Search

Objective: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO.Design: A cross-sectional study with prospective follow-up, nested in a nationwide cohort.Setting: Multicentre in the Netherlands.Population or Sample: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n = 436) or a postmenopausal RRSO ≥ age 54 (n = 205). All participants were older than 55 years at recruitment.Methods: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression.Main Outcome Measures: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO.Results: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.1–3.1) and multitasking (OR 1.9, 95% CI 1.1–3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60–70 years).Conclusions: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition.

PURPOSE After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/ 2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO. METHODS Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study. RESULTS From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO. CONCLUSION BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events.

Purpose: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers.Experimental Design: We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging.Results: Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha–positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation.Conclusions: This study demonstrates that performing real-time intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial. Clin Cancer Res; 22(12); 2929–38. ©2016 AACR.

Exploratory evaluation of potential hypersensitivity responses to compound OTL38 utilizing human, in vitro, highly sensitive models

Supplementary Material and Methods: questionnaire for practical evaluation of OTL38 and the imaging system; description of immunohistochemistry and fluorescence microscopy. Fig. S1: Case report form (CRF) used to mark the location of a lesion found during surgery Fig. S2: Structure of OTL38 Fig. S3: CONSORT Flow diagram healthy volunteer study Fig. S4: Pharmacokinetics in blood plasma of healthy volunteers and patients. Fig. S5. CONSORT Flow diagram ovarian cancer patient study Fig. S6. Tumor-to-background ratio in ovarian cancer patients per dose group Fig. S7. FRα and β staining of ovarian carcinoma tissue and a metastatic lymph node Table S1. Listing of adverse events in the healthy volunteers study Table S2. Summary of pharmacokinetic parameters Table S3. Tumor-to-background ratio per dose group in ovarian cancer patients Table S4. Listing of adverse events in the patient study Table S5. Number and characteristics of lesions and lymph nodes identified with fluorescence

Intraoperative fluorescence detection and resection of a lymph node containing ovarian cancer metastases from A Novel Tumor-Specific Agent for Intraoperative Near-Infrared Fluorescence Imaging: A Translational Study in Healthy Volunteers and Patients with Ovarian Cancer

PURPOSE The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL ( P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.

OBJECTIVE: To compare the effect of tibolone to conjugated estrogens with medroxyprogesterone-acetate (CEE + MPA) on breast density, as a predictor for breast cancer risk, in women with a high risk of breast and ovarian cancer. METHODS: Women aged 30-50 (N = 114) who had undergone risk-reducing salpingo-oophorectomy (RRSO) were randomized to tibolone or CEE + MPA. RESULTS: Breast density decreased 46% after RRSO in untreated women, 39% after treatment with tibolone, and 17% after treatment with CEE + MPA; the decrease in breast density after CEE + MPA was significantly different compared with that of untreated women (P = 0.017). CONCLUSIONS: A decline in breast density is seen after premenopausal RRSO despite the use of both CEE + MPA or tibolone, although lower breast density is seen after tibolone use.

Objective. Risk-reducing surgery is advised to BRCA1/2 pathogenic variant (PV) carriers around the age of 40 years to reduce ovarian cancer risk. In the TUBA-study, a multicenter preference study (NCT02321228), BRCA1/2-PV carriers are offered a choice: the standard strategy of risk-reducing salpingo-oophorectomy or the novel strategy of risk-reducing salpingectomy with delayed oophorectomy. We evaluated feasibility and effectiveness of a patient decision aid for this choice. Methods. Premenopausal BRCA1/2-PV carriers were counselled for risk-reducing surgical options in the TUBA study; the first cohort was counselled without and the second cohort with decision aid. Evaluation was performed using digital questionnaires for participating women and their healthcare professionals. Outcome measures included actual choice, feasibility (usage and experiences) and effectiveness (knowledge, cancer worry, decisional conflict, decisional regret and self-estimated influence on decision). Results. 283 women were counselled without and 282 women with decision aid. The novel strategy was chosen less frequently in women without compared with women with decision aid (67% vs 78%, p = 0.004). The decision aid was graded with an 8 out of 10 by both women and professionals, and 78% of the women would rec-ommend this decision aid to others. Users of the decision aid reported increased knowledge about the options and increased insight in personal values. Knowledge on cancer risk, decisional conflict, decisional regret and can-cer worry were similar in both cohorts. Conclusions. The use of the patient decision aid for risk-reducing surgery is feasible, effective and highly ap-preciated among BRCA1/2-PV carriers facing the decision between salpingo-oophorectomy or salpingectomy with delayed oophorectomy. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Contains fulltext : 291774.pdf (Publisher’s version ) (Open Access) BACKGROUND: Women with a BRCA1/2 pathogenic variant are advised to undergo premenopausal risk-reducing salpingo-oophorectomy after completion of childbearing, to reduce their risk of ovarian cancer. Several studies reported less sexual pleasure 1 to 3 years after a premenopausal oophorectomy. However, the long-term effects of premenopausal oophorectomy on sexual functioning are unknown. OBJECTIVE: This study aimed to study long-term sexual functioning in women at increased familial risk of breast or ovarian cancer who underwent a risk-reducing salpingo-oophorectomy either before the age of 46 years (premenopausal group) or after the age of 54 years (postmenopausal group). Subgroup analyses were performed in the premenopausal group, comparing early (before the age of 41 years) and later (at ages 41-45 years) premenopausal risk-reducing salpingo-oophorectomy. STUDY DESIGN: Between 2018 and 2021, 817 women with a high familial risk of breast or ovarian cancer from an ongoing cohort study were invited to participate in our study. Because of a large difference in age in the study between the premenopausal and postmenopausal salpingo-oophorectomy groups, we restricted the comparison of sexual functioning between the groups to 368 women who were 60 to 70 years old at completion of the questionnaire (226 in the premenopausal group and 142 in the postmenopausal group). In 496 women with a premenopausal risk-reducing salpingo-oophorectomy, we compared the sexual functioning between women in the early premenopausal group (n=151) and women in the later premenopausal group (n=345). Differences between groups were analyzed using multiple regression analyses, adjusting for current age, breast cancer history, use of hormone replacement therapy, body mass index, chronic medication use (yes or no), and body image. RESULTS: Mean times since risk-reducing salpingo-oophorectomy were 20.6 years in the premenopausal group and 10.6 years in the postmenopausal group (P

Simple Summary Rapid and reliable identification of patients with homologous recombination deficient (HRD) tumors is important for treatment choice as these tumors tend to respond well to platinum-based chemotherapy and PARP inhibitors (PARPi). In this study, a RAD51-based functional HRD test that can be performed on routine diagnostic formalin-fixed paraffin-embedded (FFPE) tissues (RAD51-FFPE test), was further improved and optimal test parameters were determined. The RAD51-FFPE test was able to determine tumor HR status with high sensitivity and specificity, making it an attractive test to be applied as routine diagnostic tool in the near future. Abstract PARP inhibitor (PARPi) sensitivity is related to tumor-specific defects in homologous recombination (HR). Therefore, there is great clinical interest in tests that can rapidly and reliably identify HR deficiency (HRD). Functional HRD tests determine the actual HR status by using the (dis)ability to accumulate RAD51 protein at sites of DNA damage as read-out. In this study, we further improved and calibrated a previously described RAD51-based functional HRD test on 74 diagnostic formalin-fixed paraffin-embedded (FFPE) specimens (RAD51-FFPE test) from endometrial cancer (EC n = 25) and epithelial ovarian cancer (OC n = 49) patients. We established optimal parameters with regard to RAD51 foci cut-off (≥2) and HRD threshold (15%) using matched endometrial and ovarian carcinoma specimens for which HR status had been established using a RAD51-based test that required ex vivo irradiation of fresh tissue (RECAP test). The RAD51-FFPE test detected BRCA deficient tumors with 90% sensitivity and RECAP-HRD tumors with 87% sensitivity, indicating that it is an attractive alternative to DNA-based tests with the potential to be applied in routine diagnostic pathology.

Objective 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 undergoing surgery to prevent ovarian cancer, and identified factors associated with high cancer worry. Methods Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose either novel risk-reducing salpingectomy with delayed oophorectomy or standard risk-reducing salpingo-oophorectomy. The Cancer Worry Scale was obtained before and 3 and 12 months after surgery. Cancer worry patterns were analysed using latent class growth analysis and associated factors were identified with regression analysis. Results Of all 577 BRCA1/2-PV carriers, 320 (57%) had high (≥ 14) cancer worry pre-surgery, and 54% had lower worry 12 months post-surgery than pre-surgery. Based on patterns over time, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56%), persistently high cancer worry (6%), and fluctuating, mostly declining, cancer worry (37%). Factors associated with persistently high cancer concerns were age below 35 (BRCA1) or 40 (BRCA2), unemployment, previous breast cancer, lower education and a more recent BRCA1/2-PV diagnosis. Conclusions Some degree of cancer worry is considered normal, and most BRCA1/2-PV carriers have declining cancer worry after gynaecological risk-reducing surgery. However, a subset of these BRCA1/2-PV carriers has persisting major cancer concerns up to 1 year after surgery. They should be identified and potentially offered additional support. Clinical trial registration The TUBA-study is registered at ClinicalTrials.gov since December 11th, 2014. Registration number: NCT02321228.

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.

Item does not contain fulltext IMPORTANCE: Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause. OBJECTIVE: To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant. DESIGN, SETTING, AND PARTICIPANTS: A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible. INTERVENTIONS: Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications. MAIN OUTCOMES AND MEASURES: Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes. RESULTS: A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P

ObjectiveTo assess the feasibility, safety, oncological, and obstetric outcomes in patients with cervical tumors >2 cm treated with neoadjuvant chemotherapy in preparation for abdominal radical trachelectomy.MethodsA retrospective analysis of patients with cervical cancer >2 cm (up to 6 cm) was conducted in patients who were selected to receive neoadjuvant chemotherapy before abdominal radical trachelectomy. Surgical and clinical outcomes were examined in relation to radiological and pathological results. In addition, obstetric outcomes were described. The Mann–Whitney U test and Fisher’s exact test were performed to compare radiological findings between successful and unsuccessful abdominal radical trachelectomy procedures. International Federation of Gynecology and Obstetrics (FIGO) 2009 staging classification was used for this study.ResultsA total of 19 women were treated with neoadjuvant chemotherapy for cervical tumors >2 cm at our institution between May 2006 and July 2018. The median age was 28 years (range 19–36). The distribution of FIGO stages was seven patients stage IB1 (37%), 10 patients stage IB2 (53%), and two patients (10%) stage IIA. Mean clinical tumor size was 4.4 cm (range 3.5–6.0). Histology revealed 74% cases of squamous cell carcinoma. The remaining patients had adenocarcinoma (21%) and only one patient had clear cell adenocarcinoma (5%). Chemotherapy consisted of six weekly cycles of cisplatin (70 mg/m2) and paclitaxel (70 mg/m2). In 15 of the 19 patients (74%) fertility was successfully preserved. In the four patients in whom fertility preservation failed, one patient had stable disease after three cycles and did not meet the criteria for fertility-sparing surgery and three patients had intra- or post-operative indications for adjuvant therapy. Three of the 19 patients (15.7%) had a relapse, two of whom died. One case was in the group of successful abdominal radical trachelectomy.ConclusionNeoadjuvant chemotherapy followed by fertility-sparing surgery may be a feasible and safe option in select patients with cervical tumors >2 cm. Unfavorable prognostic factors are defined as non-responsiveness and non-squamous pathology, which can help in patient selection for fertility-sparing surgery.

Objective. To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM). Materials & methods. This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis. Results. The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-riskclinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40?56%) and 31% (95% CI 23?39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno- or targeted therapy. Conclusion. Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed.Objective. To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM).Materials & methods. This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis.Results. The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-riskclinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno-or targeted therapy.Conclusion. Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Objectives. The challenge when performing cytoreductive surgery (CRS) is to balance the benefits and risks. The aim of this study was to report short term postoperative morbidity and mortality in relation to surgical outcome in patients undergoing primary debulking surgery (PDS) or interval debulking (IDS) surgery in the Netherlands. Methods. The Dutch Gynecological Oncology Audit (DGOA) was used for retrospective analysis. Patients undergoing PDS or IDS between January 1st, 2015 -December 31st, 2018 were included. Outcome was frequency of postoperative complications. Median time to adjuvant chemotherapy and severity of complications were related to outcome of CRS. Complications with Clavien-Dindo >= 3 were analyzed per region and case mix corrected. Statistical analysis was performed with R.Studio. Results. 1027 patients with PDS and 1355 patients with IDS were included. Complications with re-invention were significantly higher in PDS compared to IDS (5.7% vs. 3.6%, p = 0.048). Complete cytoreduction was 69.7% in PDS and 62.1% IDS, p < 0.001. Time to adjuvant chemotherapy was 49 days in patients with complete CRS and a complication with re-intervention. Regional variation for severe complications showed one region outside confidence intervals. Conclusions. Higher complete cytoreduction rate in the PDS group indicates that the correct patients have been selected, but is associated with a higher percentage of complication with re-intervention. As result, time to start adjuvant chemotherapy is longer in this group. Maintaining a balance in aggressiveness of surgery and outcome of the surgical procedure with respect to severe complications is underlined. Bench marked data should be discussed nationally to improve this balance. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Background BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. Objective The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. Methods We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. Results This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. Conclusions Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO. Trial Registration ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793. International Registered Report Identifier (IRRID) DERR1-10.2196/24414

Objective. The aim of this study was to assess the superiority of ICG-Tc-99m-nanocolloid for the intraoperative visual detection of sentinel lymph nodes (SLNs) in vulvar squamous cell carcinoma (VSCC) patients compared to standard SLN detection using Tc-99m-nanocolloid with blue dye.Methods. In this multicenter, randomized controlled trial, VSCC patients underwent either the standard SLN procedure or with the hybrid tracer ICG-Tc-99m-nanocolloid. The primary endpoint was the percentage of fluorescent SLNs compared to blue SLNs. Secondary endpoints were successful SLN procedures, surgical outcomes and postoperative complications.Results. Forty-eight patients were randomized to the standard (n = 24) or fluorescence imaging group (n = 24) using ICG-Tc-99m-nanocolloid. The percentage of blue SLNs was 65.3% compared to 92.5% fluorescent SLNs (p < 0.001). A successful SLN procedure was obtained in 92.1% of the groins in the standard group and 97.2% of the groins in the fluorescence imaging group (p = 0.33). Groups did not differ in surgical outcome, although more short-term postoperative complications were documented in the standard group (p = 0.041).Conclusions. Intraoperative visual detection of SLNs in patients with VSCC using ICG-Tc-99m-nanocolloid was superior compared to Tc-99m-nanocolloid and blue dye. The rate of successful SLN procedures between both groups was not significantly different. Fluorescence imaging has potential to be used routinely in the SLN procedure in VSCC patients to facilitate the search by direct visualization. Clinical Trial Registration: Netherlands Trial Register (Trial ID NL7443). (C) 2020 The Author(s). Published by Elsevier Inc.

BACKGROUND BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. OBJECTIVE The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. METHODS We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. RESULTS This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. CONCLUSIONS Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO. CLINICALTRIAL ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/24414

Simple Summary The sensitivity to PARP inhibitors (PARPi) is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2-related deficiencies. A robust method to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. In this study, we evaluated the use of a functional test (the RECAP test) for the identification of HRD ovarian carcinomas. Forty-nine epithelial ovarian carcinomas (EOC) were analyzed by the RECAP test. Thirty-nine of these tumors were of the high-grade serous (HGSOC) histologic subtype. Ten out of these 39 HGSOC specimens showed HRD (26%), whereas ovarian carcinomas of other histologic subtypes (n = 10) were all HR-proficient (HRP). Eight out of 9 sequenced HRD tumors showed pathogenic BRCA1/2 variants or BRCA1 promoter hypermethylation. This study shows that the RECAP test is a reliable and rapid test to identify functional deficiencies in HR and a good alternative to DNA-based HRD tests. Abstract Recent studies have shown that the efficacy of PARP inhibitors in epithelial ovarian carcinoma (EOC) is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2 deficient EOC. A robust method with which to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. In this study, we investigated the proficiency of a functional HR assay based on the detection of RAD51 foci, the REcombination CAPacity (RECAP) test, in identifying HRD tumors in a cohort of prospectively collected epithelial ovarian carcinomas (EOCs). Of the 39 high-grade serous ovarian carcinomas (HGSOC), the RECAP test detected 26% (10/39) to be HRD, whereas ovarian carcinomas of other histologic subtypes (n = 10) were all HR-proficient (HRP). Of the HRD tumors that could be sequenced, 8/9 showed pathogenic BRCA1/2 variants or BRCA1 promoter hypermethylation, indicating that the RECAP test reliably identifies HRD, including but not limited to tumors related to BRCA1/2 deficiency. Furthermore, we found a trend towards better overall survival (OS) of HGSOC patients with RECAP-identified HRD tumors compared to patients with HRP tumors. This study shows that the RECAP test is an attractive alternative to DNA-based HRD tests, and further development of a clinical grade RECAP test is clearly warranted.

In epithelial ovarian cancer (EOC), the strongest prognostic factor is the completeness of surgery. Intraoperative molecular imaging that targets cell-surface proteins on tumor cells may guide surgeons to detect metastases otherwise not visible to the naked eye. Previously, we identified 29% more metastatic lesions during cytoreductive surgery using OTL-38, a fluorescent tracer targeting folate receptor-alpha (FR alpha). Unfortunately, eleven out of thirteen fluorescent lymph nodes were tumor negative. The current study evaluates the suitability of five biomarkers (EGFR, VEGF-A, L1CAM, integrin alpha v beta 6 and EpCAM) as alternative targets for molecular imaging of EOC metastases and included FR alpha as a reference. Immunohistochemistry was performed on paraffin-embedded tissue sections of primary ovarian tumors, omental, peritoneal and lymph node metastases from 84 EOC patients. Tumor-negative tissue specimens from these patients were included as controls. EGFR, VEGF-A and L1CAM were highly expressed in tumor-negative tissue, whereas alpha v beta 6 showed heterogeneous expression in metastases. The expression of EpCAM was most comparable to FR alpha in metastatic lesions and completely absent in the lymph nodes that were false-positively illuminated with OTL-38 in our previous study. Hence, EpCAM seems to be a promising novel target for intraoperative imaging and may contribute to a more reliable detection of true metastatic EOC lesions.

Sensitivity to PARP inhibitors is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2-related deficiencies. Therefore, there is great interest in a robust method to identify HR-deficient (HRD) carcinomas in routine diagnostics. DNA-based assays that are developed to identify HRD are relatively complex, costly and time-consuming. As an alternative to DNA-based assays we developed the REcombination CAPacity (RECAP) test exploiting the accumulation of RAD51 protein after irradiation of fresh tumor tissue as a biomarker for HR proficiency. The RECAP test reliably identified HRD ovarian (OC) and endometrial (EC) carcinomas including those not related to BRCA1/2 deficiency. However, the implementation of the RECAP test in clinical diagnostics is hampered by dependency on ex vivo irradiation of fresh tumor tissue. We therefore explored the use of diagnostic formalin-fixed paraffin-embedded (FFPE) tumor tissue for the functional analysis of HR and aimed to determine the performance of RAD51 assessment on diagnostic FFPE blocks as compared to RECAP test. FFPE tumor tissue from tumors for which previously published RECAP scores were available (OC n = 49; EC n = 25) were subjected to a three-step quality assessment: 1) Tumor tissue quality analysis of hematoxylin and eosin stained slides by an expert pathologist, 2) Evaluation of yH2AX foci to confirm the presence of DNA damage and 3) Evaluation of the presence of a sufficient number of geminin positive (GMN+) tumor cells. When all quality criteria were met, the capacity of tumor cells to accumulate RAD51 protein at sites of endogenous DNA damage was analyzed using co-immunofluorescent staining. The RAD51-FFPE score was determined as the percentage of GMN+ cells with RAD51 foci. The performance of the RAD51-FFPE test was determined using corresponding RECAP scores. Seventy-four FFPE tumor tissues were subjected to the quality assessment. In total, 58 out of 74 (78%) met our tissue quality criteria. RAD51-FFPE scores correlated significantly with RECAP scores (p= We demonstrated that the RAD51-FFPE test on diagnostic FFPE tumor tissue is an attractive alternative to DNA-based tests to identify HRD in OC and EC. Although the optimal RAD51-FFPE threshold to identify HRD tumors needs to be established using larger cohorts with genomic and clinical trial outcome data, the RAD51-FFPE test is a promising candidate to serve as a low-cost routine diagnostic HRD test in the clinic. Citation Format: Lise M. van Wijk, Claire J. Kramer, Sylvia Vermeulen, Natalja T. ter Haar, Cor D. de Kroon, Marthe M. de Jonge, Katja N. Gaarenstroom, Harry Vrieling, Violeta Serra, Tjalling Bosse, Maaike P. Vreeswijk. The RAD51-FFPE test rapidly and reliably identifies homologous recombination deficient ovarian and endometrial carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 364.

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.

Objectives Nerve-sparing radical hysterectomy for early stage cervical cancer was introduced to improve quality of life after treatment. Sparing the pelvic autonomic nerves reduces bladder, bowel, and sexual dysfunction. The Leiden nerve-sparing radical hysterectomy (LNSRH) was modified to the Swift procedure, the latter being more radical regarding the sacrouterine and parametrial resection. We investigate whether nerve-sparing surgery has comparable oncological outcomes as the conventional radical hysterectomy (CRH). Concurrently, we investigate whether there is a difference regarding the oncological outcomes of the 2 nerve-sparing techniques. Methods This is a single-center, observational prospective cohort study analyzing oncological outcomes in women undergoing CRH (1994–1999), LNSRH (2001–2005), or Swift procedure (2006–2010) for early stage cervical cancer (International Federation of Gynecology and Obstetrics IA2–IIA). Results Three hundred sixty-three patients (124 CRH, 122 LNSRH, and 117 Swift) were included. International Federation of Gynecology and Obstetrics stage IB2 or higher (P = 0.005) was significantly more prevalent in the CRH cohort. The 5-year pelvic relapse–free survival and overall survival were not significantly different between the 3 cohorts (P = 0.116). Regarding the nerve-sparing cohorts, the Swift cohort showed a significant better 5-year overall survival (87.2%) compared with the LNSRH cohort (78.8%) (P = 0.04). In the LNSRH cohort, resection planes less than 5 mm free and need for adjuvant therapy were significantly higher than in the Swift cohort (P = 0.026 and 0.046, respectively). Conclusions The nerve-sparing radical hysterectomy shows a similar oncological outcome compared with the CRH. The more radical Swift version of nerve-sparing techniques is preferable to the former LNSRH procedure.

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 Pathology-based ‘reflex’ tumour testing for BRCA variants in tubo-ovarian carcinomas (OC) has been proposed as patient-friendly, efficient and cost-effective approach to pre-select women for germline testing and stratify for eligibility of PARP-inhibitor therapy. The aim of this study was to review our first two years‘ experience of a ‘tumour first’ approach BRCA screening in our region, using a previously validated BRCA tumour test. Methodology BRCA reflex testing for OC has been introduced in September 2017. The tumour test consisted of targeted Next Generation Sequencing (NGS) for detection of BRCA and (since July 2018) 13 additional HR genes in combination with BRCA1-specific copy number variant Multiplex Ligation-dependent Probe Amplification (MLPA). All detected variants and patient characteristics were extracted from the pathology reports. Follow-up data for patients with a likely or known pathogenic variant were collected from the clinical genetics. Results 99 reflex BRCA tumour tests were performed on 69 (69.7%) high grade serous carcinomas (HGSC), 12 (12.1%) low grade serous carcinomas, 8 (8%) mucinous carcinomas, 5 (5.1%) endometrioid carcinomas and 5 (5.1%) clear cell carcinomas. Tumour DNA was isolated from 68 (68.7%) resection specimens, 24 (24.2%) biopsies and seven (7.1%) ascites fluid. NGS and MLPA success rate was 100% and 94.6% respectively. 30 (30.3%) OC harboured a variant: 15 (15.2%) pathogenic variants, 6 (6.1%) likely pathogenic variants and 9 (9.1%) variants of uncertain significance. All cases with either a pathogenic or likely pathogenic variant were HGSC. Of the 19/21 (90.4%) patients for which genetic testing was advised, 13 (68.4%) underwent genetic testing and 6/13 cases (46.2%) harboured a germline variant. Conclusion Reflex tumour testing confirmed its effectiveness and usefulness as a routine pre-screening tool for patients diagnosed with an EOC. Furthermore all pathogenic or likely pathogenic variants were found in HGSC, which would support a histotype-based tumour testing approach in the future. Disclosure Nothing to disclose.

Introduction/Background Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumour heterogeneity of OC are limited and hard to establish. Methodology We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Results Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumour subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Conclusion Taken together, this demonstrates their potential application for research and personalized medicine. Disclosure No competing interests. Applicable funding sources: EIF | Stand Up To Cancer (SU2C) [Clevers, Kopper, Balgobind, Begthel] KWF Kankerbestrijding (Dutch Cancer Society) - UU2015-7743 [de Witte, van Roosmalen, Witteveen, Zweemer, Kloosterman] Gieskes Strijbis Foundation (1816199) [Clevers, Witteveen, Kloosterman, Zweemer, Lohmussaar, Espejo Valle-Inclan, Hami, Bos, Snippert] Published in Nature Medicine. April 2019. dx.doi.org/10.1038/s41591-019-0422-6.

Introduction/Background To assess feasibility, safety and clinical outcomes (recurrence, obstetric outcomes) in patients with cervical tumors >2 cm treated with neoadjuvant chemotherapy in preparation for fertility sparing surgery (FSS). In addition, to investigate predictive variables in these patients. Methodology A retrospective analysis of patients was conducted in patients who were selected to receive upfront chemotherapy before fertility sparing surgery. Surgical and clinical outcomes were examined in relation to radiological and pathological results. In addition, obstetrical outcomes were investigated. We compared our results with other case series in literature. Results A total of 20 women were treated with neo-adjuvant chemotherapy for >2 cm cervical tumors at our institution. Mean tumor size was 4,4 cm. Chemotherapy consisted of 6 weekly cycles of cisplatin and paclitaxel. In 15 of 20 cases (75%) fertility was successfully preserved. In 5 of 20 cases FSS failed: 2 of 20 patients had stable disease after 3 cycles and did not meet criteria for surgery and 3 patients had intra- or postoperative indication for adjuvant therapy. Four relapses occurred in total of whom 3 died. Two of these were in the group of the successful ART. Therefore, fertility is currently preserved in 13 patients. Eight spontaneous pregnancies in 3 women occurred with six babies born at term. Conclusion Neo-adjuvant chemotherapy followed by FFS is feasible and save option in in selected patients with cervical tumors >2 cm. Unfavorable prognostic factors are defined which can help in patients selection for FSS. Disclosure Nothing to disclose.

Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine. A biobank of ovarian cancer organoids recapitulates the histopathological and molecular hallmarks of patient tumors and provides a resource for preclinical research.

// Marjolijn D. Trietsch 1 , Maaike H.M. Oonk 2 , Lukas J.A.C. Hawinkels 3 , Rosalie Bor 3 , Jaap D.H. van Eendenburg 1 , Zina Ivanova 4 , Alexander A.W. Peters 5 , Hans W. Nijman 2 , Katja N. Gaarenstroom 5 , Tjalling Bosse 1 1 Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands 2 Department of Gynaecology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands 3 Gastroenterology-Hepatology and Molecular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands 4 Institute for Pathology and Parasitology, Bulgarian Academy of Sciences, 1040 Sofia, Bulgaria 5 Department of Gynaecology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands Correspondence to: Marjolijn D. Trietsch, e-mail: M.D.Trietsch@LUMC.nl Keywords: L1 cell adhesion molecule, L1CAM, vulvar cancer, squamous cell carcinoma, survival Received: December 31, 2015 Accepted: March 04, 2016 Published: March 25, 2016 ABSTRACT Background: Vulvar cancer treatment is mostly curative, but also has high morbidity rates. In a search for markers that can identify patients at risk of metastases, we investigated the prognostic value of L1-cell adhesion molecule (L1CAM) in large series of vulvar squamous cell carcinomas (VSCCs). L1CAM promotes cell motility and is an emerging prognostic factor for metastasis in many cancer subtypes. Results: L1CAM expression was observed at the invasive front or in spray-patterned parts of 17% of the tumours. L1CAM-positive tumours expressed vimentin more often, but L1CAM expression was not associated with TP53 or CTNNB1 mutations. Five-year survival was worse for patients with L1CAM expression (overall survival 46.1% vs 63.6%, P =.014, disease specific survival 63.8% vs 80.0%, P =.018). Multivariate analysis indicates L1CAM expression as an independent prognostic marker (HR 2.9, 95% CI 1.10–7.68). An in vitro spheroid invasion assay showed decreased invasion of L1CAM-expressing VSCC spindle cells after treatment with L1CAM-neutralising antibodies. Materials and Methods: Paraffin-embedded tumour tissue from two cohorts (N=103 and 245) of primary VSCCs were stained for L1CAM, vimentin and E-cadherin. Patients of the first cohort were tested for human papilloma virus infection and sequenced for TP53 and CTNNB1 (β-catenin) mutations. The expression of L1CAM was correlated to clinical characteristics and patient survival. Conclusion: This is the first study to show high L1CAM-expression at the infiltrating margin of VSCC’s. L1CAM-expressing VSCCs had a significantly worse prognosis compared to L1CAM-negative tumours. The highest expression was observed in spindle-shaped cells, where it might be correlated to their invasive capacity.

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

Objectives: The aim of this study was to investigate whether serum anti-Müllerian hormone (AMH) predicts symptom burden after risk-reducing salpingo-oophorectomy (RRSO) in order to individualize counseling. Methods: Patient-reported menopausal symptoms, sexual functioning, and psychological distress (depression and anxiety) were assessed 1 day before (T0) and 6 weeks (T1) and 7 months (T2) after RRSO. AMH was assessed before RRSO. Multivariable regression analysis was used to investigate the association between AMH and short-term and long-term change in symptom burden following RRSO. Results: Ninety-one premenopausal women at high risk of ovarian cancer were included. Presurgical AMH was not related significantly to change in symptoms post RRSO. As a secondary outcome we found that regular menses before RRSO was associated specifically with long-term increase in hot flushes (sr = 0.40, p = 0.001; total R2 = 0.171) and depression (sr = 0.29, p = 0.012; total R2 = 0.132). Earlier receipt of chemotherapy was associated with long-term improvement in sexual functioning (sr = 0.24, p = 0.041; total R2 = 0.348). Conclusion: In this cohort, AMH was not a significant predictor of change in symptoms following RRSO. Regular menses prior to RRSO and earlier receipt of chemotherapy were significantly, but relatively weakly, associated with changes in outcomes 6 weeks and/or 7 months after RRSO.

BRCA1/2 variant analysis in tumor tissue could streamline the referral of patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer to genetic counselors and select patients who benefit most from targeted treatment. We investigated the sensitivity of BRCA1/2 variant analysis in formalin-fixed, paraffin-embedded tumor tissue using a combination of next-generation sequencing and copy number variant multiplex ligation-dependent probe amplification. After optimization using a training cohort of known BRCA1/2 mutation carriers, validation was performed in a prospective cohort in which screening of BRCA1/2 tumor DNA and leukocyte germline DNA was performed in parallel. BRCA1 promoter hypermethylation and pedigree analysis were also performed. In the training cohort, 45 of 46 germline BRCA1/2 variants were detected (sensitivity, 98%). In the prospective cohort (n = 62), all six germline variants were identified (sensitivity, 100%), together with five somatic BRCA1/2 variants and eight cases with BRCA1 promoter hypermethylation. In four BRCA1/2 variant-negative patients, surveillance or prophylactic management options were offered on the basis of positive family histories. We conclude that BRCA1/2 formalin-fixed, paraffin-embedded tumor tissue analysis reliably detects BRCA1/2 variants. When taking family history of BRCA1/2 variant-negative patients into account, tumor BRCA1/2 variant screening allows more efficient selection of epithelial ovarian cancer patients for genetic counseling and simultaneously selects patients who benefit most from targeted treatment.

The optimal management of breast cancer susceptibility gene (BRCA)1/2 carriers with isolated serous tubal intraepithelial carcinoma (STIC) found at risk-reducing salpingo-oophorectomy (RRSO) is unclear. The prevalence of occult carcinoma and STIC in a consecutive series of BRCA1/2 carriers undergoing RRSO is reported. The outcome of staging procedures in BRCA1/2 carriers with isolated STIC at RRSO as well as the relationship between staging, chemotherapy treatment and risk of recurrence was assessed via a systematic review of the literature. Our series included 235 BRCA1/2 carriers who underwent RRSO. Federation of Gynaecology and Obstetrics stage IA carcinoma or STIC was found at RRSO in three (1.3%) and two (0.9%) patients, respectively. A systematic review of the literature included 82 BRCA1/2 carriers with isolated STIC found at RRSO. In 13/82 (16%) cases with STIC, staging was reported. In none of these cases staging revealed more advanced disease. Recurrent disease was found in four of 36 patients with reported follow-up. The estimated risk of recurrence in patients with isolated STIC at RRSO was about 11% (95% confidence interval 3-26%) after a median follow-up of 42 months (range 7-138). No recurrences were reported in those patients with STIC at RRSO who underwent staging or received chemotherapy. We found 1.3% occult carcinoma and 0.9% STIC at RRSO in our cohort of BRCA1/2 carriers. A systematic review of the literature suggests that additional treatment after RRSO, i.e. staging and/or chemotherapy, is associated with a lower risk of recurrence. However, data on staging and follow-up are limited.

// Leonora S.F. Boogerd 1, * , Charlotte E.S. Hoogstins 1, * , Katja N. Gaarenstroom 2 , Cornelis D. de Kroon 2 , Jogchum J. Beltman 2 , Tjalling Bosse 3 , Ellen Stelloo 3 , Jaap Vuyk 4 , Philip S. Low 5 , Jacobus Burggraaf 6, 7 and Alexander L. Vahrmeijer 1 1 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands 2 Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands 3 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands 4 Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands 5 Department of Chemistry and Center for Drug Discovery, Purdue University, West Lafayette, IN, USA 6 Centre for Human Drug Research, Leiden, The Netherlands 7 Leiden Academic Center for Drug Research, Leiden, The Netherlands * These authors contributed equally to these work and share first authorship Correspondence to: Alexander L. Vahrmeijer, email: a.l.vahrmeijer@lumc.nl Keywords: targeting; biomarker; tumor-specific imaging; FRα Received: September 05, 2017 Accepted: November 15, 2017 Published: December 11, 2017 ABSTRACT Objective: Detection and resection of all malignant lesions is pivotal in staging and cytoreductive surgery (CRS) of endometrial cancer (EC). Intraoperative EC detection could be enhanced using OTL-38, a fluorescent-labelled folate receptor-α (FRα) targeted imaging agent. The objectives of this study were to investigate which subgroups of high-risk EC patients express FRα and assess feasibility of intraoperative EC detection using OTL-38. Results: FRα expression on TMA was significantly correlated with tumor type ( p < 0.01). Eighty-two percent of serous and clear cell carcinomas showed FRα expression. Four patients were enrolled in the clinical study. Using fluorescence imaging all omental ( n = 3) and lymph node (LN) metastases ( n = 16) could be clearly identified, including one otherwise undetected omental metastasis. However, false-positive fluorescence was identified in 17/50 non-metastatic LNs, caused by OTL-38 targeting of FRβ, expressed by tumor-associated activated macrophages. Conclusions: This study describes high FRα expression in serous and clear cell EC and demonstrates the first experience of intraoperative FRα-targeted tumor detection in patients with these subtypes of EC. Although all metastases could be clearly identified using OTL-38, the role of tumor-associated macrophages should be further evaluated. Methods: Immunohistochemical (IHC) staining of FRα expression was performed on tissue micro arrays (TMA) of 116 patients with high-risk EC features. Patients with either serous or clear cell EC, planned for staging or CRS, were eligible for inclusion in the clinical study and received an intravenous dose of 0.0125 mg/kg OTL-38, 2-3 hours prior to surgery. Resected lesions, identified by standard-of-care and/or fluorescence imaging, were histopathologically assessed for FRα and tumor status.

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.

Background BRCA1/2 mutation carriers’ choice between risk‐reducing salpingo‐oophorectomy (RRSO) and salpingectomy with delayed oophorectomy is very complex. Aim was to develop a patient decision aid that combines evidence with patient preferences to facilitate decision making. Design Systematic development of a patient decision aid in an iterative process of prototype development, alpha testing by patients and clinicians and revisions using International Patient Decision Aid Standards (IPDAS) quality criteria. Information was based on the available literature and current guidelines. A multidisciplinary steering group supervised the process. Setting and participants Pre‐menopausal BRCA1/2 mutation carriers choosing between RRSO and salpingectomy with delayed oophorectomy in Family Cancer Clinics in the Netherlands. Main outcome measures IPDAS quality criteria, relevance, usability, clarity. Results The patient decision aid underwent four rounds of alpha testing and revisions. Finally, two paper decision aids were developed: one for BRCA1 and one for BRCA2. They both contained a general introduction, three chapters and a step‐by‐step plan containing a personal value clarification worksheet. During alpha testing, risk communication and information about premature menopause and hormone therapy were the most revised items. The patient decision aids fulfil 37 of 43 (86%) IPDAS criteria for content and development process. Discussion and conclusions Both BRCA1/2 mutation carriers and professionals are willing to use or offer the developed patient decision aids for risk‐reducing surgery. The patient decision aids have been found clear, balanced and comprehensible. Future testing among patients facing the decision should point out its effectiveness in improving decision making.

Contains fulltext : 182500.pdf (Publisher’s version ) (Closed access) BACKGROUND: There has been some doubts raised in earlier studies about the efficacy of hormone replacement therapy (HRT) in reducing endocrine and sexual problems in women who have undergone a risk-reducing salpingo-oophorectomy (RRSO). METHODS: In this prospective, observational study, we recruited 178 premenopausal women with a high risk for ovarian cancer. Fifty-seven women opted for RRSO and 121 for gynaecological screening (GS). Women completed questionnaires before surgery (T1) and 3 (T2) and 9 (T3) months post surgery, or at equivalent time points for the GS-group. Menopausal symptoms were assessed with the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) and sexual functioning with the Sexual Activity Questionnaire (SAQ). Groups were compared using repeated measures mixed effect models for continuous variables, and generalised estimating equations for longitudinal ordered categorical data. RESULTS: Twenty-seven women who underwent RRSO used HRT after surgery (HRT-users) and 30 did not (HRT-non-users). There were no significant group differences at baseline on the outcome variables. Compared to the HRT-users, the HRT-non-users exhibited a significant increase in overall endocrine symptoms (p = 0.001, effect size (ES) = -0.40 and p < 0.001, ES = -0.59 at T1 and T2, respectively), and in sexual discomfort (p < 0.001, ES = 0.74 and p < 0.001, ES = 1.17). The effect size provides an indication of the magnitude of the observed group differences. An effect size of 0.50 or greater is generally considered to be clinically relevant. No significant differences over time were observed between the HRT-users and the GS-group on any of the outcomes. CONCLUSION: Our results suggest that HRT use in the first year after RRSO has beneficial effects in terms of minimising endocrine symptoms and sexual symptoms in premenopausal women who have undergone RRSO.

Objective. To evaluate the cost-effectiveness of a diagnostic laparoscopy prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery (i.e. leaving >1 cm residual disease) in patients suspected of advanced stage ovarian 'cancer.Methods. An economic analysis was conducted alongside a randomized controlled trial in which patients suspected of advanced stage ovarian cancer who qualified for primary cytoreductive surgery were randomized to either laparoscopy or primary cytoreductive surgery. Direct medical costs from a health care perspective over a 6-month time horizon were analyzed. Health outcomes were expressed in quality-adjusted life-years (QALYs) and utility was based on patient's response to the EQ-5D questionnaires. We primarily focused on direct medical costs based on Dutch standard prices.Results. We studied 201 patients, of whom 102 were randomized to laparoscopy and 99 to primary cytoreductive surgery. No significant difference in QALYs (utility = 0.01; 95% CI 0.006 to 0.02) was observed. Laparoscopy reduced the number of futile laparotomies from 39% to 10%, while its costs were (sic) 1400 per intervention, making the overall costs of both strategies comparable (difference (sic) - 80 per patient (95% CI - 470 to 300)). Findings were consistent across various sensitivity analyses.Conclusion. In patients with suspected advanced stage ovarian cancer, a diagnostic laparoscopy reduced the number of futile laparotomies, without increasing total direct medical health care costs, or adversely affecting complications or quality of life. (C) 2017 Elsevier Inc. All rights reserved.

Lichen sclerosus is a chronic inflammatory skin disease and mainly occurs in the anogenital area. Occasionally patients also have extragenital skin abnormalities. It primarily occurs in postmenopausal women. Itching is the main symptom. However, a burning sensation, dyspareunia, and dysuria are frequently reported symptoms. Postinflammatory scarring may cause fusion of the labia minora, narrowing the vaginal introitus and burying the clitoris. The treatment can consist of medical treatment (cortisone creams), psychological counseling, sexological counseling, pelvic floor physical therapy, and, in exceptional circumstances, surgery may help.

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

Lynch syndrome (LS), one of the most frequent forms of hereditary colorectal cancer (CRC), is caused by a defect in one of the mismatch repair (MMR) genes. Carriers of MMR defects have a strongly increased risk of developing CRC and endometrial cancer. Over the last few years, value-based healthcare has been introduced as an approach to the cost-effective delivery of measurable patient value over complete cycles of care. This requires all involved stakeholders to formulate and validate ‘patient value’ for Lynch syndrome, as well as to identify targets and associated costs. The aim of this study was to develop a value-based care model for Lynch syndrome that can determine patient value and associated costs, and to design a coordinated care pathway from existing guidelines. All specialists in our hospital involved in the management of LS patients evaluated the care delivered to these patients at their department and formulated outcome measures relevant to patient value. Patients were then invited to complete a questionnaire that assessed the importance of these measures on a scale of 1–10. Six high-value outcomes were identified: (1) prevention of cancer or detection of early stage cancer (2) rapid results from MMR gene mutation testing (3) rapid investigation of the colon and uterus (4) no/little pain during colonoscopy and gynaecologic examination/biopsy (5) the offer of psychological help and (6) registration with the Dutch Lynch syndrome registry. A total of 38 (59 %) out of 62 patients completed the questionnaire. The relevance of all outcomes was confirmed by the patients and mean scores varied from 7.2 to 9.9. Patients underscored the relevance of both proper patient education and the efficiency of surveillance during their care cycle. Value-based care delivery for Lynch syndrome includes the implementation of six parameters related to prevention and early detection of cancer, a short cycle time and registration to ensure continuation of care. Estimated costs are € 3320 for the first cycle of care (€ 3550 including gynaecologic surveillance) and approximately 720 per subsequent annual cycle (€ 950 including gynaecologic surveillance).Keywords: Lynch syndrome, Colorectal cancer, Endometrial cancer, Prevention, Value-based health care, Patient value, Outcome measures, Lynch syndrome registry

Contains fulltext : 171109.pdf (Publisher’s version ) (Open Access) BACKGROUND: It is unknown whether a history of breast cancer (BC) affects the outcome of BRCA1/2-associated epithelial ovarian cancer (EOC). This was investigated in the current analysis. METHODS: We included 386 BRCA1/2-associated EOC patients diagnosed between 1980 and 2015. Progression-free survival (PFS), progression-free interval (PFI), overall survival (OS) and ovarian cancer-specific survival (OCSS) were compared between EOC patients with and without previous BC. RESULTS: BRCA-associated EOC patients with, vs without, a BC history had a significantly worse PFS and PFI (multivariate hazard ratio (HRmult) 1.47; 95% confidence interval (CI) 1.03-2.08 and HRmult 1.43; 95% CI 1.01-2.03), and a non-significantly worse OS (HRmult 1.15; 95% CI 0.84-1.57) and OCSS (HRmult 1.18; 95% CI 0.85-1.62). Ovarian cancer-specific survival was significantly worse for the subgroup treated with adjuvant chemotherapy for BC (HRmult 1.99; 95% CI 1.21-3.31). CONCLUSIONS: Our results suggest that BRCA1/2-associated EOC patients with a previous BC have a worse outcome than EOC patients without BC, especially when treated with adjuvant chemotherapy.

There is no consensus on the width of tumour-free margins after surgery for vulvar squamous cell carcinoma (VSCC). Most current guidelines recommend tumour-free margins of ≥8 mm. The aim of this study was to investigate whether a margin of8 mm is associated with an increased risk of local recurrence in VSCC.A meta-analysis of the available literature and a cohort study of 148 VSCC patients seen at a referral centre from 2000 to 2012 was performed. The primary end-point of the cohort study was a histologically confirmed ipsilateral local recurrence within 2 years after primary treatment in relation to the margin distance.Based on 10 studies, the meta-analysis showed that a tumour-free margin of8 mm is associated with a higher risk of local recurrence compared to a tumour-free margin of ≥8 mm (pooled risk ratio, 1.99 [95% confidence interval {CI}: 1.13-3.51], p = 0.02). In the cohort study, we found no clear difference in the risk of local recurrence in the8 versus ≥8 mm group; however, 40% of the patients in the8 mm group received additional treatment. Tumour-positive margin was the only independent risk factor for local recurrence in the multivariable analysis (hazard ratio, 0.21 [95% CI: 0.08-0.55]).This work provides important data to question the commonly used 8-mm margin as a prognosticator for local recurrence. More research is needed to address the question of whether additional treatment improves the prognosis in patients with a tumour-free margin of8 mm.

Programmed death-ligand 1 (PD-L1) is expressed in various immune cells and tumor cells, and is able to bind to PD-1 on T lymphocytes, thereby inhibiting their function. At present, the PD-1/PD-L1 axis is a major immunotherapeutic target for checkpoint inhibition in various cancer types, but information on the clinical significance of PD-L1 expression in cervical cancer is largely lacking. Here, we studied PD-L1 expression in paraffin-embedded samples from two cohorts of patients with cervical cancer: primary tumor samples from cohort I (squamous cell carcinoma, n=156 and adenocarcinoma, n=49) and primary and paired metastatic tumor samples from cohort II (squamous cell carcinoma, n=96 and adenocarcinoma, n=31). Squamous cell carcinomas were more frequently positive for PD-L1 and also contained more PD-L1-positive tumor-associated macrophages as compared with adenocarcinomas (both P

Purpose: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers. Experimental Design: We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging. Results: Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha–positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation. Conclusions: This study demonstrates that performing real-time intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial. Clin Cancer Res; 22(12); 2929–38. ©2016 AACR.