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Introduction: HER2-positive breast cancer is considered aggressive, but due to the development of targeted drugs in the past 20 years, a substantial improvement of therapy results can be postulated. Proven evidence is provided by data of randomized clinical trials. The present study aimed at demonstrating the improvement of therapy results over time using single-center real world data. Material and Methods: In our center, we prospectively built a consecutive tumor and data base from 2000 to 2020 and identified patients with early HER2-positive breast cancer (n=396). The cohort was divided in four groups by year of diagnosis according to the changing therapy concepts: A) 2000-2004 (no HER2-directed therapy, n=83), B) 2005-2011 (trastuzumab, n=96), C) 2012-2017 (trastuzumab/pertuzumab, n=135), D) 2018-2020 (T-DM1 in patients with non-pCR), n=55). HER2 was measured by IHC and ISH corresponding to the ASCO-CAP guidelines. HER2-directed therapy was indicated according to the respective national guidelines (AGO). The median follow-up was 58 months in the entire cohort (1-266), group A 84 months (10-266), group B 94 months (2-201), group C 56 months (1-118), group D 32 months (8-53). The primary endpoint was overall survival (OS), and secondary endpoint was iDFS. Kaplan-Meier estimates were calculated and multivariate analyses were performed using SPSS 28 (IBM, Armonk, NY, USA). Results: Overall, 57% of the 396 patients had an age of 50 years or more, 85% had a NST histology, 54% of the tumors were larger than 2cm, 45% were node-positive; 34% were steroid hormone receptor negative. HER2-directed therapy was delivered to 7 of 83 pts in group A (8.4%), to 62 of 96 pts in group B (64.6%), to 119 of 135 in group C (88.15%), and to 50 of 55 pts in group D (90.91%), resp.. Overall, in the first 3 years we observed 19 deaths and the probability for OS was 89.7 % for group A, 92.2 % for group B, 96.4 % for group C and 100% for group D, resp.; iDFS was 77.4% in A, 86.8% in B, 94.9% in C and 95.2% in D, resp.. After adjustment for nodal status, grading and steroid hormone receptor status, we calculated the effect size of the incremental improvement of treatment for OS and iDFS as HRs referred to group A (Table 1). Conclusion: With this prospectively established single center cohort, we are able to confirm a significant improvement of the treatment results in patients with HER2-positive early breast cancer over the last 20 years applying individualized HER2-directed therapies. Table 1. Multivariate analyses of OS and iDFS adjusted for nodal status, grading and hormone receptor status. Citation Format: Christoph Thomssen, Julia Engel, Kristin Reinhardt, Hans-Georg Strauß, Regina Große, Susanne Barrot, Marcus Bauer, Lisa van Uden, Sandy Kaufhold, Kathleen Schüler, Vanessa Wieder, Eva J. Kantelhardt, Martina Vetter. HER2-directed therapy in early breast cancer – improvement over 20 years [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-11.

Background: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described.Patients and methods: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields.Results: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months).Conclusion: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV– tumors.

Since the publication of the updated German guideline in 2015, the recommendations for performing pelvic lymphadenectomy (LAE) in patients with vulvar cancer (VSCC) have changed considerably. The guideline recommends surgical lymph node staging in all patients with a higher risk of pelvic lymph node involvement. However, the current data do not allow the population at risk to be clearly defined, therefore, the indication for pelvic lymphadenectomy is still not clear. There are currently two published German patient populations who had pelvic LAE which can be used to investigate both the prognostic effect of histologically verified pelvic lymph node metastasis and the relation between inguinal and pelvic lymph node involvement. A total of 1618 patients with primary FIGO stage ≥ IB VSCC were included in the multicenter AGO CaRE-1 study (1998 – 2008), 70 of whom underwent pelvic LAE. During a retrospective single-center evaluation carried out at the University Medical Center Hamburg-Eppendorf (UKE), a total of 514 patients with primary VSCC treated between 1996 – 2018 were evaluated, 21 of whom underwent pelvic LAE. In both cohorts, around 80% of the patients who underwent pelvic LAE were inguinally node-positive, with a median number of three affected groin lymph nodes. There were no cases of pelvic lymph node metastasis without inguinal lymph node metastasis in either of the two cohorts. Between 33 – 35% of the inguinal node-positive patients also had pelvic lymph node metastasis; the median number of affected groin lymph nodes in these patients was high (> 4), and the maximum median diameter of the largest inguinal metastasis was > 40 mm in both cohorts. Pelvic lymph node staging and pelvic radiotherapy is therefore probably not necessary for the majority of node-positive patients with VSCC, as the relevant risk of pelvic lymph node involvement was primarily found in node-positive patients with high-grade disease. More, ideally prospective data collections are necessary to validate the relation between inguinal and pelvic lymph node involvement.

Annals of surgical oncology 28(11), 6696-6704 (2021). doi:10.1245/s10434-021-09744-y, Published by Springer, Berlin [u.a.]

Cervical cancer is among the leading causes of cancer-related death in females worldwide. Infection by human papillomavirus (HPV) is an established risk factor for cancer development. However, genetic factors contributing to disease risk remain largely unknown. We report on a genome-wide association study (GWAS) on 375 German cervical cancer patients and 866 healthy controls, followed by a replication study comprising 658 patients with invasive cervical cancer, 1361 with cervical dysplasia and 841 healthy controls. Functional validation was performed for the top GWAS variant on chromosome 14q12 (rs225902, close to PRKD1). After bioinformatic annotation and in silico predictions, we performed transcript analysis in a cervical tissue series of 317 samples and demonstrate rs225902 as an expression quantitative trait locus (eQTL) for FOXG1 and two tightly co-regulated long non-coding RNAs at this genomic region, CTD-2251F13 (lnc-PRKD1-1) and CTD-2503I6 (lnc-FOXG1-6). We also show allele-specific effects of the 14q12 variants via luciferase assays. We propose a combined effect of genotype, HPV status and gene expression at this locus on cervical cancer progression. Taken together, this work uncovers a potential candidate locus with regulatory functions and contributes to the understanding of genetic susceptibility to cervical cancer.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Background: Although quantification of tumor infiltrating lymphocytes (TILs) has become of increasing interest in immuno-oncology, only little is known about TILs infiltration in the tumor microenvironment and its predictive value in vulvar cancer. Methods: Immunohistochemistry and automated digital image analysis was applied to measure the densities of CD3+ (DAKO, #IR503) and CD8+ (DAKO, #IR623) TILs at the invasive margin and in the center of 530 vulvar squamous cell cancers. Results: An elevated density of CD3+ T-cell at the invasive margin was significantly associated with low tumor stage (p = 0.0012) and prolonged survival (overall survival [OS] p = 0.0027, progression free survival [PFS] p = 0.024) and was independent from tumor stage, nodal stage, grade, and HPV-status in multivariate analysis (p < 0.05). The prognostic impact of CD3+ cells in the center of the tumor was weaker compared to the invasive margin (OS p = 0.046, PFS p = 0.031) and lacking for CD8+ T-cell densities at any location (p ≥ 0.14 each). Unsupervised clustering of CD3+ and CD8+ T-cell densities identified three major subgroups corresponding to the immune desert (137 patients), immune excluded (220 patients) and immune inflamed phenotypes (133 patients). Survival analysis revealed a particular poor prognosis for the immune desert phenotype for OS (p = 0.0071) and PFS (p = 0.0027). Conclusion: Our data demonstrate a high prognostic value of CD3+ T-cells at the invasive margin and immune phenotypes in vulvar squamous cell cancer.

Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta‐analysis, 2q14.1 (PAX8) and 6p21.32 (PBX2) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case‐control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at PAX8 and rs2856437 at PBX2, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74‐0.91, P = 2.4 × 10−4; rs2856437: OR 1.52, 95% CI 1.14‐2.02, P = .004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462: OR 0.80, 95% CI 0.68‐0.94, P = .006; rs2856437: OR 1.56, 95% CI 1.03‐2.36, P = .036) and with high‐grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70‐0.90, P = 1.9 × 10−4; rs2856437: OR 1.58, 95% CI 1.15‐2.17, P = .005). A combined analysis of high‐grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73‐0.91, P = 2.4 × 10−4; rs2856437: OR 1.57, 95% CI 1.18‐2.10, P = .002). No association was detected for rs2856437 with low‐grade dysplasia, while rs10175462 showed weak evidence of association (P = .05). RNA analyses in cervical samples revealed that PAX8 transcripts were upregulated in HPV‐positive lesions (P = .008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA PAX8‐AS1 (P

Introduction Gynaecological sarcomas are rare and there is very limited evidence about symptoms at primary diagnosis. Most knowledge is based on retrospective analysis. Methods We present data of 410 patients (pts) in the primary situation. Overall, 87.91% of pts had documented symptom data, which were analysed descriptively. A distinction was made between pre- (prem., ≤52 yrs) and postmenopausal (postm., >52 yrs.). Results The average age of pts was 56 yrs (range 15–88 yrs). Leiomyosarcoma (LMS) was diagnosed in 44.7%, endometrial stromal sarcoma (ESS) in 26.6% (62.6% low grade (LG-ESS) and 37.4% high grade (HG-ESS)). Undifferentiated sarcoma (US) and adenosarcoma (AS) were observed in 5.7% and 8.7% respectively. In prem. and postm. pts with LMS, the leading symptom (LS) was abdominal pain (ap) in 34.4%. and 39.5% respectively. In prem. HG-ESS the LS were ap and bleeding disorders (bd) in both 33.3%. In postm. HG-ESS and prem. LG-ESS the LS was vaginal bleeding (vb) in 29% and 33.3% respectively. In prem. AS the LS was ap in 27.3%, whereas in postm. AS it was postmenopausal bleeding (pb) in 29.2%. In prem. US the LS were bd and vb both at 66.7%. In postm. US the LS was ap in 47.4%. Conclusions We analyzed the LS of different histopathological subtypes in primary gynaecological sarcoma for the first time. Bleeding disorders and abdominal pain are the main symptoms in all subtypes. Symptoms are heterogeneous and about every 5th woman reported unspecific symptoms. This underlines the importance of awareness for gynaecological sarcoma.

Epithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HG-SOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here we show, that the IGF2 mRNA binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HG-SOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in a RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signaling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rational for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HG-SOC.Graphical Abstract

Background:\ud State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin–paclitaxel or carboplatin–gemcitabine) or the most active non-bevacizumab regimen: carboplatin–pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin–pegylated liposomal doxorubicin combined with bevacizumab.\ud Methods:\ud This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m 2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m 2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.\ud Findings:\ud Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin–pegylated liposomal doxorubicin–bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin–gemcitabine–bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3–21·7) in the experimental group and 11·3 months (8·0–18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7–14·2) in the experimental group versus 11·6 months (11·0–12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68–0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (

The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single-nucleotide polymorphisms in a large case-control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at HLA-DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79-0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04-1.31, P = .008) and with high-grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70-0.87, P = 7.1 × 10-6 ; rs2844511: OR 1.13, 95% CI 1.01-1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75-0.91, P = 6.9 × 10-5 ; rs2844511: OR 1.14, 95% CI 1.04-1.26, P = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low-grade dysplasia (OR 1.26, 95% CI 1.04-1.54, P = .019). In case-only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA-DQA1, suggesting extensive co-regulation. All three genes were upregulated in HPV16-positive samples. In stratified analyses, rs9272117 was associated with HLA-DQA1 levels, specifically in HPV-positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA-DQA1. Altogether, our results support 6p21.32-33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of HLA-DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.

Background: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma—a human papillomavirus–dependent pathway characterized by p16 overexpression and a human papillomavirus–independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed.Objective: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance.Study Design: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction.Results: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53− (n=132), and p16−/p53− (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53− tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16−/p53− tumors; PConclusion: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53−/p16− phenotype showing an intermediate prognosis that needs to be further characterized.

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 tumor-suppressive let-7 microRNA family targets various oncogene-encoding mRNAs. We identify the let-7 targets HMGA2, LIN28B and IGF2BP1 to form a let-7 antagonizing self-promoting oncogenic triangle. Surprisingly, 3'-end processing of IGF2BP1 mRNAs is unaltered in aggressive cancers and tumor-derived cells although IGF2BP1 synthesis was proposed to escape let-7 attack by APA-dependent (alternative polyadenylation) 3' UTR shortening. However, the expression of the triangle factors is inversely correlated with let-7 levels and promoted by LIN28B impairing let-7 biogenesis. Moreover, IGF2BP1 enhances the expression of all triangle factors by recruiting the respective mRNAs in mRNPs lacking AGO proteins and let-7 miRNAs. This indicates that the downregulation of let-7, largely facilitated by LIN28B upregulation, and the protection of let-7 target mRNAs by IGF2BP1-directed shielding in mRNPs synergize in enhancing the expression of triangle factors. The oncogenic potential of this triangle was confirmed in ovarian cancer (OC)-derived ES-2 cells transduced with let-7 targeting decoys. In these, the depletion of HMGA2 only diminishes tumor cell growth under permissive conditions. The depletion of LIN28B and more prominently IGF2BP1 severely impairs tumor cell viability, self-renewal and 2D as well as 3D migration. In conclusion, this suggests the targeting of the HMGA2-LIN28B-IGF2BP1 triangle as a promising strategy in cancer treatment.

Borderline tumors of the ovary (BOT) represent an entity of ovarian neoplasms with low malignant potential and excellent prognosis. Mainstay of therapy is surgery including adequate staging and complete tumor resection, possibly inducing long-term side effects, especially in premenopausal women. The aim of this study was to evaluate quality of life (QoL) and sexual function in patients treated for BOT, also with respect to treatment modalities.This prospective study was part of an ambidirectional multicentric cohort study in patients with BOT in Germany. Patients from seven centers completed three questionnaires after completion of therapy. QoL and sexual function data were correlated with treatment characteristics: surgical approach, lymphadenectomy, and fertility sparing surgery.One hundred ten patients returned the questionnaires. Median follow-up was 4.0 years. The majority lived in a relationship (n = 85, 77%, missing n = 4), and 49% (n = 54, missing n = 6) were sexually active. The main reason for sexual inactivity was "no partner" (38%). The women had a mean global health status of 69.8 (SD 22.7; min 0, max 100), with 100 implying perfect health. Mean QoL score was 73.7 (SD 23.3, range 0 to 100). Both scores showed no difference regarding fertility preserving surgery, surgical approach, and lymphadenectomy. Sexually active women had a significantly higher QoL (78.7 vs. 67.4, p = 0.0156) and global health status (75.9 vs. 60.9, p = 0.0013) than inactive patients.In this prospective study, patients who had been diagnosed with BOT had a very good quality of life and global health status. Sexually inactive women stated lack of a partner as the main reason and had an inferior HRQoL compared to sexually active women.

Aims: The value of ECG in the perioperative risk stratification under modern treatment options is uncertain. The main objective of the present analysis was to determine the usefulness of a pre-operative ECG derivation for evaluating the risk of perioperative morbidity and mortality. Methods: We performed a secondary analysis of the prospective, international, multicenter, observational “No-Risk” Study (N-terminal B-type natriuretic peptide [NT-proBNP] for the assessment of the perioperative cardiac risk after major noncardiac surgery) to determine the prognostic value of 12-lead ECG. Inclusion criteria were age >55 years and at least one of the following cardiovascular risk factors: arterial hypertension, diabetes mellitus, dyslipidemia, active smoking, and family history positive for coronary heart disease. The combined primary endpoint included total mortality, acute myocardial infarction (NSTEMI and STEMI), cardiopulmonary resuscitation, heart failure, and asystole or ventricular fibrillation during hospitalization. ECGs from 616 patients enrolled from 2006 to 2009 prior to noncardiac surgery in the No-Risk Study were analyzed. Results: The mean age was 67.6 (±8.1) years; 300 (48.7%) patients were male. Fourteen (2.3%) patients suffered from the combined primary endpoint while in the hospital. In Kaplan-Meier analyses, a pathologic Q wave and QTc > 500 ms were significantly related to the incidence of the primary endpoint (p < 0.001, p = 0.042, respectively), whereas other ECG parameters such as LBBB, RBBB, PQ interval, QRS interval, and others were not related to worse in-hospital outcome. Conclusion: The 12-lead ECG is still an important diagnostic tool for perioperative risk assessment of cardiovascular events in noncardiac surgery in patients at risk.

Background Borderline ovarian tumours (BOTs) are recognised as a unique entity of ovarian tumours that do not exert infiltrative destructive growth or stromal invasion. Prognosis of BOT is much better compared to the more common invasive epithelial ovarian cancer. Information regarding prognostic factors is inconclusive and no prospective studies exist that evaluate therapeutic strategies. We therefore started a retrospective–prospective cohort study to better understand BOT and identify scenarios in which future studies could be developed. Methods Consecutive patients with BOT treated between 1998 and 2008 in 24 German centres were analysed. The retrospective part of the study retrieved patients’ data from hospital records and clinical tumour registries while active follow-up and an independent central pathology review were carried out prospectively. Findings BOT was confirmed in 950 patients, two thirds had serous BOT and 30.5% mucinous BOT. Most were diagnosed in stage I (82.3%); 7.6% and 10.1% had stages II and III, respectively. Overall, 74 patients (7.8%) experienced relapse and 43 (4.5%) died within the observation period. Multivariate analysis revealed higher stage, incomplete staging, tumour residuals, and organ preservation as independent prognostic factors for disease recurrence. Neither microinvasion nor micropapillary growth pattern showed any significant impact. Of 74 relapsed patients, 30% had malignant transformation to invasive ovarian cancer with five-year progression-free survival and overall survival of 12% and 50%, respectively. Interpretation Prognosis of BOT correlates with tumour-related as well as surgery-related factors. The balance between recurrence risk and organ preservation and fertility-sparing surgery is an important issue deserving further research.

Analyzing the large patient cohort of the multicenter AGO-CaRE-1 study, we compared isolated sentinel lymph node dissection (SLND) with radical lymph node dissection (LND) of the groin in relation to recurrence rates and survival.The AGO-CaRE-1 study retrospectively collected data on treatment patterns and follow-up of vulvar cancer patients [International Federation of Gynecology and Obstetrics (FIGO) stage ≥1B] treated at 29 gynecologic cancer centers between 1998 and 2008. This subgroup analysis evaluated the influence of SLND alone on progression-free survival (PFS) and overall survival (OS).In 487 (63.1%) of 772 included patients with tumors smaller than 4 cm, an LND was performed and no metastatic lymph nodes were detected (LN0). Another 69/772 (8.9%) women underwent SLND alone, showing a negative SLN (SLN0). Tumors in the LN0 group were larger and showed a deeper invasion (LN0 vs. SLN0 tumor diameter: 20.0 vs. 13.0 mm, p 0.001; depth of invasion: 4.0 vs. 3.0 mm, p = 0.002). After a median follow-up of 33 months (0-156), no significant differences in relation to isolated groin recurrence rates (SLN0 3.0% vs. LN0 3.4%, p = 0.845) were detected. Similarly, univariate 3-year PFS analysis showed no significant differences between both groups (SLN0 82.7% vs. LN0 77.6%, p = 0.230). A multivariate Cox regression analysis, including tumor diameter, depth of invasion, age, grading, and lymphovascular space invasion was performed: PFS [hazard ratio (HR) 0.970, 95% confidence interval (CI) 0.517-1.821] and OS (HR 0.695, 95% CI 0.261-1.849) did not differ significantly between both cohorts.This subgroup analysis of the large AGO-CaRE-1 study showed similar results for groin LND and SLND alone with regard to recurrence rates and survival in node-negative patients with tumors4 cm.

Background: This phase 2 trial was designed to evaluate the efficacy and toxicity of a combination of docetaxel, gemcitabine, and oxaliplatin for platinum- and paclitaxel-pretreated epithelial ovarian cancer. Patients and Methods: Heavily pretreated patients (N = 30; median age, 61 years) received docetaxel, 55 mg/m2; gemcitabine, 500 mg/m2 (day 1); and oxaliplatin, 70 mg/m2 (day 2) biweekly. Twelve patients had platinum-sensitive disease, and 18 patients had platinum-resistant disease. Results: Median follow-up was 18.6 months. No differences in patient characteristics were observed between patients with carboplatinum-sensitive and carboplatinum-resistant disease. In patients with carboplatin-sensitive disease, an overall response (OR) of 83.3%, a progression-free survival of 10.6 months, and an overall survival of 18.9 months were observed. In patients with carboplatinum-resistant disease, an OR was seen in 38.9% with a progression-free survival of 5.3 months and an overall survival of 16.3 months. Patients with platinum-refractory disease (progression under previous carboplatinum therapy, n = 13) had an OR of 23%, whereas patients with objective response but relapse less than 6 months after carboplatinum therapy had an OR of 80.0%. Grade 3 and 4 toxicities were only observed for anemia (6.7%), neutropenia (20.0%), thrombopenia, peripheral neuropathy, and diarrhea (16.7%). No neutropenic fever or treatment-related death occurred. Conclusions: In comparison with current standard protocols, a combination of docetaxel, gemcitabine, and oxaliplatin showed considerably higher efficacy without remarkable increased toxicity; particularly for patients with early relapse after a platinum-containing therapy.

Patients with cervical cancer frequently suffer from anemia. This two-stage, adaptive-design study investigated the effect of anemia correction with epoetin beta on treatment outcomes. Patients with stage IIB–IVA cervical cancer received radiochemotherapy (RCT) and were randomized to epoetin 150 IU/kg three times weekly (n = 34) or standard care (control; n = 40) for up to 12 weeks. Primary end point for stage 1 aimed to establish a correlation between anemia correction and treatment failure (no complete response or relapsing within 6 months after RCT initiation) as a proof of concept before moving into stage 2. Secondary end points included progression/relapse-free survival, overall survival, response to RCT, hemoglobin (Hb) response, and safety. Median baseline Hb was 11.4 and 11.6 g/dL in epoetin and control groups, respectively. At treatment end point, median Hb increased by 1.3 g/dL with epoetin, but decreased by 0.7 g/dL in the control group (P < 0.0001). No significant correlation between Hb increase and treatment failure was demonstrated. There were no significant differences between epoetin and control groups in progression/relapse-free survival (29.4% vs 32.5% patients with events; P = 0.96), overall survival (23.5% vs 12.5% patients with events; P = 0.22) or overall complete response (53% vs 58%; P = 0.86). Adverse events were well matched between groups. This study shows that epoetin beta rapidly, effectively, and safely increases Hb levels in patients with cervical cancer receiving RCT. No positive correlation of Hb increase and improvement in clinical outcomes could be demonstrated.

Background: Women with node-positive vulvar cancer have a high risk for disease recurrence. Indication criteria for adjuvant radiotherapy are controversial. This study was designed to further understand the role of adjuvant therapy in node-positive disease. Methods: Patients with primary squamous-cell vulvar cancer treated at 29 gynecologic cancer centers in Germany from 1998 through 2008 were included in this retrospective exploratory multicenter cohort study. Of 1618 documented patients, 1249 had surgical groin staging and known lymph node status and were further analyzed. All statistical tests were two-sided. Results: Four hundred forty-seven of 1249 patients (35.8%) had lymph node metastases (N+). The majority of N+ patients had one (172 [38.5%]) or two (102 [22.8%]) positive nodes. The three-year progression-free survival (PFS) rate of N+ patients was 35.2%, and the overall survival (OS) rate 56.2% compared with 75.2% and 90.2% in node-negative patients (N-). Two hundred forty-four (54.6%) N+ patients had adjuvant therapy, of which 183 (40.9%) had radiotherapy directed at the groins (+/-other fields). Three-year PFS and OS rates in these patients were better compared with N+ patients without adjuvant treatment (PFS: 39.6% vs 25.9%, hazard ratio [HR] = 0.67, 95% confidence interval [CI[= 0.51 to 0.88, P = .004; OS: 57.7% vs 51.4%, HR = 0.79, 95% CI = 0.56 to 1.11, P = .17). This effect was statistically significant in multivariable analysis adjusted for age, Eastern Cooperative Oncology Group, Union internationale contre le cancer stage, grade, invasion depth, and number of positive nodes (PFS: HR = 0.58, 95% CI = 0.43 to 0.78, P < .001; OS: HR = 0.63, 95% CI = 0.43 to 0.91, P = .01). Conclusion: This large multicenter study in vulvar cancer observed that adjuvant radiotherapy was associated with improved prognosis in node-positive patients and will hopefully help to overcome concerns regarding adjuvant treatment. However, outcome after adjuvant radiotherapy remains poor compared with node-negative patients. Adjuvant chemoradiation could be a possible strategy to improve therapy because it is superior to radiotherapy alone in other squamous cell carcinomas.

Diagnostische Schritte Notwendige und erganzende diagnostische Schritte werden eingeleitet. Die Klinik fur Diagnostische Radiologie bietet neben den kompletten diagnostischen Moglichkeiten auch die bildgestutzte minimal-invasive histologischen Sicherung auf der Basis von Mammographie, Mammasonographie und Magnetresonanztomographie (MRT) mittels Hochgeschwindigkeitsund Vakuumbiopsien an. Benigne Veranderungen konnen im Einzelfall durch die Vakuumbiopsie vollstandig entfernt werden. Bei Indikation zu einer offenen Operation wird bereits jetzt, soweit moglich, das lokoregionare Therapiekonzept diskutiert und festgelegt. Bei Planung eines brusterhaltenden Vorgehens wird bei fast allen Patientinnen mit histologisch gesichertem Mammakarzinom eine praoperative MRTDiagnostik durchgefuhrt. Bei Zusatzbefunden wird zur gezielten Abklarung eine zusatzliche, gegebenenfalls MRT-gestutzte Stanzbiopsie entnommen. Somit erfolgt praoperativ die «Kartierung» der betroffenen Brust und der Ausschluss von kontralateralen Zweitherden. Eine Auswertung des aufwendigen Vorgehens ist derzeit in Arbeit.

Background/Aims: Cytostatics and human antibodies are successfully being used to treat oncological diseases. Despite the beneficial effects of these potent drugs, cardiotoxicity represents one of the most relevant side effects and limits their usage. It is very important to detect cardiotoxicity at an early stage particular in patients under curative chemotherapy to avoid long-term side effects and impairment of quality of life. The aim of this prospective study was to investigate the value of natriuretic peptides and troponin for early detection of cardiotoxicity. Patients and Methods: In this single-center study, 99 cancer patients under treatment with anthracyclines, taxanes, and/or trastuzumab were prospectively included. Clinical examination, echocardiography, and blood sampling (brain natriuretic peptide (BNP), N-terminal-proBNP, and troponin I) were performed at baseline and at 3 and 12 months, respectively. Cardiotoxicity was defined as clinical or echocardiographic signs of heart failure as defined by an increment in New York Heart Association (NYHA) class by more than one and a decline in left ventricular ejection fraction (LVEF) depending on baseline situation. Results: During the 12-month follow-up, 27 patients presented with at least one predefined endpoint. Neither BNP, nor NT-proBNP, nor troponin I was related to the incidence of cardiotoxicity as defined by the combined endpoint. In post-hoc analysis a significant association between an increasing NYHA stage and a decrease in LVEF was found (negative predictive value of 91%). Conclusion: The occurrence of cardiotoxicity could not be detected either by natriuretic peptides or troponin. However, we hypothesize that an increase of more than one NYHA stage as a marker for dyspnea may be an indicator of cardiotoxicity.

5608 Background: Recently, the standard of minimal pathological resection margin distance of 8mm in surgery for primary vulvar cancer has been challenged since several single center analyses failed...

As a cortical cytoskeletal protein, ezrin adapts the cytoplasmic tail of CD44 to the actin-based cytoskeleton and is functionally involved in migration and adhesion that are prerequisites for metastasis. To assess the importance of ezrin and its associated protein osteopontin for the progression of endometrioid carcinoma in FIGO stage I, we analyzed paraffin-embedded tissue from 164 patients by immunohistochemistry and correlated these data with clinicopathological parameters. Ezrin was expressed in normal proliferating endometrial glands, as was confirmed by quantitative PCR and immunohistochemistry. In endometrioid carcinoma, enhanced ezrin expression correlated with a reduced overall survival in univariate analysis (P = 0.041). In contrast, no significant correlation was found for osteopontin. In multivariate survival analysis, among FIGO grade 3 and age, ezrin was still found to be an independent risk factor (relative risk 2.2, confidence interval 1.0-5.4, P = 0.047). Hence, elevated ezrin expression is a new independent prognostic marker in FIGO stage I endometrioid carcinoma, and thus provides further evidence for an important role of ezrin in tumor progression.

Sertoli-Leydig cell tumors belong to the group of sex-cord stromal tumors of the ovary. They account for less than 0,5% of all ovarian neoplasms. The majority of these tumors are benign, and almost all are localised unilaterally. Herewith, we describe an ovarian Sertoli-Leydig cell tumor in an 11-year-old girl. Serum levels of estradiol and progesterone were mildly elevated. while testosterone and androstendion levels were raised to around three- and sevenfold upper normal limit respectively on presentation. A left salpingo-oophorectomy was performed. Microscopically, the tumor was intermediately differentiated. At 6 months follow-up, there was neither clinical nor sonographical evidence of recurrence, and almost all sex hormone levels had returned to within normal range. Treatment of this pathological entity has to be individualized according to patient age, stage of tumor and degree of differentiation.

Materials and Methods: From 1995 through 1999, a total number of 87 patients with squamous cell cervical cancers (FIGO stages IIB to IVA) underwent definitve radiotherapy (external beam 45-50.4Gy in 1.80Gy-fractions plus HDR-brachytherapy, 5 fractions of 7Gy in point A) in our department. All patients underwent oxygenation measurements with the Eppendorf device prior to treatment and after 19.8Gy external beam XRT. Various histological factors (including the microvessel density) and the S-phase-fraction (flow cytometry) were determined from pretreatment biopsies .