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Background: Since the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors, BRCA testing has evolved as a standard management in epithelial ovarian cancer., Objective: To analyze the implementation of molecular testing and PARP inhibitor therapy in Germany., Methods: The questionnaire contained 40 questions covering real-life data on genetic testing and the use of PARP inhibitors. It was divided into three main parts: basic demographics of respondents, genetic counseling and testing, and treatment with PARP inhibitors. The questionnaire was distributed via mail between August 2020 and May 2021., Results: A total of 315 physicians participated in the survey, of whom 54.9% were specialized in the field of gynecologic oncology. Two-thirds of respondents (67.4%) stated that they tested more than 80% of patients with primary epithelial ovarian cancer for BRCA mutation; however, only 42.5% of gynecologists who performed genetic counseling had an additional qualification in subject-specific genetic counseling, which is mandatory for predictive genetic testing in Germany. The main reasons for failure of BRCA testing were patient refusal (54.6%) and organizational or logistical issues (31.7%). Only 13.7% of respondents felt sufficiently equipped with supportive information material on patient counseling, whereas a high need for information material was indicated by 86.3% of the respondents. Molecular tumor profiling to infer homologous recombination (HR) deficiency status was provided by only 53.3% of institutions. PARP inhibitors were applied on a regular basis by 62.1% of respondents. The most important criteria for selection of appropriate PARP inhibitor therapy were the side effect profile (78.2%) and efficacy (71.2%). The majority of respondents (66.5%) preferred a combination of olaparib and bevacizumab over PARP inhibitors alone in the frontline setting., Conclusion: Adequate structure for BRCA/HR deficiency testing, and systematic education programs are needed to prevent delay in counseling and undertreatment of women with epithelial ovarian cancer. In Germany, a combination of olaparib and bevacizumab seems to be the preferred treatment in the first-line setting., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Women living with HIV have an increased risk of human papillomavirus (HPV) infection and cervical cancer. Little is known about genotype-specific HPV prevalence, the impact of antiretroviral therapy, immunological status, and additional risk factors in women living with HIV in Germany. The goal of this study was to characterize the risk profile for cervical dysplasia in these women., Methods: Patients with HIV infection presenting at Charité-Universitätsmedizin Berlin from October 2017 to September 2020 were included and underwent gynecological examination, colposcopy, cervical cytology and HPV genotype testing. HPV genotypes were stratified by carcinogenicity. Atypical squamous cells of undetermined significance or higher were considered abnormal cytology. Data were analyzed by SPSS software (version 26, 2019). A two-tailed p-value ≤0.05 was considered statistically significant., Results: A total of 84 women were evaluated. The majority (95.2%) received antiretroviral therapy. Median CD4 cell count was 564 cells/µl (range 20-1969). 95.2% were previously screened for cervical cancer. High-risk HPV prevalence was 44%. High-high-risk HPV subtypes (16, 18, 31, 33, 45, 52, 58) were significantly associated with abnormal cytology (p<0.001). HPV16 was the most common genotype (23%), was significantly associated with abnormal cytology (p=0.002) and was the main risk factor for abnormal cytology (OR 8.55, 95% CI 2.15 to 34.13, p=0.002), followed by age <35 years (OR 4.96, 95% CI 1.23 to 19.61, p=0.033) and cigarette smoking (OR 3.944, 95% CI 0.98 to 15.88, p=0.053)., Conclusions: Antiretroviral therapy and adherence to cervical cancer screening was high. High-high-risk HPV, especially HPV16, coincided with high incidence of cytological abnormalities. Women living with HIV in Germany have adequate immune status and are often pre-screened for cervical cancer, and therefore have a different risk profile for cervical dysplasia than in low-income or medium-income countries. Adapted screening programs should be defined., Competing Interests: Competing interests: JS: President Nord-Ostdeutsche Gesellschaft für Gynäkologische Onkologie (NOGGO e.V.), Member Prevention Committee European Society of Gynaecological Oncology., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The international Charité-MAYO Conference aims to promote international dialog on diagnostics, management, scientific breakthroughs, and state-of-the-art surgical procedures in gynecology and gynecologic oncology and senology. Live surgeries are a fundamental tool of interdisciplinary and international exchange of experts in their respective fields. Currently, there is a controversial and emotional debate about the true value, risks, and safety of live surgical broadcasts. The aim of the current study is to analyze peri-operative risks in patients who were operated live during the Charité-MAYO Conferences., Methods: Live surgeries were performed by the core Charité team consisting of gynecologic oncologic surgeons, breast and plastic surgeons, partly in collaboration with visiting gynecologic oncologic surgeons. We performed a retrospective analysis of live surgeries performed during seven Charité-MAYO Conferences from 2010 to 2019 held in Berlin, Germany. Patients' files and tumor databases were analyzed as required and patients were contacted to update their long-term follow-up., Results: Sixty-nine patients who were operated live were included. The types of surgery were as follows: urogynecologic procedures (n=13), breast surgery (n=21), and gynecologic oncology surgery for ovarian, uterine, vulvar or cervical cancer (n=35). Peri-operative complications were assessed according to the Clavien-Dindo classification. Despite a high rate of complete resection and the high frequency of multivisceral procedures, the rate of peri-operative complications was within the range published in the literature. Time of surgery and length of intensive unit care and hospital stay did not differ from data acquired at the home institution., Conclusions: Based on our analysis, live surgeries appear to be safe when performed within a multidisciplinary setting without an increase in surgical morbidity and mortality compared with historical controls and without compromise of patients' outcome. This is the first analysis of its kind to set the basis for patient information and consent for this type of surgeries., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chromosomal instability, a hallmark of cancer, results in changes in the copy number state. These deviant copy number states can be detected in the cell-free DNA (cfDNA) and provide a quantitative measure of the ctDNA levels by converting cfDNA next-generation sequencing results into a genome-wide copy number instability score (CNI-Score). Our aim was to determine the role of the CNI-Score in detecting epithelial ovarian cancer (EOC) and its role as a marker to monitor the response to treatment., Methods: Blood samples were prospectively collected from 109 patients with high-grade EOC. cfDNA was extracted and analyzed using a clinical-grade assay designed to calculate a genome-wide CNI-Score from low-coverage sequencing data. Stored data from 241 apparently healthy controls were used as a reference set., Results: Comparison of the CNI-Scores of primary EOC patients versus controls yielded sensitivities of 91% at a specificity of 95% to detect OC, respectively. Significantly elevated CNI-Scores were detected in primary (median: 87, IQR: 351) and recurrent (median: 346, IQR: 1891) blood samples. Substantially reduced CNI-Scores were detected after primary debulking surgery. Using a cut-off of 24, a diagnostic sensitivity of 87% for primary and recurrent EOC was determined at a specificity of 95%. CNI-Scores above this threshold were detected in 21/23 primary tumor (91%), 36/42 of platinum-eligible recurrent (85.7%), and 19/22 of non-platinum-eligible recurrent (86.3%) samples, respectively., Conclusion: ctDNA-quantification based on genomic instability determined by the CNI-Score was a biomarker with high diagnostic accuracy in high-grade EOC. The applied assay might be a promising tool for diagnostics and therapy monitoring, as it requires no a priori information about the tumor.

Research Question: What is the potential role of immune cells and their inflammatory cytokines in the pathogenesis, development and establishment of endometriosis?, Design: Peritoneal fluid from 59 women (43 with endometriosis and 16 controls) who had undergone laparoscopic surgery was analysed. Changes in the population of innate and adaptive immune cells, cytokines, chemokines and growth factor expression were measured by flow cytometry, Luminex Technology and enzyme-linked immunosorbent assay., Results: No differences were found in the frequencies of the innate and adaptive immune cells between women with and without endometriosis. In the peritoneal fluid of women with endometriosis, IL-1β, IL-1RN, IL-2, IL-4, IL-8, IL-10, IL-12 (p70), IL-17α, FGF2, G-CSF, MCP-1, MIP-1α and TNF-α were significantly increased compared with controls. A correlation between IL-2, MCP-1, MIP-1α, TNF-α and the severity of endometriosis was observed. The concentration of neopterin, a possible biomarker for this disease, was increased in women with endometriosis compared with controls., Conclusions: The functional activity of immune cells seemed to be reduced despite their numbers remaining unchanged. The data indicate that a shift of T H cytokine profile occurs, which increases the T H 1-T H 2 ratio. This is driven by the increased levels of the cytokines (TNF-α and IL-2) in women with severe endometriosis., (Copyright © 2021. Published by Elsevier Ltd.)

Background/aim: Postoperative pancreatic fistula after distal pancreatectomy represents the most frequent procedure-related complication; however, a standard treatment is currently not available., Case Report: We herein report a case of postoperative pancreatic fistula after distal pancreatectomy and splenectomy in a patient affected by a platinum-sensitive ovarian cancer recurrence. The 59-year-old patient developed a pancreatic fistula on postoperative day 4. An endoscopic transgastric double-pigtail drainage was placed on postoperative day 13. The patient was discharged after 5 days and referred to adjuvant medical treatment. A month later, computed tomography revealed complete resolution of the fistula, the drainage was removed, and the patient continued chemotherapy. She recovered uneventfully at a 3-month follow-up., Conclusion: EUS-guided drainage is a viable option in the management of postoperative pancreatic fistula, which can lead to a rapid resolution of peripancreatic fluid collections and to initiation of adjuvant chemotherapy with the slightest delay in ovarian cancer patients., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Patients with platinum-resistant ovarian cancer (PROC) have a high need for reliable prognostic markers. Since significance of primary platinum resistance (PPR) versus secondary platinum resistance (SPR) was identified for patients receiving anti-angiogenic therapy, it has not been confirmed for chemotherapy only., Methods: PROC patients from 3 prospective trials of the NOGGO study group (TOWER, NOGGO-Treosulfan, and TRIAS) were included in this meta-analysis. Exploratory Cox and logistic regression analyses were performed to correlate progression-free survival (PFS) and overall survival (OS) with the timing when platinum resistance developed., Results: Of 477 patients, 264 (55.3%) were classified as PPR, compared to 213 (44.7%) with SPR. For patients receiving chemotherapy only, SPR was associated with a significantly longer median PFS of 3.9 compared to 3.1 months for PPR (hazard ratio [HR]=0.78; p=0.015). SPR versus PPR was confirmed to be an independent prognostic factor for better PFS in multivariate analysis (HR=0.74; p=0.029). Benefit from adding sorafenib to chemotherapy was mainly seen in PPR (HR=0.40; p<0.001) compared to SPR patients (HR=0.83; p=0.465)., Conclusions: Prognostic significance of SPR versus PPR could be elucidated for patients receiving chemotherapy only. In contrast to bevacizumab, the multi-kinase inhibitor sorafenib exhibits profound therapeutic efficacy in PPR patients indicating potential to overcome this negative prognostic impact., Competing Interests: Fabian Trillsch: grants and personal fees from AstraZeneca, Clovis, Medac, MSD, PharmaMar, Roche, and Tesaro/GSK. Sven Mahner: grants and personal fees from AstraZeneca, Clovis, Medac, Novartis, Olympus Europe, PharmaMar, Pfizer, Roche, Sensor Kinesis, Tesaro/GSK, and TEVA. Pauline Wimberger: grants and personal fees from AstraZeneca, Amgen, Clovis, Medac, MSD, Pfizer, PharmaMar, Roche, Tesaro/GSK, Novartis, Eisai, Celgene and TEVA. Jalid Sehouli: grants and personal fees from Astra Zeneca, Bayer, Eisai, Clovis, Olympus, Johnsons and Johnson, PharmaMar, Pfizer, TEVA, Tesaro/GSK, MSD, Lilly, Roche and Merck. All remaining authors have declared no conflicts of interest., (Copyright © 2021. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background/aim: Angiosarcoma of primary gynecologic origin is an extremely rare and highly malignant tumor of endothelial origin with a 5-year survival rate of less than 35%. To date, only 61 cases have been described in the literature. The aim of this study was to present more cases and discuss potential therapy options., Case Report: The following case series presents three cases of gynecologic angiosarcomas that were under therapy at the Charité - University medicine of Berlin from June 2014 to February 2018., Results: Two of the cases deal with primary angiosarcomas of the uterus whereas the third case was diagnosed after the suspicion of a recurrence of a poorly differentiated squamous cell carcinoma of the cervix uteri. In case one a 75-year old patient with initial postmenopausal bleeding and a tumor mass of the uterus is described. After surgery a hemangiosarcoma of the uterus was confirmed. After two months the patient presented with a presacral peritoneal sarcomatosis. Chemotherapy of weekly paclitaxel was administered. Case two deals with a patient presenting with abdominal pain. A uterine sarcoma with infiltration of the parametry and angiosarcomatosis peritonei was diagnosed during an emergency laparotomy because of spontaneous peritoneal bleeding. Moreover, osseous metastasis was found. The patient underwent weekly paclitaxel. Due to tumor progression, chemotherapy was changed to doxorubicin and olaratumab and radiotherapy was induced. The patient died 33 months after initial diagnosis. Case three describes a 34-year old patient with suspected local recurrence of cervical cancer with infiltration of the bladder. During TURB an angiosarcoma was found. Following laparoscopy revealed peritoneal metastasis. The patient underwent weekly paclitaxel followed by a paclitaxel and pazopanib maintainance therapy which showed a regression. Due to progression afterwards, chemotherapy was changed to gemcitabine and docetaxel and gemcitabine monotherapy. The patient died 33 months after initial diagnosis., Conclusion: Even though there is no evidence on standard treatment of this extremely rare and aggressive tumor entity of the female genital tract the patients showed the longest stability of disease during chemotherapy with weekly paclitaxel., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Maintenance therapy induces remission and prolongs disease free interval in primary and recurrent ovarian disease. For the treatment decision making process, aspects of quality of life and patients' preferences are crucial, despite the fact that scientific data are lacking. Therefore, we conducted this European-wide study in patients with ovarian cancer., Methods: A 25 item questionnaire was provided to ovarian cancer patients via the internet or as a paper version in 10 European countries (Austria, Belgium, France, Germany, Italy, Romania, Slovenia, Finland, Turkey, and Spain). Data recorded were demographics, tumor stage, therapy after firstline and recurrent disease, preferences for administration, and expectations concerning maintenance therapy., Results: Overall, 1954 patients participated from September 2013 to March 2016; 42% had recurrent disease. Most patients (98%) with primary epithelial ovarian cancer underwent surgery followed by chemotherapy (91%). Almost one-third of participants (29%) were receiving maintenance therapy whereas 45% had only heard of it. For 70% of patients with primary epithelial ovarian cancer, they heard about maintenance therapy from their doctor, 10% heard about maintenance therapy from other patients, and 8% from the internet. The main source of information about maintenance therapy in patients with epithelial ovarian cancer relapse was from the treating physician (72%), from other patients (8%), and from the internet (7%). For patients undergoing maintenance therapy, the four most disturbing adverse effects were polyneuropathy (37%), nausea (36%), hair loss (34%), and vomiting (34%). The main objective of maintenance treatment, as perceived by patients, was to increase the chances of cure (73%), improvement in quality of life (47%), and delay in tumor growth (37%). Many patients were willing to undergo maintenance therapy until tumor progression (38%) and 39% would prefer oral administration. No significant differences were detected in the cross country subanalysis regarding expectations of maintenance therapy and patients with primary or relapsed ovarian cancer., Conclusion: Patients with ovarian cancer were willing to accept maintenance therapy of prolonged duration and preferred oral administration. There is still a gap between the efficacy of maintenance therapy and patient expectations. Patients need more information on the adverse effects and treatment goals of maintenance therapy to avoid misunderstandings., Competing Interests: Competing interests: FJ is on the advisory board and symposium of Astra Zeneca, Roche, Tesaro, Ipsen Pharma GmbH, Janssen, Pfizer, Bristol-Myers Squibb and MSD, outside the submitted work. RB reports personal fees from Roche and from AstraZeneca, outside the submitted work. AdB reports personal fees from Astra Zeneca, Roche, BioCard, Tesaro, Pfizer, Clovis, Genmab, and MSD, outside the submitted work. IV reports consulting or advisory role (institution) for Advaxis Inc, Eisai Inc, MSD Belgium, Roche NV, Genmab A/S, Genmab US, F Hoffmann-La Roche Ltd, Pharmamar, Millennium Pharmaceuticals, Clovis Oncology Inc, AstraZeneca NV, Tesaro Bio GmbH, Tesaro Inc, Oncoinvent AS, Immunen Inc; research funding (via KU Leuven) from Oncoinvent AS, Genmab A/S-Genmab BV; corporate sponsored research grants from Amgen, Roche, and Stichting teen Kanker; travel, accommodation, and expenses from Takeda Oncology, Pharmamar, Genmab, Roche, AstraZeneca, and Tesaro, outside the submitted work. DL reports grants and personal fees from Tesaro, personal fees from Astra Zeneca, grants and personal fees from Merck, grants and personal fees from Clovis, and personal fees from Merrimack, outside the submitted work. JM reports personal fees and non-financial support from Roche, and personal fees from Tesaro, AstraZeneca, and Clovis, outside the submitted work. JS reports honoraria from Astra Zeneca, Eisai, Clovis, Olympus, Johnson&Johnson, PharmaMar, Pfizer, TEVA, TESARO, and MSD; consulting or advisory role for Astra Zeneca, Clovis, Lilly, PharmaMar, Pfizer, Roche, TESARO, and MSD; research funding from Astra Zeneca, Clovis, Merck, Bayer, PharmaMar, Pfizer, TESARO, and MSD; travel, accommodation, and expenses from Astra Zeneca, Clovis, PharmaMar, Roche, Pfizer, TESARO, and MSD, outside the submitted work., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

High-grade serous ovarian cancer (HGSOC) likely originates from the fallopian tube (FT) epithelium. Here, we established 15 organoid lines from HGSOC primary tumor deposits that closely match the mutational profile and phenotype of the parental tumor. We found that Wnt pathway activation leads to growth arrest of these cancer organoids. Moreover, active BMP signaling is almost always required for the generation of HGSOC organoids, while healthy fallopian tube organoids depend on BMP suppression by Noggin. Fallopian tube organoids modified by stable shRNA knockdown of p53, PTEN, and retinoblastoma protein (RB) also require a low-Wnt environment for long-term growth, while fallopian tube organoid medium triggers growth arrest. Thus, early changes in the stem cell niche environment are needed to support outgrowth of these genetically altered cells. Indeed, comparative analysis of gene expression pattern and phenotypes of normal vs. loss-of-function organoids confirmed that depletion of tumor suppressors triggers changes in the regulation of stemness and differentiation., (© 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Detection of epithelial ovarian cancer (EOC) poses a critical medical challenge. However, novel biomarkers for diagnosis remain to be discovered. Therefore, innovative approaches are of the utmost importance for patient outcome. Here, we present a concept for blood-based biomarker discovery, investigating both epithelial and specifically stromal compartments, which have been neglected in search for novel candidates. We queried gene expression profiles of EOC including microdissected epithelium and adjacent stroma from benign and malignant tumours. Genes significantly differentially expressed within either the epithelial or the stromal compartments were retrieved. The expression of genes whose products are secreted yet absent in the blood of healthy donors were validated in tissue and blood from patients with pelvic mass by NanoString analysis. Results were confirmed by the comprehensive gene expression database, CSIOVDB (Ovarian cancer database of Cancer Science Institute Singapore). The top 25% of candidate genes were explored for their biomarker potential, and twelve were able to discriminate between benign and malignant tumours on transcript levels ( p < 0.05). Among them T-cell differentiation protein myelin and lymphocyte (MAL), aurora kinase A (AURKA), stroma-derived candidates versican (VCAN), and syndecan-3 (SDC), which performed significantly better than the recently reported biomarker fibroblast growth factor 18 (FGF18) to discern malignant from benign conditions. Furthermore, elevated MAL and AURKA expression levels correlated significantly with a poor prognosis. We identified promising novel candidates and found the stroma of EOC to be a suitable compartment for biomarker discovery.

Background: Elderly patients are underrepresented in clinical trials in gynecological cancer, even though they are disproportionally often affected. This study aimed to evaluate the disposition and apprehension of elderly patients toward study participation., Methods: 112 elderly gynecological cancer patients (median age 70) were surveyed in a multicenter cross-sectional study. Besides fitness, state of disease, education and domestic situation, questions aimed at the general willingness to participate in a clinical trial. Personal reasons for refusal and anticipated advantages/disadvantages that might evolve from participation were inquired., Results: Willingness to participate in a clinical study was generally high (72%, 74/102). Reasons for potential study participation were: 'better monitoring of the disease' (67.1%), 'better medical care' (46.1%), 'to help medical research' (44.7%), 'better medication' (35.5%) and 'because of my doctor's recommendation' (22.4%). Reasons for potential refusal were: 'too time consuming' (24.4%), 'fear of side effects' (21.8%), 'misuse as experimental animal' (18%), 'long distance to clinic' (14.1%) and 'too little or unclear information' (10.3%). 37.2% (29/78) of the patients stated that they had 'no objection' at all against study participation. The question if patients anticipated having a longer life due to study participation was answered with 'yes' or 'rather yes' in 42% (38/90); 28.9% answered 'no' or 'rather no' (29% undecided). No statistical significant relation between willingness to participate in a study and general fitness (p = 0.133), education (p = 0.122), age (p = 0.474) or domestic situation (p = 0.123) could be observed in a multivariate logistic regression model., Conclusions: Elderly patients are generally willing to participate in clinical studies, in our cohort regardless of their fitness. Benefits of participation seem to be unclear among a majority of potential study participants. Therefore, it might be decisive to provide more general information regarding benefits and safety for elderly patients in a clinical trial.

Background/aim: Chemotherapy-associated toxicity is one of the limiting factors regarding treatment efficacy, patient outcome and quality of life in this collective. Underweight or obese patients represent a major group in which the therapy seems to be more challenging. The aim of this analysis was to evaluate the impact of BMI on the toxicity in patients undergoing chemotherapy., Patients and Methods: The data of three prospective phase II/III studies ('Tower', 'Topotecan phase III' and 'Hector') of the North-Eastern German Society of Gynecological Oncology including 1,213 patients with recurrent ovarian cancer were retrospectively analyzed. The study was performed using logistic regression and Cox regression analysis., Results: The median age at diagnosis was 59 years. Sixty-seven (5.5%) patients had BMI <20 and 272 (22.4%) patients had BMI >30. Preterm termination of the chemotherapy was associated with lower BMI (p=0.017). Moreover, non-hematological toxicity grade III/IV was mainly observed in underweighted women as well (p<0.001). Patients with higher BMI more often presented with grade III/IV anemia (p=0.019) and as a consequence required blood transfusions more frequently (p=0.005). The overweight group was also associated with a higher number of co-medications. However, no difference in survival regarding BMI was observed in our study., Conclusion: Fewer chemotherapy cycles and preterm discontinuation were more frequent in patients with lower BMI. Hematological toxicity and higher medication intake appeared more often in patients with higher BMI., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer., Methods: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m 2 on days 1-5) plus either oral sorafenib 400 mg or placebo twice daily on days 6-15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01047891., Findings: Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43-0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8-7·6) with sorafenib versus 4·4 months (3·7-5·0) with placebo. The most common grade 3-4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%])., Interpretation: Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies., Funding: Bayer, Amgen, and GlaxoSmithKline., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: The aim of the present study was to assess in a large cohort of primary epithelial ovarian cancer patients the incidence and the clinical effect of BRCA1 genetic and epigenetic silencing mechanisms., Methods: A total of 188 primary epithelial ovarian cancer patients, treated between 2000 and 2011 at the Charité University Hospital of Berlin, were included. The patients' tumor and blood samples were obtained from the Tumor Bank Ovarian Cancer Network (www.toc-network.de). Direct sequencing of BRCA1 exon 11 was performed to detect germline mutations, whereas tumor samples were assessed for BRCA1 promoter hypermethylation by bisulphite-converted methylation-specific polymerase chain reaction. Basing on their BRCA1 status, patients were compared regarding clinicopathological variables and survival., Results: Twenty-one patients (11.2%) showed hypermethylation in BRCA1 promoter (HMB), and 18 patients (9.6%) presented germline mutations in BRCA1 exon 11 (GMB). Patients with HMB showed a significantly younger age at diagnosis compared with BRCA1 wild type (BWT) patients (54 vs 61 years, P = 0.045), and both GMB and HMB patients were more likely to have high-grade serous ovarian cancer (76.2% and 77.8% vs 52.7%, P = 0.043 and P = 0.043). Positive family history of breast or ovarian cancer (OC) was more frequently reported among GMB patients with respect to BWT patients (44.4% vs 13.5%, P = 0.003); GMB, HMB, and BWT patients did not show significant differences in terms of tumor dissemination pattern, surgical outcomes, platinum response or survival; neither mutational nor hypermethylation BRCA1 status was found to be an independent prognostic factor for OC patients., Conclusions: Hypermethylation in BRCA1 is associated with earlier occurrence of OC. In addition, the coexistence of both GBM and HMB is an infrequent event, occurring in 0.5% of OC cases. Silencing of BRCA1 through mutation and hypermethylation confers to distinct clinical characteristics of OC patients but similar clinical outcome with respect to BWT patients.

Background: Palliative systemic treatment in elderly gynaecological cancer patients remains a major challenge. In recurrent ovarian cancer (ROC), treosulfan an active alkylating drug showed similar cytotoxicity whether as oral (p.o.) or intravenous (i.v.) application. The aim of this innovative trial was to evaluate the preference of elderly patients (≥65 years) for p.o. or i.v. chemotherapy focusing compliance, outcome, toxicities, and geriatric aspects as secondary endpoints., Methods: Patients with ROC had the free choice between treosulfan i.v. (7000 mg/m 2 d1, q29d) or p.o. (600 mg/m 2 daily d1-28, q57d). Only indecisive participants were randomized., Results: Overall 123 patients with 2 nd to 5 th recurrence were registered and 119 received at least one cycle of chemotherapy. 85.7% preferred treosulfan i.v. and 14.3% oral, where only three patients were randomized. Main reasons for i.v. preference associated with individual expectations of lower rate of gastrointestinal disorders, higher activity and tolerability of treatment. Median of applied chemotherapies was three (range 1-12 cycles), with most common grade 3/4 toxicities thrombopenia (18.7%), leukopenia (15.7%), ascites (7.6%), bowel obstruction (6.7%), and abdominal pain (4.2%). Median time until progression/overall survival was 5.2/7.8 months (i.v.), and 5.6/10.4 months (p.o.), respectively, without significant differences in efficacy., Conclusions: Elderly patients with recurrent ovarian cancer asked and demonstrated active participation in the decision-making process of their oncological treatment and favoured predominantly the i.v. application. Treosulfan was generally well-tolerated despite comorbidities and heavy pre-treatment. Our study demonstrates that patients' preference did not influence prognosis negatively and remains important in gynaecologic oncology decision practice., Eudract Nr: 2004-000719-25; NCT 00170690.

Objective: In recurrent ovarian cancer (ROC), there is a high demand on effective therapies with a mild toxicity profile. Treosulfan is an alkylating agent approved as oral (p.o.) and intravenous (i.v.) formulation for the treatment of recurrent ovarian cancer. Data on safety and efficacy for either formulation are rare. For the first time we conducted a randomized phase III study comparing both formulations in women with ROC., Methods: Patients having received at least two previous lines of chemotherapy were randomly assigned to one of two treatment arms: treosulfan i.v. 7000 mg/m 2 d1 q4w or treosulfan p.o. 600 mg/m 2 d1-28 q8w. Primary endpoint was safety regarding hematological and gastrointestinal toxicity grade III/IV, secondary endpoints were other toxicities, clinical benefit rate (CBR), time to progression (TTP), overall survival (OS) and quality of life., Results: 250 patients were treated with treosulfan i.v. (128) or treosulfan p.o. (122). In general treosulfan therapy was well tolerated in both treatment arms. Leukopenia grade III/IV occurred significantly more frequently in the p.o. arm (3.9% i.v. arm, 14.8% p.o. arm, p = 0.002). Other toxicities were similar in both arms. CBR was comparable between arms (41.4% i.v. arm, 36.9% p.o. arm). No difference in TTP (3.7 months i.v. arm, 3.5 months p.o. arm) or OS (13.6 months i.v. arm, 10.4 months p.o. arm, p = 0.087) occurred., Conclusions: Given the safety and efficacy results treosulfan is an acceptable option for heavily pretreated OC patients. Regarding the toxicity profile the i.v. application was better tolerated with less grade III and IV toxicities., Competing Interests: Compliance with ethical standardsConflict of interestJalid Sehouli declares that he received an educational grant from medac. Michael Patrick Lux declares that he received honoraria for lectures, honoraria for editorial board membership of a journal as well as non-financial support for congress visit from medac. Tanja Trarbach declares that iOMEDICO received financial support from medac. Oliver Tomè, Oumar Camara, Ingo Bernhard Runnebaum, Hans Werner Tessen, Beate Rautenberg, Radoslav Chekerov and Gerald Gitsch declare that there are no conflicts of interest.Ethical approvalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.Informed consentInformed consent was obtained from all individual participants included in the study.

Introduction: The cold shock Y-box binding protein-1 (YB-1) fulfills important roles in regulating cell proliferation and differentiation. Overexpression occurs in various tumor cells. Given the existence of extracellular YB-1 we set out to determine the diagnostic, predictive and prognostic role of serum YB-1/p18 for patients with primary epithelial ovarian cancer (EOC)., Methods: The protein fragment YB-1/p18 was quantified by sandwich ELISA in serum samples from 132 healthy female volunteers and 206 patients with histological diagnosis of primary EOC. The ELISA sensitivity and specificity to detect EOC were calculated using receiver operating curves. Survival data were calculated using Kaplan Maier curves., Results: Median age at the time of diagnosis was 60years and follow-up ended with a mean of 44.8month. 188 (91%) patients were diagnosed at advanced stages (FIGO III/IV) and 188 patients (91%) suffered from high-grade serous ovarian carcinoma. YB-1/p18 levels were significantly decreased in older patients (p=0.021). Significantly lower serum levels of YB-1/p18 were detected in the EOC cohort when compared to the control group (p<0.0001, AUC=0.827; 95% CI, 0.787-0.867). Using the expression of serum YB-1/p18 in early stages I and II cases these could be differentiated from control cases (p<0.0001, AUC=0.816; 95% CI 0.704-0.929). No other significant associations between clinical prognostic factors and YB-1/p18 serum levels were detected. Immunoblotting results with serum samples suggest that masking of epitopes by the YB-1/p18 fragment in multiprotein-complexes under non reducing conditions leads to the observed reduced ELISA readings in the EOC cohort., Conclusions: The quantification of fragment YB-1/p18 derived from cold shock protein YB-1 in serum samples could be useful for the early diagnosis of EOC., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Palmoplantar erythrodysesthesia is a frequent dermal side-effect during chemotherapy. Previous investigations showed radical formation subsequent to doxorubicin infusion and preventative and therapeutic effects of an antioxidant-containing ointment., Patients and Methods: Using a non-invasive vivomeasuring system (Biozoom®; Biozoom Services GmbH, Kassel, Germany) changes in the antioxidant status (as measured by relative carotenoid concentration) of the skin prior to and after intravenous administration of paclitaxel, docetaxel and 5-fluorouracil were investigated in 42 patients with cancer., Results: A significant decrease of antioxidant concentration subsequent to intravenous administration was found for all investigated chemotherapeutic agents. The mean concentration of carotenoids decreased from 3.59±1.26 arbitrary units (a.u.) to 3.41±1.28 a.u. (p<0.001) after paclitaxel administration, from 6.33±2.43 to 5.63±2.29 a.u. after docetaxel (p=0.027) and from 4.26±1.81 to 3.98±1.53 a.u. (p=0.042) after 5-fluorouracil infusion., Conclusion: Oxidative stress might play a significant role in the pathomechanism of palmoplantar erythrodysesthesia associated with paclitaxel, docetaxel and 5-fluorouracil. Therefore, an antioxidant-containing ointment might serve as preventative and therapeutic option., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: The main goal of the current study was to compare survival differences among subgroups of primary ovarian cancer patients in International Federation of Gynecology and Obstetrics (FIGO) stages IIIC and IIIA1 after complete tumor debulking surgery., Methods: A total of 218 patients with primary ovarian cancer who received complete cytoreductive surgery were included in the current retrospective analysis of the validated Tumor Bank Ovarian Cancer Network Database, which covers the periods January 2002 until December 2012. According to their tumor spread pattern, patients were divided into three groups: Group A (peritoneum only), Group B (peritoneum and lymph nodes), and Group C (lymph nodes only). Associations between groups and clinicopathological factors were analyzed using standard statistical procedures., Results: The vast majority of patients were classified into Group B. Lymph node involvement was detected in 70.5 % of the cases where peritoneal implants presented ≥2 cm beyond the pelvis (Group A + B). The estimated 5-year overall survival (OS) rates were 47.4 % in Group A, 45.1 % in Group B, and 91.7 % in Group C (p < 0.01). In the subgroup analysis of Group B, both pelvic and para-aortic lymph node involvement was found in 57 % of patients. Patients in Group B who had para-aortic lymph node involvement only had better median progression-free survival (PFS) compared with patients with pelvic lymph node involvement only and pelvic and para-aortic lymph node involvement (28, 16, and 18 months, respectively; p = 0.02). The median OS differed significantly between patients with para-aortic lymph node involvement only versus patients with both pelvic and para-aortic involvement (68.5 vs. 46.7 months; p = 0.02). Three-year PFS was 90.0 % in FIGO IIIA1(i) and 62.6 % in FIGO IIIA1(ii) (hazard ratio 2.30, 95 % confidence interval 0.45-11.58)., Conclusions: Patients with FIGO stage IIIC with lymph node involvement only had the best clinical outcome compared with patients in the same stage with peritoneal involvement only. Furthermore, involvement of both pelvic and para-aortic lymph nodes were of the same infrequency, and involvement of only para-aortic lymph nodes in this stage resulted in a better chance of survival than involvement of pelvic lymph nodes only or both pelvic and para-aortic lymph nodes simultaneously. In accordance with the revised FIGO classification of 2013, our study revealed that FIGO IIIA1(i) is prognostically better compared with FIGO IIIA1(ii).

Background/aim: IGF-I (insulin growth factor 1) is crucially involved in cellular proliferation. Moreover, deregulation of IGF-I has been shown to be relevant in the carcinogenesis of various tumor entities. However, the impact of IGF-I in epithelial ovarian cancer (EOC) is unclear. In the present study, we investigated the predictive and prognostic role of circulatory IGF-I in primary EOC patients., Patients and Methods: In the FP6 European Project "OVCAD", 275 consecutive primary EOC patients were enrolled. Patients were eligible if radical cytoreductive surgery and platinum-based chemotherapy were performed. Plasma IGF-I was detected using ELISA., Results: Increased plasma IGF-I levels were more frequently found in well-differentiated epithelial ovarian carcinoma (p=0.0047). A weak correlation was observed between IGF-I levels and CA-125 in patients with serous EOC (p=0.04). No association between IGF-I expression and other clinico-pathological parameters was observed., Conclusion: IGF-I is overexpressed in patients with well-differentiated EOC. Further studies are warranted to elucidate the role of IGF-I in this sub-group of patients., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Data on routine systemic treatment of patients with ovarian cancer are currently available only to a limited degree. The alkylating agent treosulfan is approved in oral (p.o.) and intravenous (i.v.) form for the treatment of ovarian carcinoma. The present non-interventional study analyzed the clinical use of treosulfan in Germany, evaluating the mode of application, toxicity, and response and survival rate., Patients and Methods: Two hundred and forty-eight ovarian cancer patients in 57 Centers, who received treosulfan mainly either i.v. (5,000-8,000 mg/m(2) d1, q21d or q28d) or p.o. (400-600 mg/m(2) d1-14 or 21, q28d) for at least one therapy cycle were evaluable and were included in the study., Results: With a median age of 70 years (range=36-92 years), predominantly elderly patients received treosulfan treatment. Most participants presented serous histology (131, 52.8%) and advanced-stage FIGO III (122, 49%) or IV (55, 22%) disease. Median ECOG status was 1 (range=0-2), whereas cardiac co-morbidity was common (31%). Treosulfan was usually administered as second- (26%), third- (21%) or fourth-line (17%) therapy. Two hundred and one patients received i.v. and 47 p.o., Treatment: The most common reason for dose modifications was due to hematological toxicity (46%). The main reason for a therapy discontinuation was progressive disease (38.5%). Response was observed in 25.8% of participants, disease stabilization in 28.6 % and progress in 45.6%. The median progression-free and overall survival was 196 and 405 days, respectively., Conclusion: In predominantly elderly and heavily pre-treated patients with recurrent ovarian cancer, treosulfan featured a clinical relevant efficacy and well-manageable, mostly hematological, toxicity, which resulted in a positive therapeutic index., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: The peritoneal cancer index (PCI) is used to refer gastrointestinal malignancy patients to either palliative or curative management of their peritoneal carcinomatosis. The aim of this retrospective study was to evaluate the prognostic value of the PCI in patients with primary advanced epithelial ovarian cancer (EOC) after complete cytoreductive surgery., Methods: PCI quantitatively assesses cancer distribution on the peritoneum by calculating tumor sizes in each of 13 abdominopelvic regions. Correlation between PCI score and clinical factors were analyzed using Kendall's tau b. Univariate and multivariate survival analyses were performed with the Kaplan-Meier method and Cox regression model, respectively., Results: We retrospectively enrolled 80 consecutive patients with primary EOC treated in our gynecology department. All patients underwent complete cytoreductive surgery. Patients whose history included interval tumor debulking and completion cytoreductive surgery were excluded. Most tumors were of a serous histological subtype (96.3 %). Median age at diagnosis was 58.0 years. Their median PCI score was 12.0 (range 3-32). We found statistical correlations between PCI and ascites (p = 0.001), surgery duration (p < 0.001), T status of TNM staging (p = 0.036), and preoperative CA 125 (p = 0.025). In the univariate analysis, higher PCI scores were related to poor overall (OS) and progression-free (PFS) survival rates (p = 0.036 and p < 0.001, respectively). Multivariate analysis showed that the association remained significant only for PFS (p = 0.005), not for OS (p = 0.162)., Conclusions: PCI did not portend OS in patients with primary ovarian cancer. Further prospective and multicenter studies are needed to validate these results.

Malignant ascites is a common phenomenon in cancer patients. It poses a great challenge to the clinician, because of limited treatment options and strong impairment of the quality of life of the often palliative patients. The SECIMAS study investigated the feasibility of a re-challenge with four catumaxomab intraperitoneal infusions in patients who had already received a first cycle of four infusions in the phase III CASIMAS study, which compared catumaxomab with and without prednisolone premedication. The primary endpoint was the proportion of patients who received at least three catumaxomab infusions. Secondary endpoints included a composite safety score (CSS) summarising the worst grades for the main catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain), safety, efficacy and the occurrence of anti-drug antibodies (ADAs). Eight of nine screened patients received a second catumaxomab cycle. Compliance with a catumaxomab re-challenge was high: all eight patients (100%) received all four infusions. The median CSS was 3.0 versus 3.4 in CASIMAS. The tolerability profile of the second catumaxomab cycle was comparable to that of the first cycle. Median puncture-free survival (48 days) and overall survival (407 days) were longer than in CASIMAS (35 and 103 days, respectively), although median time to next puncture was shorter (60 vs. 97 days). Of six patients sampled, all were ADA positive at screening and remained ADA positive until the end of the study. The presence of ADAs did not affect catumaxomab's safety or efficacy. The CSS and tolerability profile for catumaxomab in SECIMAS were comparable to those in CASIMAS. The majority of patients benefitted from a second cycle of catumaxomab. A re-challenge seems to be feasible and safe for selected patients with recurrent malignant ascites due to carcinoma after a first cycle of catumaxomab.

Background: Borderline tumors of the ovary (BOT) are a distinct entity of ovarian tumors, characterized by lack of stromal invasion. Recent studies postulated that the presence of invasive implants, incomplete staging, fertility sparing surgery and residual tumor after surgery are major prognostic factors for BOT. There are no biomarkers that can predict BOT or the presence of invasive implants., Objective: The aim of our study was to assess the value of CA125 and HE4 alone, or within ROMA score for detecting BOT, and for predicting the presence of invasive implants., Methods: Retrospective, monocentric study on 167 women diagnosed with BOT or benign ovarian masses. Serum HE4, CA125 levels and ROMA were assessed preoperatively. Due to low number of BOT with invasive implants, we performed an unmatched analysis (consecutive patients) and a matched analysis (according to age and histology) to compare BOT with invasive implants, BOT without invasive implants and benign disease., Results: There were no significant differences in the HE4 and CA125 expressions in the three groups of patients (p = 0.984 and p = 0.141, respectively). The ROC analysis showed that CA125 alone is superior to ROMA and HE4 in discriminating patients with BOT with invasive implants from patients with benign diseases and BOT without invasive implants. A newly established score, ROMABOT, did not perform better than ROMA. The analysis of the matched groups revealed similar results as the analysis of all samples., Conclusions: Both HE4 and CA125 are not reliable biomarkers for the diagnosis of BOT or for predicting the presence of invasive implants.

Background: Epithelial ovarian cancer (EOC) remains the main cause of mortality due to gynecological malignancies. Optimal tumor debulking and platinum response are the most important prognostic factors for overall survival (OS) in primary EOC. In the setting of recurrence, the role of cytoreduction is not clear. A critical point is to predict preoperatively the subgroup of patients with optimal surgical outcome. The aim of the study was to analyze the predictive role of HE4 for surgical outcome and platinum response in EOC patients experiencing a first relapse. Secondary aims were the prognostic role of HE4 for OS and progression-free survival (PFS)., Methods: Plasma was obtained before secondary cytoreduction from 73 EOC patients. A total of 66.7 % underwent a total macroscopic tumor clearance; 86.3 % of the patients had disease that responded to platinum therapy. HE4 was detected by enzyme-linked immunosorbent assay. For statistical analysis, the chi-square test, Fisher's exact test, Kendall's tau b, and Mann-Whitney U test were used. OS, PFS rates, and respective 95 % confidence intervals (CI) were estimated according to the Kaplan-Meier method., Results: At a HE4 cutoff value of 250 pMk, a sensitivity of 52 % and a specificity of 93.8 % (p = 0.001, 95 % CI 0.601-0.861) were reached in predicting total macroscopic tumor clearance. Plasma HE4 concentrations together with platinum response were the only independent prognostic factors for OS (p < 0.001, hazard ratio [HR] 18.77, 95 % CI 4.68-75.25; and p = 0.044, HR 3.33, 95 % CI 1.03-10.7, respectively). Together with ascites, HE4 was the only independent predictive factor for surgical outcome (p = 0.029, odds ratio [OR] 7.2, 95 % CI 1.22-42.19 and p = 0.036, OR 10.18, 95 % CI 1.16-88.69, respectively)., Conclusions: HE4 is an independent predictive marker for surgical outcome and OS in patients with recurrent EOC. Larger population studies are needed to validate these results.

Aim: The aim of the current study was to analyze the type of variations in expression profiles of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 2 (TIMP2), and vascular endothelial growth factor A (VEGFA) before and after radiochemotherapy in patients with locally advanced FIGO stage Ib-IIb cervical cancer. We analyzed the role of these biomarkers in monitoring response to treatment., Patients and Methods: Serum from 72 patients with cervical cancer treated within a phase III trial with either simultaneous radiochemotherapy (S-RC) with cisplatin, or systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R) was analyzed by ELISA. Sera were obtained during surgery and after the end of adjuvant treatment., Results: The median age at time of diagnosis was 46 years (range=30-71 years). The most common histological types were squamous cell (73.6%) and adenocarcinoma (25%). Thirty-five (48.6%) patients underwent surgery followed by S-RC and 37 (51.4%) patients were treated with surgery followed by PC-R. Five patients developed recurrence within six months after radiochemotherapy. VEGFA levels were significantly higher before and after adjuvant treatment in patients who developed early recurrence (p=0.001). An increase of more than 500 pg/ml VEGFA and a decrease of more than 9% of the pre-therapeutic value of TIMP2 were significantly associated with a higher risk of early recurrence (RR=8.5, 95% CI=1.8-39.8 and RR=11.0, 95% CI=2.5-48.2, respectively). TIMP2 expression and risk score for early relapse (which is calculated using values of VEGFA and TIMP2) were independent prognostic factors for overall survival (p=0.043, HR=0.96, 95% CI=0.93-0.99 and p=0.002, HR=1.09, 95% CI=1.03-1.15, respectively)., Conclusion: Our results indicate a predictive value of VEGFA and TIMP2 in monitoring cervical cancer patients undergoing radiochemotherapy.

Background: Pegylated liposomal doxorubicin (PLD) is a highly efficient chemotherapeutic; however, it induces dermal side effects such as palmar-plantar erythrodysesthesia (PPE) in up to 80% of cases, probably by being emitted with the sweat onto the skin surface., Aim: The aim of the present study was to examine whether a topically applied ointment containing antioxidants with a high radical protection factor is able to prevent the formation of PPE., Methods: Twenty patients suffering from ovarian carcinoma and treated with PLD were observed., Results: 60% of the patients tolerated the regular application of the cream and developed no PPE. The remaining 40% interrupted the application. Six of them developed PPE and resumed ointment application thereafter. In these cases the PPE disappeared or was strongly reduced., Conclusion: The results of the observation clearly demonstrate that topical application of the ointment is an efficient strategy against the development of PPE during chemotherapy with PLD., (Copyright © 2013 S. Karger AG, Basel.)

Purpose: Enzastaurin is an oral serine/threonine kinase inhibitor antitumor agent. Our phase II trial tested the efficacy and safety of enzastaurin added to a standard carboplatin/paclitaxel chemotherapy regimen in patients with newly diagnosed advanced ovarian cancer., Patients and Methods: This was a randomized, placebo-controlled study in patients with International Federation of Gynecology and Obstetrics stage IIB to IV ovarian, fallopian tube, or peritoneal epithelial carcinoma. Patients were randomly assigned to six cycles of chemotherapy (paclitaxel/carboplatin ± enzastaurin [PCE/PC]) followed by maintenance therapy (enzastaurin/placebo). Primary end point was progression-free survival (PFS). Secondary measures included response rate, safety assessment, and translational research., Results: A total of 142 patients were randomly assigned to PCE (n = 69) or PC (n = 73). Patients in the PCE group had a 3.7-month longer median PFS compared with patients in the PC group; this was not statistically significant (hazard ratio [HR], 0.80; 95% CI, 0.50 to 1.29; P = .37). Safety profiles of the treatment arms were comparable. Frequency of discontinuation because of adverse events was similar (PCE, 11.9%; PC, 9.7%). Multivariate analyses confirmed the importance of optimal debulking with regard to PFS (debulking optimal v suboptimal: HR, 0.51; 95% CI, 0.30 to 0.85; P = .009). HR for covariate stage (stage IIB to IIIB v IIIC to IV) was not statistically significant (0.75; 95% CI, 0.38 to 1.47; P = .40). Translational research of immunohistochemistry protein assays did not identify any markers significantly associated with treatment difference regarding PFS., Conclusion: The PCE combination increased PFS, but it was not significantly superior to PC in this phase II study.

Aim: To gain more information about the knowledge of the clinical management of uterine sarcoma., Materials and Methods: This survey was performed among members of the North-Eastern German Society of Gynecological Oncology (NOGGO) and the German Society of Psychosomatic Medicine in Gynecology and Obstetrics (DGPFG) on the treatment of uterine sarcomas., Results: Altogether, 374 gynecologists took part. When asked about the surgical therapy of leiomyosarcoma, 64% indicated hysterectomy with bilateral adenectomy and lymph node dissection. Answers on the extent of lymphadenectomy in leiomyosarcoma differed widely. When asked about the preferred chemotherapy regimen for metastatic uterine sarcoma, more than 60% of all gynecologists would not apply any chemotherapy. Almost 40% recommended any kind of radiotherapy in this situation., Conclusion: There is a great uncertainty about the standard treatment of uterine sarcoma, even among specialists of gynecological oncology. It is time for organized efforts to improve the treatment of uterine sarcoma.

Background: Approximately one third of women diagnosed with ovarian cancer is 70 years or older. Information on the treatment reality of these elderly patients is limited., Methods: 275 patients with primary epithelial ovarian cancer FIGO stage II-IV undergoing cytoreductive surgery and platinum-based chemotherapy were prospectively included in this European multicenter study. Patients <70 and ≥70 years were compared regarding clinicopathological variables and prognosis., Results: Median age was 58 years (18-85); 47 patients (17.1%) were 70 years or older. The postoperative 60-day-mortality rate was 2.1% for elderly and 0.4% for younger patients (p < 0.001). Elderly patients were less likely to receive optimal therapy (no residual disease after surgery and platinum combination chemotherapy) compared to patients <70 years (40.4% vs. 70.1%, p < 0.001) and their outcome was less favorable regarding median PFS (12 vs. 20 months, p = 0.022) and OS (30 vs. 64 months, p < 0.001). However, in multivariate analysis age itself was not a prognostic factor for PFS while the ECOG performance status had prognostic significance in elderly patients., Conclusions: Elderly patients with ovarian cancer are often treated less radically. Their outcome is impaired despite no consistent prognostic effect of age itself. Biological age and functional status should be considered before individualized treatment plans are defined.

Aim: Our purpose was to analyze the tissue expression of human epididymis protein-4 (HE4) in borderline tumors of the ovary (BOT) and to correlate it with histological subtypes and clinical features., Patients and Methods: Tumor tissue samples from 25 patients with BOT were stained on tissue microarrays. The percentage of stained tumor cells was represented by grouped immunoreactivity scores (IRS) 0 to 4., Results: The median patient age was 47 (range=22-73) years. Tumors in most patients (19/25) were staged-FIGO I and presented serous (52%) or mucinous (40%) histology. HE4 immunoreactivity occurred exclusively within the tumor cells. No association between grouped IRS and histological type, age, CA125 and FIGO stage was found. Correlation between HE4 positivity cells and HE4 IRS was significant (p<0.001)., Conclusion: The role of HE4 in BOT remains unclear. Multicenter surveys are needed to more profoundly help in the understanding of the biological and clinical features of BOT.

Introduction: The Sixth Framework Program European Union project OVCAD, "Ovarian Cancer-Diagnosis of a Silent Killer," aimed to investigate new predictors for early detection of minimal residual disease in epithelial ovarian cancer (EOC). Here we present the main pathologic, surgical, and chemotherapy characteristics of the OVCAD patient cohort., Methods: Between February 2005 and December 2008, 5 European gynecologic cancer centers (WP2 group) enrolled prospective 275 consecutive patients with EOC into this translational study. Inclusion criteria were as follows: advanced International Federation of Obstetrics and Gynecology II to IV stage, cytoreductive surgery, platinum-based chemotherapy, and collected tumor samples. WP2 coordinated the implementation, screening, and recruiting of the patients and tumor samples into a Web-based data bank according established standard operating procedures., Results: Median age at the time of diagnosis was 58 years. Most patients presented advanced high-grade EOC: International Federation of Obstetrics and Gynecology III/IV (94.5%), grade 2/3 (96%), serous histology (86.2%), ascites (76%), peritoneal carcinomatosis (67.6%), and lymph node involvement (52%). The most common surgical procedures were omentectomy (92.4%), bilateral salpingo-oophorectomy (90.9%), hysterectomy (77.3%), pelvic (69.5%) and paraaortic (66.9%) lymphadenectomy, and large (37.7%) or small bowel resection (13.4%). Patients were treated commonly with platinum-based therapy (98.2%). The macroscopic cytoreduction rate was 68.4%. After a median follow-up of 37 months, 70 patients (25.5%) developed a platinum-resistant recurrence. Biological materials such as tumor and paraffin tissue, ascites, and blood samples were collected consecutively., Conclusions: The implementation of the OVCAD cohort demonstrated the feasibility and advantages of an open, prospective, and multicenter recruitment inside a translational research study. Essential was the predefinition of all inclusion criteria, standard operating procedures, and Web-based software, which enabled the prospective patient recruitment and tissue sampling, minimizing institutional bias and variability in the quality of the biological samples. The translational concept of the OVCAD study does not conflict with the state-of-the-art surgical and chemotherapy management and guaranteed an improved outcome of patients with EOC.

Aim: We describe the impact of a sequential dose-dense schedule of carboplatin and paclitaxel on the quality of life (QoL) of patients with ovarian cancer., Patients and Methods: In this multicenter phase II trial, four cycles of carboplatin followed by 12 cycles of weekly paclitaxel were applied after cytoreductive surgery. QoL was assessed using the QoL questionnaires EORTC QLQ-C30 and QLQ-OV28 before chemotherapy (baseline), after four cycles of carboplatin, at the end of treatment (EOT), and after 6, 12, and 24 months., Results: Out of 104 eligible patients 87 (84%) participated in at least one QoL assessment. At baseline, all QLQ-C30 scales and symptoms were significantly worse than age-adjusted values for the general population. Subsequently QoL improved in general. During chemotherapy with paclitaxel, most functioning scales and symptoms worsened slightly (not significantly). However, peripheral neuropathy and chemotherapy-related side-effects increased to clinically important levels. At the end of treatment, most QoL scores were similar to those of the general population, but physical functioning and fatigue were worse. Sexual functioning and peripheral neuropathy remained problematic., Conclusion: QoL was affected mainly by the weekly paclitaxel schedule, but effects were in most cases only temporary. A dose-dense regimen using a sequential protocol may be favourable in terms of QoL.

Objective: The objective of the study was to evaluate the prognostic impact of residual tumor size after cytoreductive surgery in patients with epithelial ovarian cancer., Methods: In this prospective, multicenter study, 226 patients with epithelial ovarian cancer (International Federation of Gynecology and Obstetrics stages IIA-IV) were included. Patients were treated with cytoreductive surgery and adjuvant platinum-based chemotherapy. Univariate and multivariable survival analyses were performed to investigate the impact of residual tumor size on progression-free and overall survival., Results: In 69.4% of patients, surgery resulted in complete tumor resection; minimal residual disease (≤1 cm) was achieved in 87.2% of patients. Advanced tumor stage was associated with a lower rate of complete tumor resection (P < 0.001). After cytoreductive surgery, 3-year overall survival rates were 72.4%, 65.8%, and 45.2% for patients without, with minimal, and with gross residual disease (>1 cm), respectively (P < 0.001). Multivariable survival analysis revealed residual tumor size (P = 0.04) and older patient age (P = 0.02) as independent prognosticators for impaired overall survival. Complete cytoreduction was predictive for a higher rate of treatment response (P = 0.001) and was associated with prolonged progression-free and overall survival (P < 0.001 and P = 0.001)., Conclusions: The size of residual disease after cytoreduction is one of the most crucial prognostic factors for patients with ovarian cancer. Patients after complete cytoreduction have a superior outcome compared with patients with residual disease. Leaving no residual tumor has to be the aim of primary surgery for ovarian cancer; therefore, patients should receive treatment at centers able to undertake complex cytoreductive procedures.

Aims: In vitro and epidemiological studies indicate an essential role for progesterone in the aetiology and progression of ovarian carcinoma. The aim of this study was to examine the prognostic role of progesterone receptor (PR) protein and mRNA expression., Methods and Results: PR expression was examined by immunohistochemistry (n=143) and kinetic reverse transcription-polymerase chain reaction (RT-PCR) from formalin-fixed and paraffin-embedded tissue (n=55). PR mRNA and protein expression correlated (P<0.0001). PR mRNA was a positive predictor for overall and progression-free survival (P=0.0005 and P<0.0001, respectively). Protein expression was also prognostic (P=0.015 and P=0.0011, respectively), whereas only PR mRNA retained its prognostic value on multivariate analysis (P=0.04). PR mRNA was still a positive prognostic marker among oestrogen receptor 1 (ESR1) mRNA-positive tumours (P=0.0007) and survival was best in patients with PR- and ESR1-positive phenotypes (P=0.0155 and P=0.0016, respectively)., Conclusion: Expression of PR and ESR1 defines a subgroup of ovarian carcinomas with a favourable prognosis. PR and ESR1 mRNA expression analysis is a sensitive, quantitative and easy-to-perform high-throughput analytical tool for the identification of this subgroup and could be predictive in clinical trials focused on patients with potential benefit from hormonal treatment., (© 2011 Blackwell Publishing Limited.)

Aim: Intraperitoneal (i.p.) treatment with the trifunctional antibody catumaxomab is a novel promising option in the clinical management of advanced or recurrent epithelial ovarian cancer (EOC). As yet, no data exists sregarding the surgical experience after i.p. catumaxomab application. Therefore we analyzed the surgical outcome of EOC patients, previously treated with i.p. catumaxomab, with special focus on the effect on adhesion formation and morbidity., Patients and Methods: We conducted a retrospective evaluation of patients with EOC, who were previously treated with catumaxomab, either at time of primary cytoreduction (n=6) or due to malignant ascites in the recurrent situation (n=4), and who underwent surgery due to various indications between 01/2007 and 03/2010. Surgical outcome, grade of adhesions and operative morbidity were analyzed based on surgical reports and a validated intraoperative documentation tool 'Intraoperative Mappinf of Ovarian Cancer'., Results: Ten patients with EOC (FIGO stage III-IV; median age 68 years; range: 45-77 years) were evaluated. The mean time between catumaxomab treatment and surgery was 187 days (range: 8-481 days). Mean operation-time was 185 minutes (range:69-32). The indications for surgery were as follows: 3 patients due to anastomotic insufficiency after primary tumor debulking; 2 patients due to secondary tumor debulking; 4 patients due to ileus in recurrent EOC; and 2 patients for restoring intestinal continuity. At the post-catumaxomab surgery 7 patients presented massive intraoperative adhesion grade 3 (score system 0-3), while 3 patients developed repeated abscesses. Four out of the six patients operated due to recurrent EOC, presented extensive tumor load with severe peritoneal carcinosis. Nevertheless, none of the relapsed patients had at surgery ascites >500 ml., Conclusion: Surgery after i.p. catumaxomab appears feasible, however, larger prospective evaluations are warranted to assess its true impact on adhesion formation and postoperative morbidity.

Background: The therapy of gynecological malignancies and breast cancer requires a multimodal therapy approach based on current individualized and risk adapted state of the art therapy concepts. The aim of this online tumor conference project is to reach a broad interdisciplinary and cross-sectoral participation of specialists in order to develop high-quality therapy recommendations for complex casuistics., Patients and Methods: The concept of the interdisciplinary online tumor conference was established in 2004 at the Department of Gynecology, Charité Campus Virchow, University Hospital of Berlin to conduct online tumor board meetings of specialists in the field of gynecological cancer from different hospitals and gynecological and oncological practitioners from the outpatient sector. Following a systematic approach, patient data, relevant external clinical evidence and therapy preference are presented to the participants. An individual therapy recommendation for each patient is reached by consensus discussion., Results: By July 2009, 131 online tumor conferences had been performed with a total of 275 participants were developed. Per session, a median of 14 participants logged in online. Additionally 398 second opinion recommendations were performed. In an anonymous survey, carried out at the beginning of 2009, 95% of the participating physicians reported being satisfied with the information content and 50% were stimulated to seek more second opinions by the possibility of the online tumor conference. All contributors attested to a high comprehension of the developed therapy recommendations; 70% confirmed further that the conference presents an optimal possibility for fast and detailed exchange of information between disciplines and care sectors (in- and out-patient) and improves advanced educational training (81%)., Conclusion: The online tumor conference provides a time saving and high quality possibility for receiving a treatment recommendation based on the best available clinical and scientific evidence and contributes to continuously advanced training for therapists in the field of gynecological cancer.

Background: Bevacizumab is an agent with a tolerable safety profile which was described to be effective in recurrent ovarian cancer in recent phase I and phase II trials. But it remains unclear if these characteristics can translate to the very special collective of heavily pre-treated ovarian cancer patients. The present analysis was conducted to answer questions regarding safety and efficacy for the use of bevacizumab in these patients., Patients and Methods: A single-center, retrospective chart review was performed including all patients with histologically confirmed ovarian cancer and treatment with bevacizumab between 1981 and 2008. Data documentation was performed with an internet-based documentation tool (Alcedis Med, Alcedis, Gießen, Germany). All data were analyzed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA)., Results: Overall, 15 patients who were treated with bevacizumab outside of a clinical study were identified. A total of 134 cycles of bevacizumab were applied, with a median of 8.9 cycles per patient. All 15 patients had platinum-resistant disease at the time of treatment, with a median of 5.4 prior lines of chemotherapy (range 1-7). The best response under treatment with bevacizumab was classified as partial response in 2 patients (13.3%). Stable disease was found in 6 (40%) and progressive disease in 7 (46.7%) patients. The median time to progression was 6.6 months and the median overall survival was 15.0 months from the first cycle of bevacizumab. At the time of analysis 3 patients were still alive and 1 patient had been lost to follow-up. No gastrointestinal perforations or treatment related deaths were observed. Severe adverse events included 3 fistulas (20%), 1 impaired wound healing (6.6%) and 1 severe blood pressure crisis (6.6 %)., Discussion: Despite previous experience of a high rate of bowel perforations in patients with ovarian cancer treated with bevacizumab, no perforation was observed in this analysis despite the fact that this collective was a heavily pretreated and platinum resistant subgroup. The most severe possible side effect in this group was the occurrence of fistula, which might suggest that bevacizumab is a therapy option with an acceptable safety profile, even though the rate of fistulas is higher than reported in previous studies. This might again be related to the nature of this very special subgroup of heavily pretreated patients., Conclusion: The results of this analysis suggest that bevacizumab might be an efficient therapy option in the setting of heavily pre-treated ovarian cancer with a tolerable safety profile even in this very special collective.

In the present study, we report the first analysis of the clinical management [corrected] of patients with primary ovarian cancer following the summarized data of the Joint Clinical Registries of the Coordinating Tumor Center of Berlin (Dachverband Tumorzentrum Berlin e.V.). All data were summarized for the period of 2005 to 2008 regarding age, histopathology, time of surgical intervention, follow-up and survival, based on 1124 provided data sets of patients with suspected ovarian tumours. We identified 946 patients with a diagnosis of primary ovarian cancer, mostly of advanced T3 tumour stage (63.7%), FIGO III and IV stage (40.6%) or grade II and III (91%) histology. The median age at time of diagnosis was 61 years (range 15 to 94 years). Most patients (n=414, 69.8%) underwent cytoreductive surgery within one month of diagnosis. The median follow-up period was 26 months; 241 patients died in the analyzed period. The calculated 3-year survival rate was 63.3%, although the median overall survival has not yet been reached. We detected positive correlation of tumour stage (p<0.001) and of FIGO stage (p<0.001) with survival, and these were evaluated as being prognostically significant. The implementation of institutional based clinical registries as part of the modern clinical management of patients with ovarian cancer is feasible and well accepted inside the gynaecological departments of Berlin.

Background: Findings for the role of E-cadherin in ovarian cancer (OC) are controversial. The aim of this study was to analyze the expression and prognostic role of E-cadherin in OC., Materials and Methods: Expression analysis of E-cadherin was performed by immunohistochemistry in 36 patients (12 primary OC, 15 recurrent OC, 9 benign ovarian lesions). Tumor specimens were collected within OC. Correlation analysis with clinicopathological factors and survival was performed., Results: E-Cadherin was significantly reduced in OC compared to benign ovarian lesions (p=0.024). In primary OC, E-cadherin was comparable in ovarian tumor and corresponding metastatic tumor tissue. E-Cadherin showed no association with clinicopathological factors. A significant correlation between increased volume of ascites and higher E-cadherin immunoexpression was found in primary OC (p=0.029). E-Cadherin expression showed no statistically prognostic significance for survival (p=0.856)., Conclusion: The function of E-cadherin in OC remains controversial and needs to be elucidated further in larger studies.

Background: For the adjuvant setting of advanced ovarian cancer (AOC) after primary radical surgery the combination of paclitaxel and platinum in a 3-week schedule has emerged as the current standard. In preclinical studies additional anti-angiogenic effects of low dose paclitaxel infusion were demonstrated. A sequential schedule of carboplatin and paclitaxel has the potential to improve the therapeutic index., Methods: In this multicenter phase II trial four cycles of carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles of weekly paclitaxel at a dose of 80 mg/m(2) (d1/q7d) were applied after primary radical surgery. Eligible were all optimally or sub-optimally debulked patients with FIGO IA-IV ovarian cancer. All patients with hemoglobin levels <12 mg/dl received erythropoietin additionally., Results: Between July 2003 and May 2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (range: 23-80 years). A median number of 16 courses (range 1-16) were applied. The incidence of non-hematological toxicities was very low. Only 41% of patients experienced alopecia (grade 1-2). Neurotoxicity (grade 3-4) was not observed. Grade 3-4 hematological toxicity (43% of all patients) included thrombocytopenia (17%), anemia (3%), leucopenia (23%), and neutropenic fever (0%). Ninety-seven percent received erythropoietin. Thromboembolic events (4%) were not increased in patients who received erythropoietin. After a median time of 23 months (range: 1-42 months) 32 patients had died, and the median overall survival was not reached. The progression-free survival was 25.4 months (95% CI: 18.8-40+)., Conclusion: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted.

MicroRNA (miRNA) deregulation is a hallmark of human cancer. However, the mechanisms underlying miRNA alteration and the specific role of proteins involved in miRNA processing remains to be elucidated. Dicer is a key enzyme in the miRNA processing pathway that is essential for the production of mature miRNAs from their precursors. We tested the hypothesis that Dicer has biological and clinical relevance in ovarian cancer, using a range of methods including in vitro manipulation of Dicer expression. We observed down-regulation of Dicer in a subgroup of ovarian carcinomas, and found that decreased Dicer expression correlates significantly with reduced patient survival in serous cancers and advanced disease stages. Moreover, microarray and functional analysis suggest that reduced Dicer expression is connected with a global down-regulation of the microRNAome and with gene expression changes, particularly reduced expression of oestrogen receptor (ER) mRNA and protein in tumour tissue and in cell culture. Our data suggest a common mechanism for miRNAs changes by alterations in the basic machinery controlling miRNA biogenesis, of which Dicer is a central enzyme. These alterations of miRNA processing are of prognostic value and may play a role in the molecular pathogenesis of ovarian carcinoma and, possibly, other tumours. Knowledge of these molecular pathways may help toward new targeted therapeutic approaches for ovarian cancer., (Copyright 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The aim of the present study was to evaluate the expression of topoisomerase IIα (TOP2A) and HER-2 in tumor epithelial and adjacent stromal cells in ovarian cancer (OvCa). Immunohistochemistry for TOP2A and HER-2 was performed on 50 OvCa specimens from the Tumor Bank of Ovarian Cancer, and was correlated to established clinicopathological parameters. TOP2A was expressed in 98% and HER-2 in 52% of the OvCa specimens. Moderate expression of TOP2A was detected in 72% of the adjacent stromal cells. TOP2A and HER-2 were strongly expressed in the tumor epithelial cells of primary OvCa, but reduced in recurrent OvCa. Stromal expression of TOP2A increased in recurrent OvCa after platinum-based chemotherapy. In conclusion, distinct epithelial and stromal cell expression of TOP2A and HER-2 is a novel feature in the tumor biology of OvCa. Differential cellular expression of TOP2A in relation to previous chemotherapy probably reflects a modified activity of the 'stromal compartment' in drug resistance. Thus, analysis of TOP2A expression in tumor and stromal OvCa cells can aid in identifying subgroups of patients who may have a more favorable response to chemotherapy.

Introduction: Systemic chemotherapy and surgery for patients with recurrent ovarian cancer (ROC) constitute a therapeutic challenge. Venous thromboembolism (VTE) seems to have a negative prognostic impact in patients with solid tumors including primary ovarian cancer in many series. Only limited contemporary data exist regarding the impact of VTE on ROC., Patients and Methods: Two large multicenter prospective controlled phase I/II-III studies on 2nd-line topotecan-based chemotherapy with platinum-sensitive or resistant ROC (N=525) were conducted on both operated and non-operative patients by the North-Eastern German Society of Gynaecologic Oncology Ovarian Cancer Study Group (NOGGO). Analysis was performed to identify incidence, predictors and prognosis of VTE. Survival analysis, univariate and Cox-regression analysis were performed to identify independent predictors of VTE, overall and progression free survival., Results: Thirty-seven (7%) VTE-episodes during chemotherapy were identified; 70% of them occurred within the first 2 months after initiation of chemotherapy. Ascites, as a sign of peritoneal carcinomatosis and advanced tumor disease, was identified as independent predictor of VTE. Advanced age and high BMI did not appear to affect significantly the VTE-incidence. High performance status, platinum-sensitivity, serous-papillary histology, lack of ascites and surgery appeared to positively affect survival by multivariate analysis. Overall survival and progression free survival were similar between the VTE and no-VTE patients., Conclusion: ROC-patients appear to have the highest risk for developing VTE when ascites exists and during the first 2 months following chemotherapy initiation. In contrast to primary ovarian cancer, VTE could not be identified to affect overall survival in relapsed malignant ovarian disease.

Objectives: The fact that ovarian cancer remains confined to the peritoneal cavity even in advanced stages has allowed us to surmise that local immunosuppressive factors could be involved in the tumor biology of ovarian cancer. In this context, IL-10 can be one of the key factors. By studying the kinetics of IL-10 concentrations prior to and after surgery, this study attempts to reveal once more the ability of tumor micro-environment to produce IL-10. Some studies indicate that IL-10 concentration correlates with the tumor burden and can thus predict the surgical outcome. Data concerning this aim from patients with ovarian cancer do not seem to exist., Methods: In this prospective study, serum blood was collected from 27 patients, one day prior to surgery as well as 24h, 4 and 8 days after surgery. The concentration of IL-10 was determined using ELISA., Results: While IL-10 levels rise within the first day post-OP, they are found to be reduced significantly when measured at later time points. IL-10 levels also correlate statistically significantly with the tumor grade, with lower IL-10 levels observed in well-differentiated and higher IL-10 levels in undifferentiated or only poorly differentiated tumors., Conclusion: IL-10 expression levels appear to be a good surrogate marker for tumor grading. If validated, this may in future contribute to the understanding of the biology stage cancers.

Background: Pegylated liposomal doxorubicin (PLD) is one of the most effective cytotoxic agents in recurrent ovarian cancer. Palmar-plantar erythrodysesthesia (PPE) is a typical and commonly noted adverse event and often represents the dose-limiting toxicity. The purpose of this multicenter study was to determine the efficacy of this regimen as second-line therapy for patients with recurrent ovarian cancer., Patients and Methods: Patients with recurrent epithelial ovarian cancer after surgery and initial treatment with carboplatin and paclitaxel were enrolled. Eligible patients were required to have an ECOG performance status of < or =2, and sufficient organ function. PLD was administered at a dose of 20 mg/m2 every two weeks., Results: Twenty patients were recruited into this trial. Overall, 155 cycles of chemotherapy with a median of six courses (range 4-24) were administered. The median patient age was 64 years (range, 41-77 years). The hematological and non-hematological toxicity profile was favorable. No grade IV toxicity was observed. PPE grade III toxicity was noted in only one patient. Median overall survival was 19.2 months (range 1.8 to 39 months; 95% confidence interval (CI) 14.2-29.7 months) Progression-free survival was 3.3 months (range 1.38 to 36.4 months; 95% CI 1.84-13.4 months)., Conclusion: Biweekly PLD is an effective second-line treatment for patients with relapsed ovarian cancer. Toxicity incidence with this treatment schedule does not appear to be associated with the number of previous chemotherapies. Our data supports the need for a randomized study comparing biweekly with conventional monthly administration of 40 mg/m2 or 50 mg/m2 PLD to determine the best therapeutic index for PLD.

Objective: The aim of this study was to evaluate the expression of topoisomerase IIalpha (TOP2A) in epithelial and stromal cells of ovarian cancer., Methods: TOP2A expression was analyzed prospectively in normal and tumor epithelial and adjacent stromal cells using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) after laser microdissection (n = 38), RNA in situ hybridization (n = 13), and immunohistochemistry (n = 69)., Results: TOP2A mRNA was detected by RNA in situ hybridization in all ovarian cancer samples, with stronger hybridization signals in tumor epithelial cells compared to adjacent stromal cells. The same expression pattern was found by immunohistochemistry (P = .0001). Very interestingly, specific change was found in recurrent ovarian cancer after platinum-based chemotherapy: TOP2A expression decreased in tumor epithelial cells of recurrent ovarian cancer compared to primary ovarian cancer (P = .056), whereas it increased in tumor-adjacent stromal cells in carboplatin-treated recurrent tumors compared to primary ovarian cancer (P = .023)., Conclusion: TOP2A mRNA and protein expression in ovarian cancer exhibits specific patterns in tumor epithelial and adjacent stromal cells, which are differentially modulated after platinum-based chemotherapy. These data support the recently discovered importance of the stromal compartment in tumor progression and suggest that tumor stromal cells might be relevant to the development of chemotherapy resistance in ovarian cancer.