T. Hawighorst

CD36-mediated activation of endothelial cell apoptosis by an N-terminal recombinant fragment of thrombospondin-2 inhibits breast cancer growth and metastasis in vivo

Thus far the clinical benefits seen in breast cancer patients treated with drugs targeting the vascular endothelial growth factor (VEGF) pathway are only modest. Consequently, additional antiangiogenic approaches for treatment of breast cancer need to be investigated. Thrombospondin-2 (TSP-2) has been shown to inhibit tumor growth and angiogenesis with a greater potency than the related molecule TSP-1. The systemic effects of TSP-2 on tumor metastasis and the underlying molecular mechanisms of the antiangiogenic activity of TSP-2 have remained poorly understood. We generated a recombinant fusion protein consisting of the N-terminal region of TSP-2 and the IgG-Fc1 fragment (N-TSP2-Fc) and could demonstrate that the antiangiogenic activity of N-TSP2-Fc is dependent on the CD36 receptor. We found that N-TSP2-Fc inhibited VEGF-induced tube formation of human dermal microvascular endothelial cells (HDMEC) on matrigel in vitro and that concurrent incubation of anti-CD36 antibody with N-TSP2-Fc resulted in tube formation that was comparable to untreated control. N-TSP2-Fc potently induced apoptosis of HDMEC in vitro in a CD36-dependent manner. Moreover, we could demonstrate a CD36 receptor-mediated loss of mitochondrial membrane potential and activation of caspase-3 in HDMEC in vitro. Daily intraperitoneal injections of N-TSP2-Fc resulted in a significant inhibition of the growth of human MDA-MB-435 and MDA-MB-231 tumor cells grown in the mammary gland of immunodeficient nude mice and in reduced tumor vascularization. Finally, increased serum concentrations of N-TSP2-Fc significantly inhibited regional metastasis to lymph nodes and distant metastasis to lung as shown by quantitative real-time alu PCR. These results identify N-TSP2-Fc as a potent systemic inhibitor of tumor metastasis and provide strong evidence for an important role of the CD36 receptor in mediating the antiangiogenic activity of TSP-2.

Agonists and antagonists of GnRH-I and -II reduce metastasis formation by triple-negative human breast cancer cells in vivo

Metastasis to bone is a frequent problem of advanced breast cancer. Particularly breast cancers, which do not express estrogen and progesterone receptors and which have no overexpression/amplification of the HER2-neu gene, so called triple-negative breast cancers, are considered as very aggressive and possess a bad prognosis. About 60% of all human breast cancers and about 74% of triple-negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a therapeutic target. Recently, we could show that bone-directed invasion of human breast cancer cells in vitro is time- and dose-dependently reduced by GnRH analogs. In the present study, we have analyzed whether GnRH analogs are able to reduce metastases of triple-negative breast cancers in vivo. In addition, we have evaluated the effects of GnRH analogs on tumor growth. To quantify formation of metastasis by triple-negative MDA-MB-435 and MDA-MB-231 human breast cancers, we used a real-time PCR method based on detection of human-specific alu sequences measuring accurately the amount of human tumor DNA in athymic mouse organs. To analyze tumor growth, the volumes of breast cancer xenotransplants into nude mice were measured. We could demonstrate that GnRH analogs significantly reduced metastasis formation by triple-negative breast cancer in vivo. In addition, we could show that GnRH analogs significantly inhibited the growth of breast cancer into nude mice. Side effects were not detectable. In conclusion, GnRH analogs seem to be suitable drugs for an efficacious therapy for triple-negative, GnRH receptor-positive human breast cancers to prevent metastasis formation.

Modern therapy concepts for endometrial cancer

Most cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.ZusammenfassungDas Endometriumkarzinom wird meist im frühen Stadium symptomatisch und hat eine günstige Prognose. Die traditionelle Therapie bestand in der abdominalen Hysterektomie mit beidseitiger Adnexexstirpation. Hiermit werden die frühen, gut differenzierten Stadien (endometrioid, pT1a, pT1b; G1, G2) wahrscheinlich gut therapiert. Bei höheren Stadien, höherem Grading und vor allem bei den Typ-II-Karzinomen (serös, klarzellig) ist diese Therapie inadäquat. Der Nutzen einer systematischen pelvinen und paraaortalen Lymphonodektomie in dieser Situation muss jedoch prospektiv evaluiert werden. Eine perkutane Strahlentherapie des Beckens verbessert im Stadium I und II zwar die lokale Kontrolle, hat aber keinen positiven Effekt auf das Überleben. Eine vergleichbare Verbesserung der lokalen Kontrolle wird, bei erheblich weniger Nebenwirkungen, auch durch eine Brachytherapie der Scheide erreicht. Eine adjuvante Chemotherapie ist beim Endometriumkarzinom wahrscheinlich wirksam. Der Einsatz einer alleinigen adjuvanten Chemotherapie oder die Kombination mit Brachy- und/oder Teletherapie muss prospektiv evaluiert werden.AbstractMost cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.

Moderne Konzepte in der Behandlung des Endometriumkarzinoms

Most cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.ZusammenfassungDas Endometriumkarzinom wird meist im frühen Stadium symptomatisch und hat eine günstige Prognose. Die traditionelle Therapie bestand in der abdominalen Hysterektomie mit beidseitiger Adnexexstirpation. Hiermit werden die frühen, gut differenzierten Stadien (endometrioid, pT1a, pT1b; G1, G2) wahrscheinlich gut therapiert. Bei höheren Stadien, höherem Grading und vor allem bei den Typ-II-Karzinomen (serös, klarzellig) ist diese Therapie inadäquat. Der Nutzen einer systematischen pelvinen und paraaortalen Lymphonodektomie in dieser Situation muss jedoch prospektiv evaluiert werden. Eine perkutane Strahlentherapie des Beckens verbessert im Stadium I und II zwar die lokale Kontrolle, hat aber keinen positiven Effekt auf das Überleben. Eine vergleichbare Verbesserung der lokalen Kontrolle wird, bei erheblich weniger Nebenwirkungen, auch durch eine Brachytherapie der Scheide erreicht. Eine adjuvante Chemotherapie ist beim Endometriumkarzinom wahrscheinlich wirksam. Der Einsatz einer alleinigen adjuvanten Chemotherapie oder die Kombination mit Brachy- und/oder Teletherapie muss prospektiv evaluiert werden.AbstractMost cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.

The impact of the time interval between two successive deliveries in an obstetric unit in terms of the mode of each delivery and the rate of perinatal mortality

Abstract Objective: To analyze the relationship of the time interval between two deliveries, done by one obstetric team, on the delivery mode of the subsequent birth; to define the length of this interval; and to evaluate this time interval as a risk factor for increased perinatal mortality in a population-based cohort. Methods: All singleton deliveries at ≥24 weeks’ gestation in Lower Saxony, Germany, between 2001 and 2005 (a total of 317,663 deliveries including 402 cases of perinatal mortality) were analyzed. The mode of the previous and the subsequent delivery, the time interval between the two deliveries, the time of birth, the hospital volume, and the existence of an affiliated neonatal ward were investigated. Results: When the first vaginal delivery was <45 min, there was a reduced probability that the subsequent birth would be a cesarean section. In case of a previous cesarean section, the cesarean rate of the following birth was influenced up to 165 min. In a multivariate analysis, vaginal deliveries following an earlier vaginal birth and occurring within <45 min were associated with increased perinatal mortality. Repeated cesarean sections within <165 min were associated with increased perinatal mortality when occurring at night or on weekends. Conclusion: A short time interval between two deliveries in an obstetric unit constitutes an independent risk factor for perinatal mortality.

Endokrine Therapie des Endometriumkarzinoms und seiner Prkanzerosen

ZusammenfassungDie Therapie der einfachen Endometriumhyperplasie ohne Atypien ist nach Ausschluss eines Östrogen produzierenden Tumors in der Regel konservativ durch Beseitigung der endokrinen Ursache oder symptomatisch durch adäquate Gestagengabe möglich. Auch bei der komplexen Hyperplasie ohne Atypien ist—insbesondere bei bestehendem Kinderwunsch—eine konservative Therapie möglich. Beim Vorliegen von Atypien ist die sicherste Therapie die Hysterektomie. Bei bestehendem Kinderwunsch kann bei hoher Compliance der Patientin und der Gewährleistung engmaschiger histologischer Kontrollen eine konservative Therapie erwogen werden, bis der Kinderwunsch erfüllt ist. Bei frühesten Stadien und hochdifferenzierten invasiven Karzinomen sind bei Kinderwunsch erfolgreich konservative Therapien durchgeführt worden, allerdings wurden auch onkologisch ungünstige Verläufe beschrieben. Der Nutzen einer adjuvanten endokrinen Therapie ist bis heute nicht belegt. Bei Rezidiven, die nicht mehr operativ oder strahlentherapeutisch beherrschbar sind, und bei metastasierten Fällen sollte bei gut differenzierten und Rezeptor-positiven Tumoren zunächst eine endokrine Therapie versucht werden, sofern keine akut lebensbedrohlichen Tumormanifestationen vorliegen. In den anderen Fällen oder beim Versagen einer endokrinen Therapie kommt eine Chemotherapie zum Einsatz, deren Effektivität jedoch bei meist hoher Toxizität begrenzt ist. Patientinnen mit disseminierten Endometriumkarzinomen sollten möglichst in Studien behandelt werden, um eine Verbesserung der unbefriedigenden Situation zu erreichen.AbstractWhen endometrial hyperplasia is found, generally an estrogen producing tumor should be ruled out. Simple endometrial hyperplasia without atypia can be safely treated conservatively by therapy of the underlying endocrine disorder or symptomatically by the application of adequate doses of progestins. Also in the case of complex hyperplasia without atypia, conservative treatment is possible, particularly if conservation of fertility is desired. The safest treatment for endometrial hyperplasia with atypia is hysterectomy. When further childbearing is desired, conservative treatment of atypical endometrial hyperplasia may be considered, if the patient is sufficiently compliant to accept the potential risks and repeated histological controls. When preservation of fertility is no longer an issue, hysterectomy should be performed in these cases.In early stages (Figo Ia) of highly differentiated invasive endometrial cancers a number of women wishing pregnancies have been successfully treated conservatively. In some cases, however, conservative treatment led to tumor progression.Available evidence does not support the concept of adjuvant endocrine treatment of endometrial cancer. Relapsed endometrial cancer which cannot be controlled by surgery or radiotherapy and metastatic disease should be initially treated by endocrine measures, provided the tumors are well differentiated, express progesterone receptors and are not acutely life-threatening. In all other cases or when endocrine therapy fails, chemotherapy is to be applied. Its efficacy, however, is limited due to high toxicity and short duration of response. Patients with disseminated endometrial cancer should be treated in the context of clinical trials to improve the unsatisfactory therapeutical options.

Kardiologische Erkrankungen in der Schwangerschaft

ZusammenfassungKardiologische Erkrankungen in der Schwangerschaft haben großen Einfluss auf die maternale und perinatale Morbidität und Mortalität. Sie führen in westlichen Industrieländern bei 0,2–4% aller Schwangerschaften zu Komplikationen. Die meisten Herzerkrankungen sind kongenitalen Ursprungs, etwa ein Viertel ist erworben. Die Anzahl der Patientinnen mit kardiovaskulären Problemen in der Schwangerschaft nimmt zu. Gründe sind einerseits die verbesserten Behandlungsoptionen bei angeborener Herzerkrankung, wodurch mehr Erkrankte ein reproduktives Alter erreichen, andererseits die steigende Prävalenz an kardiovaskulären Risikofaktoren, wie Diabetes, Übergewicht und Bluthochdruck. Aufgrund der kardiovaskulären Adaptation in der Schwangerschaft entsteht eine zusätzliche kardiale Belastung. Durch eine adäquate interdisziplinäre Betreuung von Risikopatientinnen in einem entsprechenden Zentrum kann die Morbidität und Mortalität, die mit kardiovaskulären Erkrankungen während der Schwangerschaft assoziiert ist, deutlich gesenkt werden.AbstractCardiovascular disease has a significant impact on maternal and fetal morbidity and mortality. At present 0.2–4% of all pregnancies in western industrialized countries are complicated by cardiovascular diseases. Most are congenital heart diseases and approximately 25% are acquired. The number of patients who develop cardiac problems during pregnancy is increasing. Reasons are the improved treatment of congenital heart disease resulting in a growing number of women reaching childbearing age as well as the increasing prevalence of cardiovascular risk factors such as obesity, diabetes or hypertension. In a setting of interdisciplinary management of risk patients in specialized centers morbidity and mortality associated with problems of the cardiovascular system during pregnancy can be significantly reduced.

Adipositas – Risikofaktor für onkologische Erkrankungen

ZusammenfassungDie Prävalenz der Adipositas nimmt weltweit rapide zu. Die gesundheitlichen und ökonomischen Konsequenzen dieser Entwicklung sind bedeutsam, da Adipositas mit zahlreichen Erkrankungen assoziiert ist. Neben einer Erhöhung des Risikos für Typ-II-Diabetes und kardiovaskuläre Erkrankungen bestätigen große prospektive Studien, dass Übergewicht die Inzidenz und Mortalität einer Reihe von bösartigen Tumoren erhöht. Zu diesen zählen die Karzinome des Kolons, der Mamma (postmenopausal) und des Endometriums sowie das Nierenzellkarzinom und Adenokarzinome des Ösophagus. Die gesteigerte Insulinresistenz und die daraus resultierende chronische Hyperinsulinämie, die höhere Bioverfügbarkeit von Steroidhormonen und lokale Entzündungsprozesse werden als potenzielle Mechanismen für die adipositasassoziierte Entstehung und Progression von Tumoren angeführt. Auch einige aus dem Fettgewebe stammende Hormone, Adipozytokine, scheinen die Karzinogenese zu beeinflussen. Vieles deutet darauf hin, dass diätetische Interventionsstrategien das Risiko für Krebserkrankungen vermindern und die Prognose verbessern. AbstractThe prevalence of obesity is rapidly increasing worldwide. The consequences of this development for health and economy are important, since obesity is associated with many diseases. In addition to an increase in the risk of type II diabetes and cardiovascular disease, large prospective studies confirm that excess body weight also increases the incidence and mortality of a number of malignancies including cancers of the colon, female breast (postmenopausal), endometrium, kidney (renal cell), and esophagus (adenocarcinoma). The potential mechanisms by which obesity induces or promotes tumorigenesis include insulin resistance and resultant chronic hyperinsulinaemia, as well as increased bioavailability of steroid hormones and localized inflammation. Moreover, some of the adipose tissue-derived hormones have been proposed to influence carcinogenesis. There is growing evidence that dietary intervention strategies may reduce risk and improve prognosis of cancer diseases.

Tumorstammzellen in Mamma- und weiblichen Genitalkarzinomen

ZusammenfassungIn den letzten Jahren wurden zahlreiche Hinweise für die Existenz von Stammzellen in Tumoren gefunden. Die Tumorstammzelltheorie besagt, dass Tumoren sich aus einer Subpopulation maligner Zellen entwickeln, die Stammzellcharakteristika aufweisen. Diese Zellen zeigen sowohl Züge von Stammzellen als auch von Tumorzellen. So besitzen sie die Fähigkeit zu Selbsterneuerung, asymmetrischer Zellteilung und unabhängigem Wachstum, zeigen Resistenz gegenüber Apoptoseinduktion, sind tumorigen und haben metastatisches Potenzial. Die Entwicklung aus Tumorstammzellen könnte die Heterogenität von Tumoren eines Gewebes sowie Rezidive nach Therapie erklären. In diesem kurzen Überblicksbeitrag berichten wir über den Fortschritt in der Erforschung von Tumorstammzellen, dabei liegt der Schwerpunkt auf gynäkologische Tumoren einschließlich des Mammakarzinoms.AbstractIn recent years numerous indications for the existence of stem cells in tumors have been found. The cancer stem cell theory means that cancers develop from a subset of malignant cells which exhibit characteristics of both stem cells and cancer cells. They possess the ability of self-renewal, asymmetric cell division and independent growth, show resistance to induction of apoptosis, tumorigenicity and metastatic potential. The development from cancer stem cells could explain both the heterogeneity of cancers of a tissue and the relapse of tumors after therapy. In this short review we report the progress in the research on cancer stem cells with an emphasis on gynecological tumors and breast cancer.

Moderne Konzepte in der Behandlung des Endometriumkarzinoms@@@Modern therapy concepts for endometrial cancer

Most cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.ZusammenfassungDas Endometriumkarzinom wird meist im frühen Stadium symptomatisch und hat eine günstige Prognose. Die traditionelle Therapie bestand in der abdominalen Hysterektomie mit beidseitiger Adnexexstirpation. Hiermit werden die frühen, gut differenzierten Stadien (endometrioid, pT1a, pT1b; G1, G2) wahrscheinlich gut therapiert. Bei höheren Stadien, höherem Grading und vor allem bei den Typ-II-Karzinomen (serös, klarzellig) ist diese Therapie inadäquat. Der Nutzen einer systematischen pelvinen und paraaortalen Lymphonodektomie in dieser Situation muss jedoch prospektiv evaluiert werden. Eine perkutane Strahlentherapie des Beckens verbessert im Stadium I und II zwar die lokale Kontrolle, hat aber keinen positiven Effekt auf das Überleben. Eine vergleichbare Verbesserung der lokalen Kontrolle wird, bei erheblich weniger Nebenwirkungen, auch durch eine Brachytherapie der Scheide erreicht. Eine adjuvante Chemotherapie ist beim Endometriumkarzinom wahrscheinlich wirksam. Der Einsatz einer alleinigen adjuvanten Chemotherapie oder die Kombination mit Brachy- und/oder Teletherapie muss prospektiv evaluiert werden.AbstractMost cases of endometrial cancer (EC) become symptomatic at an early stage and have a good prognosis. EC has been traditionally treated with total abdominal hysterectomy plus bilateral salpingo-oophorectomy. For early stage, low grade cases (endometrioid, pT1a, pT1b; G1, G2) this is adequate therapy. For higher stages and grades, especially for type II EC (serous, clear cell) this therapy is insufficient. The efficacy of systematic pelvic and paraaortic lymphadenectomy for high risk EC, however, remains to be evaluated. External pelvic radiotherapy has been shown to improve local control in stage I and II EC, but has no positive effect on survival. A comparable improvement of local control can be achieved by vaginal brachytherapy with significantly less toxicity. Adjuvant chemotherapy is probably efficacious in EC. Its usefulness as exclusive adjuvant therapy or in combination with brachytherapy and/or external beam therapy remains to be evaluated by prospective trials.