Publications by authors named "Nikolaus de Gregorio"

51 Publications

Ovarian cancer specific BRCA-like copy number aberration classifiers detect mutations associated with homologous recombination deficiency in the AGO-TR1 trial.

Clin Cancer Res 2021 Sep 30. Epub 2021 Sep 30.

Gynaecology and Obstetrics, University Hospital Cologne.

Purpose: Previously, we developed breast cancer like and -like copy number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated and like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer.

Experimental Design: We analyzed DNA copy number profiles of germline - and -mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent TCGA dataset. Subsequently, we assessed -like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in homologous recombination (HR) repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883).

Results: The detection rate of the -like classifier for mutations and promoter hypermethylation was 95.6 %. The -like classifier performed less accurate, likely due to a smaller training set. Furthermore, three-quarters of the -like tumors could be explained by (epi)genetic alterations in germline mutations and alterations in other genes involved in HR. Around half of the non -mutated ovarian cancer cases displayed a -like phenotype.

Conclusions: The newly trained classifiers detected most -mutated and methylated cancers and all tumors harboring a germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be -like.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1673DOI Listing
September 2021

Ki67 as Proliferative Marker in Patients with Early Breast Cancer and Its Association with Clinicopathological Factors.

Oncology 2021 Sep 14:1-10. Epub 2021 Sep 14.

Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany.

Introduction: Ki67 as a proliferative marker has prognostic and therapeutic relevance in early breast cancer (EBC). However, standard cutoffs for distinguishing low and high Ki67 do not exist.

Material And Methods: Data from all patients treated at the University Hospital Ulm for EBC between January 2013 and December 2015 with documented results for internal Ki67 assessment of the primary (n = 917) tumor were retrospectively analyzed evaluating the associations between Ki67 and other clinicopathological factors.

Results: 595 (64.9%) patients had a Ki67 <20% and 322 (35.1%) a Ki67 ≥20%. The median Ki67 was 10% (range 1-90%). Median Ki67 values according to the hormone receptor (HR)/ human epidermal growth factor receptor 2 (HER2) subtypes were 10% for HR-positive/HER2 negative (HR+/HER2-) disease (n = 717), 20% for HR+/HER2+ (n = 76), 30% for HR-/HER2+ (n = 45), and 60% for HR-/HER2- (n = 75). 75.2% or 89.3% of all patients with HER2-positive or triple-negative disease had a Ki67 ≥20%, respectively. Using a multivariable logistic regression with Ki67 (<20% vs. ≥20%) as binary dependent variable, younger age, positive nodal status, higher grading, histological nonspecific type carcinoma, negative HR status, and positive HER2 status were shown to be significantly associated with a higher proliferative index (Ki67 ≥20%).

Conclusion: This analysis described Ki67 in different subtypes in EBC and its association with clinicopathological factors. According to more aggressive tumor biology, the respective subgroups also showed higher median Ki67 levels. However, definition of low and high proliferation index itself is difficult. It is essential to interpret Ki67 indices carefully with regard to the own institutional values and other clinicopathological factors.
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http://dx.doi.org/10.1159/000517490DOI Listing
September 2021

Endometrial Cancer Lymphadenectomy Trial (ECLAT) (pelvic and para-aortic lymphadenectomy in patients with stage I or II endometrial cancer with high risk of recurrence; AGO-OP.6).

Int J Gynecol Cancer 2021 07;31(7):1075-1079

Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung Essen-Huttrop, Essen, Germany.

Background: The impact of comprehensive pelvic and para-aortic lymphadenectomy on survival in patients with stage I or II endometrial cancer with a high risk of recurrence is not reliably documented. The side effects of this procedure, including lymphedema and lymph cysts, are evident.

Primary Objective: Evaluation of the effect of comprehensive pelvic and para-aortic lymphadenectomy in the absence of bulky nodes on 5 year overall survival of patients with endometrial cancer (International Federation of Gynecology and Obstetrics (FIGO) stages I and II) and a high risk of recurrence.

Study Hypothesis: Comprehensive pelvic and para-aortic lymphadenectomy will increase 5 year overall survival from 75% (no lymphadenectomy) to 83%, corresponding to a hazard ratio of 0.65.

Trial Design: Open label, randomized, controlled trial. In arm A, a total hysterectomy plus bilateral salpingo-oophorectomy is performed. In arm B, in addition, a systematic pelvic and para-aortic lymphadenectomy up to the level of the left renal vein is performed. For all patients, vaginal brachytherapy and adjuvant chemotherapy (carboplatin/paclitaxel) are recommended.

Major Inclusion Criteria: Patients with histologically confirmed endometrial cancer stages pT1b-pT2, all histological subtypes, and pT1a endometrioid G3, serous, clear cell, or carcinosarcomas can be included when bulky nodes are absent. When hysterectomy has already been performed (eg, for presumed low risk endometrial cancer), study participation is also possible.

Exclusion Criteria: Patients with pT1a, G1 or 2 of type 1 histology or uterine sarcomas (except for carcinosarcomas), endometrial cancers of FIGO stage III or IV (except for microscopic lymph node metastases) or visual extrauterine disease.

Primary Endpoint: Overall survival calculated from the date of randomization until death.

Sample Size: 640 patients will be enrolled in the study.

Estimated Dates For Completing Accrual And Presenting Results: At present, 252 patients have been recruited. Based on this, accrual should be completed in 2025. Results should be presented in 2031.

Trial Registration: NCT03438474.
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http://dx.doi.org/10.1136/ijgc-2021-002703DOI Listing
July 2021

Coincidence of Intra-Abdominal Splenosis in a Patient with Advanced Ovarian Cancer: Case Report and Review of the Literature.

Surg J (N Y) 2021 Apr 23;7(2):e116-e120. Epub 2021 Jun 23.

Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany.

Splenosis is a rare disease, which is often discovered incidentally years after surgical procedures on the spleen or traumatic splenic lesions. Through injury of the splenic capsule, splenic cells are able to spread and autoimplant in a fashion similar to the process of metastatic cancer. Here we present the case of a 62-year-old female patient with a palpable tumor of the lower abdomen. Her medical history was unremarkable, except for splenectomy after traumatic splenic lesion in her childhood. Clinical examination and diagnostic imaging raised the suspicion of advanced ovarian cancer, which was further substantiated by the typical presentation of adnexal masses and disseminated peritoneal metastases during the following staging laparotomy. Surprisingly, we also found peritoneal implants macroscopically similar to splenic tissue. Microscopic examination of tissue specimens by intrasurgical frozen section confirmed the diagnosis of intra-abdominal splenosis. The patient then underwent cytoreductive surgery with complete resection of all cancer manifestations, sparing the remaining foci of splenosis to avoid further morbidity. This case demonstrates the rare coincidence of intra-abdominal carcinoma and splenosis, which could lead to intraoperative difficulties by misinterpreting benign splenic tissue. Therefore, splenosis should be considered in patients with medical history of splenic lesions and further diagnostic imaging like Tc-99m-tagged heat-damaged RBC scan could be used for presurgical distinguishing between tumor spread in the abdominal cavity and disseminated splenosis. The presented case report should not only raise awareness for the rare disease splenosis, but also emphasize the need to consider the possibility of simultaneous incidence of benign and malignant intra-abdominal lesions, as to our knowledge this is the first published case of simultaneous peritoneal carcinomatosis and splenosis.
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http://dx.doi.org/10.1055/s-0041-1731426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221843PMC
April 2021

Novel and flexible ultrasound simulation with smartphones and tablets in fetal echocardiography.

Arch Gynecol Obstet 2021 Jun 4. Epub 2021 Jun 4.

Department of Obstetrics and Gynaecology, University Hospital Ulm, Prittwitzstraße 43, 89075, Ulm, Germany.

Purpose: Evaluation of a novel ultrasound-simulation-app for training fetal echocardiography as a possible useful addition for students, residents and specialist doctors. Furthermore, comparison to a conventional learning-method with special attention on orientation and recognition of physiological structures.

Methods: Prospective two-arm study with the participation of 226 clinical students. 108 students were given an extract from a textbook on fetal echocardiography (PDF-group, n = 108) for 30 min to study. 118 students were able to use the new ultrasound-simulator-app (Simulator-group, n = 118) to learn for 30 min. The knowledge of the students was examined both before and after the learning-period by having them identify sonographic structures in videos using single-choice selection.

Results: There were no significant differences between the two groups regarding age (p = 0.87), gender (p = 0.28), and the number of previously performed ultrasound-examinations (p = 0.45). In the Simulator-group, there was a significantly higher learning effect regarding the proportion of students with an increase of correct answers in the video test examination (p = 0.005). At the end of learning, the students in the Simulator-group needed significantly less time to display the structures in the app's simulation (median initially 10.9 s vs. 6.8 s at the end; p < 0.001).

Conclusions: The novel ultrasound-simulation-app seems to be a useful addition and improvement to ultrasound training. Previous difficulties such as simultaneously having patients, ultrasound-machines, and professors at disposal can thus be avoided. This means that another important step towards remote learning can be taken, which has been proven increasingly essential lately, due to the COVID-19 pandemic.
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http://dx.doi.org/10.1007/s00404-021-06102-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175929PMC
June 2021

Role of Pelvic Lymph Node Resection in Vulvar Squamous Cell Cancer: A Subset Analysis of the AGO-CaRE-1 Study.

Ann Surg Oncol 2021 Oct 15;28(11):6696-6704. Epub 2021 Mar 15.

Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: As the population at risk for pelvic nodal involvement remains poorly described, the role of pelvic lymphadenectomy (LAE) in vulvar squamous cell cancer (VSCC) has been a matter of discussion for decades.

Methods: In the AGO-CaRE-1 study, 1618 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB or higher primary VSCC treated at 29 centers in Germany between 1998 and 2008 were documented. In this analysis, only patients with pelvic LAE (n = 70) were analyzed with regard to prognosis and correlation between inguinal and pelvic lymph node involvement.

Results: The majority of patients had T1b/T2 tumors (n = 47; 67.1%), with a median diameter of 40 mm (2-240 mm); 54/70 patients (77.1%) who received pelvic LAE had positive groin nodes. For 42 of these 54 patients, the number of affected groin nodes had been documented as a median of 3; 14/42 (33.3%) of these patients had histologically confirmed pelvic nodal metastases (median number of affected pelvic nodes 3 [1-12]). In these 14 patients, the median number of affected groin nodes was 7 (1-30), with a groin metastases median maximum diameter of 42.5 mm (12-50). Receiver operating characteristic analysis showed an area under the curve of 0.85, with 83.3% sensitivity and 92.6% specificity for the prediction of pelvic involvement in cases of six or more positive groin nodes. No cases of pelvic nodal involvement without groin metastases were observed. Prognosis in cases of pelvic metastasis was poor, with a median progression-free survival of only 12.5 months.

Conclusion: For the majority of node-positive patients with VSCC, pelvic nodal staging appears unnecessary since a relevant risk for pelvic nodal involvement only seems to be present in highly node-positive disease.
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http://dx.doi.org/10.1245/s10434-021-09744-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460538PMC
October 2021

Age, treatment and prognosis of patients with squamous cell vulvar cancer (VSCC) - analysis of the AGO-CaRE-1 study.

Gynecol Oncol 2021 05 26;161(2):442-448. Epub 2021 Feb 26.

Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Background: Despite an increasing incidence with simultaneous decreasing age of onset, vulvar squamous cell carcinoma (VSCC) is still a disease that mainly effects the elderly population. Data on the association of age with prognosis and treatment patterns in VSCC are sparse.

Methods: This is an analysis of the AGO-CaRE-1 cohort. Patients with VSCC (FIGO stage ≥1B), treated at 29 cancer centers in Germany from 1998 to 2008, were included in a centralized database (n = 1618). In this subgroup analysis patients were analyzed according to age [<50 yrs. (n = 220), 50-69 yrs. (n = 506), ≥70 yrs. (n = 521)] with regard to treatment patterns and prognosis. Only patients with documented age, surgical groin staging and known nodal status were included (n = 1247). Median follow-up was 27.5 months.

Results: At first diagnosis, women ≥70 yrs. presented with more advanced tumor stages (<0.001), larger tumor diameter (<0.001), poorer ECOG status (<0.001), more frequent HPV negative tumors (p = 0.03) as well as a higher rate of nodal involvement (<0.001). Disease recurrence occurred significantly more often in elderly patients (p = 0.001) and age as well as ECOG status, microscopic residual resection, tumor stage, grading, and (chemo)radiation were independent prognostic factors for death or recurrence in multivariate analysis. 2-year disease-free survival rates were 59.3% (≥70 yrs), 65.8% (50-69 yrs) and 81.1% (<50 yrs), respectively (p < 0.001).

Conclusions: Older women with VSCC present with advanced tumor stages at first diagnosis and have an increased risk of recurrence as well as a decreased 2-year DFS in comparison to younger patients. Potential reasons could be self-awareness and/or more aggressive tumor biology due to HPV independent disease.
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http://dx.doi.org/10.1016/j.ygyno.2021.02.025DOI Listing
May 2021

p53 and p16 expression profiles in vulvar cancer: a translational analysis by the Arbeitsgemeinschaft Gynäkologische Onkologie Chemo and Radiotherapy in Epithelial Vulvar Cancer study group.

Am J Obstet Gynecol 2021 06 14;224(6):595.e1-595.e11. Epub 2021 Jan 14.

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed.

Objective: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance.

Study Design: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction.

Results: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042).

Conclusion: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.
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http://dx.doi.org/10.1016/j.ajog.2020.12.1220DOI Listing
June 2021

Sensitivity and specificity of loss of heterozygosity analysis for the classification of rare germline variants in : results of the observational AGO-TR1 study (NCT02222883).

J Med Genet 2020 Dec 3. Epub 2020 Dec 3.

Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University Hospital Cologne, Cologne, Nordrhein-Westfalen, Germany

Variant-specific loss of heterozygosity (LOH) analyses may be useful to classify germline variants of unknown significance (VUS). The sensitivity and specificity of this approach, however, remains unknown. We performed comparative next-generation sequencing analyses of the genes using blood-derived and tumour-derived DNA of 488 patients with ovarian cancer enrolled in the observational AGO-TR1 trial (NCT02222883). Overall, 94 pathogenic, 90 benign and 24 VUS were identified in the germline. A significantly increased variant fraction (VF) of a germline variant in the tumour indicates loss of the wild-type allele; a decreased VF indicates loss of the variant allele. We demonstrate that significantly increased VFs predict pathogenicity with high sensitivity (0.84, 95% CI 0.77 to 0.91), poor specificity (0.63, 95% CI 0.53 to 0.73) and poor positive predictive value (PPV; 0.71, 95% CI 0.62 to 0.79). Significantly decreased VFs predict benignity with low sensitivity (0.26, 95% CI 0.17 to 0.35), high specificity (1.0, 95% CI 0.96 to 1.00) and PPV (1.0, 95% CI 0.85 to 1.00). Variant classification based on significantly increased VFs results in an unacceptable proportion of false-positive results. A significantly decreased VF in the tumour may be exploited as a reliable predictor for benignity, with no false-negative result observed. When applying the latter approach, VUS identified in four patients can now be considered benign. NCT02222883.
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http://dx.doi.org/10.1136/jmedgenet-2020-107353DOI Listing
December 2020

Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial.

Breast Cancer Res 2020 10 23;22(1):111. Epub 2020 Oct 23.

Department of Gynecology and Obstetrics, Ulm University Hospital, Prittwitzstrasse 43, 89075, Ulm, Germany.

Background: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients.

Methods: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety.

Results: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively.

Conclusion: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting.

Trial Registration: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.
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http://dx.doi.org/10.1186/s13058-020-01348-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583247PMC
October 2020

[Reconciliation of Family and Work Life in the Department of Gynecology and Obstetrics - Systematic Assessment in Different Occupational Groups of a German University Hospital].

Z Geburtshilfe Neonatol 2021 Apr 3;225(2):111-118. Epub 2020 Aug 3.

Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Ulm, Ulm.

Reconciliation of family and work life is an important topic for employees. Due to common work in shifts within the health care sector, this is even more essential for health care workers and has great implications in work satisfaction and individuals ́ health. Within all employees of the department of OB/GYN of the German university hospital Ulm, an anonymous and voluntary survey on compatibility of work and family was performed in the summer of 2017. The questionnaires consisted of established and newly designed tools to assess reconciliation of family/work life as well as work-family (WFC) and family-work conflict (FWC). Return rate of questionnaires was 63% (n=136). Physicians (n=33), nurses (n=53), and midwives (n=31) were grouped together as "medical staff" (n=115). There was no significant difference between employees with (n=73) or without children (n=59) regarding WFC and FWC. The group of nurses/midwives and the group of physicians had a significantly higher inter-role conflict (p<0.001) than the group of administrative staff. A negative correlation with "work satisfaction" was found for WFC and FWC. The group of nurses/midwives has significantly higher inter-role conflicts than the administrative staff. Especially the negative correlation of work satisfaction and inter-role conflicts shows the enormous need for improvement in sufficient compatibility of work and family life of employees in the health care sector. This needs to be addressed quickly and effectively as there is an alarming deficit of nurses and midwives in the German health care system.
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http://dx.doi.org/10.1055/a-1200-3070DOI Listing
April 2021

Association between obesity and vulvar cancer recurrence: an analysis of the AGO-CaRE-1 study.

Int J Gynecol Cancer 2020 07 28;30(7):920-926. Epub 2020 May 28.

Department of Obstetrics and Gynecology, Ludwig Maximilians University Munich, Munich, Bayern, Germany.

Objective: Obesity is associated with worse survival and an increased risk of relapse in several malignancies. The influence of obesity on vulvar cancer recurrence has not been previously described. The primary objective of this study was to evaluate the association between obesity and tumor recurrence in patients with vulvar cancer.

Methods: This is an analysis of the AGO-CaRE-1 study. Patients diagnosed with squamous cell vulvar cancer (stage IB and higher), treated in 29 cancer centers between January 1998 and December 2008, were registered in a centralized database. The cohort was divided into two gropus depending on the body mass index (BMI) (<30 vs ≥30 kg/m²). Descriptive statistics, survival analyses, and multivariate Cox regression analyses were performed in order to evaluate the association between obesity and progression-free and overall survival.

Results: In 849 (52.4%) of 1618 patients in the database, the BMI was documented. Patients were grouped according to their BMI (<30 vs ≥30 kg/m²). There were 621 patients with a BMI <30 kg/m² and 228 patients with a BMI ≥30 kg/m². Besides age, there was no difference in baseline variables (tumor diameter, depth of infiltration, tumor stage, nodal metastasis, tumor grade). Treatment variables (R0 resection, chemotherapy, radiotherapy, continuation of adjuvant therapy) did not differ between groups. However, patients with BMI ≥30 kg/m² underwent radical vulvectomy more often (61.1% vs 51.8%, p=0.04). During follow-up there was a higher recurrence rate in the group with BMI ≥30 kg/m² (43.4% vs 28.3%, p<0.01) due to an increased rate of local recurrences (33.3% vs 18.5%, p<0.01). There was a significantly shorter time to recurrence in obese patients on univariate analysis (BMI ≥30 kg/m² vs <30 kg/m²: 43.8 months (95% CI 23.3 to 64.3) vs 102.3 months (95% CI 72.6 to 131.9), p=0.001) and on multivariate Cox regression analysis (HR 1.94 (95% CI 1.4 to 2.8), p<0.001).

Conclusions: In this study a BMI ≥30 kg/m² was associated with a shorter time to recurrence in patients with vulvar cancer and this was mainly attributed to a higher risk of local recurrence.
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http://dx.doi.org/10.1136/ijgc-2019-001187DOI Listing
July 2020

Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial.

Lancet Oncol 2020 05 16;21(5):699-709. Epub 2020 Apr 16.

Department of Gynecology and Gynecological Oncology, Kliniken Essen-Mitte, Essen, Germany.

Background: State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab.

Methods: This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.

Findings: Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage).

Interpretation: Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer.

Funding: F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(20)30142-XDOI Listing
May 2020

Prognostic role of thrombocytosis in recurrent ovarian cancer: a pooled analysis of the AGO Study Group.

Arch Gynecol Obstet 2020 05 10;301(5):1267-1274. Epub 2020 Apr 10.

Department of Gynecology and Obstetrics, University Hospital Giessen and Marburg, Marburg, Germany.

Purpose: Although thrombocytosis in patients with primary ovarian cancer has been widely investigated, there are only very few data about the role of thrombocytosis in recurrent ovarian cancer. The aim of our study was to investigate the impact of pretreatment thrombocytosis prior to chemotherapy on clinical outcome in patients with recurrent platinum eligible ovarian cancer.

Methods: In our retrospective analysis we included 300 patients who were treated by AGO Study Group Centers within three prospective, randomized phase-III-trials. All patients included had been treatment-free for at least 6 months after platinum-based chemotherapy. We excluded patients who underwent secondary cytoreductive surgery before randomization to the trial. Thrombocytosis was defined as a platelet count of ≥ 400⋅10/L.

Results: Pretreatment thrombocytosis was present in 37 out of 300 (12.3%) patients. Patients with thrombocytosis responded statistically significantly less to chemotherapy (overall response rate 35.3% and 41.6%, P = 0.046). The median progression-free survival (PFS) for patients with thrombocytosis was 6.36 months compared to 9.00 months for patients without thrombocytosis (hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 0.84-1.69, P = 0.336). Median overall survival (OS) of patients with thrombocytosis was 16.33 months compared to 23.92 months of patients with a normal platelet count (HR = 1.46, 95% CI = 1.00-2.14, P = 0.047).

Conclusions: The present analysis suggests that pretreatment thrombocytosis is associated with unfavorable outcome with regard to response to chemotherapy and overall survival in recurrent ovarian cancer.
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http://dx.doi.org/10.1007/s00404-020-05529-yDOI Listing
May 2020

Lymph Node Ratio Can Better Predict Prognosis than Absolute Number of Positive Lymph Nodes in Operable Cervical Carcinoma.

Oncol Res Treat 2020 14;43(3):87-95. Epub 2020 Jan 14.

Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany.

Background: Nodal status is the most important prognostic factor in cervical cancer. However, further risk stratification in node positive cervical cancer patients is warranted for optimal therapeutic decisions.

Material And Methods: Nodal positive patients (n = 86) were retrospectively stratified into two groups according to either number of positive nodes (>3 vs. 1-3) or lymph node ratio (LNR) (≥10 vs. <10% and >6.6 vs. ≤6.6%). Univariable log-rank tests and both univariable and adjusted multivariable Cox regression models were used to evaluate the association between number of positive nodes or LNR and disease-free survival (DFS) and overall survival (OS).

Results: LNR was significantly associated with worse DFS in adjusted multivariable analysis, both when categorized as ≥10 versus <10% (HR 2.25, 95% CI 1.06-4.76, p = 0.034) and when categorized as >6.6 versus ≤6.6% (HR 2.79, 95% CI 1.23-6.37, p = 0.015). However, we found no significant association between number of positive nodes or LNR and OS.

Discussion: In operable node-positive cervical cancer, both number of positive lymph nodes and LNR can be used for further risk stratification with regard to DFS but not OS.
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http://dx.doi.org/10.1159/000505032DOI Listing
July 2020

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer.

N Engl J Med 2019 12;381(25):2416-2428

From Centre Léon Bérard (I.R.-C., D.P.), University Claude Bernard Lyon 1 (I.R.-C.), and Centre Hospitalier Lyon-Sud (B.Y.), Lyon, Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) (I.R.-C., P.P., F.S., C.L.-P., A.L., P.C., M.R., C.D., B.Y., E.P.-L.), Groupe Hospitalier Diaconesses Croix Saint-Simon (F.S.), Hôpital Européen Georges Pompidou (P.C.), Institut Curie, Hôpital Claudius Régaud (M.R.), and Association de Recherche Cancers Gynécologiques (ARCAGY) (E.P.-L.), Paris, Gustave Roussy, Villejuif (P.P.), Centre Eugène Marquis, Rennes (C.L.-P.), Centre Catherine de Sienne Hôpital Privé du Confluent, Nantes (A.L.), and Institut Curie, Hôpital René Huguenin, Saint Cloud (C.D.) - all in France; the Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, and Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Naples (S.P.), University of Milan-Bicocca and European Institute of Oncology IRCCS, and Mario Negri Gynecologic Oncology Group (MANGO) (N.C.), and Fondazione IRCCS Istituto Nazionale Tumori and MITO (D.L.), Milan, and Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica, and MITO, Rome (G.S.) - all in Italy; M.D. Anderson Cancer Center Madrid (A.G.-M.), Grupo Español de Investigación en Cáncer de Ovario (GEICO) (A.G.-M., E.M.G.A.), and Hospital Universitario Ramón y Cajal (E.M.G.A.) - all in Madrid; Medical University of Innsbruck, University Clinic for Gynecology and Obstetrics (R.B.), and Arbeitsgemeinschaft Gynäkologische Onkologie Study Group (AGO)-Austria (R.B., A.R.), Innsbruck, and Medical University of Vienna, Vienna (A.R.) - all in Austria; Saitama Medical University International Medical Center, Hidaka (K.F.), Gynecologic Oncology Trial and Investigation Consortium (GOTIC), Moroyama-cho (K.F., S.N.), and Hyogo Cancer Center, Akashi (S.N.) - all in Japan; University Hospital Leuven, Leuven Cancer Institute, and Belgium and Luxembourg Gynecologic Oncology Group (BGOG) - both in Leuven, Belgium (I.V.); Tampere University and University Hospital, Tampere, Finland (J.M.); the Nordic Society of Gynecologic Oncology (NSGO), Copenhagen (J.M.); and Charité-Medical University of Berlin (Campus Virchow Klinikum), Berlin (J.S.), German Society of Gynecologic Oncology (AGO) (J.S., U.C., F.M., N.G., P.B., A.B., P.H.), Universitätsklinikum Essen (P.B.), and Kliniken Essen Mitte (P.H.), Essen, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden (U.C.), Universitätsklinikum Heidelberg, Heidelberg (F.M.), Universitätsklinikum Ulm, Ulm (N.G.), and Klinikum der Universität München, Munich (A.B.) - all in Germany.

Background: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of mutation status is unknown.

Methods: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death.

Results: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab.

Conclusions: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).
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http://dx.doi.org/10.1056/NEJMoa1911361DOI Listing
December 2019

Feasibility of a large multi-center translational research project for newly diagnosed breast and ovarian cancer patients with affiliated biobank: the BRandO biology and outcome (BiO)-project.

Arch Gynecol Obstet 2020 01 28;301(1):273-281. Epub 2019 Nov 28.

Department of Gynecology and Obstetrics, University Hospital Ulm, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany.

Introduction: Large translational research projects may contribute to further progress in cancer treatment by exploring molecular biology, immunologic approaches and identification of new prognostic and predictive factors. Therefore, the BRandOBio-project combines a clinical registry for collection of patient and tumor characteristics with a biobank comprising tumor and liquid biopsies. In addition, sociodemographic, environmental and lifestyle factors of included patients with primary newly diagnosed breast or ovarian cancer, other rare malignant ovarian tumors or gestational trophoblastic disease are prospectively collected.

Methods: The target population includes the German "Alb-Allgäu-Bodensee Region" which constitutes the outreach area of the University Hospital Ulm with affiliated academic centers and private practices. Clinical data combined with primary tumor tissue samples and longitudinal repeatedly collected blood samples [before, 6 (in high-risk situations), 12, 36 and 60 months after treatment and at relapse] will be acquired from more than 4000 patients within the next years. Standardized questionnaires are given to patients of the University Hospital Ulm and eight selected external sites for assessing life style and cancer risk factors. Concomitantly, storage of paraffin-embedded tumor samples as well as liquid biopsy samples will allow translational research projects, for example in terms of investigating circulating DNA and germ line DNA from cell pellets.

Results: Starting in January 2016 at the University Hospital Ulm, 19 additional external sites started recruiting patients in March 2017. As of September 15th 2019, 2151 patients with newly diagnosed cancers could be recruited (2044 breast cancer; 107 ovarian cancer). Nearly all patients provided biological samples (tumor and liquid biopsy) and about 80% returned the standardized questionnaire. After 1 year follow-up, blood samples were available from more than 80% of the participating patients.

Conclusions: The BRandO BIO study is a large prospective cohort study with integrated comprehensive biobank and evaluation of sociodemographic and life style factors of gynecological cancer patients in a well-defined geographical area in the South West of Germany. Continuous high patient recruitment and stable rates over 80% for returned questionnaires as well as for repeated blood sampling show high acceptance of the BRandO study program and confirms feasibility of the project.
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http://dx.doi.org/10.1007/s00404-019-05395-3DOI Listing
January 2020

Influence of the New FIGO Classification for Cervical Cancer on Patient Survival: A Retrospective Analysis of 265 Histologically Confirmed Cases with FIGO Stages IA to IIB.

Oncology 2020 8;98(2):91-97. Epub 2019 Oct 8.

Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany,

Objective: At the end of the year 2018, a new FIGO classification for cervical cancer was published, mainly revising stage IB and introducing a new stage IIIC, which includes irrespectively of tumor size and local spread all patients with lymph node metastasis.

Methods: We retrospectively analyzed all cases of cervical cancer stage I to IIB who underwent surgery as primary treatment at our institution from 2000 until 2016 and therefore had a histological confirmation of tumor stage. We reclassified all histologies according to the new FIGO classification and calculated outcome according to the new stages.

Results: Out of 265 patients, 146 (55%) patients were reclassified into a higher FIGO stage. Most changes appeared within stage IB and from any stage to stage IIIC1. Kaplan-Meier curves for new stages showed a significant difference in disease-free survival (DFS) and overall survival (OS) between stages I versus II versus III (log-rank test, both p < 0.001). Overall, patients that were upstaged had a significant worse DFS (p = 0.012) and OS (p = 0.008) than patients whose stage did not change. Similar observations were made within sub-stages, when node-positive IB or IIB tumors were upstaged to IIIC tumors.

Conclusion: The new FIGO classification for cervical cancer reflects the strong impact of lymph node metastases on survival and is a clear improvement compared to the old FIGO classification with regard to risk stratification.
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http://dx.doi.org/10.1159/000503149DOI Listing
February 2020

Predicting the course of disease in recurrent vulvar cancer - A subset analysis of the AGO-CaRE-1 study.

Gynecol Oncol 2019 09 17;154(3):571-576. Epub 2019 Jul 17.

Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: In vulvar cancer (VSCC), the course of disease with regard to localization of recurrence and relation of different recurrence sites is poorly described.

Methods: The AGO CaRE-1 study is a retrospective survey of treatment patterns and prognostic factors in vulvar cancer. Patients (pts) with primary VSCC, FIGO stage ≥1B treated in Germany from 1998 to 2008 were included in a centralized database (n = 1618). In the current subgroup analysis, different sites of primary recurrence and their impact on disease course and survival were analyzed using multistate and competing risks methods.

Results: 1249 pts with surgical groin staging and known lymph-node status (35.8% N+) were included in the analysis. 360 pts (28.8%) developed disease recurrence; thereof 193 (53.6%) at the vulva only, with a cumulative incidence of 12.6% after 2 years. Generally, prognosis after disease depended on recurrence site: Hazard ratios (HRs) (95% confidence interval) to die for pts with compared to without recurrence at the same time: vulvar only: 5.9 (4.3-8.2); groins only: 6.0 (3.0-10.2); vulvar and groins: 14.1 (7.6-26.4); pelvic/distant: 21.2 (15.3-29.4). Fifty-eight (30.1%) pts with local recurrence developed second recurrence. 2-year mortality after any recurrence was 56.3%. After vulvar recurrence pts had a 2-year and 5-year overall survival rate of 82.2% and 66.9%.

Conclusions: Prognosis after recurrence is highly depending on recurrence site. Pts with isolated vulvar recurrence have an impaired prognosis as many affected pts develop second recurrences.
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http://dx.doi.org/10.1016/j.ygyno.2019.07.009DOI Listing
September 2019

Predictive factors for lymph node metastases in vulvar cancer. An analysis of the AGO-CaRE-1 multicenter study.

Gynecol Oncol 2019 09 18;154(3):565-570. Epub 2019 Jun 18.

Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Background: Lymph node (LN) metastasis is the most important prognostic factor in primary vulvar cancer. Assessing risk factors for the incidence and extent of LN metastases may help to select the optimal treatment strategy for each individual patient.

Methods: In a subgroup analysis of the large multicenter AGO-CaRE-1 study we included all patients treated with radical groin dissection. Univariate and multivariate regression analyses were performed in order to detect factors associated with the prevalence and extent of nodal involvement.

Results: In total, 1162 patients were analyzed. Univariate analyses detected age, ECOG as well as multiple tumor characteristics such as FIGO stage, grading, depth of invasion, tumor diameter, and (lymph)vascular space invasion to be related with the prevalence of LN metastases. Interestingly, only tumor stage, tumor diameter and depth of infiltration were found to be significantly associated with the number of LN metastases. In multivariate analysis, age (OR 1.03), lymphvascular space invasion (OR 4.97), tumor stage (OR 2.22) and depth of infiltration (OR 1.08) showed an association with the prevalence of LN metastases. Regarding the number of metastatic LNs, only tumor stage (OR 2.21) or, if excluded, tumor diameter (OR 1.02) were tested significant.

Conclusion: This large analysis of the multicenter AGO-CaRE-1-study identified lymphvascular space invasion, tumor stage, and depth of infiltration as factors with the strongest association regarding the prevalence of LN metastasis. Interestingly, tumor stage or, if excluded, tumor diameter were the only factors associated with the prevalence as well as the extent of LN metastases.
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http://dx.doi.org/10.1016/j.ygyno.2019.06.013DOI Listing
September 2019

Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883).

J Med Genet 2019 09 12;56(9):574-580. Epub 2019 Apr 12.

Department of Gynecology & Obstetrics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.

Background: For individuals with ovarian cancer (OC), therapy options mainly depend on germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy?

Methods: Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (, , , , and ) and the and genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by , and promoter methylation analyses and stratified by histological subtype; 473 individuals were included.

Results: The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; : 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding (all: 39/473, 8.2%; : 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; : 57/473, 12.1%; : 10/473, 2.1%; : 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic and/or variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles.

Conclusion: Tumour sequencing of the and genes along with and promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors.

Trial Registration Number: NCT02222883.
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http://dx.doi.org/10.1136/jmedgenet-2018-105930DOI Listing
September 2019

Lymph node ratio in inguinal lymphadenectomy for squamous cell vulvar cancer: Results from the AGO-CaRE-1 study.

Gynecol Oncol 2019 05 11;153(2):286-291. Epub 2019 Feb 11.

Department of Gynaecology and Gynaecologic Oncology, University Medical Center Hamburg-Eppendorf, Germany; Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.

Objective: Lymph node ratio (LNR) can predict treatment outcome and prognosis in patients with solid tumors. Aim of the present analysis was to confirm the concept of using LNR for assessing outcome in patients with vulvar cancer after surgery with inguinal lymphadenectomy in a large multicenter project.

Methods: The AGO-CaRE-1 study multicenter database was used for analysis. LNR was defined as ratio of number of positive lymph nodes (LN) to the number of resected. Previously established LNR risk groups were used to stratify patients. LNR was investigated with respect to clinical parameters. Univariate and multivariable survival analyses were performed to assess the value of LNR in order to predict overall (OS) and progression-free (PFS) survival.

Results: In total, 1047 patients treated with surgery including inguinal lymph node resection for squamous cell carcinoma of the vulva were identified from the database. Of these, 370 (35.3%) were found to have positive inguinal LN. In total, 677 (64.7%) had a LNR of 0% (N0), 255 (24.4%) a LNR of >0% < 20%, and 115 (11%) a LNR of ≥20%. Patients with higher LNR were found to have larger tumor size (P < .001), advanced tumor stage (P < .001), high tumor grade (P < .001), and deep stromal invasion (P < .001), more frequently. Three-year PFS rates were 75.7%, 44.2%, and 23.1% and three-year OS rates were 89.7%, 65.4%, and 41.9%, in patients with LNRs 0%, >0% < 20%, and ≥20%, respectively (P < .001, P < .001). On multivariable analyses LNR (HR 7.75, 95%-CI 4.01-14.98, P < .001), FIGO stage (HR 1.41, 95%-CI 1.18-1.69, P < .001), and patient's performance status (HR 1.59, 95%-CI 1.39-1.82, P < .001), were associated with PFS. In addition, LNR (HR 12.74, 95%-CI 5.64-28.78, P < .001), and performance status (HR 1.72, 95%-CI 1.44-2.07, P < .001) were also the only two parameters independently associated with OS. LNR generally showed stronger correlation than number of affected LN when comparing the two different multivariable models.

Conclusions: In women with vulvar cancer LNR appears to be a consistent, independent prognostic parameter for both PFS and OS and allows patient stratification into three distinct risk groups. In survival analyses, LNR outperformed nodal status and number of positive nodes.
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http://dx.doi.org/10.1016/j.ygyno.2019.02.007DOI Listing
May 2019

Axillary Surgery in Breast Cancer Patients Treated with Breast-Conserving Surgery at German Breast Cancer Centers Within the Last 14 Years - Comparison of a University Center and a Community Hospital.

Geburtshilfe Frauenheilkd 2018 Nov 26;78(11):1138-1145. Epub 2018 Nov 26.

Department of Gynecology and Obstetrics, Helios Hospital Amper, Dachau, Germany.

Guideline recommendations for axillary surgical approach in breast cancer (BC) treatment changed over the last decade. Data from all invasive BC patients (n = 5344) treated with breast conserving surgery (BCS) at the breast cancer centers of the University Hospital Ulm (U-BCC) and the community hospital Dachau (D-BCC) were included into a retrospective analysis for assessing information on axillary surgery between 2003 and 2016 based on the documented cancer registry data. The average annual rate of sentinel node biopsy (SNB) was 85.5% and 87.2% in Ulm and Dachau, respectively. SNB was performed more precisely at the U-BCC with a median of 2.4 resected lymph nodes (LN) compared to a median of 3.2 resected LN in Dachau. Median number of resected LN for axillary lymph node dissection (ALNE) showed a statistically significant reduction over time in Ulm (r  = - 0.82; p < 0.001) and Dachau (r  = - 0.76; p = 0.002). The rate of secondary ALNE (after SNB; 2° ALNE) decreased significantly in U-BCC (r  = - 0.76; p = 0.002) while it remained stable in D-BCC. The influential publication of the Z0011 study in 2010 resulted in a significant reduction of secondary ALNE (24.1% preZ0011 and 14.4% postZ0011; p < 0.001) in Ulm. Changes in axillary surgery over time can be seen in the annual statistics of the reviewed BCCs. With BCS, mostly SNB was performed and numbers of removed LN in ALNE have decreased. In the U-BCC, the rate of 2° ALNE dropped after the publication of the Z0011 data. The fact that no such decrease for 2° ALNE was found in D-BCC suggests that university hospitals implement new data and research results into clinical routine earlier than peripheral community hospitals.
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http://dx.doi.org/10.1055/a-0750-1880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255741PMC
November 2018

Results of an internal audit on the survival of patients with uterine sarcoma

J Turk Ger Gynecol Assoc 2019 02 9;20(1):15-22. Epub 2018 Oct 9.

Klinik für Frauenheilkunde und Geburtshilfe, Universität Ulm, Ulm, Germany

Objective: In the last 5 years there has been much discussion about the surgical procedure for uterine fibroids, and essentially, also uterine sarcoma. Still there exists no reliable presurgical diagnostic tool to differentiate between benign fibroids and uterine sarcomas. The aim of this study was to confirm the suspected association between intraoperative spread of tumor by morcellation and impaired outcomes in patients with sarcoma.

Material And Methods: After the local ethics commission positively reviewed the study protocol, the oncologic database of our university hospital was retrospectively reviewed for patients with uterine sarcomas over a time period of 13 years (2002-2015). Data was extracted from the medical files and survival information was collected by contacting the patient’s general practitioners if last follow-up-status was older than 6 months. For the analysis, patients were split into two groups with either intrasurgical morcellation (M+) or no morcellation (M-) regarding information provided by the surgical report.

Results: Data on 57 patients with uterine sarcoma were available for further analysis. The median age and body mass index of the patients was 63 years and 27 kg/m², respectively. The sarcoma subtypes were 25 leiomyosarcoma, 19 carcinosarcoma, 9 endometrioid stroma sarcoma, 3 adenosarcoma, and one case without further differentiation. In the majority, no morcellation was performed (M- group, n=44) and 51 patients received open surgery (3 laparoscopic, 1 vaginal, and 2 incomplete surgeries). The median time of follow-up was 31 months. The disease-free survival was 50.5 months and the Cox regression analysis showed a hazard ratio of 3.06 [no significant difference between the two subgroups (p=0.079; 95% confidence interval (CI): 0.9-10.6)]. The overall survival was found as 62.2 months and the Cox regression analysis showed a hazard ratio of 3.216 with a statistically significant difference between the two subgroups (p=0.013; 95% CI: 1.3-8.1).

Conclusion: Despite the efforts to find a pre-surgical diagnostic tool, the clinical situation remains unsatisfactory. Overall sarcoma prevalence is low during the last 13 years at our university center, but morcellation occurred in a relevant portion of patients (13 of 57). If sarcoma is suspected or diagnosed then en-bloc resection of the uterus can prolong survival. Thus, morcellation of the uterus and not the surgical technique (en-bloc resection) is the prognostic factor and should be avoided in any suspicious case.
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http://dx.doi.org/10.4274/jtgga.galenos.2018.2018.0083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501862PMC
February 2019

Seroma in breast surgery: all the surgeons fault?

Arch Gynecol Obstet 2018 11 8;298(5):951-959. Epub 2018 Sep 8.

Klinik für Frauenheilkunde und Geburtshilfe, Universität Ulm, Prittwitzstr. 43, 89075, Ulm, Germany.

Background: Despite a trend for less radical surgical approaches in breast cancer due to better understanding of tumour biology and new treatment options such as neoadjuvant chemotherapy (NAC) and intra-operative radiotherapy (IORT), seroma production remains one of the main surgical side effects that can result in prolonged recovery, delay of radiotherapy and patient discomfort. The aim of this study is to provide an update on risk factors for seroma production after breast cancer surgery considering the latest treatment options.

Methods: A retrospective analysis of seroma production in primary breast cancer patients treated between 01.01.2010 and 31.12.2014 at the Breast Cancer Centre, University Hospital Ulm, was performed. Patients with previous breast/axillary surgery or more than one intervention were excluded. Seroma formation was measured using wound drains placed in breast and axilla.

Results: In total, 581 patients met the inclusion criteria. Median age at diagnosis was 60 years, and median BMI 25.6 kg/m. 60 (10.3%) patients had a mastectomy, 175 (30.1%) patients received IORT, and 72 (12.4%) patients received NAC. Median amount of seroma production was 82.5 ml (range 0-3012.5 ml). Multivariate analysis revealed that most of the observed variation in seroma production was due to type of surgery (mastectomy vs. breast conserving), length of surgery and number of removed lymph nodes. Both NAC and IORT explained a significant but very small amount of the observed variation in seroma production.

Conclusion: The most important factors for seroma production are extent and duration of breast surgery.
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http://dx.doi.org/10.1007/s00404-018-4880-8DOI Listing
November 2018

Emergency peripartal hysterectomy - a single-center analysis of the last 13 years at a tertiary perinatal care unit.

J Perinat Med 2019 Feb;47(2):169-175

Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany.

Background Peripartal hysterectomy (PH) is a challenging surgical procedure with elevated maternal morbidity. Methods From 2004 to 2016, 41 emergency PHs were performed at the tertiary care center of the Department of Gynecology and Obstetrics at University Hospital Ulm. In our retrospective analysis, the incidence of PH in our hospital was 12.8 per 10,000 deliveries with a maternal mortality of 2.4%. PH followed in 80.5% after cesarean section (c-section). Underlying causes/indications for PH were abnormal placentation (53.7%; n=22), uterine atony (26.8%; n=11), uterine lacerations (14.6%; n=6) and in rare cases uterine infection (4.9%; n=2). The median number of transfused products was 11 packed red blood cells (range 0-55 products), 10 fresh frozen plasma units (range 1-43) and two platelet concentrates (0-16). Results Loss of blood as estimated by surgeons was significantly correlated with actual transfused blood volume (P<0.001). Clinically relevant intra- and/or postoperative complications occurred in 53.7% of patients (n=22). Abnormal placentation was the leading cause for PH with an increased incidence during the last 10 years presumptively representing the elevated rate of c-sections. Conclusion PH goes along with increased rates of blood product transfusions independently of indication for surgery and has a high morbidity with a major complication rate of more than 50%. Prepartal assessment of risk factors like abnormal invasive placenta are crucial for reducing maternal morbidity.
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http://dx.doi.org/10.1515/jpm-2018-0149DOI Listing
February 2019

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

Use of Granulocyte-colony Stimulating Factor During Chemotherapy and Its Association With CA27.29 and Circulating Tumor Cells-Results From the SUCCESS A Trial.

Clin Breast Cancer 2018 10 18;18(5):e1103-e1110. Epub 2018 Jun 18.

Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany.

Background: Little is known about the effect of granulocyte colony-stimulating factor (G-CSF) treatment during adjuvant chemotherapy on prognostic markers. The present study explored the association between G-CSF and changes in cancer antigen (CA)27.29 and circulating tumor cell (CTC) levels during therapy.

Patients And Methods: A total of 3754 node-positive or high-risk node-negative early-stage breast cancer patients were treated within the SUCCESS-A trial (simultaneous study of gemcitabine-docetaxel combination adjuvant treatment, as well as extended bisphosphonate and surveillance-trial). CA27.29 and CTCs were determined before the start and within 6 weeks after the end of chemotherapy.

Results: Overall, 1324 of the 2646 patients (50.0%) available for analysis had ≥ 1 G-CSF applications during chemotherapy. G-CSF application was significantly associated with CA27.29 status before and after chemotherapy (χ = 30.6, df = 3; P < .001), because 238 patients (18.0%) with G-CSF treatment but only 146 (11.0%) without G-CSF treatment switched from a negative CA27.29 status before to a positive CA27.29 status after chemotherapy. In addition, patients with G-CSF application showed a significantly greater increase in CA27.29 levels after chemotherapy compared with patients without any G-CSF application during chemotherapy (Mann-Whitney U test; Z = -7.81, P < .001). No significant association was found between G-CSF application and CTC status before or after chemotherapy (χ = 1.2, df = 3; P = .75).

Conclusion: Cautious interpretation is needed regarding elevated levels of MUC-1-derived tumor markers such as CA27.29 shortly after adjuvant chemotherapy when G-CSF has been given, because G-CSF treatment was associated with increased CA27.29 levels after chemotherapy.
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http://dx.doi.org/10.1016/j.clbc.2018.06.006DOI Listing
October 2018

Influence of Prognostic Factors on Lymph Node Involvement in Endometrial Cancer: A Single-Center Experience.

Int J Gynecol Cancer 2018 07;28(6):1145-1152

Department of Gynecology and Obstetrics, University Ulm, Ulm, Germany.

Objective: The requirement for and extent of lymphadenectomy in endometrial cancer is still controversial. Clinicopathological prognostic factors could be helpful to predict lymph node involvement and avoid therefore unnecessary lymphadenectomy. The aim of this study was to investigate which factors can predict lymph node involvement and how lymph node metastases are distributed in the pelvic and para-aortic regions.

Methods: This retrospective analysis was performed by analyzing data from patients with endometrial cancer treated with standard surgery and lymphadenectomy at the Department of Gynecology and Obstetrics of the University Hospital Ulm in 2000 to 2013.

Results: One hundred twenty-five patients received pelvic lymphadenectomy with a median of 25 removed nodes, and 111 patients additionally received para-aortic lymphadenectomy with a median of 12 removed nodes. Metastatic lymph nodes were found in 24.8% of the patients, and a multivariate logistic regression showed that lymphovascular space invasion, histological type, and tumor stage significantly and independently predicted lymph node involvement. Of the 111 patients with both pelvic and para-aortic lymphadenectomy, 18 (16.2%) patients had metastatic para-aortic nodes, and 3 (2.7%) patients had isolated positive para-aortic lymph nodes without involvement of pelvic lymph nodes.

Discussion: Lymphovascular space invasion, histological type, and tumor stage are significant predictors of lymph node involvement in endometrial cancer. In patients at high risk of nodal involvement, lymphadenectomy should be performed systematically up to the renal vein. Large and carefully designed prospective studies are needed to evaluate patient cohorts for which a complete lymphadenectomy provides a survival benefit. In the future, the increasing use of sentinel node biopsy may facilitate a more personalized treatment of patients with endometrial cancer.
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http://dx.doi.org/10.1097/IGC.0000000000001290DOI Listing
July 2018

Prognostic Impact of Weight Change During Adjuvant Chemotherapy in Patients With High-Risk Early Breast Cancer: Results From the ADEBAR Study.

Clin Breast Cancer 2018 04 31;18(2):175-183. Epub 2018 Jan 31.

Department of Obstetrics and Gynecology, LMU Munich, Munich, Germany.

Background: In addition to established prognostic factors, individual lifestyle-associated factors, such as obesity, physical activity, and diet, seem to modulate the course of breast cancer. The aim of this analysis was to evaluate the influence of weight changes during adjuvant chemotherapy on outcome in a large multicenter prospectively randomized trial.

Patients And Methods: The ADEBAR trial compares a sequential chemotherapy consisting of epirubicin/cyclophosphamide followed by docetaxel to an epirubicin/5-fluorouracil/cyclophosphamide regimen in patients with lymph node-positive early breast cancer. Body weight was measured before each cycle of chemotherapy. According to the relative weight change (≥ 5%) between the first and the last cycle, patients were categorized into the weight gain, weight loss, or stable weight group. Overall survival (OS) and disease-free survival were assessed by univariate Kaplan-Meier and multivariate Cox regression analyses.

Results: Concise data from 1080 of 1493 participants who completed all cycles of chemotherapy were available for analysis. Of 307 patients (24.8%) whose weight changed by ≥ 5%, 120 patients (11.1%) lost and 187 (17.3%) gained weight. Multivariate analysis showed a significant independent effect of weight change on OS (P = .039), but not on disease-free survival (P = .111). Both weight change groups had a worse OS compared to patients with stable weight (weight gain: hazard ratio, 1.55; 95% confidence interval, 1.01-2.40; P = .047; weight loss: hazard ratio, 1.55; 95% CI, 0.97-2.47; P = .067).

Conclusion: Weight change of > 5% during adjuvant chemotherapy in patients with high-risk early breast cancer is associated with poor OS.
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http://dx.doi.org/10.1016/j.clbc.2018.01.008DOI Listing
April 2018
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