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Opportunistic salpingectomy (OS) is an attractive method for primary prevention of ovarian cancer. Although OS has not been associated with a higher complication rate, it may be associated with earlier onset of menopause.To provide a systematic review and meta-analysis of the effect of OS on both age at menopause and ovarian reserve.A search was conducted in the Cochrane Library, Embase and MEDLINE databases from inception until March 2022. We included randomized clinical trials and cohort studies investigating the effect of OS on onset of menopause and/or ovarian reserve through change in anti-Müllerian hormone (AMH), antral follicle count (AFC), estradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH). Data was extracted independently by two researchers. Random-effects meta-analyses were conducted to estimate the pooled effect of OS on ovarian reserve.The initial search yielded 1047 studies. No studies were found investigating the effect of OS on age of menopause. Fifteen studies were included in the meta-analysis on ovarian reserve. Meta-analyses did not result in statistically significant differences in mean change in AMH (MD -0.07 ng/ml, 95%CI -0.18;0.05), AFC (MD 0.20 n, 95 % CI -4.91;5.30), E2 (MD 3.97 pg/ml, 95%CI -0.92;8.86), FSH (MD 0.33mIU/ml, 95%CI -0.15;0.81) and LH (MD 0.03mIU/ml; 95%CI -0.47;0.53).Our study shows that OS does not result in a significant reduction of ovarian reserve in the short term. Further research is essential to confirm the absence of major effects of OS on menopausal onset since clear evidence on this subject is lacking. Registration number PROSPERO CRD42021260966.

Contains fulltext : 249915.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To evaluate the incidence of pulmonary metastases in the preoperative work-up of patients with primary vulvar squamous cell carcinoma (SCC). DESIGN: Retrospective cohort study. SETTING: Tertiary referral centre. POPULATION: Patients treated for primary vulvar SCC from 2000 to 2018. METHODS: The pre-operative chest imaging of 452 consecutively treated patients was documented with a minimal follow-up period of 2 years. MEAN OUTCOME MEASURES: Incidence of pulmonary metastases, frequency of chest imaging and subsequent coincidental findings. RESULTS: In total, 80.8% of patients underwent pre-operative chest imaging. Seven patients (1.9%), with a median tumour size of 80 mm, presented with pulmonary metastases. None of the patients with early stage disease and tumour size

STUDY QUESTION What is the effect of salpingectomy for ectopic pregnancy or hydrosalpinx at a young age on ovarian cancer risk compared to no salpingectomy for any reason? SUMMARY ANSWER We found no significant reduction in ovarian cancer risk after salpingectomy for ectopic pregnancy or hydrosalpinx. WHAT IS KNOWN ALREADY Salpingectomy may reduce ovarian cancer incidence, although the lag-time between intervention and therapeutic effect remains to be elucidated. STUDY DESIGN, SIZE, DURATION This nationwide population-based database study uses the Dutch pathology database to identify all women who underwent salpingectomy for ectopic pregnancy or hydrosalpinx between January 1990 and December 2012 and compared ovarian cancer incidence to a control group of women who had a benign dermal nevus removed, matched for age at the time and year of procedure. PARTICIPANTS/MATERIALS, SETTING, METHODS After selection and manual control of intervention and control group, ovarian cancer incidence was recorded. Hazard ratios (HRs) with 95% CI for the development of ovarian cancer were calculated with Cox regression analyses, both unadjusted and adjusted for age. Subgroup analyses were performed to investigate lag-time between intervention and protective effect. MAIN RESULTS AND THE ROLE OF CHANCE In all, 18 961 women were included in the intervention group; 17 106 women had a unilateral salpingectomy and 1855 had a bilateral salpingectomy. The control group consisted of 23 686 women. With 14 ovarian cancer cases in the intervention group, the incidence rate (IR) of ovarian cancer was 5.4 (95% CI 3.1–8.9) per 100 000 person-years. In the control group, there were 24 ovarian cancer cases, resulting in an IR of 7.1 (95% CI 4.7–10.5) per 100 000 person-years (P = 0.34). The age-adjusted HR for ovarian cancer was 0.76 (95% CI 0.39–1.47) after salpingectomy. Unilateral salpingectomy resulted in an age-adjusted HR of 0.81 (95% CI 0.41–1.59) and bilateral salpingectomy resulted in an age-adjusted HR of 0.43 (95% CI 0.06–3.16) based on one case. None of our subgroup analysis for lag-time resulted in a significant difference in ovarian cancer incidence between intervention and control group. The difference in ovarian cancer incidence appeared largest in women with at least 8 years of follow-up (P = 0.08). LIMITATIONS, REASONS FOR CAUTION Due to the young population, ovarian cancer incidence is low, even at the end of follow-up. Furthermore, due to the anonymous nature of the pathology registry, we were unable to adjust for confounding factors. WIDER IMPLICATIONS OF THE FINDINGS Although results did not reach statistical significance, they add to the available data on ovarian cancer incidence after salpingectomy. Our subgroup analysis suggests there may be no benefit in the first years following salpingectomy. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER N/A.

Contains fulltext : 218565.pdf (Publisher’s version ) (Open Access) The new Dutch guidelines on hereditary and familial ovarian carcinoma recommend genetic testing of all patients with epithelial ovarian cancer (EOC). With this study, we aimed to obtain insight into (1) the acceptance and timing of the offer of genetic counseling in women with EOC, (2) reasons for accepting or declining genetic counseling, and (3) psychological differences between women who did and did not have genetic counseling. A multicenter questionnaire survey was performed in patients with EOC in four Dutch oncology centers. The questionnaire addressed whether, how, and when genetic counseling was offered, women's arguments to accept or decline genetic counseling, and included the Cancer Worry Scale (CWS) and the Hospital Anxiety and Depression Scale (HADS). A total of 67 women completed the questionnaire, of which 43 had genetic counseling. Despite a wide variability in the timing of the offer of genetic counseling, 89% of the women were satisfied with the timing. No significant differences were found between the CWS and HADS scores for the timing of the offer of genetic counseling and whether or not women had genetic counseling. Taking the small sample size into account, the results tentatively suggest that genetic counseling may have limited impact on the psychosocial wellbeing of women with EOC. Therefore, we assume that implementation of the new guidelines offering genetic counseling to all patients with EOC will not cause considerable additional burden to these patients.

Contains fulltext : 248977.pdf (Publisher’s version ) (Open Access) Practicing a "safe" disclosure of adverse events remains challenging for healthcare professionals. In addition, knowledge on how to deliver a disclosure is still limited. This review focuses on how disclosure communication may be practiced based on the perspectives of patients and healthcare professionals. Empirical studies conducted between September 2008 and October 2019 were included from the databases PubMed, Web of Science and Psychinfo. After full text analysis and quality appraisal this scoping review included a total of 23 studies out of 2537 studies. As a first step, the needs of patients and the challenges of healthcare professionals with the practice of providing an effective disclosure were extracted from the empirical literature. Based on these findings, the review demonstrates that specific disclosure communication strategies on the level of interpersonal skills, organization, and supportive factors may facilitate healthcare professionals to provide optimal disclosure of adverse events. These may be relevant to provide patients with a tailored approach that accompanies their preferences for information and recognition. In conclusion, healthcare professionals may need training in interpersonal (verbal and nonverbal) communication skills. Furthermore, it is important to develop an open (organizational) culture that supports the communication of adverse events and disclosure as a standard practice.

Introduction/Background* Risk-reducing salpingectomy (RRS) with delayed oophorectomy (DO) has gained interest for women at high risk for ovarian cancer in the last years. In the first place because of the increasing number of studies pointing towards the fallopian tube as tissue of origin. In the second place because two studies demonstrated the positive effect on menopause-related quality of life and sexual functioning compared to standard risk reducing salpingo-oophorectomy (RRSO). However, the strategy is not yet proven to be safe. In the current TUBA-WISP II study, we aim to investigate whether RRS with DO is non-inferior to the current standard RRSO regarding ovarian cancer risk. Methodology In this international prospective multicenter preference trial, women choose between the novel RRS with DO and the current standard RRSO. RRS can be performed after the completion of child bearing and until the age of 40 (BRCA1), 45 (BRCA2) or 50 (BRIP1, RAD51C and RAD51D pathogenic variant (PV) carriers). Subsequent DO is recommended at a maximum delay of five years beyond the upper limit of the current guideline age for RRSO. The current guideline age, which is also recommended for RRSO within the study, is 35-40 for BRCA1, 40-45 for BRCA2 and 45-50 for BRIP1, RAD51C, and RAD51D PV-carriers. The primary outcome measure is the cumulative ovarian cancer incidence at target age: 46 for BRCA1 and 51 for BRCA2-PV carriers. A total 1500 BRCA1 and 1500 BRCA2-PV carriers are needed to prove non-inferiority of RRS with DO compared to RRSO. Kaplan-Meier analysis with Inverse probability weighting will be used to estimate the cumulative incidence at the appropriate target age (46 or 51) per BRCA-type. Result(s)* Conclusion* As RRS with DO is proven to be beneficial in regard to menopause-related quality of life and sexual functioning, the current international study is investigating the non-inferiority to RRSO regarding ovarian cancer incidence. Trial registration NCT04294927

Introduction/Background* Epithelial ovarian cancer (EOC) patients undergoing splenectomy during cytoreductive surgery represent a small subgroup of patients. Splenic metastases or technical reasons due to extensive upper abdominal disease may require a splenectomy. However, there is limited knowledge on the impact of splenectomy on the long-term outcome of patients. Particularly, it has been hypothesized that as the antitumor immunologic functions of the spleen may inhibit cancer growth, splenectomy may promote the growth of residual disease during the postoperative period as observed in murine models of other cancer types [3-6]. The aim of this study was to assess the effect of a splenectomy during cytoreductive surgery on perioperative outcomes and survival of advanced stage EOC patients. Methodology In this nationwide population-based study, all consecutive patients diagnosed with FIGO stage IIIC and IV EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery combined with platinum-based chemotherapy as primary treatment were selected. Differences in clinicopathological characteristics between splenectomy and non-splenectomy patients were assessed. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier survival curves and log-rank tests. Cox proportional hazards models were used to adjust for covariates that influence survival. Result(s)* A total of 3,911 patients were identified, including 99 splenectomy and 3,812 non-splenectomy patients. Splenectomy patients were more likely to undergo extensive surgery or surgical reintervention, to receive intraperitoneal chemotherapy, intraoperative and postoperative blood transfusion, to experience postoperative infections, and to be admitted to Intensive Care Unit (all p *An additional 163 patients were excluded from the survival analysis with reference to figure 1, since these patients had unknown follow-up or survival data. *An additional 10 patients were excluded from the survival analysis with reference to figure 1, since these patients had unknown follow-up or survival data. Conclusion* While advanced stage EOC patients who undergo splenectomy during cytoreductive surgery have more extensive disease and undergo intensive treatment, no adverse effect of splenectomy on the survival was observed. Splenectomy during cytoreductive surgery is justified to achieve complete cytoreduction in advanced stage EOC patients.

Introduction/Background* Risk reducing salpingo-oophorectomy is an effective intervention to reduce the risk of high grade serous carcinoma (HGSC) in patients with a BRCA1/2 pathogenic variant (PV), but results in significant short and long-term health risks. New interventions, such as risk-reducing salpingectomy with delayed oophorectomy are promising. In this alternative approach, the detection of serous tubal intraepithelial carcinoma (STIC) as precursor to HGSC, has become more important. The detection of STIC indicates an increased risk for HGSC and would prompt for an immediate oophorectomy. Unfortunately, reproducibility of STIC diagnosis is only moderate, even among experienced gynecological pathologists. The aim of this pilot study is to develop and validate an AI algorithm for automated detection of potential STIC lesions in scanned H&E slides, to aid the pathologist in diagnosing STIC Methodology We collected and digitalised 60 cases of STIC and 65 control cases. STIC diagnosis was confirmed using p53 and Ki-67 immunohistochemical stainings (IHC). The dataset was split into 50 cases for training, five for validation and five for testing. We developed a Convolutional Neural Network and compared two appraoches: directly detecting STIC (one-step) or first detecting all epithelium and subsequently detecting STIC within epithelial regions (two-step). Additionaly, we evaluated whether we could improve the network by enriching the training data with hard negative examples. Result(s)* We found that the optimal configuration for detection of STIC was the two-step approach, with training set enrichment by hard negatives. This network reached an area under the receiver operating curve of 0.90 (figure 1). Visual inspection of cases in the test set showed concordance between the model output, p53 and Ki67 IHC, and pathologists‘ annotations (see example model output on H&E stained tissue in figure 2. Conclusion* We present a convolutional neural network that can succesfully detect STIC lesions in whole slide images. AI has the potential to aid the pathologist in the detection of STIC and assist in producing more accurate and consistent diagnosis. Additional performance and robustness is expected to be achieved by expansion of the dataset.

Introduction/Background* High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers opting for surgery to prevent ovarian cancer, and identified factors associated with high cancer worry. Methodology Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose between the standard risk-reducing salpingo-oophorectomy or a novel strategy, risk-reducing salpingectomy with delayed oophorectomy. The Cancer Worry Scale was obtained before and three and twelve months after surgery. Cancer worry patterns were analysed using latent class growth analysis and factors associated with cancer worry were identified with regression analysis. Result(s)* Of all 577 BRCA1/2-PV carriers, 320 (55.5%) had high (≥14) cancer worry pre-surgery and 70.2% had higher cancer worry pre-surgery than post-surgery. Based on the course of cancer worry, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56.4%), persistently high cancer worry (6.3%), and fluctuating cancer worry that mainly declined over time (37.3%). Factors associated with persistently high cancer concerns were: age below 35 (BRCA1) or 40 (BRCA2) years, unemployment, previous breast cancer diagnosis, lower education and more recent diagnosis with the BRCA-PV. Conclusion* High cancer worry is common among BRCA1/2-PV carriers and mainly declines after risk-reducing surgery. However, cancer worry remains high in 6% of the women and they should be identified and offered support. It should be realized that in this group, surgery does not reduce cancer concerns.

Objective Optimizing the counselling of women ≤40 years with epithelial ovarian cancer (EOC) by investigating the role of young age and tumour characteristics on overall survival (OS). Methods A retrospective population-based study was done using data of EOC patients diagnosed between 1990 and 2014 registered in the Netherlands Cancer Registry. Descriptive statistics were performed to analyse clinical and tumour characteristics. Five- and 10-year OS rates were calculated using Kaplan Meier curves. To determine prognostic factors, univariable and multivariable survival analyses were performed. Results 1407 women ≤40 years and 29,022 women >40 years old were included. OS was higher for the younger women compared to older group (5-year survival of 65.6% vs. 32.7%, 10-year survival of 57.5% vs. 22.5%, respectively). The younger women had more often a mucinous (36.4%), well-differentiated (31.8%) tumour in early stage of disease (49.9%). Serous tumours (43.0%), high-grade (36.0%) and stage III (47.1%) were most frequently found in the older women. Histology, grade, stage, incidence year, and age group are independent prognostic factors for survival. OS of the young women for several combinations of tumour characteristics were calculated. Conclusions Age is an independent prognostic factor for OS in EOC patients. Counselling on prognosis could be more individualised in young EOC patients using the tumour characteristics histology, stage and grade.

Objectives Morbidity and mortality meetings (M&MMs) at surgical departments may improve when patients participate, leading to different learning points. A gynecological oncology department invited patients to join their M&MMs. The practical constraints and experiences important from the perspective of patients and their healthcare professionals were evaluated. Methods Semi-structured interviews were conducted with patients and professionals who attended M&MMs at a gynecological oncology department between 2016 and 2018. The interviews were transcribed and coded and thematic content analysis was performed. Results Eight patients and 17 healthcare professionals participated. Eleven themes related to interpersonal dynamics. The five shared themes are: patient–doctor relationship, language, openness of communication, learning and personal impact. All participants suggested maintaining the new practical design of the M&MMs. Conclusions Patients and healthcare professionals valued patient participation in the M&MMs. Patient participation is possible when professionals are open to discussing and learning from adverse events (AEs). In this setting, patients feel that they are taken seriously and gain a better understanding of the course of an AE. Practice Implications Involving patients in M&MMs led to new insights, better understanding, and improved processing of AEs. Collaborating with patients and using their feedback seems to be effective when developing innovations in healthcare.

Objective To identify clinicopathologic factors predictive of early relapse (i.e. a platinum-free interval (PFI) of ≤6 months) in advanced epithelial ovarian cancer (EOC) in first-line treatment, and to develop and internally validate risk prediction models for early relapse. Methods All consecutive patients diagnosed with advanced EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent debulking and platinum-based chemotherapy as initial EOC treatment were selected. Two prediction models, a pretreatment and postoperative model, were developed. Candidate predictors of early relapse were fitted into multivariable logistic regression models. Model selection was performed using backward selection (p-value Results A total of 4,557 advanced EOC patients were identified, including 3,171 late or non-relapsers and 1,302 early relapsers. Early relapsers were more likely to have FIGO stage IV, mucinous or clear cell type EOC, ascites, >1 cm residual disease, and to have undergone interval debulking. The final pretreatment model demonstrated subpar model performance (AUC=0.65 [95%-CI 0.64–0.67]). The final postoperative model based on FIGO stage, histologic subtype, presence of ascites, type of debulking, and residual disease after debulking, demonstrated good model performance (AUC=0.72 [95%-CI 0.71–0.74]). Bootstrap validation revealed minimal optimism of the final postoperative model. Conclusion A good (postoperative) discriminative model has been developed and presented online that predicts the risk of early relapse in advanced EOC patients. Although external validation is still required, this prediction model can support treatment decision-making in daily clinical practice.

BACKGROUND Vulvar Paget disease (VPD) is extremely rare and thought to be associated with other malignancies. OBJECTIVES To evaluate the risk of developing breast, intestinal and urological malignancies in patients with VPD compared with the general population, and in particular to focus on the risk of malignancy in patients with cutaneous noninvasive VPD. METHODS Data on the oncological history of patients with any type of VPD between 2000 and 2015 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. Follow-up data and a control group from the general population were obtained from the Netherlands Cancer Registry. After correction for age and calendar year at time of diagnosis, standardized incidence ratios (SIRs) for the first 3 years after VPD diagnosis were estimated with 95% confidence intervals (CIs). RESULTS We identified 199 patients with a first diagnosis of VPD [164 noninvasive, 35 (micro)invasive] between 2000 and 2015. The SIR of developing an associated malignancy in the first 3 years after diagnosis was 4·67 (95% CI 2·66-7·64). This was due mainly to the high incidence of intestinal malignancies among patients with secondary VPD. Subgroup analysis for cutaneous noninvasive VPD did not reveal a significantly increased risk for associated malignancies: SIR 2·08 (95% CI 0·76-4·62). CONCLUSIONS Of our patients with VPD, 76·9% were diagnosed with cutaneous noninvasive VPD, and this group has no increased risk for developing malignancies of the breast, intestine or urological tract. Our study suggests that routine screening for these malignancies in patients diagnosed with cutaneous noninvasive VPD may not be necessary.

Contains fulltext : 174161.pdf (Publisher’s version ) (Closed access) Female renal transplant recipients (RTRs) have an increased risk for developing human papillomavirus (HPV)-related (pre)malignant lesions of the genital tract. This study aims to assess the genital prevalence of HPV before and after renal transplantation (RT). In female patients who were counseled for RT at the Radboud University Medical Center Nijmegen, the Netherlands, gynecological examination was performed at first visit, and 1 and 2 years later. HPV self-sampling and questionnaires on sexual behavior were performed every 3 months. In 65 patients who underwent RT, the high-risk human papillomavirus (hrHPV) prevalence as assessed with the highly sensitive SPF10 -LiPA25 test increased significantly from 19% before to 31% after RT (p = 0.045). Based upon the clinically validated Cobas 4800 HPV test, the hrHPV prevalence increased from 10% before to 14% after RT (p = 0.31). During follow-up, no changes in sexual behavior were reported. Thirty-three patients who did not undergo RT showed a hrHPV prevalence of 21% at study entry and of 27% after 12 months with the sensitive test, and a stable prevalence of 16% with the clinically validated test. The results of this study indicate that activation of latent HPV infections may contribute to the increased risk of HPV-related (pre)malignant lesions in female RTRs.

Introduction/Background Introduction: GROINSS-V II investigated whether radiotherapy is a safe alternative for inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). Methodology Methods: In GROINSS-V II, a prospective multicentre phase II trial, patients were included with early-stage squamous cell carcinoma (SCC) of the vulva (diameter Results From December 2005 until October 2016, 1552 eligible patients were registered. SN-metastasis occurred in 324/1552 (21%) patients. After 54 months of inclusion the stopping-rule for SN-positive patients was activated; interim analysis showed an increased risk for groin recurrence in case of SN-metastasis >2 mm and/or extranodal extension (ENE). After amendment of the protocol only patients with SN-micrometastasis ≤2 mm received radiotherapy, while those with SN metastasis >2 mm underwent IFL (with radiotherapy if >1 metastasis or ENE). Final analysis after ≥2 years of follow-up revealed six isolated groin recurrences in 157 patients with a SN-micrometastasis (3.8%). Four could not be considered radiotherapy failures: two developed recurrence in the contralateral (SN-negative) groin, two refused radiotherapy. Twenty-eight patients did not get radiotherapy (2 recurrences;7.1%). Among 129 patients who received radiotherapy to the groin(s) only two isolated groin recurrences were diagnosed (1.6%: 95%CI:0–3.8%). The combination of radiotherapy with SN was associated with minimal toxicity: 5/118(4.2%) grade 3 toxicity, no grade 4 or 5 toxicity. In 38/1222 SN-negative patients (3.1%: 95%CI:2.1–4.1%) isolated groin recurrences were diagnosed with clear protocol violations in 6 patients: incomplete treatment of the groin (n=3); primary tumor >4cm (n=1); not all SNs visualized on the lymphoscintigram removed (n=2). After exclusion of these protocol violations an isolated groin recurrence rate of 2.6% (95%CI:1.7–3.5%) was observed. Conclusion Radiotherapy to the groins is a safe alternative for IFL in patients with SN metastasis ≤2 mm, with minimal toxicity. We further established the safety of omitting IFL in patients with SCC of the vulva 2 mm, radiotherapy with a total dose of 50Gy was no safe alternative for IFL; dose escalation and/or chemoradiation should be investigated in these patients. Disclosure Funded by Dutch Cancer Society.

Introduction/Background High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy due to late detection and high recurrence rates. New treatment options focus on targeted therapy based on signal transduction pathways (STPs). Tumour growth is induced by aberrant STP activation leading to disturbed cell proliferation and differentiation. However, knowledge about STP activity in healthy tissue is needed to discriminate STP activity in HGSC. As the Fallopian tube epithelium (FTE) is considered the tissue of origin of most HGSC, the aim of our study was to determine STP activity in normal FTE during the menstrual cycle compared to HGSC. Methodology We included 10 lasermicrodissected FTE samples and 17 HGSC*. This study used Philips OncoSignal PCR, a diagnostic approach based on a computational model which infers quantitative STP activity from mRNA levels of pathway-specific target genes. Results Preliminary data suggest that the follicular phase is characterized by high phosphoinositide 3-kinase (PI3K) pathway activity and the luteal phase by high androgen receptor (AR) pathway activity. Remarkably, no significant differences in estrogen receptor (ER) pathway activity were seen in the FTE during the menstrual cycle. In addition, ER activity was low in HGSC compared to normal FTE. High PI3K activity in HGSC was comparable with activity in the follicular phase. As proliferation is a hallmark of the follicular phase, it is suggested that up-regulation of the PI3K pathway in HGSC could be promoting proliferation and therefore be an interesting target for new therapeutic options. Conclusion During the menstrual cycle, PI3K and AR pathway activity are activated in a strictly controlled manner. High PI3K activity in HGSC could indicate aberrant activation and may therefore be an attractive target. Future investigations should focus on post-menopausal FTE in order to further discriminate STP activity in HGSC. *Sample size will be expanded as the study is still ongoing. Disclosure Nothing to disclose.

Introduction/Background Local recurrences of vulvar squamous cell carcinoma (VSCC) are reported in up to 40% of patients. Knowledge of the risk of inguinofemoral lymph node metastases in local recurrences is necessary to optimally counsel patients with respect to treatment of the groins, and to explore alternative treatment regimens. The aim of our study is to determine the incidence and prognostic factors of lymph node metastases in women with a first local recurrence of VSCC. Methodology A nation-wide multicenter retrospective study was performed, including all patients with a first local recurrence of VSCC after primary surgical treatment with curative intent between 2000–2015. Interim analysis was conducted on the results of four out of eight participating gynecologic oncology centers (Academic Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam; University Medical Center Groningen, Groningen and Radboud University Medical Center, Nijmegen). Results We retrieved 292 patients with a macro-invasive local recurrence of VSCC. The median follow-up after local recurrence was 61 months (range 2–208). The median interval time between the primary VSCC and the first local recurrence was 27 months (range 1–201) with a median age of 74 years (range 28–99). Positive inguinofemoral lymph nodes were present in 15.8% of the patients with a local recurrent VSCC. Significant differences for tumor size (median 25 mm vs 14 mm, p Conclusion Our study demonstrates an incidence rate of 15.8% of inguinofemoral lymph node metastases in women with a first local recurrence of VSCC. A larger tumor size and depth of invasion were significant prognostic factors for the presence of positive lymph nodes at the time of recurrent disease. More research is needed to accurately identify patients at high risk for lymph node metastases, in order to individualize treatment and follow-up. Disclosure Nothing to disclose

Introduction/Background The opportunistic salpingectomy (OS) during hysterectomy for prevention of ovarian cancer is under discussion for the general population. The effect on ovarian cancer risk, surgery-related adverse events and ovarian reserve have not been fully elucidated. We aim to evaluate benefits and potential harms of OS during hysterectomy for benign gynaecological complaints. Methodology We searched the Cochrane register of controlled trials, CENTRAL, MEDLINE and Embase from inception to January 2019. Regarding ovarian cancer incidence, both non-randomised trials (NRTs) and randomised controlled trials (RCTs) were eligible. For surgery-related adverse events and ovarian reserve, only RCTs were included. Two review authors independently screened and selected studies, extracted data and assessed risk of bias. Results We screened 3748 trials and identified zero NRTs and seven RCTs with 347 women in total. Five trials were at high risk of bias in at least one domain. No studies were available on ovarian cancer incidence. We found no statistically significant difference in intra-operative or post-operative adverse events or in ovarian reserve, based on post-operative AMH concentration after hysterectomy with or without OS (table 1). Duration of follow-up was limited to a maximum of 6 months. Conclusion There were no studies available on the effect of OS during hysterectomy on ovarian cancer incidence that met our inclusion criteria. We found no significant difference in surgery-related adverse event or ovarian reserve after hysterectomy with or without OS. To conclude; the OS seems to be a safe procedure both surgically and with regards to ovarian reserve, however the effect on ovarian cancer risk when performed during hysterectomy is not proven. Especially in young women, for whom an effect on ovarian reserve would be more clinically relevant, long term effects should be investigated. Disclosure Nothing to disclose.

Introduction/Background The disease-free survival (DFS) of high-grade serous cancer (HGSC) varies greatly, despite comparable clinicopathological features and treatment. It is our hypothesis that the difference in DFS is caused by differences in activity of tumour-driving signal transduction pathways. Methodology Using previously described Signal Transduction pathway Activity (STA) assays (table 1), signalling pathway activity scores for AR, ER, PI3K-FOXO, HH, NFkB, TGFβ, NOTCH and Wnt were derived from publicly available mRNA expression (Affymetrix) data of primary HGSC, with clinical annotation (GSE9891). K-means cluster analysis was performed on STA-scores of AR, ER, PI3K-FOXO, HH, NFkB, TGFB, NOTCH and Wnt pathway. However, as PI3K and NFkB scores were most discriminating in cluster formation, final clusters were based on these pathways alone. Results We selected 81 out of 140 sample data with a DFS 24 months. The remaining 59 samples with a DFS of 12–24 months were kept aside to be allocated to identified clusters by discriminant analysis in a later stage. Repeated K-means clustering resulted in two stable clusters; a low PI3K/high FOXO and high NFkB cluster (n=43) with a more favourable prognosis, and a high PI3K/low FOXO and low NFkB cluster (n=38) with a less favourable prognosis (log-rank=0.011, figure 1). The remaining samples (n=59) were then allocated resulting in a low PI3K and high NFkB cluster of 73 samples, and a high PI3K and low NFkB cluster of 67 samples (log-rank=0.036, figure 2). Conclusion We identified two signalling pathway activity clusters in HGSC with a difference in DFS. The low PI3K/high FOXO and high NFkB activity of the favourable prognosis cluster may indicate apoptosis, while the high PI3K/low FOXO and low NFkB activity of the unfavourable prognosis cluster may indicate high cell division. Elucidating underlying mechanisms of HGSC aids our understanding of the disease and provides possible new leads for targeted therapies. Disclosure LvL has nothing to disclose, AvdS is employed by Philips Research, RB has nothing to disclose, JdH has nothing to disclose, JP has nothing to disclose. Funding granted by the Ruby& Rose fund and Catharina research fund.

Objective: To determine the incidence of local recurrence of vulvar squamous cell carcinoma in relation to tumor- and/or precursor lesion free pathologic margins.Methods: Consecutive patients with primary vulvar squamous cell carcinoma surgically treated in two Dutch expert centers between 2000 and 2010 were included. All pathology slides were independently reviewed by two expert gynecopathologists, and local recurrence was defined as any recurrent disease located on the vulva. Time to first local recurrence was compared for different subgroups using univariable and multivariable Cox-regression analyses.Results: In total 287 patients with a median follow-up of 80months (range 0-204) were analyzed. The actuarial local recurrence rate ten years after treatment was 42.5%. Pathologic tumor free margin distance did not influence the risk on local recurrence (HR 1.03 (95% CI 0.99-1.06)), neither using a cutoff of eight, five, or three millimeters. Multivariable analyses showed a higher local recurrence rate in patients with dVIN and LS in the margin (HR 2.76 (95% CI 1.62-4.71)), in patients with dVIN in the margin (HR 2.14 (95% CI 1.11-4.12)), and a FIGO stage II or higher (HR 1.62 (95% CI 1.05-2.48)).Conclusions: Local recurrences frequently occur in patients with primary vulvar carcinoma and are associated with dVIN (with or without LS) in the pathologic margin rather than any tumor free margin distance. Our results should lead to increased awareness among physicians of an ongoing risk for local recurrence and need for life-long follow-up. Intensified follow-up and treatment protocols for patients with dVIN in the margin should be evaluated in future research. (C) 2019 Elsevier Inc. All rights reserved.

Contains fulltext : 171336.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To describe trends in incidence, treatment and survival of patients with basal cell carcinomas and melanomas of the vulva. Also to compare survival of vulvar and cutaneous melanoma patients. METHODS: All women with a vulvar malignancy between 1989 and 2012 were selected from the Dutch Cancer Registry (n=6436). Standardized incidence rates, estimated annual percentage change (EAPC) and 5-year relative survival rates were calculated for basal cell carcinomas (BCCs) and melanomas. Patients with vulvar melanomas were matched to women with cutaneous melanomas on period of diagnosis, age, Breslow thickness, tumour ulceration, lymph node status and distant metastases. Differences in survival were evaluated using Kaplan-Meier curves and the log rank test. RESULTS: 489 women were diagnosed with a BCC and 350 with a melanoma of the vulva. The EAPC in incidence for melanomas was 0.2% and 1.1% for BCCs. Eighty-six percent of patients with BCC underwent surgical treatment in 1989-2006 and 95% in 2005-2012. Forty-five percent with BCC and 79% with melanoma were treated in a referral centre. Five-year relative survival for BCCs was 100% and for melanomas survival increased from 37% (95%CI 28-47%) in 1989-1999 to 45% (95%CI: 37-54%) in 2000-2012. Five years after diagnosis survival of women with vulvar melanoma was 15% lower compared to matched cutaneous melanoma patients (p=0.002). CONCLUSION: No trends in age-adjusted incidence have been observed but more patients with BCC received surgical treatment over time. Having had vulvar BCC did not affect life expectancy. Well-known prognostic factors explained most of the differences in survival between cutaneous and vulvar melanoma patients, however a difference of 15% remained unexplained.

Item does not contain fulltext BRCA1/2 mutation carriers are at high risk of breast and ovarian cancer. The number of studies on non-cancer endpoints in BRCA1/2 mutation carriers is still limited. BRCA1/2 mutation carriers may be at higher cardiovascular risk due to early menopause after risk-reducing salpingo-oophorectomy and/or due to the potential cardiotoxic effects of breast cancer treatment (radiotherapy and chemotherapy). Moreover, BRCA genes have a role as a gatekeeper in cardiac function and structure, which may affect susceptibility to cardiac damage. Our goal is to review current knowledge of cardiovascular risk among BRCA1/2 mutation carriers.

Objective. In 2008 GROINSS-V-I, the largest validation trial on the sentinel node (SN) procedure in vulvar cancer, showed that application of the SN-procedure in patients with early-stage vulvar cancer is safe. The current study aimed to evaluate long-term follow-up of these patients regarding recurrences and survival. Methods. From2000 until 2006 GROINSS-V-I included 377 patientswith unifocal squamous cell carcinoma of the vulva (T1

Objective To determine the efficacy of the addition of an ultrasound of the groins in routine follow up of women with vulvar squamous cell carcinoma (SCC) after a negative sentinel lymph node (SLN). Design Prospective single‐centre study. Setting A tertiary expert oncology centre for the treatment of vulvar cancer. Population All women with vulvar SCC with a negative SLN, treated between 2006 and 2014. Methods We prospectively collected data of 139 women with vulvar SCC treated with an SLN procedure. We analysed data of 76 patients with a negative SLN. Three‐monthly follow‐up visits consisted of physical examination combined with an ultrasound of the groins by a radiologist. Main outcome measures The diagnostic value of ultrasound in the follow up of women with vulvar SCC with a negative SLN during the first 2 years after treatment. Results During a routine visit, two asymptomatic isolated groin recurrences were detected. Both patients were treated by inguinofemoral lymphadenectomy and adjuvant radiotherapy and are alive without evidence of disease 39 and 120 months after diagnosis. In total, 348 ultrasounds and 29 fine‐needle aspiration were performed. The sensitivity of ultrasound to detect a groin metastasis was 100% (95% CI 16–100%), and specificity was 92% (95% CI 89–95%). Conclusions Routine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences. Further research is necessary to determine the exact role of ultrasound in the follow up of patients with vulvar SCC with a negative SLN. Tweetable abstract Routine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences., Tweetable abstract Routine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences.

Objective. To describe clinical characteristics of Lynch syndrome associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers.Methods. All Lynch syndrome associated ovarian cancer cases identified in either the Dutch Lynch syndrome registry (DLSR) between 1987 and 2016, and/or the cohort at the University Medical Center Groningen (UMCG) between 1993 and 2016 were included. Clinical data on age at diagnosis, mutation type, histological type, FIGO stage, treatment, follow-up and gynecological surveillance were collected.Results. A total of 46/798 (6%) women in the DLSR and 7/80 (9%) in the UMCG cohort were identified as LS associated ovarian cancer patients. The median age at ovarian cancer diagnosis was 46.0 years (range 20-75 years). The most frequently reported histological type was endometrioid adenocarcinoma (40%; n = 21) and serous carcinoma (36%; n = 19). Most tumors (87%; n = 46) were detected at an early stage (FIGO I/II). Forty-one of 53 (77%) patients were diagnosed with ovarian cancer before LS was diagnosed. In the other 12/53 (23%) women, ovarian cancer developed after starting annual gynecological surveillance for LS; three ovarian cancers were screen-detected in asymptomatic women. Overall survival was 83%.Conclusion. Ovarian cancer in women with LS has a wide age-range of onset, is usually diagnosed at an early stage with predominantly endometrioid type histology and a good overall survival. The early stage at diagnosis could not be attributed to annual gynecological surveillance. (C) 2018 Published by Elsevier Inc.

Contains fulltext : 154786.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The overall 5-year survival of patients with vulvar squamous cell carcinoma (SCC) is 70%. The clinical impression is that localization of SCC on the clitoris may lead to worse prognosis. The aim of this study is to assess the disease specific survival (DSS) in patients with clitoral SCC compared to patients with SCC without clitoral involvement. METHODS: All consecutive patients with primary vulvar SCC treated with surgery at the Department of Gynaecologic Oncology at the Radboud university medical centre (Radboudumc) between March 1988 and January 2012, were analysed. The clinical and histopathological characteristics and DSS rates of patients with (N = 72) and without clitoral SCC (N = 275) were compared. Furthermore, patients with clitoral involvement were compared to patients with perineal SCCs (N = 52) and other central SCCs without clitoral and/or perineal involvement (N = 117). RESULTS: Patients with clitoral SCC more often had larger and deeper invaded tumours, lymphovascular space involvement (LVSI), positive surgical margins and a higher percentage of positive lymph nodes. Kaplan-Meier survival analyses showed worse DSS in patients with a clitoral SCC compared to patients without clitoral involvement. Multivariable analysis showed that not clitoral involvement, but invasion depth, differentiation grade and lymph node status are independent prognostic factors. CONCLUSIONS: Patients with clitoral SCC have worse survival compared to patients without clitoral involvement. This is probably caused by unfavourable histopathological characteristics of the tumour rather than the localization itself. Prospective studies are needed to further assess the influence of localization of the vulvar SCC on prognosis.

Item does not contain fulltext OBJECTIVE: Inguinofemoral lymphadenectomy for patients with vulvar squamous cell carcinoma is associated with a high incidence of postoperative wound complications, which may be influenced by inguinal drain management. The aim of this nationwide prospective study (MAMBO: Morbidity And Measurement of the BOdy) was to assess the feasibility and the incidence of complications after volume-controlled versus short drainage. METHODS: The MAMBO study consisted of two observational studies in all eight oncology centers in the Netherlands, conducted between 2012 and 2016. In the first study, the drain was removed when the production was

Introduction High-grade serous (ovarian) carcinoma (HGSC) is the most lethal gynaecological malignancy with a 5 year survival rate of approximately 30%. This is caused by the fact that most tumours are detected at late stage of disease and due to limited therapeutic options. Knowledge on the cellular origin of HGSC may be of help in developing targeted therapies. These therapies interfere with signalling transduction pathways (STP), which are chains of biochemical events controlling gene expression. One such STP is the hedgehog (HH) pathway. Previous research yielded contradictory results on HH activity in HGSC, possibly due to the erroneous interpretation of separate pathway components as a marker for functional pathway activity. As most HGSC are thought to arise from Fallopian tube epithelium, the aim of our study was to determine the functional HH activity in normal oviduct epithelium, HGSC and Fallopian tube stem cells (FTSC), in order to provide new insights in the HGSC cell type of origin and the potential use of HH targeted therapies. Additionally, we studied the activity of other STP. Material and methods This study used a novel computational diagnostic approach; signal transduction pathway activation analysis (STA-analysis), enabling quantitative measurements of the functional pathway activity based on inferring mRNA levels of specific target genes. STA-analysis was based on publicly available Affymetrix data (GSE69428 and GSE69453) containing microdissected HGSC (n=10), paired normal oviduct epithelium (n=10) and cultured FTSC (n=2). Results and discussions Despite the fact that samples showed some RNA degradation we demonstrated an up-regulation of HH pathway activity in HGSC (p=0.001) and FTSC (p Conclusion Our model showed significant up-regulation of the functional HH activity in HGSC and FTSC compared to normal oviduct epithelium, suggesting the HH STP has a tumour-promoting role in most HGSC. This subset of HH-active HGSC might be of interest for HH targeted therapies.

Contains fulltext : 171122.pdf (Publisher’s version ) (Open Access) In this review, we provide an overview of the clinical aspects, histopathology, molecular genetics, and treatment options for Vulvar Paget's Disease (VPD), a rare skin disease, most commonly found in postmenopausal Caucasian women. The underlying cause of VPD remains not well understood. VPD is rarely associated with an underlying urogenital, gastrointestinal or vulvar carcinoma. In approximately 25% of the cases, VPD is invasive; in these cases, the prognosis is worse than in non-invasive cases. Recurrence rates in invasive VPD are high: 33% in cases with clear margins, and even higher when surgical margins are not clear, regardless of invasion. Historically, surgical excision has been the treatment of choice. Recent studies show that imiquimod cream may be an effective and safe alternative.

Contains fulltext : 171433.pdf (Publisher’s version ) (Open Access) Recurrent disease occurs in 12-37% of patients with vulvar squamous cell carcinoma (VSCC). Decisions about treatment of recurrent VSCC mainly depend on the location of the recurrence and previous treatment, resulting in individualized and consensus-based approaches. Most recurrences (40-80%) occur within 2 years after initial treatment. Currently, wide local excision is the treatment of choice for local recurrences. Isolated local recurrence of VSCC has a good prognosis, with reported 5-year survival rates of up to 60%. Groin recurrences and distant recurrences are less common and have an extremely poor prognosis. For groin recurrences, surgery with or without (chemo) radiotherapy is a treatment option, depending on prior treatment. For distant recurrences, there are only palliative treatment options. In this review, we give an overview of the available literature and discuss epidemiology, risk factors, and prognostic factors for the different types of recurrent VSCC and we describe treatment options and clinical outcome.

Contains fulltext : 171930.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is the only effective surgical strategy to reduce the increased risk of epithelial ovarian cancer in BRCA1/2 mutation carriers. Given the long-term health consequences of premature surgical menopause, we need insight in uptake and timing of RRSO to guide us in improving healthcare. METHODS: A single-center retrospective cohort study of BRCA1/2 mutation carriers diagnosed and counseled at the multidisciplinary Family Cancer Clinic of the Radboud university medical center in Nijmegen, The Netherlands, between 1999 and 2014. Descriptive statistics were used to analyze uptake and timing of RRSO. RESULTS: Data of 580 BRCA1/2 were analyzed. The uptake of RRSO among mutation carriers who are currently above the upper limit of the recommended age for RRSO, is 98.5% and 97.5% for BRCA1 and BRCA2 mutation carriers, respectively. The vast majority undergoes RRSO