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Background: Some countries have implemented stand-alone human papillomavirus (HPV) testing while others consider cotesting for cervical cancer screening. We compared both strategies within a population-based study. Methods: The MARZY cohort study was conducted in Germany. Randomly selected women from population registries aged ≥30 years (n = 5,275) were invited to screening with Pap smear, liquid-based cytology (LBC, ThinPrep), and HPV testing (Hybrid Capture2, HC2). Screen-positive participants [ASC-US+ or high-risk HC2 (hrHC2)] and a random 5% sample of screen-negatives were referred to colposcopy. Post hoc HPV genotyping was conducted by GP5+/6+ PCR-EIA with reverse line blotting. Sensitivity, specificity (adjusted for verification bias), and potential harms, including number of colposcopies needed to detect 1 precancerous lesion (NNC), were calculated. Results: In 2,627 screened women, cytological sensitivities (Pap, LBC: 47%) were lower than HC2 (95%) and PCR (79%) for CIN2+. Cotesting demonstrated higher sensitivities (HC2 cotesting: 99%; PCR cotesting: 84%), but at the cost of lower specificities (92%–95%) compared with HPV stand-alone (HC2: 95%; PCR: 94%) and cytology (97% or 99%). Cotesting versus HPV stand-alone showed equivalent relative sensitivity [HC2: 1.06, 95% confidence interval (CI), 1.00–1.21; PCR: 1.07, 95% CI, 1.00–1.27]. Relative specificity of Pap cotesting with either HPV test was inferior to stand-alone HPV. LBC cotesting demonstrated equivalent specificity (both tests: 0.99, 95% CI, 0.99–1.00). NNC was highest for Pap cotesting. Conclusions: Cotesting offers no benefit in detection over stand-alone HPV testing, resulting in more false positive results and colposcopy referrals. Impact: HPV stand-alone screening offers a better balance of benefits and harms than cotesting. See related commentary by Wentzensen and Clarke, p. 432

Introduction Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, molecular guided treatments may be a viable option for the treatment of advanced gynecologic cancers. Patients and Methods In this single‐center, real‐world retrospective analysis of our platform for precision cancer medicine (PCM), we describe the molecular profiling of 72 patients diagnosed with different types of advanced gynecologic malignancies. Tumor samples of the patients were examined by next‐generation sequencing panel and immunohistochemistry (IHC). Results In total, we identified 209 genetic aberrations in 72 patients. The ten most frequent alterations were TP53 (n = 42, 20%), KRAS (n = 14, 6.6%), PIK3CA (n = 11, 5.2%), PIK3R1 (n = 9, 4.3%), ATR (n = 8, 3.8%), PTEN (n = 8, 3.8%), BRCA1 (n = 6, 2.8%), NF1 (n = 4, 1.9%), NOTCH1 (n = 4, 1.9%), and POLE (n = 4, 1.9%), which account for more than half of all molecular alterations (52.6%). In 21 (29.1%) patients only one mutation could be detected, and 44 (61.1%) patients had more than one mutation. No molecular alterations were detected in seven (9.7%) patients. IHC detected expression of phosphorylated mammalian target of rapamycin and epidermal growth factor receptor in 58 (80.6%) and 53 (73.6%) patients, respectively. In over two thirds (n = 49, 68.1%), a targeted therapy was suggested, based on the identified genetic aberrations. The most frequently recommended specific treatment was the combination of everolimus with exemestane (n = 18, 25 %). Conclusion Based on our observations, it seems that PCM might be a feasible approach for advanced gynecologic cancers with limited treatment options. Implications for Practice Nowadays molecular profiling of advanced gynecologic malignancies is feasible in the clinical routine. A molecular portrait should be done for every patient with an advanced therapy‐refractory gynecologic malignancy to offer molecular‐based treatment concepts., To determine the feasibility of precision cancer medicine (PCM) in gynecologic cancers, this retrospective study analyzed patients with advanced gynecologic cancers enrolled and profiled in a PCM platform, MONDTI, focusing on the technical feasibility to map the molecular profiles of advanced, pretreated, and mainly relapsed gynecologic cancers and to subsequently target the detected molecular alterations

Background The purpose of this systematic review update and meta-analysis was to analyze resistance exercise (RE) intervention trials in breast cancer survivors (BCS) regarding their effect on breast cancer-related lymphedema (BCRL) status and upper and lower extremity strength. Methods Systematic literature search was conducted utilizing PubMed, MEDLINE, and Embase databases. Any exercise intervention studies—both randomized controlled and uncontrolled—which assessed the effects of RE on BCRL in BCS in at least one intervention group published between 1966 and 31st January 2020 were included. Included articles were analyzed regarding their level of evidence and their methodological quality using respective tools for randomized and nonrandomized trials of the Cochrane collaboration. Meta-analysis for bioimpedance spectroscopy (BIS) values as well as upper and lower extremity strength was conducted. Results Altogether, 29 studies were included in the systematic review. Results of six studies with altogether twelve RE intervention groups could be pooled for meta-analysis of the BCRL. A significant reduction of BCRL after RE was seen in BIS values (95% CI − 1.10 [− 2.19, − 0.01] L-Dex score). Furthermore, strength results of six studies could be pooled and meta-analysis showed significant improvements of muscular strength in the upper and lower extremities (95% CI 8.96 [3.42, 14.51] kg and 95% CI 23.42 [11.95, 34.88] kg, respectively). Conclusion RE does not have a systematic negative effect on BCRL and, on the contrary, potentially decreases it.

The aim of this prospective randomized, double-masked, placebo-controlled, multicenter study was to analyze the surgeon’s individual assessment of tissue quality during pelvic floor surgery in postmenopausal women pre-treated with local estrogen therapy (LET) or placebo cream. Secondary outcomes included intraoperative and early postoperative course of the two study groups. Surgeons, blinded to patient’s preoperative treatment, completed an 8-item questionnaire after each prolapse surgery to assess tissue quality as well as surgical conditions. Our hypothesis was that there is no significant difference in individual surgical assessment of tissue quality between local estrogen or placebo pre-treatment. Multivariate logistic regression analysis was performed to identify independent risk factors for intra- or early postoperative complications. Out of 120 randomized women, 103 (86%) remained for final analysis. Surgeons assessed the tissue quality similarity in cases with or without LET, representing no statistically significant differences concerning tissue perfusion, tissue atrophy, tissue consistency, difficulty of dissection and regular pelvic anatomy. Regarding pre-treatment, the rating of the surgeon correlated significantly with LET (r = 0.043), meaning a correct assumption of the surgeon. Operative time, intraoperative blood loss, occurrence of intraoperative complications, total length of stay, frequent use of analgesics and rate of readmission did not significantly differ between LET and placebo pre-treatment. The rate of defined postoperative complications and use of antibiotics was significantly more frequent in patients without LET (p = 0.045 and p = 0.003). Tissue quality was similarly assessed in cases with or without local estrogen pre-treatment, but it seems that LET prior to prolapse surgery may improve vaginal health as well as tissue-healing processes, protecting these patients from early postoperative complications.

ZusammenfassungDie Implantation spannungsfreier Bänder („tension free vaginal tape“ [TVT]) ist eine minimalinvasive Technik zur Behandlung der Belastungsinkontinenz. Um den Stellenwert und die Besonderheiten der Methode bei älteren Menschen zu evaluieren, wurde eine selektive Literaturrecherche in PubMed mit den Stichworten „urinary incontinence“/„tension free vaginal tape“/„stress incontinence“ AND „elderly“ durchgeführt. Angesichts der demografischen Entwicklung weltweit erweist sich die Harninkontinenz im Alter als zunehmendes medizinisches und sozioökonomisches Problem. Ein TVT kann selbst bei Hochaltrigen unter folgenden Bedingungen ins Auge gefasst werden: grundsätzlich fehlende Kontraindikation gegen einen chirurgischen Eingriff; Vorliegen einer Belastungs- oder Mischinkontinenz (mit hohem Belastungsanteil); Versagen der konservativen Therapie. Unter der Voraussetzung von Operationswunsch und gegebener Operabilität zeigen die Langzeitergebnisse des TVT über 11 Jahre eine persistierende Kontinenzrate von mehr als 80 %. Die Operation ist sicher und effektiv, geht allerdings mit einer erhöhten Rate von postoperativen Harnwegsinfekten und De-Novo-Dranginkontinenz einher.

// Gerald W. Prager 1, 8 , Matthias Unseld 1, 8 , Fredrik Waneck 3, 8 , Robert Mader 1, 8 , Fritz Wrba 2, 8 , Markus Raderer 1, 8 , Thorsten Fuereder 1, 8 , Phillip Staber 4, 8 , Ulrich Jager 4, 8 , Markus Kieler 1, 8 , Daniela Bianconi 1, 8 , Mir Alireza Hoda 7, 8 , Lukas Baumann 9 , Alexander Reinthaller 5, 8 , Walter Berger 6, 8 , Christoph Grimm 5, 8 , Heinz Kolbl 5, 8 , Maria Sibilia 6, 8 , Leonhard Mullauer 2, 8 and Christoph Zielinski 1, 8 1 Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria 2 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 3 Department of Interventional Radiology, Medical University of Vienna, Vienna, Austria 4 Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria 5 Department of General Gynecology and Gynecological Oncology, Medical University of Vienna, Vienna, Austria 6 Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria 7 Department of Surgery, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria 8 Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria 9 Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria Correspondence to: Gerald W. Prager, email: gerald.prager@meduniwien.ac.at Keywords: precision medicine; molecular profile Received: May 28, 2018 Accepted: January 02, 2019 Published: January 29, 2019 ABSTRACT Background: The concept of personalized medicine defines a promising approach in cancer care. High-throughput genomic profiling of tumor specimens allows the identification of actionable mutations that potentially lead to tailored treatment for individuals’ benefit. The aim of this study was to prove efficacy of a personalized treatment option in solid tumor patients after failure of standard treatment concepts. Results: Final analysis demonstrates that 34 patients (62%) had a longer PFS upon experimental treatment (PFS1) when compared to previous therapy (PFS0); PFS ratio > 1.0 ( p = 0.002). The median PFS under targeted therapy based on molecular profiling (PFS1) was 112 days (quartiles 66/201) and PFS0 = 61 days (quartiles 51/92; p = 0.002). Of the 55 patients, 31 (56%) showed disease control (DCR), consisting of 2 (4%) patients which achieved a complete remission, 14 (25%) patients with a partial remission and 15 (27%) patients who had a stabilization of disease. Median OS from start of experimental therapy was 348 days (quartiles 177/664). Conclusion: The prospective trial EXACT suggests that treatment based on real-time molecular tumor profiling leads to superior clinical benefit. Materials and Methods: In this prospective clinical phase II trial, 55 cancer patients, after failure of standard treatment options, aimed to achieve a longer progression-free survival on the experimental treatment based on the individual’s molecular profile (PFS1) when compared to the last treatment given before (PFS0). The personalized medicine approach was conceived to be clinical beneficial for patients who show a PFS ratio (PFS 1/PFS0) of > 1.0.

Purpose On January 1st, 2018, the ÖGZ (Austrian Society of Cytology) revised its cytological nomenclature to make it more similar to the 2015 Bethesda system. Following these changes, the Austrian Society of Gynecology and Obstetrics felt it necessary to revise the approach currently used in Austria to diagnose and treat CIN and to review the procedures to be followed when the quality of cytological specimens is unsatisfactory. It was not possible to adopt the German S3 guideline “Prevention of Cervical Cancer” in its entirety, because the Munich III gynecological cytology nomenclature used in Germany is not used in Austria. This made it necessary to compile a separate scientific opinion for Austria. Methodology The OEGGG worked together with the ÖGZ (Austrian Society for Cytology), AGO Austria (Austrian Working Group for Gynecological Oncology), the AGK (Colposcopy Working Group), and physicians representing gynecologists in private practice. The different scientific associations nominated representatives, who attended the various meetings. After an in-depth analysis of the recent literature, three meetings and numerous votes by telephone, we were able to achieve a consensus about the contents of this guideline. Recommendations The guideline provides recommendations for the diagnosis and treatment of CIN which take account of the gynecological cytology nomenclature used in Austria.

The COVID-19 pandemic led to dramatical changes in elective medical care. We analysed its impact on patients with female pelvic floor dysfunction during the 6 weeks of lockdown in Austria. A cross-sectional study was conducted: All 99 women who presented at the urogynaecologic outpatient clinic of the Medical University of Vienna with pelvic organ prolapse (POP) or urinary incontinence (UI) from December 2019 up to the lockdown in March 2020 were included and contacted. 97% of these women (96 participants) agreed to participate in the survey conducted to asses pelvic floor related quality of life (QoL) through telephone- interrogation. The mean age was 59 ± 14.8 years, the POP group consisted of 42 women while the UI group included 54 women. Most participants (83% of POP and 81% of UI cases) stated that their female pelvic floor dysfunction had remained equally relevant or had become even more significant during the lockdown. Associated symptoms and psychological strain also maintained their relevance during the lockdown (UI: p = 0.229, POP: p = 0.234). Furthermore, 97% of all interviewed women indicated to be strongly willing to continue their treatment. A generalised linear model regression revealed no clinical or demographic risk factors for psychological strain during the lockdown (p &gt, 0.05). Our results demonstrate that women’s QoL remains significantly impaired by their pelvic-floor disorders even during a worldwide crisis such as COVID-19. Therefore, elective disciplines such as urogynaecology urgently require novel and innovative strategies for continued patient care even in times of a lockdown.

Background: The aim of this study was to identify clinical risk factors for increased post-void residual (PVR) volumes in patients undergoing vaginal prolapse surgery and to find out whether uterus preservation or prolapse hysterectomy influences the incidence of postoperative urinary retention. Methods: This retrospective study included women who presented with pelvic organ prolapse (POP) and planned prolapse surgery between January 2017 and July 2019. PVR was assessed postoperatively and increased amounts were defined as incomplete voiding with residual urine volume greater than 150 mL. Results: Increased PVR at the first postoperative day occurred in 31.8% (56/176). Body mass index (BMI) was significantly lower in patients with increased PVR after pelvic floor surgery compared to patients with normal PVR amounts (p = 0.040). Furthermore, during multiple logistic regression analysis, low BMI (p = 0.009) as well as prolapse hysterectomy (p = 0.032) turned out to be the strongest risk factors associated with increased PVR volume. Conclusion: This is the first study identifying prolapse hysterectomy as an independent risk factor for increased PVR after surgical prolapse repair. Our results might be helpful in counseling patients prior to surgery and underline the option of uterus preservation during prolapse surgery in selected cases.

The decades-long global obesity epidemic has resulted in steady increase in the incidence of obesity-related malignancies. The associated diagnostic and therapeutic implications present a clinical challenge for gynecologic oncology treatment strategies. Recent studies have provided solid evidence for an independent, linear, positive correlation between a pathologically increased body mass index and the probability of developing endometrial or postmenopausal breast cancer. The pathogenesis is complex and the subject of current research. Proposed causes include pathologically increased serum levels of sexual steroids and adiponectin, obesity-induced insulin resistance, and systemic inflammatory processes. The scientific evidence for an association between obesity and other gynecological malignancies is, however, less solid. The clinical relevance of obesity as a risk factor for epithelial ovarian cancer, cervical cancer and vulvar cancer appears to be negligible. Nevertheless, obesity appears to have a negative impact on prognosis and oncologic outcomes for all gynecological cancers. Whether or not this effect can be interpreted as correlative or causal is still a subject of ongoing debate.

Objective Aim of the study was to investigate the expression of transforming growth factor-β1 (TGF-β1), a key regulator of the extracellular matrix composition, in the uterosacral ligaments (USLs) of women with pelvic organ prolapse (POP) compared with controls. We hypothesized that the expression pattern of TGF-β1 differs between postmenopausal women with or without POP. Methods Under ethical approval, USL samples were obtained from postmenopausal women undergoing vaginal hysterectomy for stage two or greater pelvic organ prolapse (cases, n = 70) and from postmenopausal women without pelvic organ prolapse undergoing vaginal hysterectomy for benign indications (controls, n = 30). Immunohistochemical staining was performed from paraffin embedded tissue using anti-TGF-β1 antibodies. The expression of TGF-β1 was evaluated by the pathologist, who was blinded to all clinical data. Results The expression of TGF-s1 was similar in patients with symptomatic POP (89 % positive) and in controls (90 % positive) without any signs of prolapse (p = 0.091). Age-adjusted analysis did not significantly alter these results. Regarding POP-Q stages, TGF-s1 was significantly more frequently expressed in severe prolapse cases compared to moderate/mild cases (POP-Q stage IV versus POP-Q stage II and III; p = 0.001). No significant association could be detected between TGF-s1 expression and age, BMI and parity in cases with POP (p > 0.05). As published previously, advanced patients’ age as well as early menopausal age remained independent risk factors associated with POP in multiple logistic regression analysis (p = 0.001; p = 0.02). Conclusion Although our study detected POP-Q stage related alterations in USL composition and TGF-s1 expression, there was no significant difference in the expression of TGF-β1 in cases with or without prolapse.

Precision medicine for breast cancer relies on biomarkers to select therapies. However, the reliability of biomarkers drawn from gene expression arrays has been questioned and calls for reassessment, in particular for large datasets. We revisit widely used data-normalization procedures and evaluate differences in outcome in order to pinpoint the most reliable reprocessing methods biomarkers can be based upon. We generated a database of 3753 breast cancer patients out of 38 studies by downloading and curating patient samples from NCBI-GEO. As gene-expression biomarkers, we select the assessment of receptor status and breast cancer subtype classification. Each normalization procedure is applied separately, and biomarkers are then evaluated for each patient. Differences between normalization pipelines are quantified as percentages of patients having outcomes different for each pipeline. Some normalization procedures lead to quite consistent biomarkers, differing only in 1-2% of patients. Other normalization procedures—some of them have been used in many clinical studies—end up with distrusting discrepancies (10% and more). A good deal of doubt regarding the reliability of microarrays may root in the haphazard application of inadequate preprocessing pipelines. Several modes of batch corrections are evaluated regarding a possible improvement of receptor prediction from gene expression versus the golden standard of immunohistochemistry. Finally, we nominate those normalization methods yielding consistent and trustable results. Adequate bioinformatics data preprocessing is key and crucial for any subsequent statistics to arrive at trustable results. We conclude with a suggestion for future bioinformatics development to further increase the reliability of cancer biomarkers.

Lung cancer during pregnancy represents a rare disease. In this case report, we present a patient at advanced and metastasized stage of signet ring cell carcinoma who presented in the22ndweek of gestation.

Aim: To evaluate pre-treatment serum C-reactive protein (CRP) level as a prognostic parameter in patients with adenocarcinoma of the uterine cervix. Materials and Methods: Pre-treatment CRP levels were analyzed to determine potential associations with clinicopathological parameters and to assess prognostic value in 46 patients with sole adenocarcinoma of the uterine cervix. Results: The mean (±SD) pre-treatment serum CRP level was 5.82 (7.21) mg/l. Serum CRP concentration significantly correlated positively with age at diagnosis (p=0.001), lymphovascular space invasion (p=0.0026), recurrent disease (p=0.0001) and International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.0002). In multivariate Cox regression models with age, FIGO stage, histological grade and lymph node status, elevated CRP and cancer antigen 125 levels were associated with shortened survival (p

The modern sling procedures for treating female stress urinary incontinence encompass numerous methods, materials and manufacturers. On the basis of the current S2e guidelines, the methods used most frequently in the diagnosis of and therapy for stress urinary incontinence in women are critically illustrated. An individualised procedure is necessary for the choice of the surgical method, especially in the presence of accompanying pathologies. This article is intended to help the treating physician to carry out quality-assured diagnostics and therapy for the patient and to offer the best possible urogynaecological management. In addition to the complications and chances of success of the surgical options, the legal aspects of therapy planning are also taken into consideration.Die modernen Schlingenverfahren zur Behandlung der weiblichen Belastungsinkontinenz variieren heute zwischen zahlreichen Verfahren, Materialien und Herstellern. Basierend auf der aktuellen S2e-Leitlinie werden die am häufigsten angewendeten Verfahren bei der Diagnostik und Therapie der Belastungsinkontinenz der Frau kritisch beleuchtet. Bei der Wahl der Operationsmethode ist ein individualisiertes Vorgehen erforderlich, insbesondere, wenn Begleitpathologien vorliegen. Der Beitrag soll den behandelnden Ärzten helfen, die Diagnostik und Therapie der Patientinnen qualitätsgesichert durchzuführen und die bestmögliche urogynäkologische Versorgung anbieten zu können. Dabei werden neben den Komplikationen und Erfolgsaussichten der operativen Möglichkeiten auch juristische Aspekte bei der Therapieplanung berücksichtigt.

Lymph node ratio (LNR) can predict treatment outcome and prognosis in patients with solid tumors. Aim of the present analysis was to confirm the concept of using LNR for assessing outcome in patients with vulvar cancer after surgery with inguinal lymphadenectomy in a large multicenter project.The AGO-CaRE-1 study multicenter database was used for analysis. LNR was defined as ratio of number of positive lymph nodes (LN) to the number of resected. Previously established LNR risk groups were used to stratify patients. LNR was investigated with respect to clinical parameters. Univariate and multivariable survival analyses were performed to assess the value of LNR in order to predict overall (OS) and progression-free (PFS) survival.In total, 1047 patients treated with surgery including inguinal lymph node resection for squamous cell carcinoma of the vulva were identified from the database. Of these, 370 (35.3%) were found to have positive inguinal LN. In total, 677 (64.7%) had a LNR of 0% (N0), 255 (24.4%) a LNR of0% 20%, and 115 (11%) a LNR of ≥20%. Patients with higher LNR were found to have larger tumor size (P .001), advanced tumor stage (P .001), high tumor grade (P .001), and deep stromal invasion (P .001), more frequently. Three-year PFS rates were 75.7%, 44.2%, and 23.1% and three-year OS rates were 89.7%, 65.4%, and 41.9%, in patients with LNRs 0%,0% 20%, and ≥20%, respectively (P .001, P .001). On multivariable analyses LNR (HR 7.75, 95%-CI 4.01-14.98, P .001), FIGO stage (HR 1.41, 95%-CI 1.18-1.69, P .001), and patient's performance status (HR 1.59, 95%-CI 1.39-1.82, P .001), were associated with PFS. In addition, LNR (HR 12.74, 95%-CI 5.64-28.78, P .001), and performance status (HR 1.72, 95%-CI 1.44-2.07, P .001) were also the only two parameters independently associated with OS. LNR generally showed stronger correlation than number of affected LN when comparing the two different multivariable models.In women with vulvar cancer LNR appears to be a consistent, independent prognostic parameter for both PFS and OS and allows patient stratification into three distinct risk groups. In survival analyses, LNR outperformed nodal status and number of positive nodes.

The working group recommends against contralateral prophylactic mastectomy (CPM) in women with breast cancer without a family history or genetic predisposition with unilateral breast cancer. This is based on the low risk of developing contralateral breast cancer, the lack of a survival benefit, the increased risk of surgical complications, and the lack of benefit on quality of life.

Purpose Therapeutic decisions in breast cancer patients crucially depend on the status of estrogen receptor, progesterone receptor and HER2, obtained by immunohistochemistry (IHC). These are known to be inaccurate sometimes, and we demonstrate how to use gene-expression to increase precision of receptor status. Methods We downloaded data from 3241 breast cancer patients out of 36 clinical studies. For each receptor, we modelled the mRNA expression of the receptor gene and a co-gene by logistic regression. For each patient, predictions from logistic regression were merged with information from IHC on a probabilistic basis to arrive at a fused prediction result. Results We introduce Sankey diagrams to visualize the step by step increase of precision as information is added from gene expression: IHC-estimates are qualified as ‘confirmed’, ‘rejected’ or ‘corrected’. Additionally, we introduce the category ‘inconclusive’ to spot those patients in need for additional assessments so as to increase diagnostic precision and safety. Conclusions We demonstrate a sound mathematical basis for the fusion of information, even if partly contradictive. The concept is extendable to more than three sources of information, as particularly important for OMICS data. The overall number of undecidable cases is reduced as well as those assessed falsely. We outline how decision rules may be extended to also weigh consequences, being different in severity for false-positive and false-negative assessments, respectively. The possible benefit is demonstrated by comparing the disease free survival between patients whose IHC could be confirmed versus those for which it was corrected. Electronic supplementary material The online version of this article (10.1007/s10549-018-4920-x) contains supplementary material, which is available to authorized users.

Objective: To compare the efficacy and safety of mirabegron 50 mg and solifenacin 5 mg in overactive bladder (OAB) patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy. Patients and methods: This randomized, double-blind, phase IIIb, noninferiority study, enrolled male and female patients aged ⩾18 years old, with symptoms of OAB for ⩾3 months, who were dissatisfied with their previous antimuscarinic drug due to lack of efficacy. A total of 1887 patients were randomized to receive mirabegron 50 mg ( n = 943) or solifenacin 5 mg ( n = 944) daily for 12 weeks. The primary efficacy endpoint was change from baseline to end of treatment in mean number of micturitions/24 h. Noninferiority was confirmed if the lower limit of the two-sided 95% confidence interval (CI) for the treatment difference between solifenacin and mirabegron was > −0.20. Secondary efficacy endpoints, which included change from baseline in mean number of incontinence episodes/24 h, urgency incontinence episodes/24 h, urgency episodes (grade 3 or 4)/24 h and nocturia episodes/24 h, were analyzed using analysis of covariance. Results: For the primary endpoint, adjusted mean treatment difference (95% CI) in mean number of micturitions/24 h was −0.18 (−0.42, 0.06) and therefore noninferiority of mirabegron to solifenacin was not demonstrated. Both treatments demonstrated clinically meaningful reductions in efficacy variables and were well tolerated, with a lower incidence of dry mouth with mirabegron. Conclusions: Noninferiority of mirabegron compared with solifenacin for reduction in micturition frequency could not be demonstrated in this population of OAB patients who were dissatisfied with previous antimuscarinic therapy due to lack of efficacy. Both mirabegron and solifenacin improved key OAB symptoms with no statistically significant differences observed between the two treatments. Both drugs were well tolerated.

The ethical behavior of authors, editors, and journals is increasingly placed in the spotlight, by both the public and the research community. Disclosures and conflict of interest (COI) statements of publishing authors represent one important aspect. We aimed to unravel the current management of disclosures, COI, and funding statements in the subspecialty urogynecology. A bibliometric study was carried out. We included six journals that published urogynecology articles between January and December 2013. All original articles, reviews, and opinion articles were assessed for the presence of disclosure/COI and funding statements. Information given on the official disclosure form was compared with information given in the final article (International Urogynecology Journal). All journals investigated require disclosure and funding statements in their instructions to authors. Of the 434 articles included, almost all contained a disclosure statement (98–100 %). Funding statements were present in 41–100 % of articles, indicating a difference in journal type (50 % on average among urogynecology journals; 75 % on average among general gynecology journals). The main source of funding was “grants” (58 %), followed by “none” (16 %), “industry” (16 %), and lastly “hospital/university” (10 %). Disclosure statements in the article were identical to the official disclosure form in 80 % (IUJ). Disclosure/COI statements were included in almost all urogynecology articles investigated. Their content, however, is sometimes incomplete and should possibly be monitored more closely by journals and authors. Despite universal requirements of journals, the reporting of funding seems inconsistent. This issue in addition to the completeness of disclosures should be given more attention.

Objective To investigate a possible correlation between the volume of the tubal ectopic pregnancy (EP) measured by vaginal-ultrasound (VUS) and methotrexate (MTX) therapy outcome. Study design Data of EP volume measured by one expert-sonographer, viability, clinical symptoms, previous IVF/insemination, follow-up of β-hCG and progesterone levels, and treatment of EP was collected of 100 patients with sonographically diagnosed EP, who attended the Department of Obstetrics and Gynecology of the Medical University Vienna between March 2008 and September 2011. Results The mean volume of EP (mVol.) in the group with successful MTX therapy ( n = 38) was 5.11 ml, 95%CI [2.4; 7.8] with a median 3.2 ml, IQR [5.0], in the group with unsuccessful MTX treatment ( n = 11) it was 15.24 ml, 95%CI [−2.6; 33.1], with a median 4.4 ml, IQR [11.4]. We could observe a trend towards a lower mVol. in the successful MTX group (5.11 ml vs. 15.24 ml). We could not show a significant correlation ( u -test p = 0.208). Conclusion A clear tendency was observed towards a lower mVol. in the successful MTX therapy group, but we could not verify a statistically significant correlation of volume of EP and MTX therapy outcome most likely due to the small sample size. This was the first study investigating the correlation of volume of EP and MTX therapy outcome as principal question.

To determine the optimal serum β-hCG cut-off level to predict MTX treatment success in tubal ectopic pregnancy (EP).Data of 240 women, who presented between 2003 and 2011 at the Department of Gynecology and Obstetrics, Medical University of Vienna, with tubal EP and who received MTX as primary treatment, were retrieved from the hospital information system (KIS). 198 patients could be included for final evaluation. Statistical analysis included area under the ROC curve, maximal Euclidean and Youden index, chi-squared and a five-fold cross validation.The serum β-hCG level cut-off value was calculated at 2121mlU/ml with a specificity of 76.54% and sensitivity of 80.56% (AUC 0.789; p0.001). Patients with an initial serum β-hCG level below 2121mlU/ml (n=131) experienced MTX treatment failure in 5.3% (n=7), compared to 43.3% (n=29) of patients with an initial serum β-hCG level equal to or above 2121mlU/ml (n=67). There was no statistically significant correlation between clinical symptoms and the MTX therapy outcome (p=0.580; likelihood quotient p=0.716).The correct decision of therapy in patients with tubal ectopic pregnancy still represents a challenge. In this study we can conclude that, according to our results there is no endpoint of initial serum β-hCG levels, which can be clearly used as cut-off value for the optimal management of tubal EP. However, an initial serum β-hCG level of less than 2121mlU/ml seems to be a good value to expect a successful MTX treatment. Limitations are the retrospective study design and the inability of classifying clinical symptoms like pain as an objective parameter. Wider implications of the findings may include more detailed patient information and more accurate selection of suitable patients for MTX therapy.

Background Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, precision cancer medicine (PCM) may be a viable option for the treatment of advanced gynecologic cancers. Methods In this single center, real-world retrospective analysis of our PCM platform, we describe the molecular profiling of 72 patients diagnosed with different types of metastasized BTC. Tumor samples of the patients were examined by a 162-gene next-generation sequencing (NGS) panel, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and RNA fusion panel. Results In total, we identified 209 molecular aberrations in 72 patients. The ten most frequently alterations were TP53 (n = 42), KRAS (n = 14), PIK3CA (n = 11), PIK3R1 (n = 9), ATR (n = 8), PTEN (n = 8), BRCA1 (n = 6), NF1 (n = 4), NOTCH1 (n = 4), POLE (n = 4) that make up together over half of the molecular alterations (52.6%). BRAF mutations and gene fusions each were observed in two patients. 21 patients were found to have only one mutation and 44 patients had more than one mutation. No mutations were detected in 7 patients. IHC detected expression of p-mTOR and EGFR in 58 and 53 patients, respectively. In over two-thirds (n = 51) of the 72 patients, a targeted therapy was suggested, based on the identified genetic mutations. The most frequently recommended specific treatment was the combination of everolimus with exemestan (n = 19). The median turnaround time from biopsy to discussion in our multidisciplinary tumor board was 20 days. The median turnaround time from biopsy to therapy initiation was 26 days. Conclusions Based on our observations, it seems that PCM might be a feasible treatment approach for advanced gynecologic cancers with limited treatment options. Legal entity responsible for the study Medical University of Vienna. Funding Has not received any funding. Disclosure H. Taghizadeh: Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

Objectives The aim of this study is to evaluate the activity and toxicity of fulvestrant, a pure estrogen receptor antagonist in patients with advanced or recurrent endometrial cancer, expressing estrogen and/or progesterone receptors (ER/PR). Methods Eligible patients with advanced or recurrent endometrial cancer not amenable to curative surgery and/or radiotherapy were treated with fulvestrant at a dose of 250mg by IM injection every 4weeks for at least 12weeks. Therapy was continued until disease progression, death, intolerable side effects or end of study. Response was assessed in patients with at least one target lesion according to WHO-criteria. Results Thirty-five patients were enrolled in this study and received at least one injection of fulvestrant (intention to treat-population, ITT). Twenty six patients received the intended 3 injections of fulvestrant (per protocol population, PP). There was no complete response but 4 partial responses (11.4% ITT) and 8 stable diseases. The median time to progression was 2.3months (ITT). Overall survival was 13.2months (ITT). Treatment was well tolerated. Conclusions Fulvestrant at a dose of 250mg IM every 4weeks has marginal activity and good tolerability in patients with ER and/or PR positive advanced or recurrent endometrial cancer. A loading dose strategy and the use of 500mg/4weeks might improve the efficacy of this treatment.

The association between an increased uptake of isoflavones and a reduced frequency of menopausal hot flushes was first described in 1992, based on a lower incidence of hot flushes in countries with a high consumption of soy. Since then, numerous clinical trials with various sources of isoflavones including soy and red clover have been presented, with practically all of the studies with adequate design delivering an outcome in favour of isoflavone supplementation. An in-depth risk assessment (EFSA 2015) concludes that the amply available human data does not indicate any suspected harmful effects from a potential interaction of isoflavones with hormone-sensitive tissues in the mammary gland, the uterus and the thyroid gland. Safety was ascertained with long-term intake of up to 150 mg isoflavones per day ingested for the duration of at least 3 years. Moreover, high isoflavone intake was found to have preventive effects with respect to breast cancer. Clinical findings indicate potential benefits of isoflavone exposure even during breast cancer treatment with tamoxifen or anastrozole.

The therapy of choice for breast cancer patients requiring adjuvant chemo- or radiotherapy is increasingly guided by the principle of weighing the individual effectiveness of the therapy against the associated side effects. This has only been made possible by the discovery and validation of modern biomarkers. In the last decades and in the last few years some biomarkers have been integrated in clinical practice and a number have been included in modern study concepts. The importance of biomarkers lies not merely in their prognostic value indicating the future course of disease but also in their use to predict patient response to therapy. Due to the many subgroups, mathematical models and computer-assisted analysis are increasingly being used to assess the prognostic information obtained from established clinical and histopathological factors. In addition to describing some recent computer programmes this overview will focus on established molecular markers which have already been extensively validated in clinical practice and on new molecular markers identified by genome-wide studies.Die Therapiewahl für die Mammakarzinompatientin in der adjuvanten Situation folgt immer mehr dem Prinzip, die individuelle Therapieeffektivität und die Nebenwirkungen gegeneinander abzuwägen. Die Entdeckung und Validierung moderner Biomarker ermöglicht erst dieses Vorgehen. In den letzten Jahrzehnten und insbesondere in den letzten Jahren konnten einige Biomarker in die klinische Praxis und in moderne Studienkonzepte integriert werden. Nicht nur der Vorhersage der Prognose kommt hierbei eine besondere Bedeutung zu, sondern auch der Vorhersage des Therapieansprechens durch Prädiktivfaktoren. Die Nutzung der prognostischen Information aus etablierten, klinischen und histopathologischen Faktoren erfolgt aufgrund der Vielzahl von Untergruppen mehr und mehr in Form von mathematischen Modellen und computergestützter Auswertung. Neben der Darstellung aktueller Programme soll in dieser Übersichtsarbeit des Weiteren der Fokus auf etablierten, molekularen Markern, die bereits eine umfassende klinische Validierung vorweisen können, und neuen molekularen Markern liegen, die durch genomweite Ansätze identifiziert wurden.

Background: We present a series of skin-sparing mastectomies (SSMs) with skin reduction and immediate breast reconstruction to treat large and ptotic breasts. The technique combines oncological mastectomy with immediate subpectoral implant placement as a single-step procedure. Methods: Data was collected from a prospective database from February 2009 to April 2011. A total of 24 patients with macromastia or pronounced ptosis fulfilled the criteria for skin-saving mastectomy. All operations were carried out as a single-step procedure with adaptation of the contralateral breast by reduction mastopexy. Results: A total of 27 SSMs were performed in 24 patients. The mean implant volume was 265 cm3. Immediate reconstruction of the nipple-areola complex was done in 22 patients. The cosmetic and functional results were assessed in all patients 6 months postoperatively; mean follow-up time was 13 months. Mean patient age was 49 years. The cosmetic result was assessed as “very good” or “good” by 22 patients; 2 patients graded the result as “unsatisfactory”. There was one local recurrence. Conclusion: Our results support the use of this technique as a safe oncoplastic procedure which is well tolerated by patients.

Objective P53 tumor suppressor gene plays a role in endometrial carcinogenesis. Former studies described correlations between p53 protein overexpression in endometrial cancer and prognostic factors, measured by immunohistochemistry. But data is still controversial. The aim of this study was to measure p53 and phospho-p53 overexpression by Western blot and evaluate correlations between overexpression and prognostic and clinical factors. Phospho-p53 seems to be the functional p53 protein and was examined for the first time in endometrial cancer. Methods 40 patients with endometrial cancer were included in the study. A control group of 20 patients with normal endometrial tissue samples was used. Western blot was performed for detection of p53 and phospho-p53. Clinical and pathological parameters were obtained from medical records. Statistical analysis was performed using the log-rank test, the Mann–Whitney test for two independent groups and the Fisher's exact test for dichotomous groupings. Results In 17.5% of the patients with endometrial cancer a p53 overexpression could be evaluated. There was a correlation between a p53 overexpression and recurring disease (p: 0.014), a negative progesterone receptor status (p: 0.021) and a low BMI (p: 0.022). Only one of 40 patients had a phospho-p53 expression. Conclusion Western blot is a valid method for the detection of p53 overexpression. As other authors described before, p53 overexpression seems to correlate with negative prognostic factors. The correlation between p53 overexpression and a low BMI may underline the relationship between p53 alterations and biological aggressive endometrial carcinomas.

Background: In recent years, surgeons have utilized Harmonic instruments to perform breast cancer resection. Retrospective and prospective studies have demonstrated that the use of this surgical device for mastectomy and axillary dissection can reduce perioperative blood loss, seroma formation, and duration and total amount of drainage. No study has analyzed the feasibility of Harmonic instruments in breast-conserving surgery. We conducted a prospective, randomized clinical trial comparing Harmonic instrument and conventional surgery in the performance of breast conserving surgery and axillary procedures to determine differences in surgical procedures, postoperative outcome, and complications. Methods: One hundred and forty seven patients with operable breast cancer who underwent breast-conserving surgery at a single institution between December 2009 and March 2011 were included in the analysis. Surgery was performed in 73 patients with the Harmonic Focus® device and in 74 with scissors and electrocautery. Charts were reviewed for patient demographics, histopathologic reports, surgical procedures, length of stay, volume and duration of postoperative drainage, complications such as seroma and hematoma formation, and postoperative pain. Results: We found a statistically significant difference in size of resected breast tissue (p Discussion: This is the only study comparing the Harmonic instrument with traditional surgery in both breast conserving surgery and axillary procedures. From this study, we conclude that despite higher costs, the Harmonic device is safe to use and provides key benefits in intraoperative technique, postoperative outcome, and rate of complications in breast cancer surgery. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-15-09.

Background: The EndoPredict (EP) score is a multigene classifier to predict the likelihood of distant recurrence in ER-positive, HER2−negative breast cancer patients treated with adjuvant endocrine therapy. Two large randomized phase III trials involving endocrine therapy only (n > 1700) demonstrated additional prognostic information of the EP score independent from clinicopathological parameters by classifying 49% as low risk. However, the predictive role of the EP is not clear. Therefore, we examined whether the EP Score also predicts sensitivity towards neoadjuvant chemotherapy in ER-positive, HER2−negative breast cancer patients. Methods: Four publicly available gene expression data sets (Affymetrix HG-U133A) were retrieved from the gene expression omnibus (GEO) data repository. All analyzed breast cancer patients were treated with anthracycline or taxane/anthracycline-based neoadjuvant chemotherapy. Microarray cel files were MAS5 normalized with a global scaling procedure and a target intensity of 500. The analysis was restricted to ER-positive, HER2−negative breast cancer patients according to pre-specified cut-off levels for the respective ESR1/ERBB2 Affymetrix probesets. The EP score was calculated and patients were classified as having low or high risk according to the pre-specified validated cut-off value. Pathological complete response (pCR) — defined as no residual invasive cancer in the breast or lymph nodes — was used as the primary endpoint for the assessment of treatment response. Results: The EP Score was examined in 221 ER-positive, HER2−negative breast cancer patients treated with neoadjuvant therapy. Among the 221 patients, 61 tumors (27.6%) were classified as EP-low-risk, whereas 160 tumors (72.4%) were EP-high-risk. Only one of the EP-low-risk tumors achieved a pCR after neoadjuvant therapy, whereas 24 of the 25 pCR events were classified as EP high risk. The sensitivity of the EP score was 96% and the negative predictive value 98% with an area under the receiver operating characteristic curve of 0.73. Conclusions: The EP Score is a predictor of chemosensitivity in the neoadjuvant setting. The test correctly identified all but one of the patients achieving a pCR suggesting that the benefit of cytotoxic chemotherapy is limited to the EP high risk group. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-26.

Noninvasive biomarkers are urgently needed for detecting breast cancer as early as possible since the risk of recurrence, morbidity, and mortality is closely related to disease stage at the time of primary surgery. There are currently no such biomarkers in clinical use as a diagnostic tool. Proteomic analysis of protein expression patterns in body fluids has potential for use in identifying biomarkers of breast cancer. The aim of this study was to compare protein expression levels in the sera of primary breast cancer patients and healthy controls. An antibody microarray tool with 23 antibodies immobilized on nitrocellulose slides was used to determine the levels of acute phase proteins, interleukins, and complement factors in the sera of 101 study participants (49 women with primary breast cancer and 52 healthy age-matched controls). Statistical analysis of reaction intensities identified 6 proteins that showed significantly (p0.05) different levels in breast cancer patients vs. healthy subjects. The neural network distinguished cancer patients from controls with a sensitivity of 69% and a specificity of 76%. Thus, antibody microarray analysis could be used as a tool for the development of improved diagnostics and biomarker discovery for breast cancer patients. Further validation of the results and de novo screening of new biomarkers could facilitate the early diagnosis of breast cancer.

Purpose: According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer treated with adjuvant endocrine therapy. Experimental Design: RNA levels assessed by quantitative reverse transcriptase PCR in formalin-fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n = 378, ABCSG-8: n = 1,324]. Results: In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P = 0.010, ABCSG-8: P < 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone [c-indices: 0.764 vs. 0.750, P = 0.024 (ABCSG-6) and 0.726 vs. 0.701, P = 0.003 (ABCSG-8)]. EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P < 0.001) and ABCSG-8 (P < 0.001), respectively. Conclusions: The multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors. Clin Cancer Res; 17(18); 6012–20. ©2011 AACR.

Background: Molecular tests predicting outcome of breast cancer patients may be useful for treatment decisions in addition to standard clinicopathologic features. Methods: Using human genome HG-U133A array and qRT-PCR datasets, we developed and validated a gene-expression signature predicting the likelihood of distant recurrence in postmenopausal, early-stage breast cancer patients with estrogen receptor-positive, HER2-negative tumors treated with adjuvant endocrine therapy. RNA levels assessed by qRT-PCR in formalin-fixed paraffin-embedded tumor specimens were used to calculate a risk score (T5) and to determine a risk group (low or high) for each patient. The prospectively defined T5 risk score was then validated independently in patients from two large randomized phase III trials. Distant recurrence-free survival and overall survival were analyzed with Cox models adjusted for clinicopathological factors. The primary endpoint was time to distant recurrence. Results: In a training set of 964 tumors, we identified a gene-expression signature consisting of three proliferation-related genes (BIRC5, UBE2C, DHCR7), five estrogen-regulated genes (RBBP8, IL6ST, AZGP1, MGP, STC2), and three reference genes (CALM2, OAZ1, RPL37A). For the validation, RNA analysis was possible in 1702 of 1725 (99%) tumors of both validation sets. Women were classified as having low risk (n=832; 49%) or high risk (n=870; 51%) by the T5 risk score. The T5 risk score provided prognostic information independent from clinicopathologic risk as estimated by Adjuvant!Online or Ki67 labeling index. Patients with a higher T5 risk score had a significantly shorter time to distant recurrence (adjusted hazard ratio, 1.24; 95% confidence interval [CI], 1.15 to 1.33; P Conclusions: Using formalin-fixed paraffin-embedded tumor specimens, the multigene T5 risk score provides prognostic information independent of Adjuvant!Online or Ki67 labeling index. By combining the T5 risk score with clinicopathological risk, we were able to accurately identify breast cancer patients with low risk or high risk for distant recurrence. Using this new easy-to-use multigene tool in clinical practice will assist in optimizing adjuvant therapy by reducing both undertreatment and overtreatment and thus improves outcome and quality of life of patients with early-stage breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-07.

Since suburethral vaginal slings introduced a new era for the treatment of genuine stress urinary incontinence, new surgical techniques with alloplastic meshes have begun to be used in pelvic reconstructive surgery for vaginal prolapse. Thus established procedures without artificial materials are competing directly against new techniques using modern meshes. Controlled clinical trials will be necessary to allow a direct comparison in terms of evidence-based medicine. There are a variety of different vaginal and abdominal approaches available to treat prolapse. We describe the classic procedures and the new techniques using alloplastic material. The currently available data are presented and discussed. Standard operations such as colporrhaphy, abdominal sacral colpopexy and vaginal sacrospinous fixation still offer high success rates with only few complications. Although the abdominal route may offer some advantages with respect to the recurrence of prolapse, especially in the anterior compartment, and sexual function, vaginal sacrospinous colpopexy is characterized by a lower postoperative morbidity and comparable cure rates. The problem of the simultaneous correction of accompanying stress urinary incontinence versus correction following reconstructive surgery alone is discussed. Following the widespread use of new techniques and meshes, a new spectrum of postoperative complications ranging from erosions to infections has emerged, requiring an adequate management. As the current data only covers relatively small numbers and long-term follow-up is lacking, a final statement on the use of mesh material in reconstructive pelvic surgery cannot be made so far. While classic procedures without a mesh should be preferred for primary operations, mesh enforcement offers a promising alternative for relapse cases and in high-risk situations.

Objective. A multicenter non-randomized phase II study was initiated to evaluate tolerability and efficacy of pegylated liposomal doxorubicin (PLD) in combination with carboplatin in gynecologic malignancies. Methods. One hundred forty women with recurrent or advanced endometrial ( n =31), cervical or vaginal cancer ( n =31), uterine sarcomas ( n =11), or recurrent platinum-sensitive ovarian cancer ( n =67) received six courses of PLD 40 mg/m 2 and carboplatin (AUC 6) every 28 days. Results. Hematological toxicities with NCI-CTC grade 3/4 were anemia in 8%, thrombocytopenia in 14%, neutropenia in 24%, and febrile neutropenia in 2% of 652 cycles. Grade 3/4 non-hematological toxicities included fatigue (14% of patients), pain (10%), dyspnea (9%), palmar–plantar erythrodysesthesia (7%), and nausea/vomiting (7%). Dose intensity reached 87.2% for PLD and 88.2% for carboplatin. Seventy-four percent of all non-progressive patients received at least 5 cycles. Overall response rates were (116 patients evaluable for response): ovarian cancer ( n =54) 68%, endometrial cancer ( n =27) 44%, uterine sarcomas ( n =9) 33%, and cervical/vaginal cancer ( n =26) 12%. Median progression-free survival was 11.6 months (95%CI 9.6–14.1) for ovarian cancer and 9.5 months (95%CI 6.6–12.6) for endometrial cancer. Median overall survival was 23.8 months (95%CI 19.0–30.2) and 21.4 months (95%CI 11.9–), respectively. Conclusions. The combination of PLD and carboplatin was well tolerated and feasible in patients with gynecologic malignancies. Efficacy was low in cervical/vaginal cancer, but promising in patients with endometrial cancer. Efficacy was within the expected range in recurrent platinum-sensitive ovarian cancer and is currently under further investigation in a prospective randomized phase III trial comparing PLD/carboplatin with paclitaxel/carboplatin (CALYPSO-trial; AGO-OVAR 2.9).

Die gegenwärtige Entwicklung unterschiedlicher Mesh-Materialien hat zu einer Verbesserung der individuellen operativen Sanierung des Genitalprolapses geführt. Makroporöse monofilamentäre synthetische Netze scheinen geeignet zur Verwendung beim Rezidivprolaps oder bei ausgeprägten Beckenbodeninsuffizienzen zu sein. Die Verwendung von biologischen Netzen zeigt eine deutlich bessere Verträglichkeit mit weniger Infektionen oder Erosionen, bislang ist jedoch nicht das Problem der langfristigen Haltbarkeit geklärt. Die operative Korrektur des Genitalprolapses muss alle Risiken und Nutzen zur Verbesserung der Lebensqualität abwägen, hier können Mesh- Materialien deutliche Vorteile gerade in der Rezidivsituation erbringen.

Fragestellung: Goserelin unterdruckt uber den Umweg der Blockierung der hypophysaren Gonadotropin-Synthese die ovarielle Steroidproduktion, ist aber nicht in der Lage, die periphere Steroidproduktion zu inhibieren. Der Aromatase-Inaktivator Exemestan fuhrt dagegen sowohl peripher als auch in den gonadalen Synthesestatten zu einem optimalen Abfall der Estrogen-Spiegel. Somit musste die Kombination von Goserelin und Exemestan in der adjuvanten Therapie des primaren Mammakarzinoms bei pramenopausalen Patientinnen zur Optimierung des Therapieergebnisses fuhren. Die zu erwartende klimakterische Symptomatik unter diesem Therapieregime kann moglicherweise durch Zusatz von Tibolon als Additivum gemildert werden. Ziel der vorliegenden Arbeit ist es, das Risiko und die Tolerabilitat einer solchen Medikamentenkombination aus Goserelin und Exemestan mit und ohne Tibolon zu uberprufen. Material und Methoden: Es handelt sich um eine offene, randomisierte, multizentrische ADAGIO (Adjuvante Aromasin-Goserelin Studie)-Pilotstudie, Dauer 24 Wochen. 48 pramenopausale Patientinnen (Alter 35 - 55 Jahre) mit histologisch gesichertem, rezeptorpositivem Mammakarzinom mit niedrigem Risiko (pT1, N0, M0 [Grading 1 - 2]) wurden in die Studie aufgenommen. Die Patientinnen wurden in vier Therapiearme randomisiert: Goserelin, 3,6 mg Depot, s.c. alle 28 Tage; Goserelin plus Exemestan oral, 25 mg taglich; Goserelin plus Tibolon 2,5 mg oral, taglich; Goserelin plus Exemestan plus Tibolon. Ergebnisse: In allen vier Therapiearmen kam es zu einem rapiden Abfall der Serumspiegel fur Estradiol, Estron und Estronsulfat auf postmenopausale Werte; LH und FSH wurden ebenfalls supprimiert. Die Differenzen zwischen den Therapiegruppen waren nicht signifikant. Die klimakterischen Symptome nahmen an Intensitat uber den Behandlungszeitraum zu. Die Patientinnen, die Tibolon als Zusatztherapie erhielten, wiesen signifikant weniger Hitzewallungen (p < 0,01), Schlafstorungen (p < 0,05), Libidoverlust (p < 0,01) und vaginale Trockenheit (p < 0,05) auf. Die Kombination Goserelin/Exemestan reduzierte die Knochendichte nicht mehr als Goserelin allein. Es wurde aber ein Trend hin zu einem protektiven Effekt auf die Knochendichte bei Zusatz von Tibolon beobachtet. Signifikante Differenzen hinsichtlich unerwunschter Nebenwirkungen im Vergleich aller vier Therapiearme waren nicht zu verifizieren. Schlussfolgerung: Die kombinierte Therapie von Goserelin und Exemestan ist so sicher und gut tolerabel wie die Standardtherapie mit Goserelin allein. Das Additivum Tibolon reduziert signifikant eine Reihe durch die Therapie induzierter klimakterischer Symptome und scheint positiven Einfluss auf die Knochendichte zu nehmen. Purpose: Goserelin suppresses ovarian function, but does not inhibit oestrogen production in peripheral tissues. Therefore addition of the aromatase inactivator exemestane may optimally decrease oestrogen levels. The combination of goserelin and exemestane may therefore be useful in the adjuvant treatment of primary breast cancer. The climacteric symptoms expected with this regimen may be relieved by tibolone. Material and Methods: The 24-week, open, randomised, multicentre ADAGIO (Adjuvant Aromasin combined with Goserelin) pilot study was conducted in 48 premenopausal women (aged 35 - 55 years) with histologically confirmed oestrogen and/or progesterone receptor-positive, node negative primary breast cancer (pT1, M0 [grade 1 - 2]) of low or intermediate risk. Patients were randomised to one of four groups: goserelin 3.6 mg depot implanted s.c. every 28 days; goserelin plus oral exemestane 25 mg/day; goserelin plus oral tibolone 2.5 mg/day; or goserelin plus exemestane and tibolone. Results: There was a rapid fall in serum oestradiol, oestrone and oestrone sulphate to postmenopausal levels in all four treatment groups; there were no significant differences between the groups. LH and FSH were also suppressed. Climacteric symptoms increased in intensity in all groups, although patients receiving tibolone had significantly fewer hot flushes (p < 0.01), sleep disorders (p < 0.05), loss of libido (p < 0.01) and vaginal dryness (p < 0.05). The combination of goserelin and exemestane did not reduce bone mineral density (BMD) more than goserelin alone. There was a trend towards a protective effect of tibolone on BMD. There were no significant differences in adverse events between the four groups and no serious adverse events were observed. Conclusions: Combination treatment with goserelin and exemestane is as safe and well tolerated as standard treatment with goserelin alone. The addition of tibolone reduces the severity of some climacteric symptoms and may also reduce bone loss.

Purpose: HER-2 blocking strategies, for instance with trastuzumab (Herceptin®), have been successfully used in therapy of breast cancer. To study molecular mechanisms and the efficiency of HER-2 blocking therapies we established a mouse tumor model that allows switching-off of HER-2 expression in tumor tissue. Material and Methods: NIH3T3 cells conditionally expressing HER-2 by the TET-OFF system (NIH3T3-HER-2 cells) were subcutaneously injected into the dorsal skin of nude mice. These cells allowed switching-off of HER-2 expression by exposure to anhydrotetracycline. We examined the influence of HER-2 down-regulation on tumor volume of subcutaneously growing tumors in nude mice. Tumor development was studied by magnetic resonance imaging. HER-2 expression was quantified by Western Blot analysis. Results: Eight to ten days after injection of 7 × 10 6 NIH3T3-HER-2 cells small subcutaneously growing tumors became visible. A surprisingly efficient tumor remission was observed already 7 days after switching-off of HER-2 expression: mice with initial tumor volumes of 0.8, 1.2, 3.9 and 14.9 cm 3 showed a decrease in tumor volumes to 1.9, 11.8, 11.3 and 25.8%, respectively, compared to the respective volumes before anhydrotetracycline administration. In contrast, a steady increase in tumor volume was observed for mice not exposed to anhydrotetracyclin. Conclusion: Switching-off of HER-2 expression causes a strong remission already after 7 days. Interestingly, the extent of tumor remission depends on initial tumor size, whereby a stronger remission can be achieved for smaller tumors. Our data support clinical studies testing HER-2 blocking strategies as adjuvant therapy for early breast cancer.

The main reason for the restricted use of methotrexate in the treatment of ectopic pregnancy (EP) obviously is the fear of tubal rupture in patients with lower abdominal pain after the administration of methotrexate. Therefore, we wanted to find out if patient characteristics at first presentation, such as age, pretreatment β-hCG level, adnexal mass as visualized by transvaginal ultrasonography, or history of prior EP, would identify patients at risk for tubal rupture if they were hemodynamically stable and showed no signs of peritoneal irritation. We examined whether more patients could have been treated medically with methotrexate, because tubal rupture was unforeseeable at first presentation and inclusion criteria for methotrexate treatment were fulfilled. From January 1996 to August 1998, 122 patients diagnosed as having EP were treated at the Gynecologic Department of the University Hospital of Vienna. Inclusion criteria for medical treatment with intramuscular methotrexate (50 mg/ m2 body surface area) were (1) hemodynamic stability, (2) an unruptured ectopic mass ≤5 cm at the greatest dimension demonstrated at transvaginal ultrasonography; (3) β-hCG level ≤5,000 mIU/ml; (4) no cardiac activity of the extrauterine embryo; (5) wish of future fertility, and (6) informed consent. Patients with hemodynamic instability, severe abdominal pain, an ectopic mass ≥5 cm at the greatest dimension, β-hCG levels ≥5,000 mIU/ml, cardiac activity of the extrauterine embryo, and no wish of future fertility, or disagreement with methotrexate treatment, primarily underwent surgery. Despite the fact that none of the above patient characteristics at first presentation identified patients at risk for tubal rupture, only 60/122 patients (49%) actually underwent medical treatment whereas our inclusion criteria would have granted medical treatment in 101/122 patients (83%). We determined the actual and maximal possible percentages of patients with unruptured EP eligible for medical treatment of EP with intramuscular single-dose methotrexate 50 mg/m2 body surface area. Our data show that tubal rupture in hemodynamically stable patients is not foreseeable and should not lead to a restricted use of medical treatment in patients preferring methotrexate.

OBJECTIVE: The aim of the study was to compare the perinatal outcome of spontaneously conceived twins with those conceived after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). MATERIAL AND METHODS: A retrospective study was performed. Clinical data of 188 twin pregnancies was collected from the Department of Obstetrics and Gynecology, University Hospital of Mainz for the years 1996-2006. The twins were divided into 2 groups according to the manner of conception: spontaneously conceived twins (n = 142) and twins (n = 46) conceived after IVF and ICSI. In order to investigate the perinatal outcome of spontaneous twins and twins conceived by assisted reproductive technology (ART), we evaluated the following parameters: maternal age, fertility, nulliparity rate, gestational age, mode of delivery, fetal weight and Apgar score. RESULTS: No significant difference was found in maternal age, fertility and gestational age between spontaneous twins and IVF/ICSI twins. Maternal gestational age was 255 days in the spontaneous group and 254 days in IVF/ICSI group. Fetal weight and Apgar score were similar between the two groups. The nulliparity rate was higher in IVF/ICSI group. Obviously there were more cesarean sections in the IVF/ICSI group than in the spontaneous group (76.2 % and 42.5 %, respectively). CONCLUSIONS: Duration of gestation, neonatal birth weight and Apgar score were similar between IVF/ICSI twins and spontaneous twins. IVF/ICSI twins had a higher cesarean section rate.

Objective. To determine the present state of urogynecological diagnostics, therapy and follow-up in the Departments of Gynecology and Obstetrics in Austria. Design. We sent questionnaires to all Departments of Gynecology and Obstetrics in Austria. The anonymous questionnaire consisted of 25 multiple choice questions. It was possible to choose one ore more answers by ticking applicable boxes with the casual option to give some additional information in form of free text. Results. Fifty-eight departments (58%) returned their questionnaires completely answered indicating interest in quality management in medicine. The most remarkable discrepancy was found between the interrogated people's estimation of the expressiveness of examination techniques and the actual use of such techniques. Conclusion. We regard the results of this survey as a basis for further quality management strategies in the field of urogynecology in Austria.

Objective Rigid cystoscopy is a common diagnostic tool in the assessment of lower urinary tract symptoms, but it is an invasive procedure which can cause distress. Data exist about pain perception during cystoscopy in male patients but only a few data are available in women. The purpose of this study was to investigate pain perception in urogynecologic patients during cystoscopy and compare it with pain perception during urodynamics. We also investigated the difference between anticipated and actual pain perception. Study design A cooperative, non-randomized cohort study was performed including 109 women with pelvic floor dysfunction scheduled for outpatient cystoscopy or urodynamic testing. Patients completed a questionnaire and a visual analog scale (VAS, 0–10 cm) before and after examination. Patients were called one day after examination and asked about pain and their general state of health. According to power calculation, a sample size of 52 patients per group was needed to detect a 2 cm difference in pain scores on the VAS – judged as a clinically significant – with 95% power and a two-sided significance level of 0.05. Results In 57 patients undergoing cystoscopy versus 52 patients undergoing urodynamics, the main pain scores on VAS were 1.9 cm for cystoscopy and 1.2 cm for urodynamics (p = 0.03). Patients in both groups anticipated more pain than they actually experienced: 2.7 ± 2.4 before versus 1.9 ± 1.8 after cystoscopy (p Conclusion Patients experience cystoscopy as more painful than urodynamics. Patients anticipate both cystoscopy and urodynamics to be more painful than they actually are.

Fragestellung: Eine aberrante Expression von spezifischen Isoformen (Splice-Varianten) des Adhasionsmolekuls CD44 wurde in verschiedenen malignen Tumoren des Menschen nachgewiesen. Wir wollten abklare

The value of transvaginal ultrasound in gynaecological examinations is beyond dispute. But it is of particular forensic importance that the validity of this type of imaging with regard to the reliable detection of early-stage malignancy is properly understood. Vaginal ultrasound screening in asymptomatic patients for the early detection of endometrial carcinoma is not useful from a medical point of view, nor is it cost-efficient. However, even though the validity of transvaginal ultrasound for screening has currently not been proven, the method should still be an integral part of gynaecological examinations.Die Wertigkeit der transvaginalen Ultraschalluntersuchung im Rahmen der gynäkologischen Untersuchung ist unbestritten. Es ist aber von besonderer auch forensischer Bedeutung, dass die Aussagekraft dieses Untersuchungsverfahrens im Hinblick auf das sichere Erkennen einer Krebserkrankung im Frühstadium sinnvoll eingeordnet wird. Unter Kosten-Nutzen-Gesichtspunkten ist ein generelles Screening bei asymptomatischen Patientinnen nicht sinnvoll. Zwar kann die transvaginale Sonografie das Ziel als Screeninginstrument zum gegenwärtigen Zeitpunkt nicht erreichen kann, sie bleibt aber integraler Bestandteil der gynäkologischen Untersuchung.

The new development of single-incision slings (SIS) for the treatment of female stress urinary incontinence offers comparable results with only minimal side effects and will find wide acceptance in modern incontinence surgery. This mini-sling is inserted over a single vaginal incision and fixed on both sides to the pelvic wall tissue with special anchors, without passing through the groin and avoiding a blind tape passage. Compared with the established sub-urethral tapes, there are comparable success rates with fewer complications. Randomised prospective studies are needed to evaluate whether, in the long run, the benefits of the single incision technique can be correlated with satisfying continence results.Die Neuentwicklung von Single-Incision-Schlingen (SIS) bei der operativen Therapie der Belastungsinkontinenz der Frau ist mit vergleichbaren Kontinenzraten und nur geringsten Nebenwirkungen verbunden und kann in Zukunft breite Anwendung in der Inkontinenztherapie finden. Diese minimalinvasiven Schlingen werden über eine singuläre vaginale Inzision eingebracht und bds. an der Beckenwand über verschiedene Haltesysteme verankert. Bei gleicher Wirkung durch suburethralen Bandsupport wird hier jedoch eine Blindpassage wie bei den bekannten retropubischen oder transobturatorischen Systemen vermieden. Im Vergleich zu den etablierten suburethralen Schlingen zeigen sich in den ersten Untersuchungen äquivalente Erfolgsraten und deutlich geringere Nebenwirkungen. Hierzu müssen prospektive Studien die Wertigkeit im Vergleich zu den etablierten Verfahren noch belegen.

Background In recent years, surgeons have utilized Harmonic instruments to perform breast cancer resection. Retrospective and prospective studies have demonstrated that the use of this surgical device for mastectomy and axillary dissection can reduce perioperative blood loss, seroma formation, and duration and total amount of drainage. No study has analyzed the feasibility of Harmonic instruments in breast-conserving surgery. We conducted a prospective, randomized clinical trial comparing Harmonic instrument and conventional surgery in the performance of breast-conserving surgery and axillary procedures to determine differences in surgical procedures, postoperative outcome, and complications. Methods One hundred and six patients with operable breast cancer who underwent breast-conserving surgery at a single institution between December 2009 and January 2011 were included in the analysis. Surgery was performed in 52 patients with the Harmonic Focus ® device and in 54 with scissors and electrocautery. This study focused on operative time, drainage volume, and postoperative outcome measures like blood loss, surgery related complications and patient-reported postoperative pain. Results We found a multivariable independent influence in axillary seroma formation and volume of breast drainage with HS. Evident difference in volume and duration of axillary and breast drainage, subjective and objective postoperative pain, reduction in serum hemoglobin, size and weight of resected breast tissue and length of hospital stay in favor of the Harmonic instrument could also be shown. Discussion The Harmonic instrument provides key benefits in surgical technique, postoperative outcome, and complication rates in breast cancer surgery.