Search

BACKGROUND Treatment of patients with advanced breast cancer (ABC) has evolved significantly. Nevertheless, further improvement in ABC treatment is a high medical need. Besides the prolongation of progression free survival (PFS) and overall survival (OS) the major objective of new therapeutic approaches is the enhancement of quality of life (QoL). A recent advance for the treatment of ABC was the development of the cremophor-free albumin-bound paclitaxel, nab-Paclitaxel. SPECIFIC AIMS/TRIAL DESIGN The aim of this non-interventional study is the analysis of efficacy and safety data of ABC patients within routine treatment with nab-Paclitaxel. A key focus will be the assessment of patient reported outcomes (PRO), health economic aspects and the influence of breast cancer patient characteristics on prognosis, adverse event frequencies, PRO and therapy decision making. Patients with ABC, who experienced failure of first-line treatment for metastatic disease and for whom standard anthracycline-containing therapy is not indicated, will be followed up under real-life conditions. Sixty sites, equally distributed with regard to their organizational structure (hospital and office based) and medical disciplines (gyneco-oncologists and medical oncologists) will document 1,200 patients. The primary objective is the assessment of PFS under real-life conditions. Secondary objectives include the assessment of overall and breast cancer specific survival, the influence of age on prognosis and QoL, as well as the incidence of (serious) adverse events (AE). PRO including FACT-B, FACT-Taxane, and nab-Paclitaxel treatment specific questions will be collected in a web based application and compared to paper based reporting. Furthermore, biomaterials will be collected to allow translational research projects. ELIGIBILITY CRITERIA: Adult women (>18 years) with ABC and treated with nab-Paclitaxel. STATISTICAL METHODS/TARGET ACCRUAL: In Germany nab-Paclitaxel is indicated for patients with metastatic breast cancer after failure of a previous therapy in ABC. In this therapeutic setting several studies have shown high efficacy and acceptable toxicity. However, populations within clinical trials are selected and may be different from the general patient population in clinical practice. Therefore this study aims at the capture of PFS, PRO and AE in the general population for which nab-Paclitaxel is used in clinical practice. Nab-Paclitaxel treatment will be documented over a period of up to 6 months, followed by a 30 months progression/ survival follow-up. Target accrual is 1,200 patients. We assume that at most 10% are lost to follow-up before the median survival time is reached. Kaplan-Meier curves will be calculated, especially the median survival time with 95% confidence interval. Citation Format: Fasching PA, Wallwiener M, Lux MP, Mueller V, Schneeweiss A, Tesch H, Brucker SY, Haeberle L, Spall T, Belleville E, Lück H-J. Seraphina – Safety efficacy and patient reported outcomes of advanced breast cancer patients: Therapy management with NAB-paclitaxel in daily routine. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-09.

Background: Despite improvements in the treatment of HER2+ breast cancer (BC), almost all patients (pts) progress in the metastatic setting. Three examples of resistance mechanisms are: PI3K mutations, lack of ADCC, or low expression of HER2. We recently showed that among 237 pts who had HER2 amplifications, 49% had normal or low levels of HER2 RNA. In addition, quantification of HER2 protein by selected reaction monitoring mass spectrometry (SRM-MS) accurately predicted HER2 expression status compared with IHC (3+)/ISH (≥2.0). Here we report a comprehensive panomic approach that integrates whole genome sequencing (WGS), RNASeq, quantitative proteomics, and pathway analysis to determine associations between tumor molecular profiles and prognosis among HER2+ pts. Methods: Matched tumor-normal samples (FFPE tumors and blood) were obtained from 58 pts with HER2+ BC who had received standard adjuvant chemotherapy and trastuzumab. Pts were divided into 2 groups: those who had no recurrence after 5 years and those who had developed metastases. The HER2 status of each pt was previously determined using IHC/FISH. Samples underwent WGS and RNASeq according to NantOmics CLIA-approved assay specifications. WGS data were processed using Contraster; RNASeq data confirmed the presence of gene mutations and was used to identify mutational and transcript abundance. PARADIGM was used to reveal associations between gene mutations and pathway levels. SRM-MS was used for proteomics analysis of a panel of 53 proteins. Tumor areas from FFPE tissue sections were analyzed after laser microdissection. Absolute protein quantitation was accomplished through simultaneous detection of endogenous target and synthetic labeled heavy peptide identical to analytical targets. Genetic alterations in germline and tumor DNA were compared in pts with vs without recurrence. Results: There was no statistically significant difference in the mean concentration of HER2 in the tumors of pts with vs without recurrence: 2.34 fmol/µL vs 2.56 fmol/µL. Other analyzed proteins did not appear to be associated with recurrence; however, expected correlations between pt and tumor characteristics and protein expression were found. With regard to clinically relevant mutations, we found one germline BRCA2 mutation in a pt with no family history of this mutation. The most commonly found somatic mutations were in TP53 (11 pts), AMBRA1 (11 pts), MORC4 (10 pts), SETD2 (8 pts), CDC27 (6 pts), BCLAF1 (5 pts), ZNF479 (4 pts) , PIK3CA (3 pts), PIK3R1 (3 pts), RUNX1 (3 pts), and GATA3 (3 pts). Conclusion: Whereas HER2 expression status was predictive of OS and PFS in pts treated with trastuzumab (Nuciforo et al. Mol Onc. 2015), in this small exploratory study of HER2+ BC pts, HER2 expression status was not predictive of recurrence. To better understand the molecular mechanisms driving recurrence beyond HER2 status alone, genomic sequencing may define a signature of recurrence after anti-HER2 therapy. Citation Format: Benz SC, Rabizadeh S, Cecchi F, Beckman MW, Brucker SY, Hartmann A, Golovato J, Hembrough T, Janni W, Rack B, Sanborn JZ, Schneeweiss A, Vaske CJ, Soon-Shiong P, Fasching PA. Integrating whole genome sequencing data with RNAseq, pathway analysis, and quantitative proteomics to determine prognosis after standard adjuvant treatment with trastuzumab and chemotherapy in primary breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-04-14.

Background: Completion of axillary lymph node dissection (ALND) was long lasting standard in patients with non-metastatic primary breast cancer (PBC) and axillary sentinel lymph node (SLN) involvement. However, this approach is currently questioned since recent prospective trials have found that some SLN-positive women with PBC might not benefit from subsequent ALND. Nomograms that estimate the probability of further non-sentinel lymph node (NSLN) metastases could guide clinical decisions. Methods: We compared the predictability of three different nomograms (MSKCC, Stanford University, Cambridge) on the NSLN status with an own logistic regression model in a training and validation set. SLN-positive women who underwent primary surgery including ALND at Tuebingen University, Germany, between 06/2005 - 12/2009 (training set) and 01/2010 - 02/2012 (validation set) were available for this analysis. The area under the receiver operating characteristics (ROC) curve was calculated for each nomogram. Results: 295 and 175 patients were included into the training and validation set, respectively. Of these 118 (40%) and 57 (33%) patients were NSLN-positive. Variables within our model were tumor size, proportion of positive SLNs, size of SLN metastases, lymphangiosis carcinomatosa, multicentricity and extracapsular invasion. The respective area under the ROC curve values for the MSKCC / Stanford University / Cambridge / own regression model were 0.73 / 0.70 / 0.63 / 0.75 in the training set and 0.73 / 0.66 / 0.52 / 0.73 in the validation set. Conclusion: The predictability of our logistic regression model was comparable to the MSKCC nomogram and superior to the Stanford University and Cambridge nomogram. Although a training and a validation set was used, further testing on an independent patient population is warranted. Citation Format: Hartkopf AD, Brucker SY, Helms G, Henzel M, Hahn M, Wallwiener M, Schoenfisch B, Taran F-A, Fehm TN. A nomogram to predict the likelihood of axillary non-sentinel lymph node metastases in sentinel lymph node positive primary breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-01-14.

Background Circulating tumor cells (CTC) are a heterogeneous cell population and an independent negative prognostic factor for progression-free (PFS) and overall survival (OS) in patients with metastatic breast cancer (MBC). The study aimed to prospectively assess CTC status for the subtypes apoptotic CTC (aCTC) and intact CTC (iCTC) at baseline (CTCBL) and after one cycle of a new line of systemic therapy (CTC1C). Changes from CTCBL to CTC1C (CTC kinetics, CTCKIN) were evaluated for their utility in predicting response, progression-free (PFS) and overall survival (OS). Methods 423 MBC patients were included in a prospective trial prior to a new regimen of treatment. Intact and apoptotic CTC were analyzed at baseline (CTCBL) and after one cycle of systemic therapy (CTC1C) using CellSearch™ (Veridex) and morphologic criteria. Samples with ≥5 CTC/7.5ml blood were regarded as positive. Therapy response was assessed using the RECIST-criteria on three-monthly radiological controls. CTCKIN were characterized by ≥25% change from CTCBL to CTC1C to differentiate stable, increased and decreased CTC kinetic. Results 35% of patients were iCTCBL-positive and 28% aCTCBL-positive at baseline (CTCBL). PFS and OS differ significantly between the iCTCBL-positive and the iCTCBL-negative group (PFS 4.5 vs. 8.0; OS 12.5 vs. 27.2 (months)). Positive aCTC in conjunction with positive iCTCBL at baseline has worst prognostic impact (PFS 6.3; OS 8.7). Regarding the CTCKIN (BL to 1C), aCTC-decrease (≥25%) is a positive prognostic factor compared to aCTC-stable and aCTC-increase (PFS 7.6 vs. 3.7; 3.3 and OS 21.0 vs. 4.8; 5.7). Decreasing aCTCKIN shows favorable prognostic impact versus decreasing iCTCKIN (PFS 7.6 vs. 5.9 and OS 21.0 vs 16.4). Conclusion Elevated aCTC levels at baseline have an unfavorable prognostic impact on both OS and PFS in conjunction with elevated iCTC. Additionally, the decrease of aCTC is a relevant prognostic value for systemic therapy response. aCTCKIN allows better differentiation for therapy response in patients with positive CTC-status at baseline. Differentiated enumeration of intact and apoptotic CTC should be considered in clinical application. Citation Format: Wallwiener M, Deutsch TM, Riethdorf S, Hartkopf AD, Taran F-A, Trumpp A, Brucker S, Schütz F, Rom J, Pantel K, Schneeweiss A. Impact of apoptotic circulating tumor cells in metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-06.

To compare laparoscopic supracervical hysterectomy (LSH) with total laparoscopic hysterectomy (TLH) with regard to relevant surgical parameters and risk factors of conversion to laparotomy and complications. This prospective, open, single-center, interventional study included women with benign gynecologic disease who underwent standardized LSH or TLH. The techniques were compared for conversion rate and mean operating time, hemoglobin drop, hospital stay, and complication rates using descriptive statistics and standard non-parametric statistical tests. Risk factors of conversion and complications were identified by logistic regression analysis. During January 2003 to December 2010, 1,952 women [mean age (SD): 47.5 (7.2) years] underwent LSH [1,658 (84.9 %)] or TLH [294 (15.1 %)], mostly (>70 %) for uterine fibroids. Significant differences in surgical parameters were observed for conversion rate (LSH/TLH: 2.6/6.5 %), mean operating time [87 (34)/103 (36) min], hemoglobin drop [1.3 (0.8)/1.6 (1.0) g/dL], and hospital stay [4.3 (1.5)/4.9 (2.8) days]. Overall intraoperative (0.2/0.7 %) and long-term (>6 weeks) post-operative (0.8/1.7 %) complication rates did not differ significantly, but the short-term LSH complication rate was significantly lower (0.6 vs. 4.8 %). Spotting (LSH, 0.2 %) and vaginal cuff dehiscence (TLH, 0.7 %) were long-term method-specific complications. Logistic regression showed that uterine weight and extensive adhesiolysis were significant factors for conversion while previous surgery, age, and BMI were not. Major risk factors of short-term complications were age, procedure (LSH/TLH), and extensive adhesions. Both procedures proved effective and were well tolerated. LSH performed better than TLH regarding most outcome measures. LSH is associated with very low rates of re-operation and spotting.

Objective To analyze the histologic and immunohistochemical structure of uterine rudiments focusing on the endometrium in a representative group of patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome compared with a control group. Design Prospective comparative study. Setting University hospital. Patient(s) Forty-two patients with MRKH syndrome and 13 control subjects. Intervention(s) Representative biopsies or whole uterine rudiments were removed during surgery and processed by a standardized procedure including immunohistochemical staining and analysis. Main Outcome Measure(s) Histologic structure, tissue types, hormone receptor expression, endometrial proliferative capacity, and type in correlation with cycle phase. Result(s) Twenty-two of the uterine rudiments showed a duct-like structure or small cavity, 17 of which contained endometrial epithelium and CD10-positive stroma. All rudiments contained an intact myometrial layer. Tubal epithelium and stroma were found in three rudiment samples. No significant differences were observed with regard to estrogen receptor (ER) or progesterone receptor (PR) expression in endometrium or myometrium. Interestingly, patients showed predominantly basalis-like endometrium with specific lack of CD90 expression and significantly lower proliferation compared with controls. Conclusion(s) All typical uterine tissues can be found in uterine rudiments of patients with MRKH syndrome. Expression of hormonal receptors in the latter and controls did not differ significantly. Endometrium shows predominantly basalis-like features in uterine rudiments.

The aim of this retrospective study was to analyze the outcome of patients with locally advanced cervical carcinoma treated by adjuvant radiochemotherapy and to determine risk factors for local and distant relapse. Furthermore, acute and late effects of treatment were recorded. A total of 72 patients with FIGO stages I–III cervical carcinoma were treated by radical hysterectomy, pelvic lymphadenectomy, and postoperative radiochemotherapy. Only patients with positive pelvic lymph nodes, parametrial involvement, positive margins, or tumor bulk were eligible. Patients were irradiated with a standard pelvic field (50.4 Gy in 28 fractions). The majority of patients received platinum-based chemotherapy. After a median follow-up of 37 months, estimated 1-, 2-, and 4-year disease-free survival (DFS) and overall survival (OS) rates were 89%, 80%, 68% and 95%, 88%, 76%, respectively. Nine of the 72 patients had pelvic recurrences including only 1 isolated local failure; 23 of the 72 patients presented with distant relapse. The majority of relapses occurred within the first 3 years after adjuvant treatment. The number of positive pelvic lymph nodes (> 1) was the strongest prognostic factor for DFS. Treatment was well tolerated with transient acute hematologic (~30%) and gastrointestinal (~30%) grade 3 toxicity. Small bowel obstruction (~6%) was the only important late sequelae. Adjuvant radiochemotherapy in patients with advanced cervical cancer and several risk factors is highly effective to prevent local relapse. Future efforts to improve outcome should be placed on improvement of systemic control especially in subgroups with high-risk features for distant relapse. Combined treatment was well tolerated with moderate acute and late toxicity.

To better characterize adenomyosis as a disease entity. We retrospectively reviewed the medical records of women undergoing hysterectomy with a histologic diagnosis of adenomyosis, adenomyosis and leiomyomas, and leiomyomas alone. The study included 291 women: 38 with adenomyosis alone, 56 with adenomyosis and leiomyomas, and 197 with leiomyomas alone. In univariate analysis, women with adenomyosis were younger (p = 0.018) and had lower uterine weights (p

Background Repeat radiation is a rarely used treatment strategy that must be performed with caution. The efficacy and toxicity of a second curative radiotherapy series was investigated in cases of recurrent breast cancer. Methods Forty-two patients treated from 1993 to 2003 with resection (n = 30) and postoperative re-irradiation or definitive re-irradiation (n = 12) for recurrent breast cancer were enrolled in the study. Concurrent hyperthermia was performed in 29 patients. The median age was 57 years. The median pre-radiation exposure was 54Gy. Re-irradiation was conventionally fractionated to a median total dose of 60Gy. Results After a median follow-up of 41 months (range 3-92 months) higher graded late toxicity > G3 according to CTC 3.0 and LENT-SOMA was not observed. The estimated 5-year local control rate reached 62%. The estimated 5-year overall survival rate was 59%. Significantly inferior survival was associated with recurrence within two years (40 vs. 71%, p < ([0-9]).01) and presence of macroscopic tumour load (24 vs. 75%, p = 0.03). Conclusions Repeat radiotherapy for recurrent breast cancer with total radiation doses of 60 Gy and the addition of hyperthermia in the majority of patients was feasible, with acceptable late morbidity and improved prognosis, particularly in patients with previous resection of recurrent tumours.

Background The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is present in at least 1 out of 4,500 female live births and is the second most common cause for primary amenorrhea. It is characterized by vaginal and uterine aplasia in an XX individual with normal secondary characteristics. It has long been considered a sporadic anomaly, but familial clustering occurs. Several candidate genes have been studied although no single factor has yet been identified. Cases of discordant monozygotic twins suggest that the involvement of epigenetic factors is more likely. Methods Differences in gene expression and methylation patterns of uterine tissue between eight MRKH patients and eight controls were identified using whole-genome microarray analyses. Results obtained by expression and methylation arrays were confirmed by qRT-PCR and pyrosequencing. Results We delineated 293 differentially expressed and 194 differentially methylated genes of which nine overlap in both groups. These nine genes are mainly embryologically relevant for the development of the female genital tract. Conclusion Our study used, for the first time, a combined whole-genome expression and methylation approach to reveal the etiology of the MRKH syndrome. The findings suggest that either deficient estrogen receptors or the ectopic expression of certain HOXA genes might lead to abnormal development of the female reproductive tract. In utero exposure to endocrine disruptors or abnormally high maternal hormone levels might cause ectopic expression or anterior transformation of HOXA genes. It is, however, also possible that different factors influence the anti-Mullerian hormone promoter activity during embryological development causing regression of the Müllerian ducts. Thus, our data stimulate new research directions to decipher the pathogenic basis of MRKH syndrome.

The prevalence of mullerian malformations is 1 in 200, or 0.5%. A third of the anomalies are septate, a third bicornuate uteri, 10% arcuate uterus, 10% didelphis and unicornuate uterus, and < 5% uterine and vaginal aplasia. Correct diagnosis of the malformation is most important but often very difficult. Correct treatment can only be performed if the malformation is clear. Longitudinal vaginal septums have to be removed due to potential obstetric problems. Transverse vaginal septums can cause hematocolpos and pain and have to be incised crosswise and excised so as not to shorten the vagina at the same time. Congenital vaginal agenesis occurs in Mayer-Rokitansky-Kuster-Hauser syndrome patients and in androgen insensitivity syndrome. The first choice for surgical treatment should be the new laparoscopic-assisted creation of a neovagina. Septate uterus has to be distinguished from a bicornuate uterus. Even if it is not proven to be a cause for infertility, the chance of miscarriage can be diminished by performing hysteroscopic metroplasty. Repair of a uterine septum in infertility patients often improves pregnancy rates. In contrast, surgical repair of a bicornuate uterus requires an abdominal metroplasty. This should only be performed if the patient has recurrent fetal loss due to the uterine structural defect. In a unicornuate uterus it is most important to determine if there is a second uterine horn that can cause cyclic pain if it has functioning endometrium. The only surgical option in these cases is to remove the rudimentary uterus with endometrium and hematometra, respectively.

Objective To compare different diagnostic procedures for staging malformations associated with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Design Retrospective two-center cohort study (Canadian Task Force classification II-2). Setting University hospital. Patient(s) One hundred and thirty-eight women with MRKH. Intervention(s) Clinical examinations, abdominal or perineal/rectal ultrasound, magnetic resonance imaging (MRI), and laparoscopy. Main Outcome Measure(s) Agreement between the results obtained with the other methods and the results obtained with the reference methods for correct staging of malformations, presented as kappa values (κ). Result(s) The VCUAM (vagina cervix uterus adnex-associated malformation) classification system was used to classify genital malformations in 138 women with MRKH. The reference methods for examining the individual organs were: vagina—clinical examination; cervix/uterus and adnexa—laparoscopy; and urinary tract malformations—MRI. The values obtained were as follows. Vagina was κ 0.74 for MRI versus clinical examination; ultrasound and laparoscopy did not allow adequate description of vaginal malformations. Cervical findings were rarely detailed with any of the imaging methods. Uterus was κ 0.93 for MRI versus laparoscopy, and κ 0.83 for ultrasound. For adnexa, only laparoscopy was able to describe the morphology adequately. The urinary tract was κ 0.87 for ultrasound versus MRI. Conclusion(s) For the correct staging of malformations associated with MRKH, MRI or a combination of clinical examination and ultrasound are equivalent. However, none of the imaging methods adequately describes adnexal morphology.

Background The internet portal http://www.brustkrebs-studien.de (BKS) was launched in 2000 by the German Society of Senology (DGS) and the Baden-Württemberg Institute for Women's Health (IFG) to provide expert-written information on breast cancer online and to encourage and facilitate the participation of breast cancer patients in clinical trials. We describe the development of BKS and its applications, and report on website statistics and user acceptance. Methods Existing registries, including ClinicalTrials.gov, were analysed before we designed BKS, which combines a trial registry, a knowledge portal, and an online second opinion service. An advisory board guided the process. Log files and patient enquiries for trial participation and second opinions were analysed. A two-week user satisfaction survey was conducted online. Results During 10/2005-06/2010, the portal attracted 702,655 visitors, generating 15,507,454 page views. By 06/2010, the website's active scientific community consisted of 189 investigators and physicians, and the registry covered 163 clinical trial protocols. In 2009, 143 patients requested trial enrolment and 119 sought second opinions or individual treatment advice from the expert panel. During the two-week survey in 2008, 5,702 BKS visitors submitted 507 evaluable questionnaires. Portal acceptance was high. Respondents trusted information correctness (80%), welcomed self-matching to clinical trials (79%) and planned to use the portal in the future (76%) and recommend it to others (81%). Conclusions BKS is an established and trusted breast cancer information platform offering up-to-date resources and protocols to the growing physician and patient community to encourage participation in clinical trials. Further studies are needed to assess potential increases in trial enrolment by eligibility matching services.

The purpose of this study was to analyze the probability and time course of fibrotic changes in breast reconstruction before or after postmastectomy radiotherapy (PMRT). Between 1995 and 2004, 109 patients were treated with PMRT at Tubingen University and underwent heterologous (HL) or autologous (AL) breast reconstruction prior or subsequent to radiation therapy. Fibrosis of the reconstructed breast after radiotherapy was assessed using the Baker score for HL reconstructions and the Common Terminology Criteria for Adverse Events (CTCAE) for all patients. Actuarial rates of fibrosis were calculated for the maximum degree acquired during follow- up and at the last follow-up visit documented. Median time to follow-up was 34 months (3–227 months). Radiotherapy was applied with a median total dose of 50.4 Gy. A total of 44 patients (40.4%) received a boost treatment with a median dose of 10 Gy. Breast reconstruction was performed with AL, HL, or combined techniques in 20, 82, and 7 patients, respectively. The 3-year incidence of iÝ grade III maximum fibrosis was 20% and 43% for Baker and CTCAE scores, respectively. The corresponding figures for fibrosis at last follow-up visit were 18% and 2%. The 3-year rate of surgical correction of the contralateral breast was 30%. Initially unplanned surgery of the reconstructed breast was performed in 39 patients (35.8%). Boost treatment and type of cosmetic surgery (HL vs. AL) were not significantly associated with the incidence of fibrosis. We found severe fibrosis to be a frequent complication after PMRT radiotherapy and breast reconstruction. However, surgical intervention can ameliorate the majority of high grade fibrotic events leading to acceptable long-term results. No treatment parameters associated with the rate of fibrosis could be identified.

Background: The presence of disseminated tumor cells (DTC) in the bone marrow (BM) of primary breast cancer (PBC) patients is associated with a worsened prognosis. This is the largest single-center study that determines the impact of DTC on disease free (DFS) and overall survival and compares it to predefined molecular subtypes of PBC. Methods: BM aspirates were collected from patients that underwent surgery for PBC at Tuebingen University Hospital, Germany between 01/2001 and 01/2013. DTC were identified by immunocytochemistry (pancytokeratin antibody A45/B3) and cytomorphology. Patients were divided into three subgroups based on immunohistochemical staining of the primary tumor: (1) hormone receptor-positive/HER2-negative (HR+/HER2-), (2) HER2-positive (HER2+), and (3) HR-negative/HER2-negative (HR-/HER2-) patients. The DTC-status was compared to other prognostic factors by use of the chi-squared test and survival was analyzed in an univariate (log-rank test) and multivariate analysis (cox regression). Results: 3,141 patients were available for this retrospective analysis. Of these 803 (26%) were DTC-positive. DTC-positivity was associated with larger tumors (p Conclusion: This study confirms the strong and independent prognostic value of DTC-determination in primary breast cancer patients. With respect to analysis of different molecular subtypes, the DTC-status was found to be of prognostic significance especially in HR+/HER2- patients. The DTC-status might help to identify HR+/HER2- patients that are at an increased risk of death or disease relapse and thus in need for an aggressive adjuvant treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-7.

Background The main study objectives were: to develop a set of requirements of comprehensive breast centres; to establish a nationwide voluntary certification programme for breast centres based on such requirements, a certified quality management system (QMS), and scheduled independent, external audits and periodic recertification; and to demonstrate the general acceptance of such a certification programme with a view to introducing similar certification programmes for other major cancers. Methods Breast centres introduced a QMS and voluntarily participated in an external certification procedure based on guideline-derived Requirements of Breast Centres specifically developed for the application procedure, all subsequent audits and recertification. All data (numbers of pending and successful applications, sites/centre, etc.) were collected by a newly founded, independent organisation for certification of cancer services delivery. Data analysis was descriptive. Results Requirements of Breast Centres were developed by the German Cancer Society (DKG), the German Society of Senology (DGS) and other relevant specialist medical societies in the form of a questionnaire comprising 185 essential items based on evidence-based guidelines and the European Society of Breast Cancer Specialists' (EUSOMA) requirements of specialist breast units. From late 2002 to mid 2008, the number of participating breast centres rose from 1 to 175. As of mid 2008, 77% of an estimated 50,000 new breast cancers in Germany were diagnosed and treated at certified breast centres, 78% of which were single-site centres. Conclusion Nationwide voluntary certification of breast centres is feasible and well accepted in Germany. Dual certification of breast centres that involves certification of breast services to guideline-derived requirements in conjunction with independent certification of a mandatory QMS can serve as a model for other multidisciplinary site-specific cancer centres.

Background The main study objectives were: to establish a nationwide voluntary collaborative network of breast centres with independent data analysis; to define suitable quality indicators (QIs) for benchmarking the quality of breast cancer (BC) care; to demonstrate existing differences in BC care quality; and to show that BC care quality improved with benchmarking from 2003 to 2007. Methods BC centres participated voluntarily in a scientific benchmarking procedure. A generic XML-based data set was developed and used for data collection. Nine guideline-based quality targets serving as rate-based QIs were initially defined, reviewed annually and modified or expanded accordingly. QI changes over time were analysed descriptively. Results During 2003–2007, respective increases in participating breast centres and postoperatively confirmed BCs were from 59 to 220 and from 5,994 to 31,656 (> 60% of new BCs/year in Germany). Starting from 9 process QIs, 12 QIs were developed by 2007 as surrogates for long-term outcome. Results for most QIs increased. From 2003 to 2007, the most notable increases seen were for preoperative histological confirmation of diagnosis (58% (in 2003) to 88% (in 2007)), appropriate endocrine therapy in hormone receptor-positive patients (27 to 93%), appropriate radiotherapy after breast-conserving therapy (20 to 79%) and appropriate radiotherapy after mastectomy (8 to 65%). Conclusion Nationwide external benchmarking of BC care is feasible and successful. The benchmarking system described allows both comparisons among participating institutions as well as the tracking of changes in average quality of care over time for the network as a whole. Marked QI increases indicate improved quality of BC care.

Objective To find a potential underlying cause for Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) discordance in monozygotic twins. Design Prospective comparative study. Setting University hospital. Patient(s) Our study genetically analyzed 5 MRKHS-discordant monozygotic twin pairs with the unique opportunity to include saliva and rudimentary uterine tissue. Intervention(s) Blood, saliva, or rudimentary uterine tissue from five MRKHS-discordant twins was analyzed and compared between twin pairs as well as within the same individual where applicable. We used copy number variations (CNVs) to identify differences. Main Outcome Measure(s) CNVs in blood, rudimentary uterine tissue, and saliva, network analysis, and review of the literature. Result(s) One duplication found in the affected twin included two genes, matrix metalloproteinase 14 ( MMP14 ) and low-density lipoprotein receptor–related protein 10 ( LRP10 ), which have known functions in the embryonic development of the uterus and endometrium. The duplicated region was detected in rudimentary uterine tissue from the same individual but not in saliva, making a tissue-specific mosaicism a possible explanation for twin discordance. Additional network analysis revealed important connections to differentially expressed genes from previous studies. These genes encode several molecules involved in extracellular matrix (ECM) remodeling and neoangiogenesis. Conclusion(s) MMP-14, LRP-10, ECM, and neoangiogenesis genes are identified as candidate genes in a tissue-specific mosaicism. The detected clusters provide evidence of deficient vascularization during uterine development and/or disturbed reorganization of ECM components, potentially during mullerian duct elongation signaled by the embryologically relevant phosphatidylinositol 3-kinase/protein kinase B pathway. Therefore, we consider these genes to be new candidates in the manifestation of MRKHS.

Objective To compare the effects of solid barriers (PDLA membrane and foil, Interceed), innovative barrier solutions (Adept and Hyalobarrier Gel, phospholipid emulsion), and Ringer’s lactate solution in preventing postsurgical peritoneal adhesions in the rat. Design Prospective, randomized experimental study. Setting Rat model in an academic research environment. Animal(s) Female, nonpregnant Wistar rats. Intervention(s) Standardized surgical injuries were applied to the parietal and visceral peritoneum and the uterine horns. The barrier agents were applied and the wound was closed. A second-look laparoscopy was performed 31 days after surgery to assess adhesion formation. Main Outcome Measure(s) Severity and extent of adhesion formation assessed using a multidimensional adhesion scoring system. Result(s) Significantly fewer postsurgical adhesions were seen after treatment with Adept, Hyalobarrier Gel, Interceed, PDLA membrane, and phospholipid emulsion than after Ringer’s lactate solution. Severe, clinically relevant adhesions were not observed after Hyalobarrier Gel and in only one animal after Adept. Conclusion(s) Both solid and liquid barriers can prevent adhesions. Hydroflotation formulas, such as Adept and Hyalobarrier Gel, avoid suture-induced adhesions, are easy to use, and their protective effects are evenly distributed. They are suitable for adhesion prevention after multifocal trauma in rats, and require further testing in the everyday clinical situation.

11044 Background: The role of the addition of bisphosphonates (BPs) to adjuvant breast cancer treatment is unclear. Recent trials have reported different results in terms of survival. In a large me...

5598 Background: The presence of disseminated tumor cells (DTC) in the bone marrow (BM) of breast cancer patients is associated with poor prognosis. Several studies demonstrated that tumor cell dissemination may occur in gynecologic cancer and affect clinical outcome. The aim of our study was to evaluate the incidence of DTC and to assess their prognostic significance in patients with gynecologic malignancies. Methods: Bone marrow aspirates from 623 patients with primary endometrial (331), cervical (228), and vulvar cancer (64) undergoing surgery at the Department of Gynecology and Obstetrics, University Hospital, Tuebingen, Germany between November 2001 and May 2012, were included into the study. Disseminated tumor cells were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. Results: Disseminated tumor cells were detected in 18% of BM aspirates from patients with gynecological malignancies. Incidences of DTC in endometrial, cervical, and vulvar cancer were 21%, 16% and 16%, respectively. The presence of DTC was associated with a lower tumor grade in endometrial cancer For patients with vulvar cancer, no correlation with established clinicopathological factors was observed. In case of cervical cancer, BM positivity was correlated with International Federation of Gynecology and Obstetrics stage, nodal involvement and the presence of lymphangiosis carcinomatosa. For all analyzed tumor entities, no association between BM status and clinical outcome could be observed. Conclusions: Disseminated tumor cells are a common phenomenon in solid tumors. However, only in cervical cancer DTC postivity was associated with advanced disease. The consequences for DTC positive patients have to be determined.

Summary One major obstacle to the application of stem cell-derived cardiomyocytes (CMs) for disease modeling and clinical therapies is the inability to identify the developmental stage of these cells without the need for genetic manipulation or utilization of exogenous markers. In this study, we demonstrate that Raman microspectroscopy can non-invasively identify embryonic stem cell (ESC)-derived chamber-specific CMs and monitor cell maturation. Using this marker-free approach, Raman peaks were identified for atrial and ventricular CMs, ESCs were successfully discriminated from their cardiac derivatives, a distinct phenotypic spectrum for ESC-derived CMs was confirmed, and unique spectral differences between fetal versus adult CMs were detected. The real-time identification and characterization of CMs, their progenitors, and subpopulations by Raman microspectroscopy strongly correlated to the phenotypical features of these cells. Due to its high molecular resolution, Raman microspectroscopy offers distinct analytical characterization for differentiating cardiovascular cell populations., Graphical Abstract, Highlights • Raman microspectroscopy identifies intrinsic molecular signatures of individual cells • Cardiovascular cell fate decisions can be assessed non-invasively • Chamber specificity is monitored marker-free and without genetic manipulation • Cardiac cell maturation and cell quality can be screened online in real time, Application of stem cell-derived cardiomyocytes (CMs) for disease modeling and clinical therapies is limited by the inability to identify these cells without genetic manipulation or exogenous markers. In this article, Schenke-Layland and colleagues demonstrate that Raman microspectroscopy is a suitable tool for the real-time marker-free identification and characterization of chamber-specific primary and pluripotent stem cell-derived CMs, their progenitors, and subpopulations, and to monitor CM maturation.

ObjectiveTo compare the mean hospital discharge times and perioperative outcomes for radiofrequency volumetric thermal ablation (RFVTA) of fibroids and laparoscopic myomectomy (LM).MethodsThe present postmarket, randomized, prospective, single-center, longitudinal, comparative study, conducted in Tübingen, Germany, evaluated the outcomes of RFVTA and the current standard of care (LM) for symptomatic uterine fibroids in women who desired uterine conservation. The surgeons were blinded to the treatment until all fibroids had been mapped by laparoscopic ultrasound.ResultsThe mean hospitalization times were 10.0±5.5 (median 7.8 [range 4.2–25.5]) hours for the RFVTA group and 29.9±14.2 (median 22.6 [range 16.1–68.1]) hours for the LM group (P

ObjectiveTo compare 24-month patient-reported outcomes following laparoscopic radiofrequency volumetric thermal ablation (RFVTA) and laparoscopic myomectomy in patients with uterine fibroids.MethodAn interim analysis of 24-month follow-up data from a randomized controlled trial was performed at Tübingen University Women’s Hospital between November 1, 2012 and May 30, 2015. Premenopausal patients, at least 18years of age, who were menstruating, were randomly assigned to be treated for symptomatic uterine fibroids with either RFVTA or laparoscopic myomectomy. The outcomes included in the present per-protocol analysis were patients’ responses to validated questionnaires and long-term safety.ResultsThe study enrolled 51 patients; 21 and 22 patients in the RFVTA and laparoscopic myomectomy groups, respectively, completed 24months of follow-up. Improvements in the severity of symptoms from baseline were reported by participants in both the RFVTA (P