotherapy in a patient with metastatic triple negative breast cancer.

Triple negative breast cancer is a recently defined subgroup of tumors which do not express receptors for estrogen or progesterone and which do not show any overexpression of HER2 receptors. Tumors with these histopathologic features have an unfavorable prognosis and at present there is no standard chemotherapy regimen available. However, experimental studies and very recently some clinical data showed a benefit from platinum-based chemotherapy. We treated a 52-year-old caucasian female with metastatic triple negative breast cancer. She suffered from extensive liver disease resistant to taxane treatment and yttrium radiotherapy. Cisplatin/ifosfamide (12 cycles) induced regression of the liver metastasis from over 30 cm to 6 cm as revealed by CT scan. Dose-limiting toxicity was impairment of renal function and pancytopenia. The patient has now been stable for over ten months on a metronomic regimen of oral cyclophosphamide. This case report adds to recent evidence suggesting good clinical benefits of platinum-based regimens in early and advanced triple negative breast cancers.

Targeting of preexisting and induced breast cancer stem cells with trastuzumab and trastuzumab emtansine (T-DM1).

The antibody trastuzumab (Herceptin) has substantially improved overall survival for patients with aggressive HER2-positive breast cancer. However, about 70% of all treated patients will experience relapse or disease progression. This may be related to an insufficient targeting of the CD44(high)CD24(low) breast cancer stem cell subset, which is not only highly resistant to chemotherapy and radiotherapy but also a poor target for trastuzumab due to low HER2 surface expression. Hence, we explored whether the new antibody-drug conjugate T-DM1, which consists of the potent chemotherapeutic DM1 coupled to trastuzumab, could improve the targeting of these tumor-initiating or metastasis-initiating cells. To this aim, primary HER2-overexpressing tumor cells as well as HER2-positive and HER2-negative breast cancer cell lines were treated with T-DM1, and effects on survival, colony formation, gene and protein expression as well as antibody internalization were assessed. This revealed that CD44(high)CD24(low)HER2(low) stem cell-like breast cancer cells show high endocytic activity and are thus particularly sensitive towards the antibody-drug conjugate T-DM1. Consequently, preexisting CD44(high)CD24(low) cancer stem cells were depleted by concentrations of T-DM1 that did not affect the bulk of the tumor cells. Likewise, colony formation was efficiently suppressed. Moreover, when tumor cells were cocultured with natural killer cells, antibody-dependent cell-mediated cytotoxicity was enhanced, and EMT-mediated induction of stem cell-like properties was prevented in differentiated tumor cells. Thus our study reveals an unanticipated targeting of stem cell-like breast cancer cells by T-DM1 that may contribute to the clinical efficacy of this recently approved antibody-drug conjugate.

PI3K inhibitor D-116883 is effective in in vitro models of ovarian cancer.

BACKGROUND: D-116883 (Aeterna Zentaris GmbH, Frankfurt, Germany) is an orally effective drug that acts via inhibition of phosphatidylinositol 3-kinase (PI3K). The PI3K/AKT signal transduction pathway is involved in ovarian cancer tumorigenesis. Phosphatase and Tensin homolog (PTEN) loss and other activating mutations frequently contribute to the activation of this pathway. We tested whether D-116883 exerts cytostatic effects in in vitro models of ovarian cancer and analyzed the induced programmed cell death. MATERIALS AND METHODS: We evaluated the potency of D-116883 in four ovarian carcinoma cell lines with different cellular assays. The effects of D-116883 on cell proliferation was analysed by crystal-violet staining and tetrazolium salt [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTT] assay. The capacity for anchorage-independent growth was analyzed in two ovarian carcinoma cell lines without and with D-116883 addition by using the soft agar assay. Fluorescence activated cell sorting (FACS) cell cycle analyses were performed. Cells were incubated with multicaspase inhibitor benzyloxycarbonyl-val-ala-asp(OMe)-fluoromethylketone (zVAD) and inhibitor of necroptosis necrostatin. RESULTS: Growth inhibition occurred in all ovarian carcinoma cell lines studied (A2780, A2780cis, OAW42 and SKOV3) in a micromolar range (IC(50)<1 µM). By using soft agar assay, a reduced capacity for anchorage-independent growth, a hallmark of tumor cells, caused by D-116883 was demonstrated. Cell cycle analyses showed that D-116883 dose-dependently increased apoptotic cells. Multicaspase inhibitor zVAD and inhibitor of necroptosis necrostatin did not abrogate the growth-inhibiting effect of the compound. CONCLUSION: PI3K inhibitor D-116883 showed substantial cytotoxic effects in various in vitro models of ovarian cancer. Our results make D-116883 a good candidate for further ovarian cancer research including in vivo experiments.

Peptidomimetic GnRH antagonist AEZS-115 inhibits the growth of ovarian and endometrial cancer cells.

BACKGROUND: AEZS-115 (Aeterna Zentaris GmbH, Frankfurt/M, Germany) is an orally active peptidomimetic antagonist of gonadotropin-releasing hormone (GnRH). In various tumors, an autocrine growth-promoting loop has been described for GnRH. The current study evaluates the antitumor activity and mechanism of action of AEZS-115 in models of ovarian and endometrial cancer. MATERIALS AND METHODS: Human A2780, Acis2780, OAW-42, Ovcar-3, SKOV-3, Hec1A and Ishikawa cells were analyzed for GnRH receptor expression by reverse transcription polymerase chain reaction (RT-PCR). These cell lines were incubated with AEZS-115 at 1, 10 and 100 µM for 24 h, 48 h, and 72 h and the number of viable cells was determined. Fluorescence activated cell sorting (FACS) cell cycle analyses were performed with increasing concentrations of AEZS-115. Co-treatment experiments of cancer cells with GnRH antagonist cetrorelix and peptidomimetic GnRH antagonist AESZ-115 were carried out. RESULTS: A2780, Acis2780, OAW-42, Ovcar-3, SKOV-3, Hec1A and Ishikawa cells expressed GnRH receptors as demonstrated by RT-PCR. GnRH antagonist AEZS-115 inhibited growth of all cell lines in a dose- and time-dependent manner. Half maximal inhibitory concentration (IC(50)) values at 48 h of incubation were between 7 and 17.5 µM and for 72 h between 4.5 and 12.5 µM. IC(50) values for ovarian and endometrial cancer cells were rather similar. These results were obtained by tetrazolium salt [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; MTT] assay and confirmed by additional crystal violet staining. Cell cycle FACS analysis revealed that AEZS-115 dose-dependently increased the fraction of apoptotic cells. Co-treatment experiments carried out with AEZS-115 and peptidic GnRH-antagonist cetrorelix suggest that the antitumor effect of AEZS-115 is not mediated by blockade of the GnRH receptor. CONCLUSION: GnRH antagonist AEZS-115 exhibited substantial antitumor activity in ovarian as well as endometrial cancer cell lines. However, this antitumor effect was not mediated by the tumoral GnRH receptors. To identify the mechanism of action of this compound, further research is warranted. Its in vitro antitumor activity makes AEZS-115 a promising candidate for in vivo studies of ovarian and endometrial cancer.

Overexpression of polycomb protein BMI-1 in human specimens of breast, ovarian, endometrial and cervical cancer.

INTRODUCTION: The polycomb group (PcG) proteins form chromatin-modifying complexes that are commonly deregulated in cancer. The PcG protein BMI-I is overexpressed by various tumours and thus may contribute to malignant transformation. The current study investigated the expression of BMI-I in human specimens of breast, ovarian, endometrial and cervical cancer. MATERIALS AND METHODS: Expression of BMI-I was evaluated in human ovarian cancer samples by Western blot analysis and immunohistochemistry (IHC) and compared to healthy ovarian tissue. BMI-I expression in human specimens of breast, endometrial and cervical cancer was evaluated by IHC and then compared with the respective benign tissues. RESULTS: BMI-I was significantly (p<0.05) overexpressed in human breast, ovarian, endometrial and cervical cancer specimens as compared to benign controls. BMI-I expression was also more pronounced in the ovarian cancer samples as demonstrated by Western blot analysis. In human breast cancer samples, BMI-I expression was most pronounced in the invasion front of the tumour. CONCLUSION: The current study showed for the first time that the BMI-I protein is significantly overexpressed in ovarian, endometrial and cervical cancer and may thus be a potential target for novel antitumor therapies.

Expression of transketolase-like 1 protein (TKTL1) in human endometrial cancer.

BACKGROUND: Malignant tumors metabolize glucose to lactate even in the presence of oxygen (aerobic glycolysis). The metabolic switch from oxidative glycolysis to non-oxidative fermentation of glucose and proteins performed by the tumor cells seems to be associated with TKTL1 and pAkt overexpression. Therefore the aim of the present study was to investigate the expression of TKTL1 and pAkt in human specimens of endometrial cancer as compared to benign endometrium. Additionally, expression of the glucose transporter GLUT1 was also investigated as aerobic glycolysis is associated with an increased need for glucose. MATERIALS AND METHODS: Levels of TKTL1, pAkt, and GLUT1 expression were immunhistochemically evaluated on paraffin embedded biopsy material from 10 benign and 41 malignant endometrial tissue samples. TKTL1 mRNA levels in the endometrial cancer cell lines Ishikawa and HEC-1A were evaluated by RT-PCR. RESULTS: Expression of TKTL1, GLUT1 and pAKT was significantly increased in endometrial carcinomas as compared to benign endometrial tissue. There was a significantly weaker TKTL1 expression in highly differentiated G1 tumors. In the human endometrial cancer cell lines Ishikawa and HEC-1A, TKTL1 mRNA was clearly detectable. CONCLUSION: The levels of TKTL1, GLUT1 and pAKT expression point to the glycolytic phenotype of malignant endometrial tissue. Given the pronounced TKTL1 expression across all different subtypes of endometrial cancer, this protein could serve as a target for future cancer treatments.

Gender and the environment: recent initiatives to improve sustainable development policy, planning and practice.

PIP: This article describes the conceptual transition between a women, environment, and development (WED) approach to planning and policy development and a gender, environment, and sustainable development (GED) approach. The article explains different initiatives to include gender within environment-related development policies and programs and new participatory approaches to natural resource management. Most development aid is allocated for large-scale infrastructure development programs, which pay little attention to gender or environmental issues. Moser (1993) argues that the existing planning methodology needs to be revised in order to change power relations between men and women through gender development planning. Levy (1992) points out that when gender and environment are "tacked on" to other tasks of foreign aid bureaucracies, the result is understaffed, underfunded, and marginal units. Levy proposes that the alternative is to begin with a working definition of sustainable development and implementation at the local level. Programs would secure nondegradation of the environment, support of local livelihoods, and nonexploitative use of natural resources by institutions and organizations at all levels. People must appreciate that gender and environment are socially constructed notions. Gender and environment are context-specific; they change over time and are dynamic processes; and their relations represent a particular set of power relations that are reflected in institutional settings. Sectoral changes in traditional gender and environment planning requires action in the political, technical, organizational, and research spheres. There is a need for complementary actions and holistic analysis at all levels, within scientific procedures, between governments, within civil society, and within historical, economic, political, legal, and social dimensions.^ieng