Publications by authors named "Rolf Richter"

75 Publications

Results of a German wide survey towards current surgical approach in early stage cervical cancer NOGGO MONITOR 11.

Sci Rep 2021 May 7;11(1):9774. Epub 2021 May 7.

Department of Gynecology with Center for Oncological Surgery, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Virchow Campus Clinic, Charité Medical University, Augustenburger Platz 1, 13353, Berlin, Germany.

Minimally invasive surgery (MIS) has become the standard approach in early stage cervical cancer (ECC). However, the recently published "LACC" trial and even others could show inferior PFS and OS of MIS compared to open radical hysterectomy. The results led to a widespread debate about the best surgical approach in ECC. The present survey aimed to get first insights after publication. NOGGO and AGE conducted a nationwide digital survey among 186 Gynecological Cancer Centers. Descriptive statistics and t-tests were performed using SPSS. A majority of the centers were of high expertise and/or experience in treatment of ECC and were highly aware of the LACC trial results. Trial quality and scientific value were rated as very good/good. However, still 40% would not change the standard of care to open surgery. Centers with higher volume and participating in clinical trials were more likely to change. This survey represents insights after the surprising results of recently published trials towards the surgical approach of ECC. There still seems to be a high need of future trials and possible explanations for the unexpected worse outcomes in the MIS group.
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http://dx.doi.org/10.1038/s41598-021-89071-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105313PMC
May 2021

Primary platinum resistance and its prognostic impact in patients with recurrent ovarian cancer: an analysis of three prospective trials from the NOGGO study group.

J Gynecol Oncol 2021 May;32(3):e37

Charité Universitaetsmedizin Berlin, Department of Gynecology, Campus Virchow Klinikum, Berlin, Germany.

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.
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http://dx.doi.org/10.3802/jgo.2021.32.e37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039167PMC
May 2021

Prognostic Value and Therapeutic Implications of Pleural Carcinosis and Malignant Pleural Effusion in Advanced Epithelial Ovarian Cancer.

Anticancer Res 2021 Apr;41(4):2033-2038

Department of Gynecological Oncology and Tumor Surgery, European Competence Center for Ovarian Cancer, Charité Campus Virchow Clinic, Berlin, Germany;

Aim: To demonstrate the prognostic value of pleural carcinosis/effusion in a cohort of patients with advanced epithelial ovarian cancer (EOC) and the associated therapeutic implications.

Patients And Methods: Overall, data for 388 patients with EOC with confirmed malignant pleural effusion (MPE) or pleural carcinosis were retrospectively analyzed. Exclusion criteria were non-epithelial ovarian malignancies and presence of other comorbidities associated with pleural effusions.

Results: The prognosis after the occurrence of MPE during the EOC in relapsed cases was poor with an overall survival of 9.9 months. In the multivariate analysis, the time point of the manifestation of the pleural effusion (p<0.001), platinum sensitivity (p=0.003), performance status (p=0.045) and presence of ascites (p=0.004) were significant prognostic factors for overall survival.

Conclusion: Even in this less favorable collective, well-established EOC prognostic factors were associated with a significantly better overall survival. This suggests that the overall behavioral pattern of the disease has strong similarities in patients with and without pleural effusion or carcinosis and merits an equally high therapeutic effort.
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http://dx.doi.org/10.21873/anticanres.14971DOI Listing
April 2021

[Use of emergency rooms by so-called multiple users: results of a prospective study with special consideration of the migration status].

Notf Rett Med 2021 Feb 24:1-7. Epub 2021 Feb 24.

Campus Virchow-Klinikum, Klinik für Gynäkologie mit Zentrum für onkologische Chirurgie, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Deutschland.

Objectives: Can we identify predictive factors for the group of so-called multiple users (MU; 4 and more uses of an emergency department [ED] in the past 12 months)? Are people with a migration background more likely to be classified in the MU group?

Methodology: Included were consecutive patients who visited three EDs in Berlin from July 2017 to July 2018. Using a questionnaire, diseases, reasons for visiting the ED and socioeconomic factors were recorded. Comparisons between migrants (1st generation), their descendants (2nd generation) and nonmigrants were assessed using logistic regression.

Results: A total of 2339 patients were included in the evaluation (repeat rate 56%), of which 901 had a migration background. Young women (<30 years), chronically ill, pregnant women, patients with severe complaints and people with (self-assessed) moderate and poor health quality as well as those without medical referral had a greater chance of multiple use of ED.

Conclusion: MU burden the already increasing patient volume of ED. However, they represent a heterogeneous group of patients, among whom people with a migration background are not common. Further research is warranted to better understand the factors that lead to frequent use and to develop effective strategies to address the complex health needs of MUs.
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http://dx.doi.org/10.1007/s10049-021-00851-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904028PMC
February 2021

Frailty Index for prediction of surgical outcome in ovarian cancer: Results of a prospective study.

Gynecol Oncol 2021 May 16;161(2):396-401. Epub 2021 Feb 16.

Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Gynecology, European Competence Center for Ovarian Cancer, Berlin, Germany.

Background: Complete macroscopic tumor resection is the strongest prognostic factor for patients with ovarian cancer, which requires complex surgery for achievement. Based on the mostly advanced tumor stage and high symptom burden many patients are classified as frail which may limit optimal surgical outcome. Aim of this study is to evaluate the predictive ability of Frailty Index for surgical outcomes in patients with ovarian cancer.

Methods: This prospective study enrolled patients with ovarian cancer undergoing cytoreductive surgery. We classified frailty proposed by Mitnitski et al. regarding the cumulative deficit model of frailty. Utilizing Receiver Operator Characteristic (ROC) analysis and logistic regression, we determined predictive clinical factors for severe postoperative complications. The Kaplan-Meier method and log-rank test were used for overall survival analysis.

Results: Out of f 144 enrolled patients, the overall prevalence of frailty based on a Frailty Index >0.26 and Frailty Index >0.15 was 33% and 74%, respectively. The logistic regression shows that frail patients with a Frailty Index >0.26 (Odds ratio (OR): 3.64, 95% CI: 1.34-9.85, p = 0.01), ECOG PS > 1 (OR 6.33, 95% CI:1.31-30.51, p = 0.02) and high surgical complexity score (OR 8.86, 95% CI:1.88-41.76, p = 0.006) had a significant higher risk for severe postoperative complications. According to multivariable cox regression Frailty Index >0.15 (hazard ratio (HR) (HR 1.87, 95% CI: 1.01-3.47, p = 0.048), residual tumor <1 cm (HR 2.75, 95%CI: 1.53-4.99, p = 0.001), residual tumor >1 cm (HR 5.00, 95% CI: 2.74-9.13, p < 0.001) and albumin<35.5 g/dl (HR 1.92, 95% CI: 1.08-3.43, p = 0.03) resulted as significant parameters for poor overall survival. Resulted as significant parameters for poor overall survival.

Conclusion: Next to surgical complexity score, ECOG PS > 1 and recurrent surgery, Frailty Index >0.26 is associated with severe postoperative complications in patients with ovarian cancer. Besides tumor residuals and low albumin levels a Frailty Index >0.15 predicts poor survival.
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http://dx.doi.org/10.1016/j.ygyno.2021.02.012DOI Listing
May 2021

Evaluation of Biomarkers in Myoma Patients: A Prospective Study Investigating the Role of LDH, CA 125, and IGF-1 after Uterus-Preserving Surgical Therapy.

Gynecol Obstet Invest 2021 12;86(1-2):100-107. Epub 2021 Feb 12.

Department of Gynecology with Center for Oncological Surgery, Campus Virchow Charité University Hospital Berlin, Berlin, Germany,

Objective: Myomas are one of the most common tumors of the lower abdomen in women. At present, sonography and clinical examination are the prevalent diagnostic standards for these tumors, and no biomarkers have been established yet. The primary aim of this study was to determine if the surgical removal of myomas leads to a drop of lactate dehydrogenase (LDH), CA 125, and/or insulin-like growth factor (IGF-1) and therefore if these parameters are suitable as potential biomarkers for the presence or recurrence of a myoma.

Study Design: The blood levels of LDH, CA 125, and IGF-1 were determined in 83 patients (age 18-50) with a verified diagnosis of myomas and surgical therapy at 3 different timepoints: preoperative (T0), 2 days postoperative (T1), and 6 months postoperative (T2). Vaginal sonography was performed preoperatively and once again at 6 months postoperatively.

Results: The median (Q1-Q3) LDH values dropped significantly postoperatively: 239 (217-266) U/L at T0 versus 217 (190-255) U/L at T1, p < 0.001. The median (Q1-Q3) IGF-1 values also dropped: 140.4 (118.6-179.0) ng/mL versus 112.4 (99.5-143.0), p < 0.001. By contrast, the CA 125 values rose slightly but not significantly. At 6 months (n = 34), the LDH values were not significantly different from either the preoperative or the immediate postoperative values. This was observed both in patients with and without a recurrence of myoma. In contrast, the median (Q1-Q3) IGF-1 level at T2 was significantly elevated both in patients with sonographic evidence of new myomas (129.0 [116.0-163.1] ng/mL, p = 0.023) and in patients with sonographic proof of no new myomas (161.0 [130.2-198.5] ng/mL, p < 0.001).

Conclusion: Both LDH and IGF-1 dropped significantly in the immediate postoperative days in women with myomas after uterus-preserving surgeries were performed. The postoperative concentration of IGF-1 was correlated with the evidence of new myomas and can be potentially used for further monitoring. Future studies should be able to confirm these results. This study concludes that myomas do influence LDH and IGF-1 and could possibly be suitable as biomarkers.
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http://dx.doi.org/10.1159/000513045DOI Listing
February 2021

Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (HR-QoL) in Patients with Ovarian Cancer: What Is Different Compared to Healthy Women?

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Department of Gynecology with Center for Oncological Surgery, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany.

Introduction: The aim of this analysis was to evaluate the health-related quality of life (HR-QoL) in patients with ovarian cancer using a patient-reported outcome (PRO) based questionnaire and to compare it to the healthy female population in Germany and to other ovarian cancer patients worldwide. Additionally, we looked for differences in the HR-QoL with respect to the patients' ages in our cohort.

Methods: The HR-QoL for 155 enrolled patients with ovarian cancer was assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) prior to surgery and then compared with 501 healthy females in Germany, as well as to the previously published European Organization for Research and Treatment of Cancer (EORTC) reference data for 917 patients with ovarian cancer worldwide. Moreover, we grouped our cohort by ages <65 and >65 years and analyzed them for further differences. To identify the differences, T-tests were applied.

Results: Overall, 155 patients were enrolled, and 126 patients had advanced-stage ovarian cancer (FIGO III-IV) (82.4%). Fifty-five (36%) patients were >65 years. Except for the physical functioning scale, all other domains of the functioning scales were significantly lower in our patients with ovarian cancer than in the healthy female population. The emotional (50 points versus 60 points, = 0.02), cognitive (76 points versus 88 points, = 0.005), and social functioning scales (68 points versus 81 points, = 0.006) were lower in the younger subgroup. Further, the younger subgroup exhibited significantly more fatigue (40 points versus 29 points, = 0.03) and financial difficulties (20 points versus 2 points, < 0.001) than the older subgroup.

Discussion: Interestingly, the patients with ovarian cancer had no significant differences in the physical functioning scale when compared with the healthy women. In contrast, the patients, especially in the younger group, needed special support for the emotional and social areas of their daily lives.
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http://dx.doi.org/10.3390/cancers13040631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915143PMC
February 2021

Effects of sarcopenia and malnutrition on morbidity and mortality in gynecologic cancer surgery: results of a prospective study.

J Cachexia Sarcopenia Muscle 2021 Apr 4;12(2):393-402. Epub 2021 Feb 4.

Department of Gynecology, European Competence Center for Ovarian Cancer, Berlin, Germany, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Background: Malnutrition and sarcopenia often occur simultaneously in cancer patients and are thought to have harmful effects on both surgical and oncological outcomes. Therefore, we want to evaluate the effects of sarcopenia and malnutrition on severe postoperative complications and overall survival in gynecologic cancer patients.

Methods: We assessed nutritional parameters and run a bioelectrical impedance analysis in 226 women. Extracellular mass to body cell mass index, phase angle alpha, muscle mass, and fat mass were evaluated. To determine if patients suffer from sarcopenia, we ran the Timed 'Up and Go' test, performed hand grip strength, and calculated a skeletal muscle index. Postoperative complications were categorized using Clavien-Dindo Classification. Utilizing ROC analysis and logistic regression, we determined predictive clinical factors for severe postoperative complications. Kaplan-Meier method and log-rank test were used for overall survival analysis.

Results: Of the 226 female patients, 120 (53%) had a BMI ≥ 25 kg/m , 56 (26%) had a phase angle < 4.75°, and 68 (32%) were sarcopenic according to skeletal muscle index < 27%. Within 30 days after surgery, 40 (18%) patients developed severe postoperative complications, and 4% had died. According to multivariable regression analysis, ECOG status > 1 (OR 4.56, 95% CI: 1.46-14.28, P = 0.009), BMI ≥ 25 kg/m (OR 8.22, 95% CI: 3.01-22.48, P < 0.001), phase angle < 4.75° (OR 3.95, 95% CI: 1.71-9.10, P = 0.001), and tumour stage ≥ III A (OR 3.65, 95% CI: 1.36-9.76, P = 0.01) were predictors of severe postoperative complications. During 59 months of follow-up, 108 (48%) patients had died. According to multivariable Cox regression ECOG status > 1 (HR 2.51, 95% CI: 1.25-5.03, P = 0.01), hypoalbuminemia (HR 2.15, 95% CI: 1.28-3.59, P = 0.004), phase angle < 4.5° (HR 1.76, 95% CI 1.07-2.90, P = 0.03), tumour stage ≥ III A (HR 2.61, 95% CI: 1.53-4.45, P < 0.001), and severe postoperative complications (HR 2.82, 95% CI: 1.80-4.41, P < 0.001) were predictors of overall mortality.

Conclusions: We observed that preoperatively assessed ECOG status > 1, BMI > 25 kg, as well as phase angle alpha < 4.75° and FIGO stage ≥ III A are significantly associated with severe postoperative complications within the first month. Whereas ECOG status > 1, hypoalbuminemia, phase angle < 4.5° as well as FIGO stage ≥ III A and severe postoperative complications within 30 days correlate significantly with poor overall survival.
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http://dx.doi.org/10.1002/jcsm.12676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061344PMC
April 2021

Effects of epigallocatechin gallate-enriched green tea extract capsules in uterine myomas: results of an observational study.

Arch Gynecol Obstet 2021 05 2;303(5):1235-1243. Epub 2021 Jan 2.

Klinik für Gynäkologie mit Zentrum für onkologische Chirurgie, Campus Virchow-Klinikum (Clinic for Gynecology with Centre for Oncological Surgery, Campus Virchow Klinikum), Charité-Universitätsmedizin Berlin (University Medicine Berlin), Augustenburger Platz 1, 13353, Berlin, Germany.

Purpose: The daily ingestion of green tea extract (GTE) capsules in women with oligo- or asymptomatic uterine myomas was monitored over 6 months with regard to their quality of life, myoma-associated complaints and side effects.

Methods: The participants were interviewed and examined at the beginning of the study (T1) and then again after 6 months (T3). Quality of life was assessed using a SF-12 questionnaire while their myoma-associated complaints were ascertained by using a self-developed myoma symptom questionnaire. Changes in the size of the myomas were evaluated by vaginal sonography. Side effects after 3 months (T2) and 6 months were documented by systematic interviews.

Results: Overall; 25 participants (median 45 years) have been enrolled. The analysis of the SF-12 questionnaire showed a significant improvement of the physical cumulative score of the SF-12 during the 6 month GTE capsule ingestion (T1: mean value (M) = 52.731; 95% confidence interval (KI): 49.791-55.671; T3: M = 55.862; KI%: 55.038-56.685; p = 0.019). However, the mental cumulative score of the SF-12 did not change significantly (p = 0.674). No significant correlation could be established between the capsule ingestion and changes in the symptom questionnaire, the laboratory parameters nor the myoma size. No relevant adverse side effects were reported.

Conclusion: Women who took GTE capsules showed a significant improvement in their physical cumulative score on the SF-12, but not in the global QoL score. Myoma size or other objective parameters did not change.
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http://dx.doi.org/10.1007/s00404-020-05907-6DOI Listing
May 2021

Patients' subjective assessment as a decisive predictor of malignancy in pelvic masses: results of a multicentric, prospective pelvic mass study.

J Psychosom Obstet Gynaecol 2020 Nov 30:1-6. Epub 2020 Nov 30.

Department of Gynecology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Objective: The prognosis for ovarian cancer patients remains poor. A key to maximizing survival rates is early detection and treatment. This requires an accurate prediction of malignancy. Our study seeks to improve the accuracy of prediction by focusing on early subjective assessment of malignancy. We therefore investigated the assessment of patients themselves in comparison to the assessment of physicians.

Methods: One thousand three hundred and thirty patients participated in a prospective and multicenter study in six hospitals in Berlin. Using univariate analysis and multivariate logistic regression models, we measured the accuracy of the early subjective assessment in comparison to the final histological outcome. Moreover, we investigated factors related to the assessment of patients and physicians.

Results: The patients' assessment of malignancy is remarkably accurate. With a positive predictive value of 58%, the majority of patients correctly assessed a pelvic mass as malignant. With more information available, physicians achieved only a slightly more accurate prediction of 63%.

Conclusions: For the first time, our study considered subjective factors in the diagnostic process of pelvic masses. This paper demonstrates that the patients' personal assessment should be taken seriously as it can provide a significant contribution to earlier diagnosis and thus improved therapy and overall prognosis.
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http://dx.doi.org/10.1080/0167482X.2020.1850684DOI Listing
November 2020

Role of predictive markers for severe postoperative complications in gynecological cancer surgery: a prospective study (RISC-Gyn Trial).

Int J Gynecol Cancer 2020 12 27;30(12):1975-1982. Epub 2020 Nov 27.

Department of Gynecology with Center for Oncological Surgery, European Competence Center for Ovarian Cancer, Charite Universitatsmedizin Berlin, Berlin, Germany.

Background: Surgery for gynecological cancer involves highly invasive and complex procedures potentially associated with various complications, which can cause extended hospital stays and delay of subsequent therapy, with a detrimental effect on the prognosis. The aim of this study was to explore and define the predictors of severe postoperative complications in patients undergoing surgery for gynecologic cancer.

Methods: Patients undergoing surgery for gynecologic cancers were analyzed prospectively from October 2015 through January 2017. Using validated assessment tools preoperatively, we assessed comorbidities, performance status, quality of life, nutritional and body composition by bioelectrical impedance analysis, and the surgical data of each patient. Surgical complications were graded using the Clavien-Dindo criteria. Using stepwise logistic regression models, we identified predictive markers for postoperative complications.

Results: Of the 226 enrolled patients, 40 (17.7%) experienced a grade ≥IIIb complication according to the Clavien-Dindo criteria. In the regression analysis, overweight/obesity (body mass index >25) (OR 6.41, 95% CI 2.38 to 17.24; p<0.001) and impaired physical functioning defined by a quality of life questionnaire (OR 4.19, 95% CI 1.84 to 9.50; p=0.001) emerged as significant predictors of postoperative complications. Moreover, postoperative complications were predicted by phase angle of bioelectrical impedance analysis <4.75° (OR 3.11, 95% CI 1.35 to 7.16; p=0.008) and Eastern Cooperative Oncology Group (ECOG) performance status >1 (OR 2.51, 95% CI 1.06 to 5.92; p=0.04). Intraoperative factors associated with higher risk of postoperative complications were increased use of norepinephrine (>11 µg/kg/min) (OR 5.59, 95% CI 2.16 to 14.44; p<0.001) and performance of large bowel resection (OR 4.28, 95% CI 1.67 to 10.97; p=0.002).

Conclusion: In patients undergoing surgery for gynecological cancer, preoperative evaluation of performance status according to ECOG, domains of quality of life and nutritional status, as well as intraoperative monitoring of risk factors, might help to identify patients at high risk for severe postoperative complications, and thus reduce surgical morbidity and mortality.
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http://dx.doi.org/10.1136/ijgc-2020-001879DOI Listing
December 2020

Lymphovascular space invasion and Ki67 as predictors of lymph node metastasis in primary low grade serous ovarian cancer.

Int J Gynecol Cancer 2021 Jan 30;31(1):98-103. Epub 2020 Oct 30.

Department of Gynecology with Center of Oncological Surgery, Campus Virchow Klinikum, Charite Universitatsmedizin Berlin, Berlin, Germany.

Objective: Low grade serous ovarian cancers characterize a unique clinical pattern and likely less frequent incidence of lymphatic metastasis. The expression level of Ki67 is associated with differences in prognosis and therapy outcome. However, its expression in combination with lymphovascular space invasion has not been evaluated in the prediction of lymphatic metastasis.

Methods: Patients with low grade serous ovarian cancer were identified in an institutional database. Patients with primary low grade serous ovarian cancer diagnosed and/or treated at our center between September 2000 and December 2018 were identified. Receiver operator characteristics curve analysis was performed to find the cut-off values of per cent Ki67 to discriminate patients with lymph node metastasis. The association between the presence of lymphovascular space invasion and lymph node involvement was analyzed.

Results: A total of 109 patients with primary low grade serous ovarian cancer were identified in our institution's database. Of these, 72 (66.1%) patients underwent primary surgery with pelvic and para-aortic lymph node dissection. Complete data for Ki67 expression and lymphovascular space invasion were obtained for 61 (84.7%) of these patients. Among them, 37 (60.7%) patients had lymph node metastasis. The presence of lymphovascular space invasion was associated with an increased risk of lymph node metastases (odds ratio (OR)=12.78, 95% confidence interval (CI) 3.15 to 51.81; p<0.001). In multivariate analysis including age >65 years, peritoneal carcinomatosis, and ascites>500 mL, lymphovascular space invasion remained a significant risk factor for lymphatic metastases (OR=35.11, 95% CI 2.38 to 517.69; p=0.010). Ki67 ≥6% was associated with a higher risk of lymphovascular space invasion (OR=3.67, 95% CI 1.26 to 10.64; p=0.017). No significant correlation between Ki67 expression level and nodal metastases was found (OR=2.19, 95% CI 0.76 to 6.26; p=0.14). Neither presence of lymphovascular space invasion or nodal metastases was associated with a statistically poorer prognosis.

Conclusions: We showed an association between lymphovascular space invasion, Ki67 expression, and risk of lymph node metastasis in primary low grade ovarian cancer. Further prospective trials evaluating lymphovascular space invasion and Ki-67 as predictors of lymph node metastasis are needed.
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http://dx.doi.org/10.1136/ijgc-2020-001950DOI Listing
January 2021

Preoperative quality of life as prediction for severe postoperative complications in gynecological cancer surgery: results of a prospective study.

Arch Gynecol Obstet 2021 04 29;303(4):1057-1063. Epub 2020 Oct 29.

Department of Gynecology with Center of Surgical Oncology, Charité University Hospital of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Purpose: The aim of this study was to investigate preoperative quality of life (QoL) as a predictive tool for severe postoperative complications (POC) in gynecological cancer surgery.

Methods: This is a prospective study of patients undergoing gynecologic cancer surgery at an academic center in Germany. QoL was assessed by the EORTC Quality of Life Questionnaire (QLQ-C30) and the NCCN Distress Thermometer (DT). Several geriatric assessment tools have been applied. POC were graded using Clavien-Dindo criteria. Using multivariable logistic regression models, we identified predictive clinical characteristics for postoperative complications.

Results: Within 30 days of surgery, 40 patients (18%) experienced grade ≥ 3b complications including 9 patients (4%) who died. The dominant complication was anastomosis insufficiency with 13 patients (5.8%). In the multivariable stepwise logistic regression through all univariate significant variables, we found that impaired physical functioning was predictive of POC, defined by an EORTC score < 70 (OR 5.08, 95% CI 2.23-11.59, p < 0.001). Regarding symptoms nausea/vomiting assessed as an EORTC score > 20 (OR 3.08, 95% CI 1.15-8.26, p = 0.025) indicated a significant predictive value. Being overweight or obese (BMI > 25) were also identified as predictive factors (OR 5.44, 95% CI 2.04-14.49, p = 0.001) as were reduced Mini Mental State Examination (MMSE) results < 27 (OR 7.94, 95% CI 1.36-45.46, p = 0.02).

Conclusion: Preoperative QoL measurements could help to predict postoperative complications in patients with gynecological cancer. Patients with limitations of mobility, debilitating symptoms and cognitive impairment have an increased risk for developing severe POC.
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http://dx.doi.org/10.1007/s00404-020-05847-1DOI Listing
April 2021

Can Fried Frailty Score predict postoperative morbidity and mortality in gynecologic cancer surgery? Results of a prospective study.

J Geriatr Oncol 2021 Apr 6;12(3):428-433. Epub 2020 Oct 6.

Charité - University Medicine of Berlin, Department of Gynecology, Center of Oncological Surgery, Berlin, Germany.

Background: Aim of this study is to evaluate the predictive ability of Fried Frailty Score for surgical outcomes in patients undergoing gynecologic cancer surgery.

Methods: This is a prospective cohort study at an academic gynecological cancer center from Oct 2015 through Jan 2017. We applied systematically numerous screening tools, geriatric questionnaires and single measurements which may provide predictions for surgical outcomes. We classified frailty according to the Fried definition and surgical complications were graded according Clavien-Dindo criteria. Using logistic regression analysis, we identified predictive clinical variables for postoperative complications (POC).

Results: Overall 226 patients were enrolled (median age 59 years, range 18-87 years). The prevalence of frailty based on the presence of three or more frailty criteria was 14.2%, the presence of one or two frailty criteria was classified as prefrail with 59.4% and without any presence as robust with 26.5%. Within 30 days of surgery, nine (3.8%) patients have died and 40 (18.3%) experienced a grade ≥ IIIb complication. In the regression analysis obesity (OR: 5.37, 95% CI 1.99-14.49, p = 0.001) as well as ECOG >1 (OR: 4.32, 95% CI 1.28-1.55, p = 0.018) and Albumin<3.6 g/dl (OR: 3.88, 95% CI 1.37-10.98, p = 0.011) emerged as significant predictors of postoperative complications (POC). Fried Frailty Score (OR: 2.41, 95% CI 0.91-6.41, p = 0.077) showed no significant additional predictive value.

Conclusion: Fried Frailty Score could help the surgeon to estimate the risk for POC among patients undergoing gynecologic cancer surgery. But preoperatively determined ECOG, BMI and Albumin can predict severe POC in patients undergoing gynecologic surgery more precisely and should be assessed routinely.
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http://dx.doi.org/10.1016/j.jgo.2020.09.029DOI Listing
April 2021

Perioperative management of positioning in gynecological cancersurgery: a national NOGGO-AGO intergroup survey.

Int J Gynecol Cancer 2020 10 16;30(10):1589-1594. Epub 2020 Aug 16.

Young Academy of Gynecologic Oncology (JAGO), Berlin, Germany

Introduction: The daily clinical routine in the operating room includes patient positioning. The number of perioperative positioning-related complications is growing, along with the legal proceedings concerning this topic, and only a few guidelines exist to provide specific recommendations. The aim of this survey was to assess perioperative positioning and associated adverse events during gynecological cancer surgery in Germany.

Methods: A total of 633 gynecological departments of primary, secondary, and maximum healthcare hospitals in Germany were invited to participate in this multiple-choice online questionnaire. The survey was conducted anonymously for a period of six months. The survey was divided into five different sections: descriptive information about the respondent department, pre- and postoperative management, management of positioning in the operating room based on two fictional case examples, and quality management.

Results: The response rate of our survey was 29.1 % (184/633). Nearly half of the departments (46.7 %) reported to have had one to five patients with positioning-related complications during the prior 12 months, and 29.1 % had experienced a legal dispute due to positioning-related complications. Departments with more than 50 gynecologic-oncological surgeries per year more often reported positioning-related complications (p=0.003). Standard operating procedures exist in almost every department for laparoscopic (97 %) and open surgery (95.1 %), respectively.

Discussion: The high number of positioning-related complications throughout all departments of different healthcare levels underlines the relevance of this issue and supports the need for a prospective European registry for further analysis. Training and education for all staff members should be routinely implemented to reduce and prevent positioning-related complications.
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http://dx.doi.org/10.1136/ijgc-2020-001433DOI Listing
October 2020

3D ultrasound as a surgical quality control of conization in patients with severe dysplasia: a prospective study.

Arch Gynecol Obstet 2020 11 1;302(5):1189-1196. Epub 2020 Aug 1.

Department of Gynecology, Medical University of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Purpose: To compare the techniques for cone measurement with ultrasound to determine the size of the resected tissue and to evaluate parameters which may be relevant for stratifying women at risk who need surveillance when pregnant.

Methods: The present study included women with a pathological cervical biopsy. Cervical length and volume were determined by transvaginal ultrasound prior to conization. The pathologist measured the volume of the removed tissue by the fluid displacement technique and using a ruler. A repeat transvaginal ultrasound was performed during a follow-up visit. Factors affecting cone volume as well as the correlation between measurement techniques were analyzed.

Results: A total of 28 patients underwent cervical excision treatment. The mean cervical volumes measured sonographically before and after the operation were 17.72 ± 7.34 and 13.21 ± 5.43 cm, respectively. The proportion of volume excised was 25.50 ± 17.43%. A significant correlation was found between the cone depth and the cone volume measured by the fluid displacement technique, and histopathologically and sonographically measured difference in cervical volume. The interobserver reliability coefficient was > 0.9. Analyzing influential parameters, only age affected the extent of cone volume and the correlation between the three measurement techniques.

Conclusion: Commonly applied techniques of cervical and cone measurement are equivalent and interchangeable. Our ultrasound data show variety in the volume and length of the cervix, and in the proportion of the volume excised at conization. Ultrasound measurements may help the surgeon to estimate not only the dimension of the remaining cervix but also its function.
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http://dx.doi.org/10.1007/s00404-020-05718-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524827PMC
November 2020

[Effects of hyperemesis gravidarum on the course of pregnancy and birth, with special attention to the risk factor of migration background].

Z Geburtshilfe Neonatol 2021 Feb 6;225(1):39-46. Epub 2020 Jul 6.

Klinik für Gynäkologie, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin.

Main Questions: In this investigation of hospitalized cases of HG and subsequent births, we examine differences between patients who have and who have not experienced migration as well as the effect of HG on perinatal outcome.

Methods: Retrospective quantitative data of hospitalized patients suffering from HG (1997-2015) was analyzed. Also analyzed was a retrospective record of perinatal data on a subgroup of patients (2002-2016), and a control group (matched pairs) based on the register of births created.

Results: 1103 women with HG were hospitalized; in 434 cases birth outcome data could be evaluated as well. Migrants suffer from HG earlier in pregnancy; they are, however, less frequently exposed to psychosocial stress (according to anamnestic data). HG patients are younger and have more multiple pregnancies; the newborns are lighter (-70g) but have fewer congenital malformations (aOR 0.32, 95% CI 0.11-0.96) and are less frequently in need of treatment on the neonatology ward (aOR 0.59, 95% CI 0.36-0.97).

Conclusion: Pregnant migrants are a special risk group for HG, possibly because of migration-caused stress. With severe HG, there are no adverse outcomes on the rest of the pregnancy.
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http://dx.doi.org/10.1055/a-1144-3811DOI Listing
February 2021

Total retroperitoneal en bloc resection of multivisceral-peritoneal packet (TROMP operation): a novel surgical technique for advanced ovarian cancer.

Int J Gynecol Cancer 2020 05 26;30(5):648-653. Epub 2020 Mar 26.

Department of Gynecology with Center for Oncological Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Virchow Campus Clinic, Charité Medical University, Berlin, Germany.

Background: A Total Retroperitoneal en bloc resection Of Multivisceral-Peritoneal packet (TROMP operation) is a no-touch isolation technique in a retroperitoneal space to resect the parietal peritoneum and the affected organs in advanced ovarian cancer. The study prescribed and analysed the results of this novel technique for primary cytoreductive surgery.

Methods: The study included 208 patients operated between January 2015 and December 2017 in Charité, Berlin. The TROMP operation was performed in 58 patients, whereas the other 150 patients were operated with the conventional cytoreductive method.

Results: The complete tumor resection rate accounts for 87.9% in TROMP group and 61.3% in the conventional surgery group. (p=0.001). This difference was even stronger in the sub-group of very advanced stages (T3c+T4) (85.1% of TROMP group and in only 53.1% in the conventional surgery group, p=0.001). The duration of the primary cytoreductive surgery was about 33 minutes shorter in TROMP group (median: 335 minutes vs 368 minutes; TROMP vs conventional, respectively) in spite of the fact that the most advanced cytoreductive procedures were performed statically significant more in TROMP operation arm in comparison with the conventional surgery arm. There was no statistically significant difference between the groups regarding the postoperative complication, blood loss or the length of stay in intensive care unit.

Conclusion: Total retroperitoneal en bloc resection of multivisceral-peritoneal packet (TROMP operation) is a feasible and very effective technique of surgical therapy in advanced ovarian cancer. This technique increased the complete tumor resection rate to 87.9% without increasing the blood loss, postoperative complications or the duration of surgery. A prospective randomized study is advised to validate these results.
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http://dx.doi.org/10.1136/ijgc-2019-001161DOI Listing
May 2020

Expectations and preferences of patients with primary and relapsed ovarian cancer to maintenance therapy: A NOGGO/ENGOT-ov22 and GCIG survey (Expression IV).

Int J Gynecol Cancer 2020 04 5;30(4):509-514. Epub 2020 Mar 5.

Department of Gynecology, European Competence Center for Ovarian Cancer, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Charite, Germany.

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.
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http://dx.doi.org/10.1136/ijgc-2019-000892DOI Listing
April 2020

Ki67 expression as a predictor of chemotherapy outcome in low-grade serous ovarian cancer.

Int J Gynecol Cancer 2020 04 28;30(4):498-503. Epub 2020 Jan 28.

Department of Gynecology with Center of Oncological Surgery, Virchow Campus Clinic, Charite Universitatsmedizin Berlin, Berlin, Germany.

Objective: Low-grade serous ovarian cancers characterize a unique clinical pattern and lower chemotherapy responsiveness. The expression level of Ki67 is associated with differences in prognosis; however, this has not yet been evaluated in regard to predicting the outcome of therapy.

Methods: Patients with low-grade serous ovarian cancers were identified in an institutional database. Receiver-operator characteristics (ROC) curve analysis was performed to find cut-off values of Ki67 to discriminate patients with residual tumor mass after surgery from maximal debulked patients: therapy response and therapy-free interval (TFI).

Results: A total of 68 patients with low-grade serous ovarian cancer were identified. All patients underwent surgery. 61 (89.7%) patients received platinum-based first-line chemotherapy; of these 61 patients, 13 (21.3%) had residual mass (>0 mm) after primary cytoreduction and 11 (18%) received neo-adjuvant chemotherapy. Ki67 ≥3.6% was associated with higher risk of residual mass after surgery (OR 8.1, 95% CI 1.45 to 45.18; p=0.017). Patients with Ki67 <3.6% showed a therapy-free interval of ≥6 months more often (OR 13.9, 95% CI 1.62 to 118.40; p=0.016). In the multivariate analysis of TFI <6 months, including CA125, age at diagnosis, peritoneal carcinomatosis, and ascites, Ki67 <3.6% remained a significant prognostic factor (OR 18.8, 95% CI 1.77 to 199.09; p=0.015). Chemotherapy responsiveness was evaluated in 21 patients who had residual disease and/or received neo-adjuvant chemotherapy. Ki67 ≥4.0% (OR 44.1, 95%CI 2.36-825.17, p = 0.011) was related to a significantly higher response rate (complete and partial response).

Conclusions: This is the first study to show an association between Ki67 expression and chemotherapy response, duration of TFI to platinum-based chemotherapy as well as outcome of surgery in low-grade serous ovarian cancers. Further prospective trials should use Ki-67 as a stratification factor to explore the effect of chemotherapy and endocrine strategies.
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http://dx.doi.org/10.1136/ijgc-2019-000976DOI Listing
April 2020

Pre-operative serum CA125, peritoneal cancer index and intra-operative mapping score as predictors of surgical results in primary epithelial ovarian cancer.

Int J Gynecol Cancer 2020 01 19;30(1):62-66. Epub 2019 Nov 19.

Ovarian Cancer Tumor Bank, Virchow Campus Clinic, Charité Medical University, Berlin, Germany.

Objective: Prediction of post-operative residual disease after ovarian cancer cytoreductive surgery remains a topic of interest to gynecologic oncologists. The aim of this study was to explore the correlation between serum CA125, peritoneal cancer index, and intra-operative mapping of ovarian cancer and their predictive value for post-operative outcome.

Methods: A total of 70 patients with primary epithelial ovarian cancer, who underwent primary cytoreductive surgery at Charité, Berlin between January 2013 and February 2014 were included. In all patients, pre-operative CA125 values, intra-operative peritoneal cancer index, and intra-operative mapping of ovarian cancer were determined.

Results: Using a receiver operating characteristic analysis, cut-off values for CA125, peritoneal cancer index, and intra-operative mapping of ovarian cancer score could be defined. Patients with pre-operative serum CA125 >600 U/mL had a three times higher risk for residual tumor after primary cytoreductive surgery (p=0.037). A peritoneal cancer index score >20 indicated a nine times increased risk for residual tumor (p=0.003). More than six affected abdominopelvic fields on the intra-operative mapping of ovarian cancer was associated with a 25 times higher risk of residual tumor after primary cytoreductive surgery (p≤0.05). The combination of all three values predicted residual tumor in up to 90% of patients.

Conclusion: We found that pre-operative CA125 >600 U/mL, peritoneal cancer index >20, and intra-operative mapping of ovarian cancer score >6 could be used as predictors of complete tumor resection. The combination of all these three values predicted the incomplete resection of disease in up to 90% of patients even in experienced centers.
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http://dx.doi.org/10.1136/ijgc-2019-000778DOI Listing
January 2020

Incidence and Pattern of Spread of Lymph Node Metastasis in Patients With Low-grade Serous Ovarian Cancer.

Anticancer Res 2019 Oct;39(10):5617-5621

Department of Gynecology, Virchow Campus Clinic, Charité Medical University Berlin, Berlin, Germany

Background/aim: Involvement of lymph nodes (LNs) and their surgical resection in low-grade ovarian cancer remains a field of discussion. The aim of this study was to determine the incidence and pattern of distribution of lymph node metastases in patients with low-grade serous ovarian cancer.

Patients And Methods: A retrospective analysis was carried out in patients with primary low-grade serous ovarian cancer who underwent primary surgery including systematic lymphadenectomy. Analysis of the affected LNs along with pattern of lymphatic spread was performed.

Results: Thirty-seven patients who underwent systematic pelvic and para-aortal LN dissection were identified. The median age was 48 years (range=26-76 years). The majority of patients had International Federation of Gynecology and Obstetrics stage III (89.2%). A median of 41 (range=10-97) LNs were resected. LN metastases were found in 27 (72.9%) patients. In 15 (55.5%) patients, both pelvic and para-aortic LNs were affected concomitantly, in isolated para-aortal and pelvic lymph nodes in three (11.1%) and eight (29.6%) patients, respectively. The most frequently affected region was the right obturator fossa, found in 14 (51.8%) patients, followed by the left obturator fossa in 11 (40.7%) patients.

Conclusion: Low-grade serous ovarian cancer exhibits a high percentage of lymphatic spread, with more confinement to the pelvic compared to the para-aortic region.
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http://dx.doi.org/10.21873/anticanres.13757DOI Listing
October 2019

Anxiety of myoma patients: results of standardized interviews with the State Trait Anxiety Inventory and the Kessler 10 questionnaire.

J Psychosom Obstet Gynaecol 2020 06 10;41(2):122-130. Epub 2019 Jun 10.

Department of Gynecology, Virchow Campus; Charité - University Hospital Berlin, Humboldt University of Berlin, Berlin Institute of Health, Berlin, Germany.

The aim of this study was to explore a possible relation between myoma-related anxieties and general state or trait anxiety or psychological distress, to get a better understanding of the impact of anxiety on the patients. This prospective study was conducted at the myoma clinic of a large university hospital in a major European city from November 2016 to February 2017. Patients completed standardized questionnaires on myoma-related fears, the State Trait Anxiety Inventory (STAI), and the Kessler 10. Eighty-five out of 88 women agreed to participate. State-anxiety on the STAI had a mean of 49.4 (11 points above the norm ( < .001)), and trait-anxiety had a mean of 42.0 (5 points above the norm ( = .001)). Thirty-seven percent of the patients had distress values on the K10 above the norm (defined as <20). More myoma-related fears correlated with higher scores on the Kessler and STAI. The scores were not related to the level of information about myomas or duration of illness. Myoma-related fears correlated with higher mental distress and elevated state and trait anxiety levels. Thus, physicians can contribute to the overall well-being of patients when they relieve them of the myoma-related anxiety. Further research is needed to determine whether treatment has any impact on anxiety or mental distress.
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http://dx.doi.org/10.1080/0167482X.2019.1624951DOI Listing
June 2020

Vascular endothelial growth factor receptor 2 (VEGFR2) correlates with long-term survival in patients with advanced high-grade serous ovarian cancer (HGSOC): a study from the Tumor Bank Ovarian Cancer (TOC) Consortium.

J Cancer Res Clin Oncol 2019 Apr 27;145(4):1063-1073. Epub 2019 Feb 27.

Department of Gynecology, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.

Objective: The impact of angiogenesis on long-term survival of high-grade serous ovarian cancer (HGSOC) patients remains unclear. This study investigated whether angiogenic markers correlated with 5-year progression-free survival (PFS) in a large cohort of matched advanced HGSOC tissue samples.

Methods: Tumor samples from 124 primary HGSOC patients were retrospectively collected within the Tumor Bank Ovarian Cancer ( http://www.toc-network.de ). All patients were in advanced stages (FIGO stage III-IV). No patient had received anti-angiogenesis therapy. The cohort contains 62 long-term survivors and 62 controls matched by age and post-surgical tumor residuals. Long-term survivors were defined as patients with no relapse within 5 years after the end of first-line chemotherapy. Controls were patients who suffered from first relapse within 6-36 months after primary treatment. Samples were assessed for immunohistochemical expression of vascular endothelial growth factor (VEGF) A and VEGF receptor 2 (VEGFR2). Expression profiles of VEGFA and VEGFR2 were compared between the two groups.

Results: Significant correlation between VEGFA and VEGFR2 expression was observed (p < 0.0001, Spearman coefficient 0.347). A high expression of VEGFR2 (VEGFR2) was found more frequently in long-term survivors (77.4%, 48/62) than in controls (51.6%, 30/62, p = 0.001), independent of FIGO stage and VEGFA expression in multivariate analysis (p = 0.005). Also, VEGFR2 was found the most frequently in women with PFS ≥ 10 years (p = 0.001) among all 124 patients. However, no significant association was detected between VEGFA expression and 5-year PFS (p = 0.075).

Conclusions: VEGFR2 overexpression significantly correlated with long-term PFS in HGSOC patients, independent of age, FIGO stage, tumor residual and VEGFA expression.
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http://dx.doi.org/10.1007/s00432-019-02877-4DOI Listing
April 2019

Prognostic significance of Ki-67 levels and hormone receptor expression in low-grade serous ovarian carcinoma: an investigation of the Tumor Bank Ovarian Cancer Network.

Hum Pathol 2019 03 11;85:299-308. Epub 2018 Nov 11.

Department of Gynecology, Charité University Hospital, 13353 Berlin, Germany; Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, 45136 Essen, Germany.

Low-grade serous ovarian carcinoma (LGSOC) has recently come up as a distinct rare entity of epithelial ovarian cancer. Predictive and prognostic markers are not well studied yet. Because Ki-67 and hormone receptors (HR) have been established as relevant cancer biomarkers in several malignant tumors, we evaluated Ki-67 and HR expression rates by immunohistochemistry in 68 patients with LGSOC. We used a standardized cutoff finder algorithm to analyze prognostic significance for overall survival (OS) and progression-free survival (PFS). Cox regression showed a significant continuous decrease in OS for higher proliferation rates with an HR  of 1.07% (95% confidence interval, 1.01%-3.67%; P = .048) but not in PFS (P = .86). Cutoff finder analysis revealed the best possible cutoff for OS at 6.28% (P = .04) and for PFS at 1.85% proliferative activity (P = .04). Estrogen receptors (ERs) were expressed in most LGSOC patients (n = 61; 89.7%), progesterone receptor (PR) in about half of patients (n = 33; 48.5%). For both ER/PR, a statistically significant cutoff for PFS could be determined, which was at 75% of positive tumor cells for ER (P = .02) and at 15% of positive tumor cells for PR (P = .03). For OS, HR expression showed a tendency toward better OS for HR-positive tumors but did not turn out statistically significant. Our results show that Ki-67 is a valuable prognostic marker in the subgroup of LGSOC. We could also show that most LGSOCs express HRs but that this expression is associated with a better PFS, a finding valuable in times of antihormonal therapy in LGSOC.
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http://dx.doi.org/10.1016/j.humpath.2018.10.020DOI Listing
March 2019

Impact of Body Mass Index (BMI) on Chemotherapy-associated Toxicity in Ovarian Cancer Patients. A Pooled Analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO) Databank on 1,213 Patients.

Anticancer Res 2018 Oct;38(10):5853-5858

European Competence Center for Ovarian Cancer (EKZE), Department of Gynecology, Campus Virchow Klinikum, Charité - University Medicine of Berlin, Berlin, Germany.

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.
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http://dx.doi.org/10.21873/anticanres.12927DOI Listing
October 2018

Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

Lancet Oncol 2018 09 9;19(9):1247-1258. Epub 2018 Aug 9.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Department of Gynecology with Center for Oncological Surgery, Berlin, Germany.

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 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.
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http://dx.doi.org/10.1016/S1470-2045(18)30372-3DOI Listing
September 2018

Clinical Outcome After Completion Surgery in Patients With Ovarian Cancer: The Charite Experience.

Int J Gynecol Cancer 2018 10;28(8):1491-1497

European Competence Center for Ovarian Cancer, Charité Comprehensive Cancer Center, Department of Gynecology, Charité-University Medicine of Berlin, Campus Virchow Clinic.

Objective: The aim of this study was to estimate surgical outcome and survival benefit after completion surgery.

Methods: We evaluated 164 patients with epithelial ovarian cancer who underwent incomplete primary cytoreductive surgery or rather received only staging procedures from January 2000 to December 2014 in outside institutions. Patient-related data were registered in prospective database of Tumor Bank Ovarian Cancer. The outcome analyses were performed for early and advanced stages of ovarian cancer separately.

Results: The majority of patients were at the time of completion surgery in advanced stages of disease. From overall 111 advanced epithelial ovarian cancer patients, 74 (66.6%) could be operated macroscopically tumor free, minimal residual disease 1 cm or less was achieved in 15.3% of the cases. Mean overall survival for patients without versus those with any tumor residual was 70 months (95% confidence interval, 61.3-81.5) versus 24.7 months (95% confidence interval, 7.1-42.4; P ≤ 0.0001). After applying completion surgery, 47 (28.6%) and 12 (6.7%) patients were upstaged in FIGO (International Federation of Gynecology and Obstetrics) IIIC and IV stages, respectively. Upstaging resulted in therapy changes in 10 patients (19%) with assumed FIGO IA stages. Major operative complications were registered in 28.8% of advanced cases, and 30-day mortality reached 1.8%.

Conclusions: Recent research has shown that the most profound impact on survivorship occurs when women get proper care from surgeons trained in the latest techniques for treating ovarian cancer. Completion surgery maintained that even after initial incomplete cytoreduction outside of the high specialized units, after applying appropriate surgery techniques macroscopically, disease-free situation is achievable and outcomes are comparable with the results of primary debulking surgery.
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http://dx.doi.org/10.1097/IGC.0000000000001328DOI Listing
October 2018

Preoperative CA-125 Value as a Predictive Factor for Postoperative Outcome in First Relapse of Platinum-sensitive Serous Ovarian Cancer.

Anticancer Res 2018 Aug;38(8):4865-4870

Department of Gynecology, Virchow Campus Clinic, Charité Medical University, Berlin, Germany

Aim: The purpose of the study was to evaluate whether preoperative cancer antigen 125 (CA-125) levels predict outcome of secondary cytoreductive surgery (SCS) in patients with serous recurrent ovarian cancer and whether this could be used as a prognostic factor for progression-free (PFS) and overall (OS) survival.

Patients And Methods: A cohort of 111 patients with first recurrence of platinum-sensitive serous ovarian cancer, who had undergone SCS at the Department of Gynecology and Oncological Surgery, Charité, Campus Virchow Clinic was analyzed in correlation with the preoperative CA-125 value.

Results: The median preoperative CA-125 level was 164 U/ml. Complete tumor resection was achieved in 58.6% of the patients. PFS and OS for patients with preoperative CA-125 of less than 164.5 U/ml was significantly better than those with preoperative CA-125 ≥164.5 U/ml (p=0.025 and p<0.001, respectively).

Conclusion: Preoperative CA-125 is not a statistically significant predictive factor for complete tumor resection after SCS. Preoperative CA-125 <164.5 U/ml can predict significantly better PFS and OS for patients with first recurrence of platinum-sensitive ovarian cancer.
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http://dx.doi.org/10.21873/anticanres.12799DOI Listing
August 2018

Development of a Questionnaire for Monitoring Risk Factors for Chemotherapy-induced Nausea and Vomiting - A NOGGO Pilot Study.

Anticancer Res 2018 Aug;38(8):4859-4864

Department of Gynaecology, Charité - University Medicine of Berlin, European Competence Centre for Ovarian Cancer, Berlin, Germany.

Background: Despite many years of clinical research and development, nausea and vomiting remain challenging toxicities related to chemotherapy. The aim of our study was to clarify the significance of non-pharmacological, patient-related risk factors for chemotherapy-induced nausea and vomiting. Furthermore, we aimed to develop a unique patient-related risk score predicting nausea and vomiting in patients with gynaecological malignancies under chemotherapy.

Materials And Methods: Based on a literature research, 27 risk factors were identified and a preliminary questionnaire was generated. This questionnaire was assessed in 20 patients diagnosed with gynaecological malignancies.

Results: The majority of questions were easy to understand and could be answered unambiguously. Questions regarding alcohol consumption and nutrition needed optimization due to problems with suitable answer option finding.

Conclusion: Patient-related factors are currently not included when selecting antiemetic prophylaxis in patients under chemotherapy. After a few amendments, our questionnaire will be used in prospective study. To our knowledge, this is the first practicable questionnaire addressing these issues.
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http://dx.doi.org/10.21873/anticanres.12798DOI Listing
August 2018