Showing papers by "Sven Mahner published in 2017"

European Society of Gynaecological Oncology Guidelines for the Management of Patients With Vulvar Cancer

Abstract: Objective The aim of this study was to develop clinically relevant and evidence-based guidelines as part of European Society of Gynaecological Oncology's mission to improve the quality of care for women with gynecologic cancers across Europe. Methods The European Society of Gynaecological Oncology Council nominated an international development group made of practicing clinicians who provide care to patients with vulvar cancer and have demonstrated leadership and interest in the management of patients with vulvar cancer (18 experts across Europe). To ensure that the statements are evidence based, the current literature identified from a systematic search has been reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group (expert agreement). The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 181 international reviewers including patient representatives independent from the development group. Results The guidelines cover diagnosis and referral, preoperative investigations, surgical management (local treatment, groin treatment including sentinel lymph node procedure, reconstructive surgery), radiation therapy, chemoradiation, systemic treatment, treatment of recurrent disease (vulvar recurrence, groin recurrence, distant metastases), and follow-up.

Bevacizumab may differentially improve ovarian cancer outcome in patients with proliferative and mesenchymal molecular subtypes

Abstract: Purpose: Recent progress in understanding the molecular biology of epithelial ovarian cancer has not yet translated into individualized treatment for these women or improvements in their disease outcome. Gene expression has been utilized to identify distinct molecular subtypes, but there have been no reports investigating whether or not molecular subtyping is predictive of response to bevacizumab in ovarian cancer.Experimental Design: DASL gene expression arrays were performed on FFPE tissue from patients enrolled on the ICON7 trial. Patients were stratified into four TCGA molecular subtypes. Associations between molecular subtype and the efficacy of randomly assigned therapy with bevacizumab were assessed.Results: Molecular subtypes were assigned as follows: 122 immunoreactive (34%), 96 proliferative (27%), 73 differentiated (20%), and 68 mesenchymal (19%). In univariate analysis patients with tumors of proliferative subtype obtained the greatest benefit from bevacizumab with a median PFS improvement of 10.1 months [HR, 0.55 (95% CI, 0.34-0.90), P = 0.016]. For the mesenchymal subtype, bevacizumab conferred a nonsignificant improvement in PFS of 8.2 months [HR 0.78 (95% CI, 0.44-1.40), P = 0.41]. Bevacizumab conferred modest improvements in PFS for patients with immunoreactive subtype (3.8 months; P = 0.08) or differentiated subtype (3.7 months; P = 0.61). Multivariate analysis demonstrated significant PFS improvement in proliferative subtype patients only [HR, 0.45 (95% CI, 0.27-0.74), P = 0.0015].Conclusions: Ovarian carcinoma molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment that includes bevacizumab. Validation of our findings in an independent cohort could enable the use of bevacizumab for those patients most likely to benefit, thereby reducing side effects and healthcare cost. Clin Cancer Res; 23(14); 3794-801. ©2017 AACR.

LION: Lymphadenectomy in ovarian neoplasms—A prospective randomized AGO study group led gynecologic cancer intergroup trial.

Abstract: 5500Background: So far, there is no level-1 evidence regarding the role of systematic pelvic and para-aortic lymphadenectomy (LNE) in patients with advanced ovarian cancer (AOC) with macroscopic complete resection und clinically negative lymph nodes (LN). Therefore, surgical management regarding LNE worldwide is very heterogeneous. Methods: Prospective randomized trial including patients with newly diagnosed AOC FIGO IIB-IV with macroscopic complete resection and pre- and intra-operatively clinical negative LN were randomized intra-operatively to LNE versus no-LNE. All centers had to qualify regarding surgical skills before participation in this trial. The primary endpoint was overall survival. Results: 647 patients were randomized between 12/08 and 1/12 to LNE (n=323) or no-LNE (n=324). The median number of removed LN in patients randomized to LNE was 57 (pelvic 35 and para-aortic22). Post-op platinum-taxane based chemotherapy was applied in 85% of the patients in the no-LNE arm and 80% in the LNE arm. M...

Chemotherapy and Post-traumatic Stress in the Causation of Cognitive Dysfunction in Breast Cancer Patients.

Abstract: Background Cancer-related cognitive dysfunction has mostly been attributed to chemotherapy; this explanation, however, fails to account for cognitive dysfunction observed in chemotherapy-naive patients. In a controlled, longitudinal, multisite study, we tested the hypothesis that cognitive function in breast cancer patients is affected by cancer-related post-traumatic stress. Methods Newly diagnosed breast cancer patients and healthy control subjects, age 65 or younger, underwent three assessments within one year, including paper-and-pencil and computerized neuropsychological tests, clinical diagnostics of post-traumatic stress disorder (PTSD), and self-reported cognitive function. Analysis of variance was used to compare three groups of participants—patients who did or did not receive chemotherapy and healthy control subjects—on age- and education-corrected cognitive performance and cognitive change. Differences that were statistically significant after correction for false discovery rate were investigated with linear mixed-effects models and mediation models. All statistical tests were two-sided. Results Of 226 participants (166 patients and 60 control subjects), 206 completed all assessment sessions (attrition: 8.8%). Patients demonstrated overall cognitive decline (group*time effect on composite z-score: –0.13, P = .04) and scored consistently worse on Go/Nogo errors. The latter effect was mediated by PTSD symptoms (mediation effect: B = 0.15, 95% confidence interval = 0.02 to 0.38). Only chemotherapy patients showed declined reaction time on a computerized alertness test. Overall cognitive performance correlated with self-reported cognitive problems at one year (T = –0.11, P = .02). Conclusions Largely irrespective of chemotherapy, breast cancer patients may encounter very subtle cognitive dysfunction, part of which is mediated by cancer-related post-traumatic stress. Further factors other than treatment side effects remain to be investigated.

Chromosomal Instability in Cell-Free DNA as a Highly Specific Biomarker for Detection of Ovarian Cancer in Women with Adnexal Masses

Abstract: Purpose: Chromosomal instability is a hallmark of ovarian cancer. Here, we explore copy-number alteration (CNA) profiling in cell-free DNA as a potential biomarker to detect malignancy in patients presenting with an adnexal mass.Experimental Design: We prospectively enrolled 68 patients with an adnexal mass, of which 57 were diagnosed with invasive or borderline carcinoma and 11 with benign disease. Cell-free DNA was extracted from plasma and analyzed by low-coverage whole-genome sequencing.Results: Patterns of chromosomal instability were detectable in cell-free DNA using 44 healthy individuals as a reference. Profiles were representative of those observed in matching tumor tissue and contained CNAs enriched in two large datasets of high-grade serous ovarian cancer (HGSOC). Quantitative measures of chromosomal instability, referred to as genome-wide z-scores, were significantly higher in patients with ovarian carcinoma than in healthy individuals or patients with benign disease. Cell-free DNA testing improved malignancy detection (AUC 0.89) over serum CA-125 (AUC 0.78) or the risk of malignancy index (RMI, AUC 0.81). AUC values of cell-free DNA testing even further increased for HGSOC patients specifically (AUC 0.94). At a specificity of 99.6%, a theoretical threshold required for ovarian cancer screening, sensitivity of cell-free DNA testing was 2- to 5-fold higher compared with CA-125 and RMI testing.Conclusions: This is the first study evaluating the potential of cell-free DNA for the diagnosis of primary ovarian cancer using chromosomal instability as a read-out. We present a promising method to increase specificity of presurgical prediction of malignancy in patients with adnexal masses. Clin Cancer Res; 23(9); 2223-31. ©2016 AACR.

TRUST: Trial of radical upfront surgical therapy in advanced ovarian cancer (ENGOT ov33 / AGO‐OVAR OP7).

Abstract: TPS5602Background: Primary cytoreductive surgery (PDS) followed by chemotherapy has been considered as standard management for advanced ovarian cancer patients (pts) over decades. An alternative ap...

Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases

Abstract: Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM) degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL), preeclampsia, intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM) in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS). In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future.

Clinically assessed posttraumatic stress in patients with breast cancer during the first year after diagnosis in the prospective, longitudinal, controlled COGNICARES study.

Abstract: Objective There is ongoing debate whether cancer qualifies as traumatic stressor. We investigated prevalence and course of posttraumatic stress in patients with early breast cancer (BC) during their first year after diagnosis and determined effects of mastectomy and chemotherapy. Methods Patients with stage 0–III BC aged ≤65 years were evaluated with the Structured Clinical Interview for DSM-IV modules for acute and posttraumatic stress disorder (ASD and PTSD, respectively) before treatment, after chemotherapy, and 1 year after diagnosis. Matched controls were assessed at matched intervals. Effects of time, mastectomy, and chemotherapy on BC-related PTSD symptom severity were tested with linear mixed model analysis. Results Stress disorder (ASD or PTSD) related to BC was diagnosed in 6 (3.6%) of 166 patients before treatment and in 3 patients (2.0%) 1 year later. The rate of patients who experienced PTSD symptoms related to BC decreased from 82.5 to 57.3% (p < 0.001), and the mean of BC-related PTSD symptoms diminished from 3.1 to 1.7 (p < 0.001). Only university education significantly predicted the course of BC-related PTSD symptom severity (p = 0.009). In 60 controls, no diagnosis of stress disorder, a rate of 18% women experiencing PTSD symptoms, and a mean of 0.4 PTSD symptoms (p vs. patients <0.001) were found. Conclusions Most newly diagnosed patients with BC experience PTSD symptoms, whereas full diagnoses of DSM-IV stress disorder are rare. Symptoms diminish somewhat within 1 year furthered by university education but independently from mastectomy and chemotherapy. Throughout the year after diagnosis, having BC entails markedly increased PTSD symptom burden. Copyright © 2016 John Wiley & Sons, Ltd.

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer

Abstract: Tesaro; Amgen; Genentech; Roche; AstraZeneca; Myriad Genetics; Merck; Gradalis; Cerulean; Vermillion; ImmunoGen; Pfizer; Bayer; Nu-Cana BioMed; INSYS Therapeutics; GlaxoSmithKline; Verastem; Mateon Therapeutics; Pharmaceutical Product Development; Clovis Oncology; Janssen/Johnson Johnson; Eli Lilly; Merck Sharp Dohme

Vitamin D and VDR in Gynecological Cancers-A Systematic Review.

Abstract: In recent years, a vast amount of studies have centered on the role of vitamin D in the pathogenesis of certain types of cancers such as breast, colorectal and lung cancer. Increasing evidence suggests that vitamin D and its receptor play a crucial role in the development of gynecological cancers. In this review, we systematically analyzed the effect of vitamin D and the vitamin D receptor on endometrial, ovarian, cervical, vulvar and vaginal cancer. Our literature research shows that vitamin D levels and vitamin-D-related pathways affect the risk of gynecological cancers. Numerous ecological studies give evidence on the inverse relationship between UVB exposure and gynecological cancer risk. However, epidemiologic research is still inconclusive for endometrial and ovarian cancer and insufficient for rarer types of gynecological cancers. The vitamin D receptor (VDR) is upregulated in all gynecological cancers, indicating its influence on cancer etiology. The VDR polymorphism FokI (rs2228570) seems to increase the risk of ovarian cancer. Other nuclear receptors, such as the RXR, also influence gynecological cancers. Although there is limited knowledge on the role of the VDR/RXR on the survival of endometrial, cervical, vulvar or vaginal cancer patients, some studies showed that both receptors influence survival. Therefore, we suggest that further studies should focus on the vitamin D- and its hetero dimer receptor RXR in gynecological cancers.

Role of Placental VDR Expression and Function in Common Late Pregnancy Disorders.

Abstract: Vitamin D, besides its classical role in bone metabolism, plays a distinct role in multiple pathways of the feto-maternal unit. Calcitriol is the major active ligand of the nuclear vitamin D receptor (VDR). The vitamin D receptor (VDR) is expressed in different uteroplacental parts and exerts a variety of functions in physiologic pregnancy. It regulates decidualisation and implantation, influences hormone secretion and placental immune modulations. This review highlights the role of the vitamin D receptor in physiologic and disturbed pregnancy, as preeclampsia, fetal growth restriction, gestational diabetes and preterm birth. We discuss the existing literature regarding common VDR polymorphisms in these pregnancy disorders.

Circulating tumor cells: potential markers of minimal residual disease in ovarian cancer? a study of the OVCAD consortium.

Abstract: // Eva Obermayr 1 , Natalia Bednarz-Knoll 2 , Beatrice Orsetti 3, 4 , Heinz-Ulrich Weier 5 , Sandrina Lambrechts 6 , Dan Cacsire Castillo-Tong 1 , Alexander Reinthaller 1 , Elena Ioana Braicu 7 , Sven Mahner 8, 10 , Jalid Sehouli 7 , Ignace Vergote 6 , Charles Theillet 3, 4 , Robert Zeillinger 1, * and Burkhard Brandt 9, * 1 Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria 2 Institute of Tumor Biology, University Medical Center Eppendorf, Hamburg, Germany 3 INSERM U1194, IRCM, Universite de Montpellier, Montpellier, France 4 Institut du Cancer de Montpellier, Montpellier, France 5 Department of Cancer and DNA Damage Responses, Life Sciences Division, University of California, Lawrence Berkeley National Laboratory, Berkeley, CA, USA 6 Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium 7 Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charite - Universitatsmedizin Berlin, Berlin, Germany 8 Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 9 Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany 10 Department of Gynecology and Obstetrics, University of Munich, Munich, Germany * These authors contributed equally to this work Correspondence to: Burkhard Brandt, email: burkhard.brandt@uksh.de Keywords: circulating tumour cells; minimal residual disease; ovarian cancer; multi-marker analysis; FISH on CTCs Received: November 01, 2016 Accepted: October 11, 2017 Published: November 16, 2017 ABSTRACT Purpose: In 75% of ovarian cancer patients the tumor mass is completely eradicated by established surgical and cytotoxic treatment; however, the majority of the tumors recur within 24 months. Here we investigated the role of circulating tumor cells (CTCs) indicating occult tumor load, which remains inaccessible by established diagnostics. Experimental design: Blood was taken at diagnosis (baseline samples, n = 102) and six months after completion of adjuvant first-line chemotherapy (follow-up samples; n = 78). CTCs were enriched by density gradient centrifugation. A multi-marker immunostaining was established and further complemented by FISH on CTCs and tumor/metastasis tissues using probes for stem-cell like fusion genes MECOM and HHLA1. Results: CTCs were observed in 26.5% baseline and 7.7% follow-up blood samples at a mean number of 12.4 and 2.8 CTCs per ml blood, respectively. Baseline CTCs indicated a higher risk of death in R0 patients with complete gross resection (univariate: HR 2.158, 95% CI 1.111–4.191, p = 0.023; multivariate: HR 2.720, 95% CI 1.340–5.522, p = 0.006). At follow-up, the presence of CTCs was associated with response to primary treatment as assessed using RECIST criteria. Chromosomal gains at MECOM and HHLA1 loci suggest that the observed cells were cancer cells and reflect pathophysiological decisive chromosomal aberrations of the primary and metastatic tumors. Conclusions: Our data suggest that CTCs detected by the multi-marker protein panel and/or MECOM/HHLA1 FISH represent minimal residual disease in optimally debulked ovarian cancer patients. The role of CTCs cells especially for clinical therapy stratification of the patients has to be validated in consecutive larger studies applying standardized treatment schemes.

Galectins-1, -3, and -7 Are Prognostic Markers for Survival of Ovarian Cancer Patients

Abstract: There is a tremendous need for developing new useful prognostic factors in ovarian cancer. Galectins are a family of carbohydrate binding proteins which have been suggested to serve as prognostic factors for various cancer types. In this study, the presence of Galectin-1, -3, and -7 was investigated in 156 ovarian cancer specimens by immunochemical staining. Staining was evaluated in the cytoplasm and nucleus of cancer cells as well as the peritumoral stroma using a semi quantitative score (Remmele (IR) score). Patients' overall survival was compared between different groups of Galectin expression. Galectin (Gal)-1 and -3 staining was observed in the peritumoral stroma as well as the nucleus and cytoplasm of tumor cells, while Gal-7 was only present in the cytoplasm of tumor cells. Patients with Gal-1 expression in the cytoplasm or high Gal-1 expression in the peritumoral stroma showed reduced overall survival. Nuclear Gal-3 staining correlated with a better outcome. We observed a significantly reduced overall survival for cases with high Gal-7 expression and a better survival for Gal-7 negative cases, when compared to cases with low expression of Gal-7. We were able to show that both tumor and stroma staining of Gal-1 could serve as negative prognostic factors for ovarian cancer. We were able to confirm cytoplasmic Gal-7 as a negative prognostic factor. Gal-3 staining in the nucleus could be a new positive prognosticator for ovarian cancer.

Value of Neoadjuvant Chemotherapy for Newly Diagnosed Advanced Ovarian Cancer: A European Perspective

Abstract: Christina Fotopoulou, Imperial College London, London, United Kingdom Jalid Sehouli, Charité Medical University of Berlin, Berlin, Germany Giovanni Aletti, European Institute of Oncology, Milan, Italy Philipp Harter, Kliniken Essen Mitte, Essen, Germany Sven Mahner, Ludwig-Maximilians-University, Munich, Germany Denis Querleu, Institut Bergonié, Bordeaux, France Luis Chiva, Clı́nica Universidad de Navarra, Navarra, Spain Hani Gabra, Imperial College London, London, United Kingdom Nicoletta Colombo, European Institute of Oncology, Milan, Italy Andreas du Bois, Kliniken Essen Mitte, Essen, Germany

Improved systemic treatment for early breast cancer improves cure rates, modifies metastatic pattern and shortens post-metastatic survival: 35-year results from the Munich Cancer Registry

Abstract: Systemic therapies (ATHs) in early breast cancer have improved the survival of breast cancer (BC) patients in recent decades. The magnitude of the changes in overall, metastasis-free (MFS) and post-metastatic (PMS) survival and in the metastasis (MET) pattern will be described. We analysed 60,227 patients with a diagnosis of T-N-M0 BC between 1978 and 2013 and 11,983 patients with metastases (MET) in the Munich Cancer Registry. Patients will be divided into four time periods to identify relationships between BC and METs. Survival was estimated using Kaplan–Meier curves, and Cox proportional hazards models were used to explore the impact of the BC subtype and MET status on survival with the time periods as surrogate markers for ATH evolution. During the observation period, 5-year relative survival has improved from 80.3 to 93.6% with an adjusted hazard ratio of 0.54 (P < 0.0001). Successful implementation of ATH has changed the MET pattern. The percentage of liver and CNS METs has more than doubled, the rate of lung METs remains stable, and the rate of bone METs has been reduced by approximately 50%. MFS has been prolonged with a hazard ratio 0.75 (P < 0.0001), but PMS has declined (hazard ratio 1.36; P < 0.0001); however, effects of adjuvant and palliative treatments cannot be separated. These results do not contradict improvements in advanced BC and do not suggest alterations of MET tumour biology by ATH. Over the past three decades, ATHs have dramatically improved patient survival after BC diagnosis—most likely, by eradicating prevalent micro-METs; as a result, the MET pattern has changed. Eradicating only a portion of the first METs results in delaying the onset of subsequent MET, which leads to an apparently paradoxical effect: an extension of the MET-free interval and a reduction in PMS.

Outcome After Sentinel Lymph Node Dissection in Vulvar Cancer: A Subgroup Analysis of the AGO-CaRE-1 Study

Abstract: Purpose Analyzing the large patient cohort of the multicenter AGO-CaRE-1 study, we compared isolated sentinel lymph node dissection (SLND) with radical lymph node dissection (LND) of the groin in relation to recurrence rates and survival.

Increased trace amine-associated receptor 1 (TAAR1) expression is associated with a positive survival rate in patients with breast cancer

Abstract: A correlation between breast cancer and thyroid disorders has been described in previous studies. Degraded thyroid hormones are referred to as trace amines. These endogenous amines have the ability to bind to the G-protein-coupled receptor TAAR1 (trace amine-associated receptor) and thereby activate it. TAAR1 is able to modulate the serotonergic and dopaminergic system in the brain and has so far been studied in the neurological field. The following study represents the first investigation of the regulation of TAAR1 in primary breast cancer (no metastases, M0). Immunohistochemical analyses were carried out to detect TAAR1 expression in formalin fixed paraffin embedded breast cancer samples. Survival times of primary breast cancer patients (M0) with and without TAAR1 expression in their tumours were compared by Kaplan–Meier curves, and correlations between ordinal variables were determined with Spearman’s rank correlation coefficient. The investigation showed a correlation between TAAR1 expression and tumour differentiation grade. A well differentiated tumour grade (G1) was associated with higher TAAR1 expression and HER2 and HER4 positivity predicted higher TAAR1 expression. A TAAR1 overexpression (IRS ≥ 6) was associated with significantly longer overall survival (OS) (p = 0.02) than that of reduced TAAR1 expression (IRS < 6) during a maximum follow-up of 14 years, demonstrating that TAAR1 has a favourable effect on OS of early breast cancer patients. We conclude that TAAR1 seems to be an independent predictor for breast cancer survival. Modulation of TAAR1 may represent a novel targeting strategy for breast cancer prevention and therapy.

Survival of de novo stage IV breast cancer patients over three decades

Abstract: De novo stage IV breast cancer patients (BCIV) depict a clinical picture not influenced by adjuvant therapy. Therefore, the time-dependent impact of changes in diagnostics and treatments on progression and survival can best be evaluated in this subgroup. BCIV patients from 1978 to 2013 registered in the Munich Cancer Registry were divided into four periods, and the trends were analysed. Survival was estimated by Kaplan–Meier methods, and prognostic factors were fitted with Cox proportional hazard models. Between 1978 and 2013, 88,759 patients were diagnosed with 92,807 cases of invasive and non-invasive BC. Of these patients, 4756 patients had distant metastases (MET) at diagnosis. The 5-year survival rate improved from 17.4 to 24.7%, while the pattern of metastases did not change. Improved staging diagnostics, a screening programme and primary systemic therapy changed the composition of prognostic strata. Patients with a similar composition as the 1978–1987 cohort exhibited a median survival difference of 13 months; however, neither univariate nor multivariate analysis showed a survival effect for the four periods as a surrogate indicator for changing treatments. HER2+ patients have with 27.6 months a slightly longer survival than all other BCIV patients. Survival of de novo BCIV has only modestly improved since the late 1970s, partially masked by changing distributions of prognostic factors due to changes in diagnostics.

Cancer of the ovary, fallopian tube, and peritoneum: a population-based comparison of the prognostic factors and outcomes.

Abstract: The objective was to compare the prognostic factors and outcomes among primary ovarian cancer (OC), fallopian tube cancer (FC), and peritoneal cancer (PC) patients in a population-based setting. We analysed 5399 OC, 327 FC, and 416 PC patients diagnosed between 1998 and 2014 in the catchment area of the Munich Cancer Registry (meanwhile 4.8 million inhabitants). Tumour site differences were examined by comparing prognostic factors, treatments, the time to progression, and survival. The effect of the tumour site was additionally analysed by a Cox regression model. The median age at diagnosis, histology, and FIGO stage significantly differed among the tumour sites (p < 0.001); PC patients were older, more often diagnosed with a serous subtype, and in FIGO stage III or IV. The time to progression and survival significantly differed among the tumour sites. When stratified by FIGO stage, the differences in time to progression disappeared, and the differences in survival considerably weakened. The differences in the multivariate survival analysis showed an almost identical outcome in PC patients (HR 1.07 [0.91–1.25]) and an improved survival of FC patients (HR 0.63 [0.49–0.81]) compared to that of OC patients. The comparison of OC, FC, and PC patients in this large-scale population-based study showed differences in the prognostic factors. These differences primarily account for the inferior outcome of PC patients, and for the improved survival of FC compared to OC patients.

MR pelvimetry: prognosis for successful vaginal delivery in patients with suspected fetopelvic disproportion or breech presentation at term.

Abstract: The purpose of this study was to correlate MR pelvimetric pelvic inlet measurements with mode of delivery and neonatal outcome in patients with suspected fetopelvic disproportion or breech presentation. For this retrospective monocentric study, 237 consecutive MR pelvimetry reports (1999–2016) of pregnant women due to either suspected fetopelvic disproportion, pelvic deformation after trauma, or persistent breech presentation were retrieved from the radiologic database and matched with corresponding information from the obstetric database. Of 223 included women, 95 (42.6%) underwent planned cesarean section (pCS) and 128 (57.4%) underwent a trial of vaginal labour (TOL), of whom 93 (72.7%) delivered vaginally. Vaginal delivery was successful in 45 out of 64 (70.3%) cephalic cases and in 48 out of 64 (75.0%) breech cases. We found statistically significant differences in conjugata vera obstetrica (CV) and diameter transversalis (DT) between the groups TOL and pCS (CV: 12.5 ± 1.0 vs 12.1 ± 1.2 cm, p value 0.001; DT: 13.3 ± 0.9 vs 12.7 ± 0.9 cm, p value <0.001, respectively). However, there was no significant difference between successful VD and cesarean section after TOL (CV: 12.5 ± 0.9 vs 12.3 ± 1.1 cm, p value 0.194; DT: 13.4 ± 0.9 vs 13.2 ± 0.9 cm, p value 0.358, respectively). In our cohort, MR pelvimetry was a useful tool for prepartal assessment of the female pelvis in the selection of TOL candidates. Yet, it does not seem to yield additional predictive value for women with a previous vaginal delivery.

The Prostaglandin EP3 Receptor Is an Independent Negative Prognostic Factor for Cervical Cancer Patients

Abstract: We know that one of the main risk factors for cervical cancer is an infection with high-risk human papillomavirus (HR-HPV). Prostaglandins and their receptors are very important for the tumour growth and tumour-associated angiogenesis. Little is known about the expression of the Prostaglandin E receptor type 3 (EP3) or the Prostaglandin (PG)E₂-EP3 signalling in cervical cancer, so the aim of the study was to analyse the expression of the EP3 receptor in cervical cancer and find prognostic factors in relation to survival; EP3 immunohistological staining of 250 cervical cancer slides was performed and analysed with a semi-quantitative score. The statistical evaluation was performed with Statistical Package for the Social Sciences (SPSS) to evaluate the staining results and the survival analyses of the cervical cancer cases. A significant difference was observed in EP3 expression in Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stadium I versus FIGO stadium II-IV cases. High expression of EP3 (IRS ≥ 1.5) in cervical cancer patients was correlated with poor prognosis in overall survival rates. Survival in adenocarcinoma (AC) of the cervix was lower than in squamous cell carcinoma (SCC). Cox regression analysis shows that EP3 is an independent prognosticator. In this study we could show that the membrane-bound prostaglandin receptor EP3 is an independent prognosticator for cervical cancer patient survival. Targeting the EP3 receptor seems to be an interesting candidate for endocrine therapy. Therefore, more research is needed on the influence of the receptor system and its influence on cervical cancer growth.

VEGF-C expression attributes the risk for lymphatic metastases to ovarian cancer patients

Abstract: // Sascha Kuerti 1, * , Leticia Oliveira-Ferrer 1, * , Karin Milde-Langosch 1 , Barbara Schmalfeldt 1 , Karen Legler 1 , Linn Woelber 1 , Katharina Prieske 1 , Sven Mahner 2 and Fabian Trillsch 2 1 Department of Gynaecology and Gynaecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany 2 Department of Obstetrics and Gynaecology, University of Munich, Munich 81377, Germany * These authors have contributed equally to this work Correspondence to: Fabian Trillsch, email: FabianTrillsch@meduni-muenchende Keywords: ovarian cancer, (VEGF)-A, -C, -D, mesenchymal phenotype, tumour dissemination, lymph node metastases Received: February 20, 2017 Accepted: March 31, 2017 Published: May 18, 2017 ABSTRACT Background: Peritoneal dissemination and retroperitoneal lymph node involvement are main routes for progression of epithelial ovarian cancer (EOC) Vascular endothelial growth factor (VEGF) mediated angiogenesis has been identified as an important mechanism promoting tumour progression Methods: Tumour tissue of 100 patients with EOC was analysed for protein expression of vascular endothelial growth factor (VEGF)-A, -C, -D by Western Blot analysis Expression patterns in patients with ‘extensive intraperitoneal’ metastases (pT3c pN1 and pT3b-pT3c pN0, n=80) were compared to patients with ‘predominantly retroperitoneal’ metastases (pT1a-pT3b, pN1, n=20) Overall and progression-free survival was analysed by Kaplan-Meier method Results: While no significant differences in expression levels among the different modes of metastases were noted for VEGF-A and -D, VEGF-C expression was significantly higher in the group of predominantly retroperitoneal metastases compared to the group with extensive intraperitoneal metastases Patients with high VEGF-C expression had a significantly worse overall survival compared to patients with low expression levels Conclusions: Retroperitoneal tumour progression in EOC patients is associated with high VEGF-C expression VEGF-C may serve as a molecular marker to identify patients with assumed high risk for lymphatic metastases, who might benefit from specific treatment strategies

Clinical significance of the estrogen-modifying enzymes steroid sulfatase and estrogen sulfotransferase in epithelial ovarian cancer

Abstract: 17β-estradiol (E2) can contribute to the progression of epithelial ovarian cancer (EOC). Although the majority of patients with EOC are postmenopausal woman, when de novo estrogen production in the ovary has ceased, ovarian cancer cells remain exposed to estrogens synthesized locally in the cancer cells from inactive sulfonated steroid hormone precursors-such as estrone sulfate taken up from the circulation via the sulfatase pathway. An abundance of the estrogen-modifying enzymes, including estrogen-activating steroid sulfatase (STS) and estrogen-inactivating estrogen-sulfotransferase (SULT1E1), is important for providing active estrogen to EOC cells. Therefore, the present study determined the levels of SULT1E1, STS and estrogen receptor α (ERα) protein in paraffin-embedded specimens from 206 patients with Federation of Gynecology and Obstetrics stage II-IV EOC treated with debulking surgery and standard platinum-based adjuvant chemotherapy. The levels of STS, SULT1E1 and ERα were assessed by automated quantitative microscopy-based image analysis subsequent to immunohistochemical staining. Significantly higher SULT1E1 levels were observed in better differentiated EOC tumors compared to grade 3 EOC tumors (P=0.001). STS and SULT1E1 levels were positively associated with ERα abundance (P<0.001 and P=0.001, respectively). In advanced stage high-grade serous EOC (HGSOC; n=132), the most frequent and lethal type of ovarian cancer, SULT1E1 expression was significantly associated with a better overall survival rate (hazard ratio 0.66, 95% confidence interval, 0.45-0.94; P=0.005). These results highlight the importance of SULT1E1-mediated estrogen inactivation in EOC, particularly HGSOC. Therefore, targeting the sulfatase pathway is a potential endocrine therapeutic intervention for certain patients with estrogen-responsive EOC.

Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer.

Abstract: // Katharina Prieske 1, * , Stefan Prieske 1, * , Simon A. Joosse 2 , Fabian Trillsch 3 , Donata Grimm 1 , Eike Burandt 4 , Sven Mahner 3 , Barbara Schmalfeldt 1 , Karin Milde-Langosch 1 , Leticia Oliveira-Ferrer 1 and Linn Woelber 1 1 Department of Gynecology and Gynecologic Oncology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany 2 Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany 3 Department of Gynecology and Obstetrics, University of Munich, 81377 Munich, Germany 4 Department of Pathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany * These authors have contributed equally to this work Correspondence to: Katharina Prieske, email: k.prieske@uke.de Keywords: BRCA methylation, ovarian cancer, platinum, recurrence, high-grade Received: May 30, 2017 Accepted: July 25, 2017 Published: September 15, 2017 ABSTRACT Background: Approximately 20-25% of ovarian cancers are attributable to germline or somatic BRCA1/2 mutations, resulting in defects in the homologous recombination pathway. Inactivation of these genes can also be mediated by epigenetic changes, e.g., hypermethylation of CpG islands in the promoter regions. In such homologous recombination deficient tumors, platinum based chemotherapy is in general effective, however, loss of hypermethylation might lead to refractory disease. The aim of this study was to evaluate the stability of BRCA1 promoter hypermethylation in recurrent disease after platinum based chemotherapy. Methods: Tumor tissue from 76 patients with primary and 48 patients with platinum-sensitive recurrent high-grade ovarian cancer was collected. In a subgroup of 12 patients, ‘paired’ tumor tissue from primary and recurrent surgery was available. BRCA1 promoter methylation status was assessed using methylation specific polymerase chain reaction and was verified by Sanger Sequencing. Results: 73.7% (56/76) of primary and 20.8% (10/48) of recurrent tumors displayed BRCA1 promoter hypermethylation. BRCA1 promoter methylation status was not associated with progression-free- or overall survival. In the paired subgroup 83.3% (10/12) of the primary vs. 16.7% (2/12) of the recurrent tumors showed hypermethylation. In eight patients loss of BRCA1 hypermethylation was observed, whereas two patients had stable methylation status. Conclusions: Loss of BRCA1 promoter methylation may be a mechanism to restore BRCA1 function in recurrent disease. However, currently the clinical significance is still unclear and should be evaluated in prospective clinical trials.

Prevalence of human papillomavirus infection of the anal canal in women: A prospective analysis of high-risk populations.

Abstract: Infection with certain types of human papillomavirus (HPV) has been associated with the development of cervical and anal cancer. Worldwide, the incidence of anal cancer has increased markedly. The present study aimed to evaluate the prevalence of HPV infection of the uterine cervix and anal canal in human immunodeficiency virus (HIV)- and non-HIV-infected risk populations. Cervical and anal HPV swabs and cytology samples were collected from 287 patients at the University Hospital of Munich, Germany between 2011 and 2013. Patients were divided into HIV-negative controls (G1) and two risk groups, including HIV-negative patients with cytological abnormalities of the cervix (G2) and HIV-infected patients (G3). Data, including clinical parameters, were analysed. The risk groups had significantly more positive results for HPV in the anus (71.03 and 83.15% for G2 and G3, respectively), as compared with G1. The predominant HPV genotypes found in the anus were high-risk HPV genotypes, which were significantly correlated with concomittant cervical HPV findings. In the risk groups, a significant association between the cytological findings and HPV detection in the cervix was found, while the results of the anus revealed no significance. The results of the present study suggested that the prevalence of HPV infection in the anal canal of risk populations is high. Furthermore, patients with abnormal cervical cytology results and HIV-infected women, irrespective of their individual cervical findings, may have a risk of concomittant anal high-risk HPV infection. Based on the predominant HPV genotypes found in the study, HPV vaccination could reduce the incidence of anal cancer. Nevertheless, high-risk patients should be intensively screened for anal squamous intraepithelial abnormalities to avoid invasive cancer stages.

Induction of DNA damage and apoptosis in human leukemia cells by efavirenz

Abstract: As part of the efforts to drug repurposing, some HIV drugs have recently been identified to exert anticancer effects. Selected nucleoside analogues of nucleosidic reverse-transcriptase inhibitors (NRTIs) have been shown to interfere with RNA transcription of HI viruses as well as with the replication of DNA in cancer cells. Non-nucleosidic reverse transcriptase inhibitors (NNRTIs) are believed to have less effects on human DNA replication and, thus, on cancer cell proliferation. Assessment of the effect of the NNRTI efavirenz in human cancer cells, however, revealed a high sensitivity of leukemia cells to this agent at pharmacologically relevant concentrations of less than 10 mu g/ml. Cell death induced by efavirenz was caused by apoptosis, as shown by FACScan analysis (Annexin binding) and western blot analysis (cleavage of caspases and PARP). Western blot analyses also revealed a pronounced activation and phosphorylation of the DNA damage marker proteins p53, chk2 and H2AX, indicating DNA replication and genomic integrity as primary targets of efavirenz in leukemia cells.

Investigation of RIP140 and LCoR as independent markers for poor prognosis in cervical cancer.

Abstract: // Aurelia Vattai 1 , Vincent Cavailles 2 , Sophie Sixou 3 , Susanne Beyer 1 , Christina Kuhn 1 , Mina Peryanova 1 , Helene Heidegger 1 , Kerstin Hermelink 1 , Doris Mayr 4 , Sven Mahner 1 , Christian Dannecker 1 , Udo Jeschke 1 and Bernd Kost 1 1 Department of Gynaecology and Obstetrics, Ludwig-Maximilians University of Munich, 80337 Munich, Germany 2 Institut de Recherche en Cancerologie de Montpellier (IRCM), INSERM U1194, Universite Montpellier, F-34298 Montpellier, France 3 Universite Toulouse III - Paul Sabatier, F-31062 Toulouse, France 4 Department of Pathology, Ludwig-Maximilians University of Munich, 81337 Munich, Germany Correspondence to: Udo Jeschke, email: udo.jeschke@med.uni-muenchen.de Keywords: cervical carcinoma; squamous cell carcinoma; adenocarcinoma; RIP140/NRIP1; LCoR Received: May 18, 2017 Accepted: July 25, 2017 Published: October 31, 2017 ABSTRACT Introduction: RIP140 (Receptor Interacting Protein) is involved in the regulation of oncogenic signaling pathways and in the development of breast and colon cancers. The aim of the study was to analyze the expression of RIP140 and its partner LCoR in cervical cancers, to decipher their relationship with histone protein modifications and to identify a potential link with patient survival. Methods: Immunohistochemical analyses were carried out to quantify RIP140 and LCoR expression in formalin-fixed paraffin-embedded tissue sections cervical cancer samples. Correlations of RIP140 and LCoR expression with histopathological variables were determined by correlation analyses. Survival rates of patients expressing low or high levels of RIP140 and LCoR were compared by Kaplan-Meier curves. Results: RIP140 overexpression was associated with a significantly shorter overall survival of cervical cancer patients. This effect was significant in the squamous cell carcinoma subtype but not in adenocarcinomas. RIP140 is no longer a significant negative prognosticator for cervical cancer when LCoR expression is low. Discussion: RIP140 is an independent predictor of poor survival of patients with cervical cancer. Patients with tumors expressing low levels of both RIP140 and LCoR showed a better survival compared to patients expressing high levels of RIP140. Modulation of RIP140 and LCoR may represent a novel targeting strategy for cervical cancer prevention and therapy.

Triple-negative breast cancer: New therapeutic options via signalling transduction cascades

Abstract: Triple-negative breast cancer is a highly aggressive type of mammalian carcinoma. It is defined by a rather weak expression of estrogen-, progesterone- and Her2-receptor, and is thus difficult to treat, resulting in low disease-free and overall survival rates of the affected patients. Hence it is important to find new therapeutic options. To this aim we analysed the incidence of some molecules from different signal transduction cascades by immunohistochemistry, which are known to correlate with triple-negative breast cancer, and correlated the expression of these molecules to different tumour traits, such as size, grading, menopausal stage, histology, lymph node affection, remote metastasis formation, and to the incidence of local and lymph node recurrence and metastasis by statistical analysis. Statistically significant correlations were found for a number of tumour characteristics and signalling molecules: HIF1α is correlated to tumour grading, β-catenin to the menopausal state of the patient, and for Notch1 a relation to lymph node affection is seen. In terms of different recurrences, a correlation of β-catenin to metastasis formation and lymph node affection could be shown, as well as coherences between XBP1 and lymph node recurrence, Notch1 and metastasis formation and FOXP3 and the occurrence of local recurrence. The presented results are in accordance with formerly published studies and therefore might comprise opportunities to develop new therapeutical strategies, which could help to handle this aggressive form of breast cancer in a manner, by which side effects would be reduced and therapeutical efficiency is increased.