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High‐risk HPV (hrHPV)‐based screening has led to many unnecessary colposcopy referrals, mainly because of direct referral after low‐grade cytology (ASC‐US/LSIL). DNA methylation and genotyping tests on ASC‐US/LSIL samples have the potential to significantly improve the efficiency of screening. In this study, 12 triage strategies were constructed from FAM19A4/miR124‐2 or ASCL1/LHX8 methylation, HPV16/18 or HPV16/18/31/33/45 genotyping and 1‐year repeat cytology. The performance was evaluated on 215 hrHPV‐positive ASC‐US/LSIL samples from the IMPROVE trial (NTR5078). Performance was measured by colposcopy referral rate, positive predictive value (PPV) for detecting precancer (CIN3), and negative predictive value (NPV). To evaluate efficiency, strategies were ordered by the cumulative colposcopy referral rate after 1‐year cytology and compared by the marginal PPV to detect one additional CIN3 (mPPV). The most conservative strategy (referral when HPV16/18 and FAM19A4/miR124 methylation results are positive) had a direct referral rate of 5.2%, a cumulative referral rate after 1‐year cytology of 54.1%, and mPPV of 19.3%. Replacing HPV16/18 by HPV16/18/31/33/45 increased the cumulative 1‐year referral rate to 54.6%, and yielded an mPPV of 10.0%. Similar results were obtained for strategies with ASCL1/LHX8 methylation. Of all strategies, referral after an HPV16/18/31/33/45 positive, ASCL1/LHX8 methylation‐positive, and/or 1‐year cytology‐positive result yielded the highest direct and cumulative 1‐year colposcopy referral rates of 64.4% and 79.1%, respectively. The NPVs after 1‐year cytology varied between 98.1% and 99.4%, warranting a return to routine screening. Altogether, DNA methylation‐based triage strategies are recommended as they are discriminative for CIN3 and control the number of immediate colposcopy referrals. [ABSTRACT FROM AUTHOR]

Simple Summary: This study examined the cost-effectiveness of sentinel lymph node mapping versus routine pelvic lymphadenectomy for assessing lymph nodes in patients with high-risk endometrial cancer. Using a decision analytic model, we compared the two methods based on costs and health outcomes. We found that sentinel lymph node mapping was more effective and less expensive than lymphadenectomy. The cost savings and improved outcomes primarily stemmed from the fewer side effects associated with sentinel lymph node mapping. The analysis confirmed that sentinel lymph node mapping is the best option for determining the need for additional treatment in these patients. Overall, this study suggests that sentinel lymph node mapping should be the preferred method for lymph node assessment in people with high-risk endometrial cancer. Objectives. The aim was to evaluate the cost-effectiveness of sentinel lymph node (SLN) mapping in comparison to routine pelvic lymphadenectomy for lymph node assessment in patients with high-risk endometrial cancer (EC). Methods. A decision–analytic model was developed to compare SLN mapping with pelvic lymphadenectomy for guiding adjuvant therapy in patients with high-risk endometrioid and non-endometrioid EC, focusing on costs and health outcomes. The input data were obtained from systematic literature searches and expert consensus. Quality-adjusted life years (QALYs) was utilized as the measure of effectiveness. The model was constructed from a healthcare perspective, and the impact of uncertainty was evaluated through sensitivity analyses. Results. The base case analysis indicated that sentinel lymph node mapping is the dominant strategy for lymph node assessment in patients with high-risk endometrial cancer, as it was found to be both more effective and less costly than lymphadenectomy. The improved outcomes and reduced costs associated with SLN mapping primarily result from a decrease in the side effects related to lymph node assessment. Sensitivity analyses demonstrated that the outcome of the model was robust to variations in input values. Conclusion. SLN mapping is the most cost-effective strategy to determine the need for adjuvant therapy in patients with high-risk endometrioid and non-endometrioid endometrial cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer is difficult to treat because there are several subtypes that differ on the cell level and in their physical characteristics. Cells in the laboratory are used to test the success of a treatment before introducing it in clinical practice. However, these cell line models often fail to accurately represent real-life ovarian cancer tumors. Cells contain a communication network with ''chains" called signal transduction pathways. These pathways control the cell's behavior. Aberrant activity in these pathways can cause disbalance in cell's processes, like cell multiplication and cell death. Ovarian cancer could be represented more accurately by mirroring its behavior through pathway activity. We identified 12 cell lines that had similar pathways compared to an actual patient's ovarian cancer tissue samples. This could improve the development of promising new treatments that are more effective in patients, making research results more reliable and potentially benefiting future ovarian cancer therapies. Background/Objectives: Advances in treatment options have barely improved the prognosis of ovarian carcinoma (OC) in recent decades. The inherent heterogeneity of OC underlies challenges in treatment (development) and patient stratification. One hurdle for effective drug development is the lack of patient-representative disease models available for preclinical drug research. Based on quantitative measurement of signal transduction pathway (STP) activity in cell lines, we aimed to identify cell line models that better mirror the different clinical subtypes of OC. Methods: The activity of seven oncogenic STPs (signal transduction pathways) was determined by previously described STP technology using transcriptome data from untreated OC cell lines available in the GEO database. Hierarchal clustering of cell lines was performed based on STP profiles. Associations between cell line histology (original tumor), cluster, and STP profiles were analyzed. Subsequently, STP profiles of clinical OC tissue samples were matched with OC cell lines. Results: Cell line search resulted in 80 cell line transcriptome data from 23 GEO datasets, with 51 unique cell lines. These cell lines were derived from eight different histological OC subtypes (as determined for the primary tumor). Clustering revealed seven clusters with unique STP profiles. When borderline tumors (n = 6), high-grade serous (n = 51) and low-grade (n = 31) OC were matched with cell lines, twelve different cell lines were identified as potentially patient-representative OC cell line models. Conclusions: Based on STP activity, we identified twelve different cell lines that were the most representative of the common subtypes of OC. These findings are important to improve drug development for OC. [ABSTRACT FROM AUTHOR]

Objective: Cytology performed directly on hrHPV-positive self-samples (reflex cytology) is feasible and for women with abnormal cytology, an additional cytology test at the general practitioner could be omitted. The aim of this study is to assess the added value of digital imaging (ThinPrep® Imaging System) on the clinical utility of reflex cytology by reducing screening error. Design: A secondary analysis of a prospective cohort study. Setting: One of five Dutch screening laboratories. Population: Women tested hrHPV-positive on self-samples between December 2018 and August 2019. Methods: Self-samples were used for reflex cytology with and without digital imaging. The follow-up data (cytological and histological results within 1 year of follow- up) were obtained through the Dutch Pathology Registry (PALGA). Main outcome measures: Test performance of the reflex cytology was determined by comparing it with physician-collected follow-up results. Results: The sensitivity for detecting abnormal cells by reflex cytology on self-samples increased significantly from 26.3% (42/160; 95% confidence interval [CI] 19.6–33.8) without digital imaging to 35.4% (56/158; 95% CI 28–43.4) with digital imaging (P < 0.05) without compromising specificity. Importantly, 41.7% of women with ≥CIN2 (35/84) and 45.6% with ≥CIN3 (26/57) were detected by reflex cytology with digital imaging on hrHPV-positive self-samples. Conclusion: Digital imaging is of added value to reflex cytology on hrHPV-positive self-samples with a 9% increase in sensitivity. If reflex cytology on self-samples analysed with digital imaging had been implemented in the screening programme, 35.4% of the hrHPV-positive women with abnormal cytology on additional physician-collected samples could have been referred directly for colposcopy. [ABSTRACT FROM AUTHOR]

Simple Summary: Sentinel lymph node (SLN) mapping is safe, feasible, and cost-effective to determine the lymph node status in endometrial cancer (EC). The aim of our prospective SLIM study was to investigate the incidence of SLN metastases and the contribution of SLN mapping in the management of presumed low- and intermediate-risk EC, i.e., clinical early-stage EC, endometrioid histology, grade 1 or 2. SLN metastases were present in 11.2% of 152 patients. Adjuvant management was adjusted based on the SLN status in 7.9% of patients: in 5.9% adjuvant treatment was added due to a positive sentinel node, and in 2.0% adjuvant treatment was limited due to unexpected grade 3 disease with a negative SLN. SLN mapping seems important in patients with presumed low- and intermediate-risk EC and may avoid undertreatment as well as overtreatment. The aim was to investigate the incidence of sentinel lymph node (SLN) metastases and the contribution of SLN mapping in presumed low- and intermediate-risk endometrial cancer (EC). A multicenter, prospective cohort study in presumed low- and intermediate-risk EC patients was performed. Patients underwent SLN mapping using cervical injections of indocyanine green and a minimally invasive hysterectomy with bilateral salpingo-oophorectomy. The primary outcome was the incidence of SLN metastases, leading to adjusted adjuvant treatment. Secondary outcomes were the SLN detection rate and the occurrence of complications. Descriptive statistics and univariate general linear model analyses were used. A total of 152 patients were enrolled, with overall and bilateral SLN detection rates of 91% and 61%, respectively. At final histology, 78.9% of patients (n = 120) had truly low- and intermediate-risk EC. Macro- and micro-metastases were present in 11.2% (n = 17/152), and three patients had isolated tumor cells (2.0%). Nine patients (5.9%) had addition of adjuvant radiotherapy based on SLN metastases only. In 2.0% of patients with high-risk disease, adjuvant therapy was more limited due to negative SLNs. This study emphasizes the importance of SLN mapping in presumed early-stage, grade 1 and 2 EC, leading to individualized adjuvant management, resulting in less undertreatment and overtreatment. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the SLN detection rate in presumed early stage, low- and intermediate-risk endometrial cancers, the incidence of SLN metastases, and the negative predictive value of SLN mapping performed with indocyanine green (ICG). Methods: A systematic review with meta-analyses was conducted. Study inclusion criteria were A) low- and intermediate-risk endometrial cancer, B) the use of ICG per cervical injection; C) a minimum of twenty included patients per study. To assess the negative predictive value of SLN mapping, D) a subsequent lymphadenectomy was an additional inclusion criterion. Results: Fourteen studies were selected, involving 2,117 patients. The overall and bilateral SLN detection rates were 95.6% (95% confidence interval [CI]=92.4%-97.9%) and 76.5% (95% CI=68.1%-84.0%), respectively. The incidence of SLN metastases was 9.6% (95% CI=5.1%-15.2%) in patients with grade 1-2 endometrial cancer and 11.8% (95% CI=8.1%-16.1%) in patients with grade 1-3 endometrial cancer. The negative predictive value of SLN mapping was 100% (95% CI=98.8%-100%) in studies that included grade 1-2 endometrial cancer and 99.2% (95% CI=97.9%-99.9%) in studies that also included grade 3. Conclusion: SLN mapping with ICG is feasible with a high detection rate and negative predictive value in low- and intermediate-risk endometrial cancers. Given the incidence of SLN metastases is approximately 10% in those patients, SLN mapping may lead to stage shifting with potential therapeutic consequences. Given the high negative predictive value with SLN mapping, routine lymphadenectomy should be omitted in low- and intermediaterisk endometrial cancer. [ABSTRACT FROM AUTHOR]

We aim to compare endometrial cancer survival in women with or without histological proven endometriosis or adenomyosis. We identified all women with endometrial cancer between 1990 and 2015 from the Netherlands Cancer Registry (NCR). Data were linked to the Dutch pathology database (PALGA) to select all women with histological proven endometriosis/adenomyosis. Overall survival was compared between women with endometrial cancer with or without endometriosis/adenomyosis. We used multivariable Cox proportional hazard analysis to estimate hazard ratios (HRs). We included 1701 women with endometrial cancer and endometriosis/adenomyosis, of whom 1236 (72.7%) women had adenomyosis, 320 (18.8%) had endometriosis and 145 (8.5%) had both. We compared these women to 39 139 women with endometrial cancer without endometriosis/adenomyosis. Women in the combined endometriosis/adenomyosis cohort were younger at endometrial cancer diagnosis, had earlier disease stage, more often had endometrioid endometrial cancer and low grade tumors. The 5‐year survival rate in the combined endometriosis/adenomyosis cohort was 84.8% (95% CI 84.6‐88.1) and 71.6% (95% CI 71.1‐72.0) in the nonendometriosis/adenomyosis cohort. Univariable analysis resulted in a crude HR of 0.63 (95% CI 0.59‐0.69). Significant confounding factors were age, stage, cancer subtype, histological grading, surgery and chemotherapy rate. Correction for these confounders resulted in a HR of 0.98 (95% CI 0.90‐1.06). Including endometriosis/adenomyosis status as a categorical factor resulted in similar HRs. In conclusion, women with endometrial cancer and histologically proven endometriosis/adenomyosis have a better overall survival when compared to women with endometrial cancer without endometriosis/adenomyosis. This better survival was correlated to stage, grade, age and histological subtype, but not to the presence of endometriosis/adenomyosis. [ABSTRACT FROM AUTHOR]

Internationally, little consensus exists about the best treatment for cervical adenocarcinoma in situ (AIS). This study aimed to determine the incidence of recurrent high-grade cervical dysplasia and development of local cervical cancer after treatment for AIS. This nationwide, retrospective cohort study included patients with AIS, who were treated by a large loop excision of the transformation zone (LLETZ), cold-knife conization (CKC), or hysterectomy between January 1, 1990 and December 31, 2021 in the Netherlands. Pathology reports were retrieved from the Dutch Nationwide Pathology Databank (Palga). Primary outcomes were the cumulative incidences of high-grade cervical dysplasia (cervical intraepithelial neoplasia grade 2 or 3, and AIS) and local cervical cancer up to 20 years after primary treatment. In total, 4243 patients with AIS were included. The primary treatment was a LLETZ, CKC, or hysterectomy in 1593, 2118, and 532 patients, respectively. The incidence of recurrent high-grade cervical dysplasia after LLETZ (10.5%; 95%CI: 8.6-12.3) was higher than after CKC (5.5%; 95%CI: 4.4-6.6, p <.0001). When a radical excision, that is, surgical margins free of dysplasia at end of treatment, was achieved, the incidence of recurrent high-grade dysplasia and local cervical cancer did not differ between LLETZ (5.6% [95%CI: 3.3-7.9] and 1.9% [95%CI: 0-4.4]) and CKC (4.7% [95%CI: 3.5-5.8], p = .631 and 1.5% [95%CI: 0.7-2.3], p = .918). After hysterectomy, none of the patients developed cervical dysplasia or local cervical cancer. Conservative treatment for AIS can be considered a safe and final treatment modality when a radical excision is achieved., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: In endometrial cancer (EC), preoperative anaemia, thrombocytosis and leucocytosis appear to be associated with worse prognosis. It remains unclear whether these parameters solely reflect tumour aggressiveness, or also impact response to adjuvant treatment. Therefore, our primary aim is to evaluate the prognostic relevance of anaemia, thrombocytosis and leucocytosis on survival in EC. Secondary, to explore their predictive relevance in response to radiotherapy in EC., Methods: A retrospective multicentre cohort study was performed within 10 hospitals. Preoperative haematological parameters were defined as: Anaemia - haemoglobin <7.45 mmol/L (<12 g/Dl), thrombocytosis - platelets >400 × 10 9 platelets/L, leucocytosis - leukocytes >10 × 10 9 /L. The relationship of haematological parameters with clinicopathological characteristics, ESGO/ESTRO/ESP risk groups and survival were evaluated. Furthermore, the predictive value of haematological parameters was determined on the overall response to adjuvant radiotherapy and for the ESGO/ESTRO/ESP intermediate-risk group solely receiving radiotherapy., Results: A total of 894 patients were included with a median follow-up of 4.5 years. Anaemia was present in 103 (11.5%), thrombocytosis in 79 (8.8%) and leucocytosis in 114 (12.7%) patients. The presence of anaemia or thrombocytosis was significantly associated with ESGO/ESTRO/ESP high-risk (respectively, P  = 0.002 and P  = 0.041). In the entire cohort, anaemia remained independently associated with decreased disease-specific survival (HR 2.31, 95% CI (1.19-4.50), P  = 0.013) after adjusting for age, the abnormal haematological parameters and ESGO/ESTRO/ESP risk groups. In patients that were treated with adjuvant radiotherapy ( n  = 239), anaemia was associated with significant reduced 5-year disease-specific and recurrence-free survival ( P  = 0.005 and P  = 0.025, respectively). In ESGO/ESTRO/ESP intermediate risk patients that received solely vaginal brachytherapy ( n  = 74), anaemia was associated with reduced disease-specific survival ( P  = 0.041)., Conclusions: Current data demonstrate the importance of preoperative anaemia as independent prognostic factor in patients with EC. Moreover, anaemia seems to be associated with reduced response to radiotherapy. Prospective validation in a larger study cohort is needed to verify anaemia as predictive biomarker for radiotherapy. What is already known on this subject? In endometrial cancer, preoperative abnormal haematological parameters like, anaemia, thrombocytosis and leucocytosis appears to be associated with FIGO advanced-stage and unfavourable outcome. What do the results of this study add? It remains unclear whether anaemia, thrombocytosis or leucocytosis solely reflecting worse prognosis by advanced tumour stage, or also impact response to adjuvant treatment. Current data demonstrate that anaemia is independent associated with decreased disease-specific survival and anaemia seems related with reduced response to radiotherapy and in specific to vaginal brachytherapy in ESGO/ESTRO/ESP intermediate risk patients. What are the implications of these findings for clinical practice and/or further research? Specific applied adjuvant treatment is needed if patients with anaemia have a reduced response to radiotherapy in EC. Prospective validation in a larger study cohort is required to verify anaemia as predictive biomarker for radiotherapy and to further evaluate the prognostic/predictive impact of anaemia in addition to the molecular subgroups.

Background: In the FIGO 2018 classification, women with cervical cancer and a depth of invasion ≤ 5 mm and a horizontal spread of > 7 mm in excisional biopsy with tumour-free margins, are now classified as stage IA instead of IB. This stage shift may reduce the likelihood of surgical lymph node staging. It is therefore crucial to estimate the risk and risk factors of lymph node metastasis (pN+) in this group., Methods: Women diagnosed with cervical cancer between 2005 and 2022 were identified from nationwide population-based registries from the Netherlands, Denmark, and Sweden. Inclusion criteria were squamous cell carcinoma or adenocarcinoma, FIGO 2009 stage IB1, a depth of invasion ≤ 5 mm and horizontal spread of > 7-≤ 40 mm. All cases underwent radical hysterectomy or radical trachelectomy, and surgical lymph node staging. Logistic regression was used to identify risk factors of pN+., Results: We included 992 women (pN+ 4.1 %; n = 41). Lymphovascular space invasion (LVSI) was a significant risk factor of pN+ (odds ratio 4.26, 95 % confidence interval 2.24-8.32). Accordingly, the risk of pN+ was ≥ 7.3 % in LVSI-positive tumours. The risk was lowest in LVSI-negative tumours with a size of > 7-≤ 20 mm (2.2 %), although this varied by depth of invasion and histological subtype (pN+ range 0.6-5.1 %)., Conclusion: Women with LVSI-positive FIGO 2018 IA cervical cancer and a horizontal spread > 7 mm, should undergo surgical lymph node staging. In LVSI-negative tumours, lymph node staging should not be routinely performed; tumour size, depth of invasion and histology should be considered., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HF: Board Member Surgical Science, PJ: MSD Advisory Board for cervical cancer, All other authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Chemotherapy treatment modifications can impact survival in patients with ovarian cancer, particularly when the relative dose intensity falls below 85%. Exercise and dietary interventions may benefit treatment tolerability. This study aimed to explore the effects of a combined exercise and dietary intervention on secondary outcomes of the Physical Activity and Dietary intervention in OVArian cancer (PADOVA) trial, specifically relative dose intensity and progression-free survival., Methods: 81 patients with ovarian cancer were randomized into a combined supervised exercise and dietary intervention during (neo)adjuvant chemotherapy or a usual care control group. Relative dose intensity was calculated as the ratio of delivered dose intensity (dose per actual time) to the standard dose for six chemotherapy cycles. The effect on relative dose intensity was analyzed using logistic regression and Bayesian posterior probability of correctly identifying the best study arm. The effect on progression-free survival was examined using Cox regression., Results: The proportion of patients achieving a relative dose intensity ≥85% was 74.4% in the intervention group compared with 61.5% in the control group (OR 2.04, 95% CI 0.75 to 5.84). The Bayesian posterior probability that the intervention group had a higher proportion of patients with a relative dose intensity ≥85% was 88.4%. Intervention effect on progression-free survival was not statistically significant (HR 1.63, 95% CI 0.82 to 3.23). At 18 months, the proportion of patients without disease progression was 73% in the intervention group and 51% in the control group., Conclusion: The proportions of patients with ovarian cancer with a relative dose intensity ≥85% and an 18-month progression-free survival were numerically higher in the intervention group compared with the control group, but these differences were not statistically significant. The higher proportions and the 88.4% probability that intervention is superior to usual care for clinical outcomes support future studies on exercise and dietary interventions with a focus on clinical outcomes as primary endpoints., Trial Registration Number: Registered in the Netherlands Trial Registry (NTR6300)., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To study physical activity and dietary intake among patients with ovarian cancer and to examine which demographic, clinical, and sociocognitive determinants are associated with these behaviours., Methods: This cross-sectional study included 139 patients with ovarian cancer scheduled for (neo)adjuvant chemotherapy. Physical activity was measured with the Physical Activity Scale for the Elderly questionnaire (PASE). Dietary intake was measured with a questionnaire assessing energy and protein intake and a questionnaire assessing adherence to the World Cancer Research Fund (WCRF) lifestyle recommendations. Demographic, clinical, and sociocognitive (e.g., self-efficacy) determinants of physical activity and dietary intake were examined using backward linear regression analyses., Results: Patients reported a median PASE score of 50 (IQR 24-94), a mean ± SD dietary intake of 1831 ± 604 kcal/day and 76 ± 27 g protein/day. Patients adhered to 3 out of 5 WCRF lifestyle recommendations. The absence of comorbidities, lower physical outcome expectations, and higher cancer specific outcome expectations were independently associated with higher physical activity levels. Higher age, lower cancer specific outcome expectations, and higher diet-related self-efficacy were significantly associated with adhering to more WCRF lifestyle recommendations, whilst no variables associated with total caloric or protein intake were identified., Conclusions: Patients with ovarian cancer have low physical activity levels and a suboptimal diet, particularly low fruit and vegetable consumption and dietary fibre intake. Interventions aiming to improve physical activity and dietary intake could focus on increasing self-efficacy and outcome expectations, and should consider age and comorbidity as factors that may impact behaviour., Trial Registration: Netherlands Trial Registry NTR6300., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Lymph node metastases (pN+) in presumed early-stage cervical cancer negatively impact prognosis. Using federated learning, we aimed to develop a tool to identify a group of women at low risk of pN+, to guide the shared decision-making process concerning the extent of lymph node dissection., Methods: Women with cervical cancer between 2005 and 2020 were identified retrospectively from population-based registries: the Danish Gynaecological Cancer Database, Swedish Quality Registry for Gynaecologic Cancer and Netherlands Cancer Registry. Inclusion criteria were: squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma; The International Federation of Gynecology and Obstetrics 2009 IA2, IB1 and IIA1; treatment with radical hysterectomy and pelvic lymph node assessment. We applied privacy-preserving federated logistic regression to identify risk factors of pN+. Significant factors were used to stratify the risk of pN+., Results: We included 3606 women (pN+ 11%). The most important risk factors of pN+ were lymphovascular space invasion (LVSI) (odds ratio [OR] 5.16, 95% confidence interval [CI], 4.59-5.79), tumour size 21-40 mm (OR 2.14, 95% CI, 1.89-2.43) and depth of invasion>10 mm (OR 1.81, 95% CI, 1.59-2.08). A group of 1469 women (41%)-with tumours without LVSI, tumour size ≤20 mm, and depth of invasion ≤10 mm-had a very low risk of pN+ (2.4%, 95% CI, 1.7-3.3%)., Conclusion: Early-stage cervical cancer without LVSI, a tumour size ≤20 mm and depth of invasion ≤10 mm, confers a low risk of pN+. Based on an international privacy-preserving analysis, we developed a useful tool to guide the shared decision-making process regarding lymph node dissection., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To assess the incidence of ovarian cancer in women with histologically proven endometriosis after bilateral salpingo-oophorectomy (BSO)., Design: Retrospective nationwide cohort study., Setting: Dutch pathology database., Patient(s): Women with histologically proven endometriosis who had undergone BSO between 1990 and 2015 (n = 7,984). This study consists of 2 control cohorts: women with histologically proven endometriosis without BSO (n = 42,633) and women with a benign dermal nevus (n = 132,535)., Intervention(s): Observational study., Main Outcome Measure(s): Number of histologic diagnoses of (extra-)ovarian cancers. Incidence rate ratios (IRR) were estimated for (extra-)ovarian cancer. The number needed to treat was calculated., Result(s): We identified 9 (0.1%) (extra-)ovarian cancers in the BSO cohort and 170 (0.4%) and 444 (0.3%) ovarian cancers in the endometriosis and nevus control cohorts, respectively. We found an age-adjusted IRR of 0.34 (95% confidence interval [CI], 0.15-0.76) when the BSO cohort was compared with the endometriosis cohort. Comparing the BSO cohort with the nevus control cohort resulted in an age-adjusted IRR of 0.38 (95% CI, 0.17-0.85). The number needed to treat when the BSO cohort was compared with the endometriosis control cohort was 351 (95% CI, 272-591)., Conclusion(s): In this nationwide study, we found that the (extra-)ovarian cancer incidence in women with histologically proven endometriosis decreased to less than the background population risk after BSO. Additionally, we found a significant reduction of the incidence of ovarian cancer when compared with women with histologically proven endometriosis without BSO. Endometriosis surgery could in the future be a preventive strategy in women with endometriosis and a high-risk profile for ovarian cancer., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity in normal Fallopian tube epithelium (FTE)., Methods: We assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathways., Results: There were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression., Conclusion: Our observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC., Competing Interests: Declaration of Competing Interest PvdP is employed by the Catharina Hospital, where her research is funded by the Catharina Research fund and Molecular Pathway Diagnostics, Philips. YJWWR and AvdS are employed by Molecular Pathway Diagnostics, Philips. The other authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)