Venöse Thrombosen bei Patientinnen mit gynäkologischen Malignomen

Malignancy has long been described as a risk factor for venous thrombembolism (VTE) with its associated complications such as pulmonary embolism. Several reports have described possible associations and explanations at a molecular level to this thrombophilic phenomenon. In addition, therapy for a malignancy may also pose an additional risk factor for VTE. In this report, we review the pathophysiology and clinical relevance of gynecological malignancies, their multimodal treatment, and VTE. A critical discussion of current national and international guidelines to prophylaxis and treatment is presented.     

孤儿受体-雌激素受体相关受体(ERRs)在雌激素信号途径中的研究进展

雌激素是一种促进细胞有丝分裂的甾体激素，是女性生殖系统发育和功能维持的重要因素，此外在机体多种生理过程中均有重要作用。雌激素功能失常能够引发乳腺、子宫、心脏等多种疾病，特别是与内分泌相关的癌症。雌激素的多种生理效应通过的两种经典雌激素受体α和β传导（estrogen receptor α and β），核受体命名委员会（nuclear receptors nomenclature committee，NRNC）1999年命名为NR3A1和NR3A2，这两种受体均是核受体超家族（nuclear moeptor superfamily，NRs）的成员。     

The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients

Aim

Despite promising preclinical findings regarding clinical utility of farnesyltransferase inhibitors (FTI), such as lonafarnib, success of clinical trials is limited. A multicentre AGO-OVAR-15 phase II trial reported an unfavourable effect of lonafarnib on the outcome of patients with advanced ovarian cancer. This study was performed as a genetic subgroup analysis of the AGO-OVAR-15 trial, and investigated the utility of the promoter polymorphism rs11623866 of the farnesyltransferase ß-subunit gene (FNTB) in predicting the clinical effectiveness of lonafarnib.

Methods

The influence of rs11623866 (c.-609G > C) on FNTB promoter activity was investigated by electrophoretic-mobility-shift assay, luciferase-reporter assay and RT-qPCR. A total of 57 out of 105 patients from the AGO-OVAR-15 trial, treated with carboplatin and paclitaxel ± lonafarnib, was genotyped for rs11623866 by restriction fragment length polymorphism analysis. Genotype-dependent survival analysis was performed by Kaplan–Meier analysis.

Results

The presence of the G allele was associated with increased FNTB promoter activity compared with the C allele. An unfavourable effect of lonafarnib was limited to patients carrying a GG genotype (HR_PFS 6.2, 95%CI = 2.01, 19.41, P = 0.002; HR_OS 9.6, 95%CI = 1.89, 48.54, P = 0.006). Median progression free survival (PFS) for patients with the GG genotype in the lonafarnib treated arm was 10 months, whereas median PFS without FTI-treatment was 40 months. Median overall survival (OS) in the lonafarnib-treated group was 19 months, whereas median OS was not reached in the untreated group.

Conclusions

Discrepancies between preclinical success and clinical failure may be due to the patients'' genetic variability of FNTB. Therefore, our results may encourage retrospective evaluation of FNTB polymorphisms in previous FTI studies, especially those reporting positive FTI response.     

New aspects of adjuvant therapy in endometrial cancer: current standards and future directions

Endometrial cancer is one of the most common gynaecological cancers in western countries. Most women are diagnosed at an early stage of the disease and can be cured by surgery alone. In patients with poor prognostic factors or an advanced disease, the chance of progression-free survival and overall survival is greatly diminished. Adjuvant chemotherapy is effective for patients with advanced disease. The combination of doxorubicin and cisplatin achieves overall response rates ranging from 34 to 60%, and the addition of paclitaxel seems to improve the outcome of patients with advanced disease, but it induces a significantly higher toxicity. A Gynecologic Oncology Study Group phase-III study is currently exploring the triplet paclitaxel+doxorubicin+cisplatin plus G-CSF vs. the less toxic combination of paclitaxel+carboplatin. Ongoing and planned phase-III trials are evaluating newer combination chemotherapy regimens, a combination of irradiation and chemotherapy and the implementation of targeted therapies with the goal of improving the tumour control rate and quality of life.     

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.     

Zukunft der Gynäkoonkologie

The gynecologist as gynecologic oncologist: Comprehensive knowledge about oncologic diseases of the breast and the female genital tract is an essential part of the residency program in Obstetrics and Gynecology. Medical training includes prevention, diagnostics, surgical, medical as well as complementary therapy and follow-up of female cancer. The fellowship in Gynecologic Oncology aims to deepen these basic skills. Knowledge in diagnosis and indications, respectively, for medical and surgical oncologic treatment strategies is expanded. Surgical skills in oncologic procedures including breast and abdominal surgery are acquired. After finishing the fellowship, the gynecologic oncologist should be capable to indicate, plan and perform medical and surgical treatments in cancerous diseases of the breast and the female genital tract. Moreover, it is essential for gynecologic oncologists to understand and include multidisciplinary treatment strategies in cooperation with radiotherapists, general surgeons and medical oncologists to achieve optimal results for their cancer patients