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Purpose As a Doppler sonographic parameter, the cerebroplacental ratio (CPR) provides information about fetal hemodynamics and the redistribution of fetal blood volume in response to a metabolic change. The present study was undertaken to determine the extent to which CPR can be used as a valid parameter in routine obstetric assessment. We investigated whether CPR can be used to assess the neonatal outcome in appropriate for gestational age (AGA) fetuses and its association with secondary cesarean section due to fetal distress. Methods In this retrospective analysis 1739 pregnant women were admitted to the University Women‘s Clinic Magdeburg, Germany, between January 2016 and December 2017. Of them, 710 AGA fetuses were eligible for analysis. SGA fetuses with an estimated fetal weight Results In our study cohort decreased CPR in AGA fetuses was associated with threefold increased rate of cesarean sections due to fetal distress (p Conclusion Decreased CPR in AGA fetuses correlated with impaired neonatal outcome and secondary cesarean section due to fetal distress. The potential role of CPR for obstetric screening should be investigated in further studies.

We aimed to evaluate the role of the chorioallantoic membrane model (CAM) in breast cancer research.The following is an overview of the use of the CAM in the field of breast cancer research based on a PubMed literature query.The CAM is a 3D in vivo model that can be used for the analysis of tumor growth, biology and angiogenesis of primary tumor tissue or tumor cell lines. The CAM model has been used in breast cancer research for drug testing, migration assays and the evaluation of vascularization, amongst others. The CAM model is a valuable method that offers a better imitation of the physiological phenomena compared to 2D or 3D in vitro models.The CAM model has primarily and successfully been utilized for the assessment of the tumor biology of established breast cancer cell lines. Further, the CAM model is a promising method to analyze patient derived primary tumor material and could be used as a "patient-specific 3D-tumor-therapy-model" for the cost-efficient evaluation of anti-cancer drugs to find the optimal treatment for breast cancer patients.

Patients with estrogen receptor positive breast cancer are usually receiving an anti-estrogen therapy by either aromatase inhibitors or selective estrogen receptor mediators such as tamoxifen. Nevertheless, acquired resistance to tamoxifen under treatment frequently hampers therapy. One proposed explanation for this phenomenon is the interaction of the tumor cells with cells of the tumor microenvironment via the Insulin-like growth factor RNA binding protein 5/B-cell lymphoma 3 (IGFBP5/BCL3) axis. Here we investigated whether a high expression of BCL3 either cytoplasmic or nuclear is associated with the occurrence of a relapse under anti-estrogen therapy in patients. Formaldehyde-fixed, paraffin-embedded samples of 180 breast cancer patients were analyzed for BCL3 expression by immunohistochemistry. An immunoreactive score (IRS) was calculated from staining intensity in cytoplasm and nucleus as well as the percentage of positive tumor cells. These scores were correlated with clinico-pathological parameters using cross-tabulation analysis and patients’ relapse free and overall survival by Kaplan–Meier analysis and Cox regression. A tamoxifen-adapted MCF-7 derived cell line was investigated for BCL3 localization by immunofluorescence. The cytosolic BCL3-IRS significantly correlated with the proliferation marker Ki-67, and with the occurrence of a relapse under tamoxifen treatment. Nuclear score correlated only with tamoxifen-relapse. In survival analysis, both scores were highly significant prognostic factors for relapse free, but not for overall survival. This was especially obvious for estrogen receptor positive and HER2/NEU negative cases as well as lobular breast cancer. Tamoxifen-treated, but not aromatase-treated patients had a poor survival when BCL3 scores were high. A tamoxifen adapted cell line exhibited a reduced expression and mainly nuclear localization of BCL3, compared to the parental estrogen receptor positive cell-line MCF-7. Altogether, these data strongly support a function of BCL3 in tamoxifen resistance and its potential use as a predictive biomarker for tamoxifen resistance.

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

ALK fusions were first described by Morris et al1 in 1994. Several studies have reported genetic alterations of the ALK gene in various tumor types since then, consisting of mutations, amplifications, and fusions.1-3 Fusion proteins have an active C-terminal tyrosine kinase domain in common.3 Here, we describe an STRN-ALK fusion in malignant peritoneal mesothelioma (MPM), which has previously been documented in other neoplasms, including thyroid cancer, renal carcinoma, leukemia, lymphoma, colon adenocarcinoma, head and neck adenocarcinoma, pericardial and peritoneal mesothelioma, and cutaneous squamous cell carcinoma.4-6 MPM is a rare disease with an incidence of approximately seven per million people per year.7 Patients' life expectancy is low (on average 12 months) because of the late clinical presentation with abdominal or pelvic pain or lymphadenopathy.8,9 Recently, ALK rearrangements have gained attention, especially in young female patients with MPM. Hung et al10 identified three ALK fusions in 88 consecutively screened patients with MPM. Fusion partners were ATG16L1, TPM1, and STRN. In another study by Mian et al,11 among 32 patients ��� 40 years old with mesothelioma (of which 25 were MPM), an ALK rearrangement was detected by fluorescence in situ hybridization in two patients (6%). One of the cases harbored an STRN-ALK fusion as described in the current case. Argani et al12 described additional five cases of ALK fusions in pediatric MPM. Subsequently, three more cases of STRN-ALK rearrangements in MPM have been published individually.6,13,14 In non���small-cell lung cancer (NSCLC), the discovery of specific drugs targeting ALK rearrangements led to significant therapeutic advances. Currently, various ALK inhibitors, namely, ceritinib, crizotinib, and alectinib, are used as first-line treatment in adult ALK-positive advanced NSCLC. Although crizotinib as a first-generation ALK inhibitor has already proven superiority over chemotherapy,15 next-generation ALK inhibitors such as ceritinib yielded even better survival rates.16 Moreover, both brigatinib and alectinib demonstrated superior effectiveness when directly compared with crizotinib.17,18 Unfortunately, resistance is frequently observed following an initial response in all these agents.19 Mechanisms of resistance, which often include ALK mutations, are in general universal although variable mutational frequencies are observed depending on the inhibitor.20 Despite this large base of knowledge for lung cancer, the evaluation of ALK fusions in other entities remains challenging because of limited available data.

BACKGROUND: Neuronatin (NNAT) determined by immunohistochemistry is a negative prognostic biomarker for breast cancer, independent of the major clinicopathological markers. OBJECTIVE: Here, we investigated whether NNAT is also a predictive biomarker for pathological remission after neoadjuvant chemotherapy. METHODS : One hundred and four breast cancer patients, treated with systemic neoadjuvant chemotherapy were included in this retrospective study. NNAT was detected in formaldehyde fixed, paraffin embedded primary cancer tissue by immunohistochemistry and an immuno-reactive score (IRS) determined. Pathological remission was scored according to Sinn and by evaluation of cytopathic effects. NNAT-IRS was correlated with clinicopathological parameters as well as relapse free and overall survival and for pathological remission after neoadjuvant therapy. RESULTS: NNAT IRS was an independent prognostic marker for relapse free and overall survival and the time from diagnosis to the “tumor-free” state. NNAT IRS was associated with Luminal-A tumors and correlated slightly negative with age and lymph-node metastasis. There was no significant correlation of NNAT-IRS with Sinn’s remission score, but with cytopathic effects of chemotherapy. CONCLUSIONS: We confirmed the prognostic impact of NNAT-IRS in an independent cohort of neoadjuvantly treated patients. Additionally, a correlation with a score for pathological remission under systemic neoadjuvant chemotherapy for breast cancer was found.

Due to insufficient and conflicting prospective evidence, the recommendations on when to apply adjuvant radiochemotherapy in early-stage cervical cancer vary between international guidelines. In this population-based study, we evaluated the outcome of patients with early-stage cervical cancer based on risk factors and the adjuvant therapy they received. The effect of primary therapy (surgery and radiochemotherapy RCT, surgery and radiotherapy RT, and surgery alone) on overall survival (OS) and recurrence-free survival (RFS) was evaluated in the complete cohort of 442 patients and in subgroups according to risk profile and nodal status. In low-risk patients, there was no difference in OS (p = 0.276) depending on whether patients received adjuvant therapy or not. Concerning RFS, patients with RT (including one patient with RCT) exhibited a significantly worse outcome compared to the group with surgery alone (p = 0.015). In intermediate-risk patients, the administration of adjuvant RT significantly benefited RFS when compared to surgery only in multivariate analysis (p = 0.031). Concerning OS, no significant influence for adjuvant treatment could be seen (p = 0.354). Though trends towards better OS and RFS could be observed in patients of the high-risk group—both in RCT and RT groups compared to surgery alone—the effects did not prove to be significant. Our study reaffirms the evidence against the use of adjuvant radio(chemo)therapy in low-risk early-stage cervical cancer. In intermediate-, and less pronounced in high-risk patients, however, it seems to be beneficial. The role of adjuvant radio(chemo)therapy in early cervical cancer should be further investigated in prospective randomized trials.

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

We investigated the survival effect of lymphadenectomy in ovarian cancer. The five-year progression-free and overall survival in early-stage ovarian cancer were not affected. Preliminary, unadjusted analysis in advanced ovarian cancer suggested an improvement in survival. However, after adjusting for other factors, e.g. ECOG performance status and patients' age, this survival advantage vanished. Our analysis suggests that systemic pelvic and para-aortic lymphadenectomy was not associated with an improvement of the progression-free and overall survival of patients with optimally debulked ovarian cancer.

Young breast cancer patients aged 35 years and younger are a small group of women who tend to present at high-risk form of the disease. More analysis of the data on tumor characteristics, treatment, and survival is necessary to help improving treatment and outcome.In this retrospective study, we compared the clinical and tumor characteristics, the treatments, and the survival of 257 women aged ≤ 35 years, with 6566 women aged 50-69 years. We used a registry-based data of patients with invasive, non-metastatic breast cancer diagnosed between 2000 and 2015.Young women showed lower rate of hormone receptor (HR) positivity. Their tumors were more often HER2-positive, which showed lower rate of differentiation and higher rate of Ki-67 expression compared to their older counterparts. Women aged 35 years and younger were more likely to undergo neoadjuvant therapy and mastectomy. Endocrine therapy was underrepresented in young patients. 5-Year disease-free survival (DFS) was significantly lower in the younger patient group (81.7% vs. 91.3%, p 0.001), while 5-year overall survival (OS) was not impaired (91.4% vs. 91.1%, p = 0.847).The unfavorable disease-free survival in the group of younger patients might be explained by their unfavorable tumor characteristics. The surgical treatment appears to be more aggressive in young breast cancer patients and is more frequently combined with chemotherapy and immunotherapy, either in a neoadjuvant or in an adjuvant setting.

Background Due to the lack of prospective data, current treatment of male breast cancer (MBC) is based on information obtained from retrospective analysis or by extrapolation from studies on female patients. In this prospectively enrolled cohort study, we retrospectively examined the survival effect of tamoxifen in MBC patients. Methods In this prospectively enrolled cohort study, 448 patients with MBC were treated between May 2009 and June 2018. The primary endpoint was disease-free survival (DFS). Results Between May 2009 and June 2018, 448 men with breast cancer were identified, with a median age at diagnosis of 69 years (range 27–96 years). The median follow-up was 39 months (range 3–89 months). Most tumours were larger than 20 mm; invasive ductal carcinoma was of no special histological type and with an intermediate grade of differentiation. Almost half of the men were diagnosed with positive axillary lymph nodes (43.5%). Hormone receptor (HR) positivity was observed in 98.4% of the patients. Notably, DFS among men who did not receive tamoxifen was significantly reduced as compared with those who underwent tamoxifen therapy (P = 0.002). The recurrence rate and mortality in the group of patients without and with tamoxifen treatment were 18.2% and 11.2%, respectively. The most common localisation of metastases was the bone. After adjustment for prognostic factors, we found that tamoxifen was found to reduce the recurrence rate by 68% (hazard ratio HR = 0.32; 95% confidence interval, CI: 0.14–0.74). Conclusions Tamoxifen treatment was associated with improved DFS for MBC patients. Clinical trial registration DRKS00009536.

Background. In this prospective analysis, we aimed to characterize the treatment opinions on male breast cancer (MBC). Patients and methods. In this prospective cohort study we included patients treated between May2009 and June 2018 for MBC. Results. The median follow-up was 30 months (range 2-84 months) and the median age at diagnosis was 69 years (range 27-96 years). Radical mastectomy was performed in 354 (96.2%) cases. Most (n=194, 52.9%) patients underwent sentinel-node biopsy (SNB). However, the vast majority of patients with clinical and sonographic suspicious axillary lymph nodes (n=72, 81.8%) underwent ALND. Adjuvant radiation of chest wall post mastectomy or of the breast post breast conserving surgery was performed in 193 (51.9%) patients. Systemic therapy was administered to 155 (41.0%) patients, and was administered predominantly in the adjuvant setting. Most common was anthracycline-taxane-based therapy. Of patients with HER2 (n=43) overexpressing tumors, 29 (67.4%) received trastuzumab. Adjuvant endocrine therapy was administered to 92.3% of patients, predominantly tamoxifen. Important decision criteria for adjuvant radiation and chemotherapy were advanced stage of disease, lymph node metastases, undifferentiated tumors, lymph- and blood vessel invasion. During the follow up period 609 cycles of chemotherapy were administered (median 6 cycles per person). Haematological and non-haematological toxic effects were observed in 68 (16.4%) and 57 (53.3%) patients, respectively. Grade 3 and 4 haematological events were rare. The most common was neutropenia in 17 (15.8%) and febrile neutropenia in 10 (9.3%) cases. Nausea and vomiting were the most commonly observed grade 3 and 4 non-haematological adverse events observed in 7 (4.6%) cases. Endocrine therapy was discontinued in 53 (16.2%) patients and chemotherapy in 25 (16.1%) cases. Conclusions. In this large prospective study, we found that MBC is treated according to current guidelines and treatment seems to be not inferior in comparison with that treatment of FBC. Citation Format: Holm Eggemann, Cosima Brucker, Susen Schirrmeister, Uta Ringsdorf, Doris Augustin, Michael Schrauder, Marc Thill, Felix Flock, Susanne Kraudelt, Gabriele Gad, Anke Kleine-Tebbe, Mattea Reinisch, Serban- Dan Costa, Atanas Ignatov. Treatment strategies in male breast cancer: Results of a prospective multicenter study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-17-06.

The primary therapy for intermediate- and high-risk endometrial cancer includes pelvic and paraaortic lymph node evaluation. Laparoscopic surgery is an increasingly popular intervention due to decreased risk and better short-term morbidity; however, a recent study casts doubt on the benefit of this approach in terms of oncological safety. In this cancer registry study, we sought to evaluate the benefit of laparoscopy versus laparotomy and retrospectively compared overall survival, recurrence rates, and recurrence-free survival among patients with intermediate- and high-risk endometrial cancer who underwent either laparoscopic or open surgery. This observational study included 419 patients who have been treated from 2011 to 2017. We employed Kaplan–Meier method, and univariable and multivariable Cox-regression to compare overall survival, recurrence rates, and recurrence-free survival in 110 patients, who underwent laparoscopic, with 309 patients, who underwent open surgery. To address the confounding bias in this retrospective study, we also performed a propensity score matching (PSM) analysis including 357 patients (laparoscopy: n = 107; open surgery: n = 250). We found a benefit for laparoscopic over open surgery in patients with intermediate- and high-risk endometrial cancer for overall survival in both univariable (p = 0.002; PSM: p = 0.016) and multivariable analyses (p = 0.019; PSM: p = 0.007). In contrast, there was no statistically significant difference between both patient groups regarding the cumulative recurrence rates. A univariable analysis identified a significant benefit for laparoscopy regarding recurrence-free survival (p = 0.003; PSM: p = 0.029) but a multivariable analysis failed to confirm this finding (p = 0.108; PSM: p = 0.118). Our study provides evidence that laparoscopic systematic lymphadenectomy does not present a lower oncological efficacy than open surgery in the treatment of patients with endometrial cancer.

Endocrine therapies using tamoxifen and/or aromatase inhibitors are important therapeutic options for the targeted treatment of hormone-responsive breast cancer. In addition to nuclear estrogen receptors ERα and β, G-protein-coupled estrogen receptor GPER-1 is a third receptor-mediating estrogen effects in breast cancer cells. The aim of this study was to examine to what extent GPER-1 expression might affect the efficacy of primary endocrine treatment of breast cancer. GPER-1 expression was determined in tissue samples from patients with early breast cancer by means of immunohistochemistry and a GPER-1 score of ≥ 3 was considered to be positive. In a total of 165 patients, the response to a primary therapy with tamoxifen (TAM) or aromatase inhibitors (AI) was assessed by ultrasound imaging for up to 6 months. The primary endpoint of this study was the response to treatment evaluated by RECIST 1.1 criteria. GPER-1 expression was observed in 127 (77.0%) out of 165 cases. Based on GPER-1 expression and the type of endocrine treatment, the patients were divided into 4 groups: GPER-1 negative/TAM (12.1%), GPER-1 negative/AI (10.9%), GPER-1 positive/TAM (44.8%), and GPER-1 positive/AI (32.1%). The groups were well balanced regarding different clinical and pathological factors. After 4 and 6 months of treatment, a high level of stable disease or progressive disease was observed in the GPER-1 positive/TAM group only (p

The aim of this study was to investigate the impact of pre-operative conization on disease-free survival (DFS) in early-stage cervical cancer.In this population-based cohort study we analysed from clinical cancer registries to determine DFS of women with International Federation of Gynecology and Obstetrics (FIGO) stage IA1-IB1 cervical cancer with respect to conization preceding radical hysterectomy performed between January 2010 and December 2015.Out of 993 datasets available for the analysis, 235 patients met the inclusion criteria of the current study. The median follow-up was 5.4 years. During the study period, 28 (11.9%) recurrences were observed. All of these occurred in patients with FIGO stage IB1. For further evaluation, patients with FIGO IB1 tumors2 cm were further analysed and divided into two groups, based on pre-operative conization. Pre-operative conization was associated with a reduced rate of recurrence (p = 0.007), with only three (5.2%) recurrences in this group (CO) compared to 25 recurrences (21.0%) in the group without conization (NCO) preceding radical hysterectomy. DFS was estimated at 79.0% and 94.8% in NCO and CO, respectively (p = 0.008). After adjustment for other prognostic covariates, conization remained a favourable prognostic factor for DFS (HR 0.27; 95% CI 0.08-0.93, p = 0.037). Lymph node involvement was the only unfavourable factor (HR 4.38; 95% CI 1.36-14.14, p = 0.014) in the multivariable analysis.Pre-operative conization is associated with improved DFS in early-stage cervical cancer independently of the surgical approach.

Simple Summary In node-positive vulvar squamous cell cancer, questions of when and how to perform pelvic lymphadenectomy (LAE) as well as the optimal extent of pelvic treatment in general have been surrounded by considerable controversy. In Germany, systematic pelvic LAE is currently recommended as a staging procedure in patients at risk for pelvic nodal involvement in order to prevent morbidity caused by pelvic radiotherapy (RT) in patients without histologically-confirmed pelvic involvement. However, the population at risk for pelvic metastases remains insufficiently described, resulting in the potential overtreatment of a considerable proportion of patients with groin-positive disease. This applies to the indication to perform surgical staging but also to adjuvant RT of the pelvis without previous pelvic staging. Our study aims to describe the risk for pelvic lymph node metastasis with regard to positive groin nodes and to clarify the indication criteria for pelvic treatment in node-positive vulvar cancer. Abstract The need for pelvic treatment in patients with node-positive vulvar cancer (VSCC) and the value of pelvic lymphadenectomy (LAE) as a staging procedure to plan adjuvant radiotherapy (RT) is controversial. In this retrospective, multicenter analysis, 306 patients with primary node-positive VSCC treated at 33 gynecologic oncology centers in Germany between 2017 and 2019 were analyzed. All patients received surgical staging of the groins; nodal status was as follows: 23.9% (73/306) pN1a, 23.5% (72/306) pN1b, 20.4% (62/306) pN2a/b, and 31.9% (97/306) pN2c/pN3. A total of 35.6% (109/306) received pelvic LAE; pelvic nodal involvement was observed in 18.5%. None of the patients with nodal status pN1a or pN1b and pelvic LAE showed pelvic nodal involvement. Taking only patients with nodal status ≥pN2a into account, the rate of pelvic involvement was 25%. In total, adjuvant RT was applied in 64.4% (197/306). Only half of the pelvic node-positive (N+) patients received adjuvant RT to the pelvis (50%, 10/20 patients); 41.9% (122/291 patients) experienced recurrent disease or died. In patients with histologically-confirmed pelvic metastases after LAE, distant recurrences were most frequently observed (7/20 recurrences). Conclusions: A relevant risk regarding pelvic nodal involvement was observed from nodal status pN2a and higher. Our data support the omission of pelvic treatment in patients with nodal status pN1a and pN1b.

To date, information on risk factors and temporal patterns of recurrences in patients with vulvar cancer is sparse. Conclusive data for an optimal surveillance strategy are lacking.This multicenter, retrospective population-based register study included 1412 patients who have been treated from 2000 to 2017 for vulvar cancer in the German districts of Upper Palatinate, Lower Bavaria, and Saxony-Anhalt. Kaplan-Meier method, and univariate and multivariate Cox regression were employed to evaluate prognostic factors and temporal course of overall survival, cumulative recurrence, and recurrence-free survival rates.After exclusion, the final study cohort comprised 829 patients. Most recurrences occurred within the first 3 years after diagnosis. Notably, a significant subset of patients were recurrent even after 5 years. The cumulative recurrence rate from all relapses was 18.6% 1 year after primary diagnosis. The recurrence rate increased to 34.7% after 3, to 41.8% after 5, and to 56.6% after 10 years post-diagnosis. The risk of relapse was significantly increased in patients over 70 years of age (hazard ratio (HR) = 2.7; p 0.001; 95% CI 1.6-4.4), and in patients with positive nodal status N1 (HR = 2.0; p = 0.019; 95% CI 1.1-3.5) and N2/3 (HR = 2.2; p = 0.033; 95% CI 1.1-4.4).Our study provides compelling evidence that follow-up care should be carried out for longer than 5 years, especially for high-risk patients.

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

Introduction The G protein-coupled oestrogen receptor 1 (GPER-1) is a potential prognostic marker in breast cancer. However, its role in male breast cancer (MBC) is still unknown. This study evaluates the expression of GPER-1 in MBC samples and correlates these data with clinical and pathological parameters including patients' survival. Material and methods For this retrospective analysis of a prospectively maintained cohort of patients with MBC, we examined 161 specimens for GPER-1 expression using immunohistochemistry. An immunoreactive score (IRS) was calculated based on staining intensity and the percentage of positive tumour cells. Then, we correlated GPER-1 IRS with clinical and pathological parameters, and overall and relapse-free survival. Results About 40% of MBC samples were positive for GPER-1 expression (IRS ≥ 4). There was no significant correlation with clinicopathological parameters, such as hormone receptor status or grading. However, a statistical trend was observed for tumour size (≥ 2 cm, p = 0.093). Kaplan-Meier survival analysis revealed no significant correlation with relapse-free survival. However, there was a significant correlation with overall survival, but when we adjusted the log-rank p-value to compensate for the cut-off point optimization method, it rose above 0.1. Additionally, GPER-1-positive patients were older at diagnosis. When adjusted for age by multivariable Cox regression analysis, the significance of GPER-1 status for survival was further reduced. Conclusions We found no significant prognostic value of GPER-1 in this MBC cohort as anticipated from studies on female BC. Future studies with higher sample size are needed to further verify a potential sex-specific role of GPER-1.

Although puerperal mastitis is a common disease, published data are poor. Increasing rates of community-acquired MRSA (CA-MRSA) cases are reported in the USA. However, information about common pathogens and CA-MRSA in Germany is still insufficient. The aim of this study was to investigate the most common pathogens of puerperal mastitis in the last decade, its therapy, resistance rate and the effectiveness of the current treatment strategies. The pathogens, the respective antibiograms and the treatment strategies of patients treated for puerperal mastits at the University Clinic Magdeburg (Germany) between 2006 and 2016 were retrospectively reviewed. Statistical analysis was performed using SPSS Version 21. In our series, 59 cases with puerperal mastitis were reviewed, 26 (44.1%) of these developed a breast abscess. In 37 of 59 (67.3%) cases the symptoms occurred in the first 8 weeks postpartum. The most common pathogens were Staphylococcus aureus (64.9%) and Coagulase-negative Staphylococcus (13.5%). Methicillin-resistant Staphylococcus aureus (MRSA) was found in one case. Of the 19 cases with Staphylococcus aureus, 17 were resistant to Penicillin. Conservative management was mainly performed with Flucloxacillin (60%), which was successful in most cases. Sixteen of 26 (61.5%) women with abscesses underwent ultrasound (US)-guided needle aspiration. In this cohort, MRSA was not a main pathogen responsible for breast abscesses. Conservative treatment strategies remained constant during the observed period and Flucloxacillin was the most frequent antibiotic used. The analysis of the courses of diseases leads to the conclusion that surgical incision is progressively replaced by US-guided needle aspiration.

HER2 expression has been reported to be discordant between primary tumor and metastatic tissue. HER2 discordance and relation to HER2-targeted treatment was investigated in 227 patients with primary breast cancer. HER2 discordance between primary biopsy and second biopsy after neoadjuvant or adjuvant treatment was observed in 20.7%. This discordance was related only to the use of HER2-targeted treatment: 30 of 33 (90.9%) women with downgraded HER2 expression underwent a HER2-targeted therapy, whereas in the group of patients with concordant HER2 expression, only 32 of 180 (17.8%) received HER2-targeted treatment (p

Similarities in outcome between grade 3 endometrioid cancer and non-endometrioid histologies have been reported by a number of studies. Other reports, however, stated a significantly better prognosis for G3 endometrioid compared to type II histology. In this population-based study, we compared the outcome and treatment approaches of high-grade endometrial cancer patients with FIGO stages I-III depending on their histology.284 high-grade endometrial cancer patients diagnosed between 1998 and 2015 were retrospectively analyzed. Overall survival (OS), recurrence-free survival (RFS), and recurrence rates were compared depending on histology.Type I G3 patients had a statistically significant OS advantage over women suffering from type II carcinoma (HR 1.527, 95%-CI 1.024-2.276;The prognosis of patients with type I G3 endometrial cancer patients seems to be significantly superior to patients with type II cancer and particularly carcinosarcoma. Systematic LND seemed to be beneficial in all of the three subtypes. The benefit of adjuvant treatment methods may differ between histologies.

Introduction The risk of contralateral lymph node metastases following unilateral sentinel lymph node (SLN) metastases in patients with vulvar cancer(s) remains to be systematically assessed. Material and methods We performed a multicenter, retrospective registry-based study of 476 patients with vulvar cancer. The primary outcome measure was the rate of contralateral non-SLN metastases in the case of positive unilateral SLN. Results Out of 476 patients with primary vulvar cancer, 202 received SLN biopsy: 58 unilateral and 144 bilateral. Out of 66 patients with unilateral metastatic SLN, 62 (93.9%) received contralateral lymphadenectomy—18 after unilateral and 44 after bilateral SLN biopsy. In the study group, 132 SLN were assessed with a median number of 2 (range 1–4) per patient and 76 of these were positive. Lymph node-positivity was associated with advanced tumor stage, as well as lymph and vascular space invasion. In the group of patients with bilateral inguino-femoral lymphadenectomy, 1004 lymph nodes were resected with a median number of 15 (range 10–29) per patient. After full dissection of the inguino-femoral lymph nodes, no contralateral non-SLN metastases were found. Conclusions The risk of contralateral non-SLN metastases in patients with unilateral SLN metastases was low. Therefore, the impact of contralateral lymphadenectomy on patient survival should be investigated in further studies.

Treatment according to guidelines has been demonstrated to improve survival in a number of different cancer entities. Deviations from guidelines depend on several factors, including the patient’s preferences, age and comorbidities. The aim of this study was to assess the adherence to guideline recommendations concerning surgical and adjuvant treatment in endometrial cancer. Furthermore, we sought to evaluate the reasons for non-adherence to guidelines by further examining the influence of comorbidities and age. The influence of age, comorbidities, tumor stage and histological subtype on guideline adherence was evaluated by multivariable logistic regression in a cohort of 353 high-grade endometrial cancer patients. High-grade endometrial cancer was defined as carcinosarcoma, Type II (serous, clear cell, mixed cell carcinoma) and Type I G3 histology. Extensive surgical procedures, particularly systematic LNE, were less frequently applied in patients with comorbidities (p = 0.015) or higher age (p

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.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.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).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.

The axillary lymph node status is one of the most important prognostic factors in patients with early breast cancer. However, the impact of axillary lymph node micrometastases on survival remains unclear. There are no consistent recommendations for adjuvant chemotherapy (CHT). In this context, we aimed to investigate the impact of micrometastases on the clinical outcome of breast cancer patients according to the adjuvant CHT performed.We conducted a retrospective population-based registry study of 26,465 patients aged between 24 and 97 years with primary breast cancer diagnosed between 2003 and 2017. Of these patients, 8856 with early breast cancer were eligible for analysis: 8316 (93.9%) were node negative and 540 (6.1%) had lymph node micrometastases.The median follow-up was 7.2 years, with a confidence interval (CI) of 7.1-7.3 years. Patients with lymph node micrometastases (pN1mi) without adjuvant CHT have reduced 10-year overall survival (OS) and recurrence-free survival (RFS) compared to patients who had axillary lymph node micrometastases and received an adjuvant CHT. However, this effect disappeared after adjustment for age, tumor size and tumor grading. Furthermore, in the group of patients with lymph node micrometastases, the administration of adjuvant CHT did not improve OS or RFS, compared to patients with lymph node micrometastases without adjuvant CHT: hazard ratio for treated patients was 1.51 (95% CI 0.80-2.85, p = 0.208) for OS and 1.12 (95% CI 0.63-1.97, p = 0.705) for RFS.Patients with axillary lymph node micrometastases showed a comparable outcome to node negative patients and their outcome was not significantly improved with CHT. Thus, axillary lymph node micrometastases should not be considered in the treatment decision.

The usage of radioactive TechnetiumIn this double-arm retrospective study, we sought to establish the usefulness of indocyanine green as an alternative or an addition to the conventional TechnetiumAmong the 161 patients who underwent primary SLNB, 34 patients had at least 1 SLN with metastasis. Among these patients with SLN metastasis, 33 had the SLN detected by ICG; while 31 had the SLN detected by TcOur results show that ICG is as effective as the radioisotope for SLNB even among patients who have undergone NACT. This trial is registered with the German Clinical Trial Register, ID: DRKS00013606.

The aim of the study was to compare recurrence-free survival (RFS) and overall survival (OS) of patients with early stage cervical cancer in dependence of surgical approach and treatment center. A population-based cohort study including women with early stage IA1-IIB2 cervical cancer treated by radical hysterectomy between January 2010 and December 2015 was performed. The median follow-up time was 5.6 years. After exclusions, 413 patients were eligible for analysis: 111 (26.9%) underwent minimal-invasive surgery (MIS) and 302 (73.1%) open surgery. Both treatment groups were well balanced regarding the clinical and pathological characteristics. The mean age of the patients was 51.0 years. MIS was associated with improved RFS and OS compared with the open surgery. The 5-year RFS rates were 89.2% in the MIS group and 73.4% in the open surgery group (p = 0.004). The 5-year OS rates were 93.7% in the MIS group and 81.8% in the open surgery group (p = 0.016). After adjustment for other prognostic covariates, the MIS was further associated with improved RFS (HR = 0.45, 95% CI 0.24–0.86; p = 0.015) but not with OS. Nevertheless, after adjustment for treatment center, the surgical approach was not associated with significant difference in RFS (HR = 0.61, 95% CI 0.31–1.19; p = 0.143). Overall survival of patients treated in university cancer centers was significantly increased compared to patients treated in non-university cancer centers. The treatment center remains a strong prognostic factor regarding RFS (HR = 0.49, 95% CI 0.28–0.83; p = 0.009) and OS (HR = 0.50, 95% CI 0.26–0.94; p = 0.031). The treatment center but not the surgical approach was associated with the survival of patients treated with radical hysterectomy for early stage cervical cancer.

Glyoxalase-1 (GLO-1) is the key enzyme in aldehyde defence in cancer cells. We here evaluated the prognostic impact and association with clinico-pathological parameters and relapse-free as well as overall survival in tumor samples from 187 breast cancer patients. The determined GLO1-immunoreactive score (GLO1-IRS) did not correlate with parameters such as grading, size, hormone receptors or ki67. However, an association of GLO1-IRS with the advanced glycation end product Ne-(carboxymethyl)lysine (p = 0.07) and HER2 (p = 0.06), and a strong correlation with VEGF (p = 0.008) was found. In survival analysis, no significant impact of GLO-1 IRS could be deduced for all patients. However, GLO1-IRS correlated with treatment by radiotherapy (p = 0.008) and high GLO1-IRS predicted a shorter relapse free survival after radiotherapy (log-rank p = 0.067). METABRIC- and TCGA expression-data were analyzed for correlation of regulatory genes of the NF-κB-pathway (RELA, RELB, IRAK1), the oxidative-stress associated transcription factor nrf2 (NFE2L2), the receptor for AGEs (AGER, RAGE) as well as enzymes associated with aldehyde defense. Here, RELA, RELB and NFE2L2 correlated significantly with GLO1 expression, but there were conflicting results between the two data sources. In conclusion, GLO1 was highly expressed in cancer cells, correlated surprisingly weak with survival, but we could show a positive association with the AGE CML as well as VEGF. Gene expression data suggest a regulation of GLO-1 mRNA via both, inflammation (NF-kB) and oxidative stress (NFE2L2) in tumors.

The present study intended to further elucidate the role of G protein-coupled estrogen receptor 1 (GPER-1) in ovarian cancer by comparing the effects of a GPER-1 knockdown and treatment with its agonist G-1 on cell growth, apoptosis, and the transcriptome of two ovarian cancer cell lines. Furthermore, the role of GPER-1 in ovarian cancer survival was examined. GPER-1 expression in OVCAR-3 and OAW-42 ovarian cancer cells was knocked down by RNAi. The effects on cell growth were measured by means of the fluorimetric cell titer blue assay and on the transcriptome by Affymetrix GeneChip analysis. The effect of GPER-1 on patient’s survival was examined using open source mRNA and clinical data of 1657 ovarian cancer patients. GPER-1 knockdown resulted in a significant growth stimulation of both cell lines, whereas treatment with agonist G-1 decreased growth of both cell lines in a dose-dependent manner. Transcriptome analyses revealed a set of 18 genes being conversely regulated after GPER-1 knockdown and G-1 treatment. Generally, treatment with G-1 led to a transcriptome response associated with growth inhibition. In contrast, knockdown of GPER-1 exerted opposite effects, stimulating pathways activating mitosis, but inhibiting pathways associated with apoptosis or interferon signaling. Further analyses using open-access mRNA and clinical data by bioinformatical online tools revealed a longer OS (HR = 0.86, p = 0.057) and PFS (HR = 0.81, p = 0.0035) of ovarian cancer patients with high GPER-1 mRNA expression. The results of this study clearly support the hypothesis that GPER-1 acts as a tumor suppressor in ovarian cancer.

BACKGROUND: The positive effect of systematic lymphadenectomy on survival of patients with endometrial cancer is a topic of ongoing debate. METHODS: We aimed to investigate whether systemic lymphadenectomy is beneficial for patients with early endometrial cancer. For this purpose, we analyzed a population-based registry with of 2392 women with endometrioid endometrial cancer, stage I and II at intermediate and high risk of recurrence. The primary outcome measure was overall survival. RESULTS: After exclusions, 868 women were eligible for analysis. Of those, 511 and 357 were categorized as intermediate (pT1A G3 and pT1B G1-2) and high risk (pT1B G3 and pT2 G1-3) early stage endometrial cancer, respectively. Lymphadenectomy was performed in 527 (60.7%) of the cases. Patients in the lymphadenectomy group were significantly younger, presented with more tumors of intermediate or undifferentiated grade and exhibited significantly lower co-morbidity rates and Eastern Cooperative of Oncology Group (ECOG) performance status. Median follow-up was 6.7 years. Recurrence-free survival was not improved by lymphadenectomy in the intermediate and high-risk group of patients. During the follow-up period, 111 (12.8%) women had disease recurrence and 302 (34.8%) died. Systematic lymphadenectomy was associated with significant improvement of overall survival in the pT1A G3 and pT1B G3 patient subgroups. Notably, adjustment for patient age and ECOG status abolished the improvement of overall survival by systematic lymphadenectomy in all groups. Thus, lymphadenectomy did not improve recurrence-free survival in the intermediate risk or the high-risk group of patients CONCLUSIONS: Systematic pelvic and para-aortic lymphadenectomy did not improve the survival of patients with early stage I and II endometrioid endometrial cancer at intermediate and high risk of recurrence.

BackgroundBRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data.MethodsData of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided.Results430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non–BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16; P = .98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18; P = .96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non–BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97; P = .02; OS: HR = 0.80, 95% CI = 0.63 to 1.00; P = .05) on mixed-effects modeling.ConclusionBRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.

To evaluate the pattern of endometrial cancer recurrence according to its biological subtype in a large cohort of patients. Patients were stage eligible if they had a description of registry risk of recurrence status and were not primary metastatic. Data were prospectively collected. The primary endpoints were the subtype-dependent pattern and time of recurrence. The median follow-up time was 84 months. The highest 10-year recurrence-free and overall survival were seen in the group of patients at low risk of recurrence, 83.1 and 94.1%, respectively. The 10-year recurrence-free survival for intermediate and high risk group was 65.7 and 56.2%, respectively, whereas the estimated 10-year overall survival for both groups was 84.5 and 79.3%, respectively. Patients at high risk demonstrated the highest levels of disease recurrence in the first 3–4 years after diagnosis and the most common site of metastasis was the lung. In contrast, the rate of recurrence for patients at intermediate and low risk of recurrence in the first 5 years was relatively low but remained continuous up to 10 years of follow-up. Overall, the most common site of relapse was local recurrence. Endometrial cancer subtypes are associated with different times and patterns of recurrence and this should be considered when determining the treatment strategy.

To compare the impact of peritoneal closure on postoperative pain after vaginal (VH) and laparoscopic-assisted vaginal hysterectomy (LAVH). A prospective, randomized, double-blind study was designed to investigate as primary outcome the postoperative pain after VH and LAVH with and without peritoneal closure. The postoperative pain was measured using visual analogue scale (VAS). The patients were recruited between August, 2007 and July, 2014. A total of 192 patients with benign uterine diseases were eligible for analysis and were divided in four groups: LAVH and VH with and without peritoneal closure (PC), respectively. The patients’ characteristics including parity, BMI, previous abdominal operations, and uterus weight were well balanced between the groups. The patients who received LAVH were significantly younger (p = 0.0443). LAVH was associated with increased postoperative pain and reduced patients’ mobility in the first 72 and 24 h, respectively, after surgery. The use of analgesics remained similar in all four groups. The operating time was significantly shorter after VH (VH + PC 59 ± 17; VH − PC 56 ± 19) than after LAVH (LAVH + PC 106 ± 29 min; LAVH − PC 99 ± 30) (p

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

Neuronatin (NNAT) is a proteolipid involved in cation homeostasis especially in the developing brain. Its expression has been associated with the progression of lung cancer, glioblastoma, and neuroblastoma as well as glucose induced apoptosis in pancreatic cells. We performed a retrospective study of 148 breast cancer specimens for NNAT expression by immunohistochemistry to evaluate this protein as a prognostic marker for breast cancer. We found a high NNAT immunoreactivity score (by multivariate cox regression) to be an independent prognostic marker for relapse-free (hazard ratio HR = 3.55, p = 0.002) and overall survival (HR = 6.29, p

Recently, we found that G-protein-coupled estrogen receptor (GPER) protein expression decreased during breast carcinogenesis, and that GPER promoter is methylated. Here we analyzed GPER promoter methylation in 260 primary breast cancer specimens by methylation-specific polymerized chain reaction. The results demonstrated that GPER protein down-regulation significantly correlated with GPER promoter hypermethylation (p < .001). Comparison of 108 tumors and matched normal breast tissues indicated a significant GPER down-regulation in cancer tissues correlating with GPER promoter hypermethylation (p < .001). The latter was an unfavorable factor for overall survival of patients with triple-negative breast cancer (p = .025). Thus GPER promoter hypermethylation might be used as a prognostic factor.

Introduction/Background Detecting tumor-specific genetic alterations in cell-free DNA (cfDNA) obtained from cancer patients allows for a quantification of the tumoral fraction, i.e. the circulating tumor DNA (ctDNA). Previous studies in metastatic cancer patients showed that early changes of this fraction during therapy are indicative of therapeutic response. We tested this hypothesis on cfDNA samples collected in the GANNET53 clinical trial (FP7, funded by the European Commission, grant no 602602). Methodology Patients with high-grade serous/endometrioid and/or undifferentiated PROC were recruited for treatment with weekly paclitaxel with or without Hsp90-inhibitor ganetespib. Archival biopsy samples were used for tumor TP53 genotyping. CfDNA was prospectively collected prior to treatment at baseline (cycle 1 day 1, C1D1), 24 hours later (cycle 1 day 2, C1D2) and after 4 and 8 weeks, at day 1 of cycle 2 (C2D1) and 3 (C3D1) respectively. Targeted TP53 resequencing was performed on cfDNA and allelic frequencies of the known TP53 variant (TP53 VAF) were quantified and correlated with clinical outcome. Results For 125 of the 133 randomized patients, at least 1 C1D1 cfDNA sample was available. For 119 tumor samples, TP53 genotyping was successful and identified deleterious TP53 mutations in 106 patients (89.1%). The median ctDNA level was 1.82% (IQR:0.17–8.34%) at C1D1 which decreased significantly after 4–8 weeks of therapy. Overall, ctDNA was detectable in 64.6% (64/99) of baseline samples. Baseline CA125 did not differ between cases with and without detectable ctDNA at C1D1. Detection of ctDNA at C1D1 (HR 2.3; 95%CI:1.4–3.9), C1D2 (HR 2.2; 95%CI:1.3–3.9) and C2D1 (HR 2.8; 95%CI:1.6–4.9) predicted a worse overall survival. A subgroup of patients for whom TP53 ctDNA was undetectable at C2D1 or C3D1 (14/64) had a high overall response rate of 64.2%. Conclusion Quantification of TP53 mutations in cfDNA of PROC patients has prognostic value at baseline. Favorable early changes during treatment may predict therapeutic response. Disclosure The presenting author, A.Vanderstichele, has no conflict of interest.

Lymph node metastasis is a significant predictive factor for disease recurrence and survival in cervical cancer patients and relevant for therapeutic strategies. We evaluated the clinical value of indocyanine green (ICG) by measuring the sensitivity and negative predictive value of sentinel lymph node mapping compared with the gold standard of complete lymphadenectomy in detecting lymph node metastases for cervical cancer. We utilized the near-infrared imaging agent ICG to detect tumor-infested lymph nodes in the pelvis analogue to a classical sentinel lymph node procedure by analyzing data from 20 patients who had undergone surgery for cervical cancer at our institution. A laparoscopic lymph node mapping procedure by means of ICG, followed by a complete pelvic lymphadenectomy with or without paraaortic lymphadenectomy was done in all patients. Histological examination identified seven patients with tumor-positive pelvic nodes, whereas mapping with ICG identified only five of these patients. Detection rate of positive nodes by ICG mapping and false negative rate was 71.4% and 28.6%, respectively; bilateral detection rate was 83.3%. One of the two false negative patients additionally suffered from deep infiltrating endometriosis. Our results indicate that ICG can identify the relevant pelvic nodes independent of tumor size, provided bilateral detection is achieved and additional, related diseases are excluded. This trial is registered within the German Clinical Trial Register (DRKS-ID: DRKS00014692).