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BACKGROUND: Targeting of VEGF is a potential therapeutic option in patients with malignant ovarian ascites. We present the final results of a multicentre study of the efficacy and safety of aflibercept, a potent inhibitor of both VEGF and placental growth factor, in the treatment of malignant ascites. METHODS: In this double-blind, placebo-controlled, parallel-group, phase 2 study, patients with advanced chemoresistant ovarian cancer and recurrent symptomatic malignant ascites were randomly assigned (1:1) via an interactive voice response system to either intravenous aflibercept (4 mg/kg every 2 weeks) or placebo, stratified by interval of time (<=2 weeks vs >2 weeks) between the two most recent paracenteses before randomisation. Patients participated in the double-blind period (during which patients, investigators, and sponsor personnel were masked to treatment assignment) until they had a repeat paracentesis and for at least 60 days, and could also participate in an optional open-label period during which all patients received aflibercept. The primary efficacy endpoint was time to repeat paracentesis based on response during the double-blind period alone, and was analysed in the intention-to-treat population with censoring of patients who did not have a repeat paracentesis as of the last day of the double-blind period. Safety analyses included both double-blind and open-label periods. This study is registered at ClinicalTrials.gov, number NCT00327444. FINDINGS: 55 patients with a median of four (range two to 11) previous lines of chemotherapy were randomly assigned to receive placebo (n=26) or aflibercept (n=29). Mean time to repeat paracentesis was significantly longer with aflibercept than with placebo (55·1 [SE 7·3] vs 23·3 [7·7] days; difference 31·8 days, 95% CI 10·6-53·1; p=0·0019). In the aflibercept group, two patients did not need a repeat paracentesis during 6 months of double-blind treatment. The most common grade 3 or 4 treatment-emergent adverse events were dyspnoea (six [20%] aflibercept vs two [8%] placebo), fatigue or asthenia (four [13%] vs 11 [44%]), and dehydration (three [10%] vs three [12%]). The frequency of fatal gastrointestinal events was higher with aflibercept (three intestinal perforations) than with placebo (one intestinal fistula leading to sepsis). INTERPRETATION: This study shows the effectiveness of VEGF blockade in the reduction of malignant ascites, but confirms the significant clinical risk of fatal bowel perforation in this population of patients with very advanced cancer. VEGF blockade should be used with caution in advanced ovarian cancer with abdominal carcinomatosis, and the benefit-risk balance should be thoroughly discussed for each patient. FUNDING: Sanofi Oncology. [ABSTRACT FROM AUTHOR]

Study Objective: To characterize robotic surgery publications in gynecologic oncology, and to identify factors associated with high citation metrics., Design: A cross-sectional study SETTING: Original articles on robotic surgery in gynecologic oncology., Patients: No patients involved., Interventions: Robotic surgeries in gynecologic oncology., Measurements and Main Results: We performed PubMed Medical Subject Headings search for original articles on robotic surgery in gynecologic oncology. We analyzed citation scores and income level of country of publication, as well as factors associated with high citation metrics. Overall, 566 studies during 2005 to 2023 were included. Of those 292, 51.6% were from North America, and 182 32.2% from Europe. The leading tumor site studied was endometrial cancer (57.4%). The majority (87.6%) of studies were retrospective and 13 (2.3%) were randomized controlled trials. Most studies (94.2%) originated in high-income countries. Articles from middle-income countries had lower citations per year as compared to high-income countries (median 1.6 vs 2.5, p =.002) and were published in lower-impact factor journals (median 2.6 vs 4.3, p < .001) when compared with high-income countries. Cervical cancer studies had higher representation in middle-income countries than in high-income countries (48.5% vs 18.4%, p < .001). In a multivariable regression analysis, journal's impact factor [aOR 95% CI 1.26 (1.12-1.40)], cervical cancer topic [aOR 95% CI 3.0 (1.58-5.91)], and North American publications [aOR 95% CI 2.07 (1.08-3.97)] were independently associated with higher number of citations per year., Conclusion: The majority of robotic surgery research in gynecologic oncology is retrospective and from high-income countries. Middle-income countries are not as frequently cited and are predominantly in lower-impact factor journals., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 AAGL. Published by Elsevier Inc. All rights reserved.)

Interleukin-10 (IL-10) has been shown to be present at high levels in the ascites of ovarian cancer (OC) patients; however, little is known about its prognostic value. We sought to correlate IL-10 levels in ascites and sera of OC patients with clinicopathologic characteristics and oncologic outcomes. IL-10 levels and clinical data from biobanked ascites and serum samples of OC patients were evaluated. Receiver operating characteristic curves were used to quantify marker performance and identify IL-10-high and IL-10-low groups. Correlations between IL-10 levels and clinicopathologic data were performed. Survival outcomes were calculated, while the factors affecting them were also investigated. A total of 106 patients had ascites samples, of which 44 serum samples were also available. Mean ascites IL-10 levels were significantly higher in patients with serous histology compared to endometrioid histology ( p = 0.024). Fold-change in ascites IL-10 during treatment positively correlated with clinical response, as determined by a change in serum cancer antigen (CA)-125 levels ( p = 0.0126). Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with high compared with low ascites IL-10 levels (PFS: 18 versus 60 months; p = 0.007, OS: 42 versus 85 months; p = 0.029). A significant positive correlation was seen between ascites and sera IL-10 levels ( p = 0.019). In multivariable analyses, a high ascites IL-10 level was associated with a significantly worse prognosis (PFS hazard ratio (HR) = 1.93; p = 0.02). Patients with high ascites levels of IL-10 have worse outcomes, which are likely reflective of the immunosuppressive effect of IL-10. This highlights its potential role as an immunomodulator in the tumor microenvironment, leading to OC immune evasion.

Interleukins serve as communicating molecules between cells, mediating key interactions in the tumor microenvironment (TME) between immune cells and non-immune cells. Interleukin-10 (IL-10), a multifunctional cytokine with multiple properties, has been extensively studied in various aspects of immunology and cancer biology. IL-10 is pleiotropic, promotes cytotoxicity, yet inhibits antitumor-responses. In recent years, the role of IL-10 in ovarian cancer (OC) progression and treatment has gained significant scientific attention, elucidating the signaling pathways triggered by IL-10 action. OC, the leading cause of gynecologic cancer-related deaths, is characterized by ascites, which hosts an intricate TME that is not responsive to treatment by immune checkpoint inhibition. IL-10, known for its immunosuppressive and anti-inflammatory properties, plays a complex role in OC progression, immune modulation, and therapeutic response and has a potential therapeutic property as a target and as an effector. As the literature of basic science research studying the role of IL-10 in the TME of OC scopes a few decades and some data is contrasting, it is important to review the literature and provide concise input derived from it. This review aims to provide a comprehensive overview of the current understanding of IL-10 in OC, highlighting its influence on tumor growth, immune evasion, and potential as a therapeutic target.

Objectives: To compare surgical outcomes of patients with endometrial cancer who underwent robotic surgery across different BMI categories., Methods: A retrospective study including all consecutive patients with endometrial cancer who underwent robotic surgery at a tertiary cancer center between December 2007 and December 2022. The study analyzed outcome measures, including blood loss, surgical times, length of hospitalization, perioperative complications, and conversion rates with the Kruskal-Wallis test for BMI group differences and the Chi-squared test for associations between categorical variables., Results: A total of 1329 patients with endometrial cancer were included in the study. Patients were stratified by BMI: <30.0 (n = 576; 43.3%), 30.0-39.9 (n = 449; 33.8%), and ≥ 40.0 (n = 304; 22.9%). There were no significant differences in post-anesthesia care unit (PACU) stay (p = 0.105) and hospital stay (p = 0.497) between the groups. The rate of post-op complications was similar across the groups, ranging from 8.0% to 9.5% (p = 0.761). The rate of conversion to laparotomy was also similar across the groups, ranging from 0.7% to 1.0% (p = 0.885). Women with a BMI ≥40.0 had a non-clinically relevant but greater median estimated blood loss (30 mL vs. 20 mL; p < 0.001) and longer median operating room (OR) time (288 min vs. 270 min; p < 0.001). Within the OR time, the median set-up time was longer for those with a higher BMI (58 min vs. 50 min; p < 0.001). However, skin-to-skin time (209 min vs. 203 min; p = 0.202) and post-op time (14 min vs. 13 min; p = 0.094) were comparable between groups., Conclusion: BMI does not affect the peri-operative outcome of patients undergoing robotic staging procedures for endometrial cancer., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gynecologic perivascular epithelioid cell (PEC) tumors, or 'PEComas,' represent a rare and intriguing subset of tumors within the female reproductive tract. This systematic literature review aims to provide an updated understanding of gynecologic PEComas based on available literature and data. Although PEComa is rare, there are varied tumor-site presentations across gynecologic organs, with uterine PEComas being the most prevalent. There is scarce high-quality literature regarding gynecologic PEComa, and studies on malignant PEComa underscore the challenges in diagnosis. Among the diverse mutations, mTOR alterations are the most prominent. Survival analysis reveals a high rate of local recurrence and metastatic disease, which commonly affects the lungs. Treatment strategies are limited, however mTOR inhibitors have pivotal role when indicated and chemotherapy may also be used. with some cases demonstrating promising responses. The paucity of data underscores the need for multicentric studies, an international registry for PEComas, and standardized reporting in case series to enhance clinical and pathological data., (© 2024. The Author(s).)

The integration of innovation into routine clinical practice is faced with many challenges. In 2007, we received the mandate to evaluate how the introduction of a robotic program in gynecologic oncology affected patient-centered care by studying its impact on clinical outcomes and hospital resource utilization. Here we summarize the history and experience of developing a robotic surgery program for gynecologic cancers over 16 years. Analysis of the data indicates that robotic surgery improved perioperative patient clinical parameters, decreased blood loss, complications, and hospital stay, maintained the oncologic outcome, and is cost-effective, resulting in it becoming the dominant surgical approach in gynecologic oncology in a tertiary cancer care institution.

Introduction: Canadian gynecological oncology (GYNONC) is constantly evolving. We aim to study the patterns in Canadian GYNONC research using a systematic search approach and bibliometric analysis., Evidence Acquisition: We used Web of Science to identify all relevant publications in the field of GYNONC by Canadian. We analyzed bibliometric data obtained from the iCite database. Publications were evaluated for specific characteristics including the province of all co-authors. We compared bibliometric metrics among provinces., Evidence Synthesis: Overall, 1511 publications, published in 138 different journals during 1973-2022 were analyzed. Of those, 23.5% (N.=355) were of interprovincial origin. Interprovincial publications were constantly increasing, now reaching 34.1%. Publications of interprovincial setting had higher RCR, CPY, FCR and NIH percentile scores when compared to any single province (P=0.009, P>0.001, P<0.001, and P<0.001, respectively). The proportion of publications in high impact factor journals were higher in the interprovincial setting: 35 (9.9%) vs. 48 (4.2%), P<0.001. Excluding the interprovincial publications there were 1156 publications. Half of the publications were authored by authors from Ontario (N.=587, 50.6%), 278 (24.1%) by authors from Quebec, and 161 (14.0%) by authors from British Columbia. The mean FCR was higher in British Columbia as compared to Ontario, Quebec and Manitoba (6.0±2.1 vs. 5.3±2.1, 5.3±1.5, and 4.1±3.0 respectively; P=0.006, P=0.034, and 0.037, respectively). Only Ontario, Quebec, British Columbia and Alberta had publications in high impact factor journals, with similar rate (P=0.806)., Conclusions: Interprovincial publications have the highest citation metrics in all domains. This underscores the importance of collaboration for the purpose of impactful research.

Objective: To evaluate the use of manipulators on the outcome of women who had minimally invasive surgery for endometrial cancer. Methods: Retrospective analysis of patients operated with or without an intrauterine manipulator. Results: Six hundred ninety-nine patients were included. The median follow-up was 44 months (range, 29-67). Nineteen (8.8%) patients had positive cytology in the manipulator group versus 21 (4.4%) in the comparison group ( p  = 0.02). Total recurrence rate was similar between the groups (12.3% vs. 11.9%; p  = 0.8). Vaginal vault recurrence was the most common site of recurrence with higher incidence in the manipulator group (4.5% vs. 1.3%; p  = 0.007). Subgroup analysis of low-risk patients who did not receive adjuvant treatment showed higher recurrence rate (8.3% vs. 3%; p  = 0.023) and worse disease-free survival ( p  = 0.01) for the manipulator group. After controlling for other variables, the use of a manipulator did not affect the risk of recurrence for the whole cohort (hazard ratio [HR], 1.28; confidence interval [95% CI], 0.7-2.1, p  = 0.3) and for the low-risk subgroup of patients who did not receive adjuvant treatment (HR, 2.47; 95% CI, 0.8-7, p  = 0.08). Conclusion: The use of a manipulator increases the risk of positive cytology as well as vaginal vault recurrences, but it does not reduce the overall survival of patients.

Objective: To identify predictive clinico-pathologic factors for concurrent endometrial carcinoma (EC) among patients with endometrial intraepithelial neoplasia (EIN) using machine learning., Methods: a retrospective analysis of 160 patients with a biopsy proven EIN. We analyzed the performance of multiple machine learning models (n = 48) with different parameters to predict the diagnosis of postoperative EC. The prediction variables included: parity, gestations, sampling method, endometrial thickness, age, body mass index, diabetes, hypertension, serum CA-125, preoperative histology and preoperative hormonal therapy. Python 'sklearn' library was used to train and test the models. The model performance was evaluated by sensitivity, specificity, PPV, NPV and AUC. Five iterations of internal cross-validation were performed, and the mean values were used to compare between the models., Results: Of the 160 women with a preoperative diagnosis of EIN, 37.5% (60) had a post-op diagnosis of EC. In univariable analysis, there were no significant predictors of EIN. For the five best machine learning models, all the models had a high specificity (71%-88%) and a low sensitivity (23%-51%). Logistic regression model had the highest specificity 88%, XG Boost had the highest sensitivity 51%, and the highest positive predictive value 62% and negative predictive value 73%. The highest area under the curve was achieved by the random forest model 0.646., Conclusions: Even using the most elaborate AI algorithms, it is not possible currently to predict concurrent EC in women with a preoperative diagnosis of EIN. As women with EIN have a high risk of concurrent EC, there may be a value of surgical staging including sentinel lymph node evaluation, to more precisely direct adjuvant treatment in the event EC is identified on final pathology., (© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Endocervical sampling is performed traditionally with an endocervical curette (ECC). The current study objective is to compare the histopathological performance of endocervical brush (ECB) and endocervical curette (ECC). A retrospective review was performed including patients included that underwent colposcopy with endocervical sampling using either method. A total of 127 samples were obtained with ECC and 98 with ECB. Histopathological diagnosis was obtained in 124 (97.6%) ECC samples and in 94 (95.9%) ECB samples ( p  = 0.46). The incidence of benign results was similar between ECC and ECB (117 (92.1%) versus 88 (89.8%) respectively ( p  = 0.28)). When combining information from endocervical sampling with cervical biopsies, the detection rate of high-grade pathologies was similar between the groups with 14 cases (17.7%) for ECC and 8 cases (17.0%) for ECB ( p  = 0.43). A scope review of the topic was performed, illustrating that studies favour either method. In conclusion, ECB and ECC perform similarly for providing a histopathological diagnosis on endocervical samples.IMPACT STATEMENT What is already known on this subject? Endocervical samples in colposcopy were traditionally obtained using an endocervical curette. Similarly, a brush can be used for histological sampling of the endocervical canal. However, it is unclear how the ability to obtain a histopathological diagnosis compares between the two techniques. What do the results of this study add? This single-institution experience with using endocervical brush and curette for endocervical sampling finds that both methods are acceptable and have a high ability to provide a histopathological diagnosis. Precisely, 4.1% of brush and 2.4% of curette samples had insufficient tissue. What are the implications of these findings for clinical practice and further research? The endocervical brush is an adequate sampling method for colposcopy, and can be safely used instead of the curette, based on clinician preference. Further studies could investigate how these methods compare from a patient perspective.

Pain during sexual intercourse, also called dyspareunia, affects most women after treatment for gynecological cancer. Previous work adopted a biomedical approach to depict dyspareunia in this population, which provided a narrow perspective of this condition. Taking into account women's experiences of dyspareunia and the factors influencing their care-seeking behaviors would provide insight to improve care in the context of gynecological cancer. The aim of this study was to describe gynecological cancer survivors' experiences of dyspareunia and factors influencing care-seeking behavior. A qualitative study was performed with 28 gynecological cancer survivors with dyspareunia. Individual telephone interviews were conducted based on the Common-Sense Model of Self-Regulation. Interviews were recorded and transcribed for analysis using the interpretative description framework. Concerning their experience, participants reported the oncological treatments as the primary cause of dyspareunia. Loss of libido, lower vaginal lubrication, and smaller vaginal cavity were described as being linked with dyspareunia. Women explained how dyspareunia and these changes had led them to engage less in, and even interrupt, sexual activity. They expressed that they were distressed, felt less of a woman, and experienced low control and/or self-efficacy. Regarding the factors influencing women's care-seeking behaviors, participants emphasized that they were provided with insufficient information and support. Balancing priorities, denial or reluctance, misbeliefs, resignation and acceptance, and negative emotions were reported as barriers, whereas acknowledgement of sexual dysfunction, desire for improvement, awareness of treatment possibilities, willingness to undertake treatment and treatment acceptability were reported as facilitators to seeking care. Findings suggest that dyspareunia is a complex and impactful condition after gynecological cancer. While this study highlights the importance of alleviating the burden of sexual dysfunction in cancer survivors, it identified factors that should be considered in the provision of services to improve care., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To investigate the association between alcohol intake over the lifetime and the risk of overall, borderline, and invasive ovarian cancer., Methods: In a population-based case-control study of 495 cases and 902 controls, conducted in Montreal, Canada, average alcohol intake over the lifetime and during specific age periods were computed from a detailed assessment of the intake of beer, red wine, white wine and spirits. Multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between alcohol intake and ovarian cancer risk., Results: For each one drink/week increment in average alcohol intake over the lifetime, the adjusted OR (95% CI) was 1.06 (1.01-1.10) for ovarian cancer overall, 1.13 (1.06-1.20) for borderline ovarian cancers and 1.02 (0.97-1.08) for invasive ovarian cancers. This pattern of association was similarly observed for alcohol intake in early (15- < 25 years), mid (25- < 40 years) and late adulthood (≥ 40 years), as well as for the intake of specific alcohol beverages over the lifetime., Conclusions: Our results support the hypothesis that a higher alcohol intake modestly increases the risk of overall ovarian cancer, and more specifically, borderline tumours., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction and Hypothesis: Multimodal pelvic floor physical therapy (PFPT) is recommended after gynecological malignancies to treat dyspareunia. However, data to strongly support its implementation in the cancer care continuum are lacking. The aim of this study was to explore the views and experiences of gynecological cancer survivors with dyspareunia regarding the acceptability of multimodal PFPT., Methods: This qualitative study was conducted with the participants (n = 28) of a study investigating a 12-week multimodal PFPT treatment. Individual semi-structured telephone interviews served to collect qualitative data pertaining to women's views and experiences of the treatment they received. Interviews were recorded and transcribed for analysis using the interpretative description framework., Results: Our cohort described the appropriateness of the treatment in terms of modalities, physical therapist, care delivery, and intensity (Theme 1). While the intensity was reported as demanding by a few, all participants stressed that it was relevant to see significant improvements (Theme 2). In addition to the treatment characteristics and women's beliefs and attitudes, noticing the treatment effects motivated their participation (Theme 2). Women expressed being highly satisfied with the treatment based on their positive experiences and the balance between their efforts and the results they obtained (Theme 3). As a result, they all recommended this treatment (Theme 3)., Conclusions: This is the first study to examine the acceptability of multimodal PFPT in the context of gynecological malignancies. This treatment was found acceptable and can be offered to gynecological cancer survivors., (© 2022. The Author(s).)

Background: Ovarian cancer (OC) is the deadliest gynecological cancer, often diagnosed at advanced stages. A fast and accurate diagnostic method for early-stage OC is needed. The tumor marker gangliosides, GD2 and GD3, exhibit properties that make them ideal potential diagnostic biomarkers, but they have never before been quantified in OC. We investigated the diagnostic utility of GD2 and GD3 for diagnosis of all subtypes and stages of OC., Methods: This retrospective study evaluated GD2 and GD3 expression in biobanked tissue and serum samples from patients with invasive epithelial OC, healthy donors, non-malignant gynecological conditions, and other cancers. GD2 and GD3 levels were evaluated in tissue samples by immunohistochemistry (n=299) and in two cohorts of serum samples by quantitative ELISA. A discovery cohort (n=379) showed feasibility of GD2 and GD3 quantitative ELISA for diagnosing OC, and a subsequent model cohort (n=200) was used to train and cross-validate a diagnostic model., Results: GD2 and GD3 were expressed in tissues of all OC subtypes and FIGO stages but not in surrounding healthy tissue or other controls. In serum, GD2 and GD3 were elevated in patients with OC. A diagnostic model that included serum levels of GD2+GD3+age was superior to the standard of care (CA125, p<0.001) in diagnosing OC and early-stage (I/II) OC., Conclusion: GD2 and GD3 expression was associated with high rates of selectivity and specificity for OC. A diagnostic model combining GD2 and GD3 quantification in serum had diagnostic power for all subtypes and all stages of OC, including early stage. Further research exploring the utility of GD2 and GD3 for diagnosis of OC is warranted., Competing Interests: Authors HS and WT disclose patent filings protecting claims of intellectual property and the monoclonal antibodies within this report, under License to AOA Dx where authors AJ and PG work and where HS, AD and SB served as consultants. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Galan, Papaluca, Nejatie, Matanes, Brahimi, Tong, Hachim, Yasmeen, Carmona, Klein, Billes, Dawod, Gawande, Jeter, Mes-Masson, Greenwood, Gotlieb and Saragovi.)

There is an emerging focus on the role of robotic surgery in ovarian cancer. To date, the operational and cost implications of the procedure remain unknown. The objective of the current study was to evaluate the impact of integrating minimally invasive robotic surgery on patient flow, resource utilization, and hospital costs associated with the treatment of ovarian cancer during the in-hospital and post-discharge processes. 261 patients operated for the primary treatment of ovarian cancer between January 2006 and November 2014 at a university-affiliated tertiary hospital were included in this study. Outcomes were compared by surgical approach (robotic vs. open surgery) as well as pre- and post-implementation of the robotics platform for use in ovarian cancer. The in-hospital patient flow and number of emergency room visits within 3 months of surgery were evaluated using multi-state Markov models and generalized linear regression models, respectively. Robotic surgery cases were associated with lower rates of postoperative complications, resulted in a more expedited postoperative patient flow (e.g., shorter time in the recovery room, ICU, and inpatient ward), and were between $10,376 and $7,421 less expensive than the average laparotomy, depending on whether or not depreciation and amortization of the robotic platform were included. After discharge, patients who underwent robotic surgery were less likely to return to the ER (IRR 0.42, p = 0.02, and IRR 0.47, p = 0.055, in the univariate and multivariable models, respectively). With appropriate use of the technology, the addition of robotics to the medical armamentarium for the management of ovarian cancer, when clinically feasible, can bring about operational efficiencies and entails cost savings., (© 2022. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objective: To determine the prevalence of underlying high-intermediate (high-IM) and high-risk endometrial cancer (EC) in patients with preoperative diagnosis of Endometrial intraepithelial neoplasia (EIN) and to assess the impact of the information retrieved from the sentinel lymph node (SLN) on adjuvant therapy., Methods: Retrospective cohort study of women undergoing hysterectomy, optional bilateral salpingo-oophorectomy (BSO) and lymph nodes assessment for EIN between December 2007 and August 2021., Results: One hundred and sixty two (162) eligible patients were included, of whom 101 (62.3%) had a final diagnosis of EIN, while 61 (37.7%) were ultimately diagnosed with carcinoma. Out of 15 patients with high-IM to high-risk disease (9.25% of all EIN), 12 had grade 2-3 EC including 8 with >50% myometrial invasion, 2 with serous subtype, 1 with cervical invasion and 2 with pelvic lymph nodes involvement. Of the 3 patients with grade 1 EC, one patient had disease involving the adnexa and 2 patients had tumor invading >50% of the myometrium and with lymphovascular space invasion (LVSI). Ten patients received vaginal brachytherapy after surgery, 3 patients with extrauterine spread were treated with systemic chemotherapy followed by vaginal brachytherapy and pelvic external-beam radiotherapy and 2 patients with early-stage serous carcinoma received chemotherapy followed by vaginal brachytherapy., Conclusions: Information from SLN, even when negative, can be helpful in the management of patients with EC after preoperative EIN, as some patients are found to have high-IM to high-risk disease on final pathology. These patients would require either re-staging surgery or adjuvant external beam radiotherapy, both could be avoided by proper staging., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To develop machine-learning models to predict recurrence and time-to-recurrence in high-grade endometrial cancer (HGEC) following surgery and tailored adjuvant treatment., Methods: Data were retrospectively collected across eight Canadian centers including 1237 patients. Four models were trained to predict recurrence: random forests, boosted trees, and two neural networks. Receiver operating characteristic curves were used to select the best model based on the highest area under the curve (AUC). For time to recurrence, we compared random forests and Least Absolute Shrinkage and Selection Operator (LASSO) model to Cox proportional hazards., Results: The random forest was the best model to predict recurrence in HGEC; the AUCs were 85.2%, 74.1%, and 71.8% in the training, validation, and test sets, respectively. The top five predictors were: stage, uterus height, specimen weight, adjuvant chemotherapy, and preoperative histology. Performance increased to 77% and 80% when stratified by Stage III and IV, respectively. For time to recurrence, there was no difference between the LASSO and Cox proportional hazards models (c-index 71%). The random forest had a c-index of 60.5%., Conclusions: A bootstrap random forest model may be a more accurate technique to predict recurrence in HGEC using multiple clinicopathologic factors. For time to recurrence, machine-learning methods performed similarly to the Cox proportional hazards model., (© 2022 Wiley Periodicals LLC.)

DNA repair by homologous recombination (HR) is critical for the maintenance of genome stability. Germline and somatic mutations in HR genes have been associated with an increased risk of developing breast (BC) and ovarian cancers (OvC). However, the extent of factors and pathways that are functionally linked to HR with clinical relevance for BC and OvC remains unclear. To gain a broader understanding of this pathway, we used multi-omics datasets coupled with machine learning to identify genes that are associated with HR and to predict their sub-function. Specifically, we integrated our phylogenetic-based co-evolution approach (CladePP) with 23 distinct genetic and proteomic screens that monitored, directly or indirectly, DNA repair by HR. This omics data integration analysis yielded a new database (HRbase) that contains a list of 464 predictions, including 76 gold standard HR genes. Interestingly, the spliceosome machinery emerged as one major pathway with significant cross-platform interactions with the HR pathway. We functionally validated 6 spliceosome factors, including the RNA helicase SNRNP200 and its co-factor SNW1. Importantly, their RNA expression correlated with BC/OvC patient outcome. Altogether, we identified novel clinically relevant DNA repair factors and delineated their specific sub-function by machine learning. Our results, supported by evolutionary and multi-omics analyses, suggest that the spliceosome machinery plays an important role during the repair of DNA double-strand breaks (DSBs)., (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Cancer.)

Objective: To investigate the changes in pelvic floor morphometry and muscle function after multimodal pelvic floor physiotherapy treatment in gynaecological cancer survivors suffering from painful intercourse (dyspareunia)., Design: Prospective interventional study., Setting: Three university hospitals., Participants: Thirty-one gynaecological cancer survivors with dyspareunia., Intervention: The treatment consisted of 12 weekly sessions of physiotherapy combining education, pelvic floor muscle exercises with biofeedback, manual therapy and home exercises., Main Outcome Measures: Women were assessed at baseline and post-treatment. Pelvic floor morphometry was evaluated at rest and on maximal contraction by measuring bladder neck position, anorectal and levator plate angles as well as levator hiatal dimensions with three-dimensional/four-dimensional transperineal ultrasound imaging. Pelvic floor muscle function was evaluated by measuring passive forces (muscle tone measure), flexibility, stiffness, strength, coordination and endurance with an intra-vaginal dynamometric speculum., Results: Significant changes in pelvic floor morphometry and muscle function were found post-treatment. The parameters assessing the changes from rest to maximal contraction significantly improved (e.g., mean change of levator hiatal area narrowing 14%, 95% CI 11-18, Cohen's d effect size 1.48)), supporting the hypothesis of decreased muscle tone and improved muscle contractility following treatment. Women also presented with a significant decrease in tone (mean change -0.4N, 95% CI -0.7 to -0.1, Cohen's d effect size 0.57) and stiffness (mean change -0.1N/mm, 95% CI -0.2 to -0.1, Cohen's d effect size 0.59), as well as significant improvements in flexibility (mean change 9.0mm, 95% CI 5.8-12.2, Cohen's d effect size 1.08), coordination (mean change 3 rapid contractions, 95% CI 2-4, Cohen's d effect size 0.85) and endurance (mean change 683%*s, 95% CI 388-978, Cohen's d effect size 0.90)., Conclusion: Our findings suggest significant improvements in pelvic floor morphometry and muscle function after a multimodal physiotherapy treatment in gynaecological cancer survivors with dyspareunia. These effects may represent key treatment mechanisms to reduce dyspareunia, supporting the rationale for multimodal physiotherapy in this population. CLINICAL TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT03935698., (Copyright © 2021 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

Background: Caffeine intake has been inconsistently associated with the risk of ovarian cancer in previous studies. The measure of caffeine in these studies has not always distinguished between caffeinated and decaffeinated sources, and the time for which intake was assessed was often for late adulthood and thus may have excluded the etiologic window. We investigated lifetime caffeine intake from caffeinated coffee, black tea, green tea and cola sodas in relation to ovarian cancer risk., Methods: Among 497 cases and 904 controls in a population-based case-control study in Montreal, Canada, lifetime intake of caffeinated coffee, black tea, green tea and cola sodas was assessed and used to calculate lifetime total intake of caffeine. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between caffeine intake and ovarian cancer risk overall, as well as by menopausal status. Multivariable polytomous logistic regression was used to estimate the associations for invasive and borderline ovarian cancers separately., Results: Almost all participants (98.4% of cases and 97.5% of controls) had consumed caffeine in their lifetime. The mean (standard deviation) daily consumption of caffeine over the lifetime was of 117 (89) mg/day among cases and 120 (118) mg/day among controls. The OR (95% CI) of ovarian cancer for the highest versus lowest quartile of lifetime caffeine intake was 1.17 (0.83-1.64). According to menopausal status, the OR (95% CI) was 1.56 (0.85-2.86) for premenopausal women and 0.94 (0.66-1.34) for postmenopausal women, comparing the highest to lowest tertiles of intake. Associations for invasive and borderline ovarian cancers separately were similar to that observed for ovarian cancer overall., Conclusion: Lifetime caffeine intake was not strongly associated with ovarian cancer risk. A difference in relationship by menopausal status is possible., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: A large proportion of gynecological cancer survivors suffer from pain during sexual intercourse, also known as dyspareunia. Following a multimodal pelvic floor physical therapy (PFPT) treatment, a reduction in pain and improvement in psychosexual outcomes were found in the short term, but no study thus far has examined whether these changes are sustained over time., Purpose: To examine the improvements in pain, sexual functioning, sexual distress, body image concerns, pain anxiety, pain catastrophizing, painful intercourse self-efficacy, depressive symptoms and pelvic floor disorder symptoms in gynecological cancer survivors with dyspareunia after PFPT, and to explore women's perceptions of treatment effects at one-year follow-up., Methods: This mixed-method study included 31 gynecological cancer survivors affected by dyspareunia. The women completed a 12-week PFPT treatment comprising education, manual therapy and pelvic floor muscle exercises. Quantitative data were collected using validated questionnaires at baseline, post-treatment and one-year follow-up. As for qualitative data, semi-structured interviews were conducted at one-year follow-up to better understand women's perception and experience of treatment effects., Results: Significant improvements were found from baseline to one-year follow-up on all quantitative outcomes (P ≤ 0.028). Moreover, no changes were found from post-treatment to one-year follow-up, supporting that the improvements were sustained at follow-up. Qualitative data highlighted that reduction in pain, improvement in sexual functioning and reduction in urinary symptoms were the most meaningful effects perceived by participants. Women expressed that these effects resulted from positive biological, psychological and social changes attributable to multimodal PFPT. Adherence was also perceived to influence treatment outcomes., Conclusions: Findings suggest that the short-term improvements following multimodal PFPT are sustained and meaningful for gynecological cancer survivors with dyspareunia one year after treatment., Competing Interests: The authors have declared that no competing interests exist.

Background: Poly ADP-ribose glycohydrolase (PARG) is responsible for the catabolism of PARP-synthesized PAR to free ADP-ribose. Inhibition of PARG leads to DNA repair interruption and consequently induces cell death. This study aims to evaluate the effect of a PARG inhibitor (PARGi) on epithelial ovarian cancer (OC) cell lines, alone and in combination with a PARP inhibitor (PARPi) and/or Cisplatin., Methods: PARG mRNA levels were studied in three different OC datasets: TCGA, Hendrix, and Meyniel. PARG protein levels were assessed in 100 OC specimens from our bio-bank. The therapeutic efficacy of PARGi was assessed using cell migration and clonogenic formation assays. Flow cytometry was used to evaluate the cell apoptosis rate and the changes in the cell cycle., Results: PARG protein was highly expressed in 34% of the OC tumors and low expression was found in another 9%. Similarly, Hendrix, Meyneil and TCGA databases showed a significant up-regulation in PARG mRNA expression in OC samples as compared to normal tissue (P=0.001, P=0.005, P=0.005, respectively). The use of PARGi leads to decreased cell migration. PARGi in combination with PARPi or Cisplatin induced decreased survival of cells as compared to each drug alone. In the presence of PARPi and Cisplatin, PARG knockdown cell lines showed significant G2/M cell cycle arrest and cell death induction., Conclusions: PARG inhibition appears as a complementary strategy to PARP inhibition in the treatment of ovarian cancer, especially in the presence of homologous recombination defects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Matanes, López-Ozuna, Octeau, Baloch, Racovitan, Dhillon, Kessous, Raban, Kogan, Salvador, Lau, Gotlieb and Yasmeen.)

Objective: Although its use in endometrial cancer staging is relatively new, sentinel lymph node (SLN) sampling has been shown to be highly accurate and is associated with few complications. However, some studies report lower rates of detection with SLN sampling among patients with obesity. The aim of the current study is to evaluate the feasibility of SLN sampling in endometrial cancer for patients with obesity, and to determine whether omitting lymph node dissection (LND) in surgical staging using SLN sampling impacts oncologic outcomes., Methods: we conducted a retrospective study of patients with obesity (BMI ≥35 kg/m 2) , diagnosed with endometrial carcinoma between 2007 and 2017, that compared surgical and oncologic outcomes of 2 cohorts: patients who underwent LND and patients who underwent SLN without lymphadenectomy. The primary outcome was operative time. Secondary outcomes included intraoperative bleeding; lymph node assessment information; intraoperative and postoperative adverse events; and oncologic outcomes including progression-free survival (PFS), overall survival (OS), and disease-specific survival (DSS). PFS was defined as the time from surgery to the recurrence or death from any cause. OS was defined as time from diagnosis to death or the last date the patient was known to be alive, and DSS was defined as the time from the surgery to death from the disease., Results: Out of 223 patients with a median BMI of 40.6 kg/m 2 , 140 underwent LND and 83 underwent SLN alone. The median operative time for patients in the SLN group was shorter than that of patients in the LND group (190.5 [range 108-393] vs. 238 [131-440] min; P < 0.001), and the SLN group had lower median estimated blood loss than the LND group (30 [range 0-300] vs. 40 [range 0-800] mL; P = 0.03). At the 24-month follow-up cut-off, 98% of patients were alive and 95.5% were disease free, with no significant differences in OS, DSS, and PFS between the 2 groups (P = 0.7, P = 0.8, and P = 0.4, respectively)., Conclusions: In patients with obesity, omitting LND from surgical staging with SLN sampling was associated with shorter operative times and less bleeding and did not affect survival at 2 years., (Copyright © 2021 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. All rights reserved.)

Objective: A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280)., Data Sources: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials., Study Eligibility Criteria: We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data., Methods: We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool., Results: We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44-82.5 years) and the study-level median body mass index was 28.6 kg/m 2 (range, 19.4-43.7 kg/m 2 ). The pooled detection rates were 91% per patient (95% confidence interval, 85%-95%; I 2 =59%) and 64% bilaterally (95% confidence interval, 53%-73%; I 2 =69%). The overall node positivity rate was 26% (95% confidence interval, 19%-34%; I 2 =44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%-96%; I 2 =0%), a false negative rate of 8% (95% confidence interval, 4%-16%; I 2 =0%), and a negative predictive value of 97% (95% confidence interval, 95%-99%; I 2 =0%)., Conclusion: Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca 2+ ) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca 2+ channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca 2+ transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca 2+ -dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers., (© 2021. The Author(s).)

Background: Minimally invasive surgery (MIS) is a standard surgical approach for comprehensive surgical staging in women with endometrial cancer. As rates and complexity of MIS are steadily increasing, it is important to identify potential risk factors which may be associated with this approach. This study evaluates the impact of local factors on the risk of disease recurrence., Methods: A retrospective cohort study was conducted of patients diagnosed with high grade endometrial cancer (HGEC) who underwent MIS between 2012 and 2016 at eight Canadian centers. Data was collected from medical records. The 75th percentile was calculated for estimated uterine volume and weight. All recurrences were categorized into two groups; intra-abdominal vs. extra-abdominal. To search for significant covariates associated with recurrence-free survival a Cox proportional hazard model was performed., Results: A total of 758 patients were included in the study. Intra-uterine manipulator was used in 497 (35.8%) of patients. Vaginal lacerations were documented in 9.1%. Median follow-up was 30.5 months (interquartile range 20-47). There were 157 who had disease recurrence (20.71%), including 92 (12.14%) intra-abdominal and 60 (7.92%) extra-abdominal only recurrences. In univariate analysis myometrial invasion, LVI, stage, uterine volume and weight > 75th percentile and chemotherapy were associated with increased risk of intra-abdominal recurrence. In multivariable analysis only stage, and specimen weight > 75th percentile (OR 2.207, CI 1.123-4.337) remained significant. Uterine volume, and weight were not associated with increased risk of extra-abdominal recurrences., Conclusion: For patients diagnosed with HGEC undergoing MIS, extracting a large uterus is associated with a significantly increased risk for intra-abdominal recurrence., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

Study Objective: Surgical staging for apparent early-stage ovarian cancer includes systematic pelvic and para-aortic lymph node evaluation to detect occult stage III disease [1]. Although, lymphadenectomy procedure is associated with increased duration of surgery and a 13% risk of lymphocyst formation [2]. Sentinel lymph node (SLN) biopsy is still investigational, and no standardized approach has been studied. Recent mounting evidence has approved the applicability of SLN technique in early-stage ovarian cancer [3,4]. The objective of this video is to demonstrate a surgical technique for robotic performance of SLN biopsy in presumed early-stage ovarian cancer., Design: Stepwise demonstration of the robotic technique for SLN sampling in presumed early-stage ovarian cancer. This video report is part of an institutional, investigational review board-approved study., Setting: Academic tertiary referral center., Interventions: This video presents our team's robotic technique for SLN sampling in a 37-year-old woman who presented to our center with a 10-cm right complex adnexal mass, suspicious for malignancy. A 27-gauge spinal needle was inserted through the abdominal wall under direct visualization. We injected 0.5 mL of dilute indocyanine green solution (Novadaq Technologies, Mississauga, Ontario, Canada) (1.25 mg/mL) subperitoneally into the utero-ovarian ligament. The SLN was checked with the fluorescence-guided camera of the Xi DaVinci robotic system (Sunnyvale, CA). Eight to 10 minutes after the injection, a right para-aortic SLN was identified, and dissection was performed. After dissection, the node was extracted and sent to pathology for evaluation by ultra-staging. The final pathology revealed a stage IA low-grade serous ovarian cancer., Conclusion: SLN sampling appears to be feasible in presumed early-stage ovarian cancer and may allow the avoidance of systematic lymph node dissection in this set of patients., (Copyright © 2021 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate if the prognostic value of lymphovascular space invasion (LVSI) is different in endometrial cancer patients with negative lymph nodes following sentinel lymph node (SLN) mapping or lymph node dissection (LND) as staging procedure., Material and Methods: A retrospective study of 510 patients diagnosed with endometrial carcinoma in our institution between 2007 and 2014. We excluded patients that were diagnosed with positive nodes (Stage IIIc). We compared patients' characteristics and survival outcomes as function of their LVSI status (positive LVSI vs negative LVSI subgroups) in each cohort separately., Results: 413 patients met the inclusion criteria, out of whom 239 underwent SLN and 174 patients underwent LND only. In the SLN group, life table analysis showed 5-year OS and PFS of 80% and 72% in patients with LVSI compared to 96%, and 93% without LVSI. Same trend was observed among patients with LND with 5-year OS and PFS of 74% and 64% in patients with LVSI compared to 97%, and 90% without LVSI. On multivariable analysis, adjusted for age, FIGO stage, grade and maximal tumor size, the favorable survival of negative LVSI remained only in the LND cohort (SLN cohort: HR 1.2, CI [0.3-4.0], P = 0.8 and HR 1.7, CI [0.7-4.3], p = 0.2 for OS and PFS, respectively; LND cohort: HR 3.1, CI [1.4-6.5], p < 0.001 and HR 2.5, CI [1.2-4.9], p = 0.01 for OS and PFS, respectively)., Conclusions: The prognostic value of LVSI disappears when patients undergo staging with SLN and are found to have negative nodes in contrast to those who have undergone LND. Future studies should confirm our observation on patients with negative sentinel nodes, and plan on tailoring adjuvant treatment to this specific subgroup., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Obesity, an established risk factor for endometrial cancer (EC), is also associated to increased risks of intraoperative and postoperative complications. A reliable tool to identify patients at low risk for lymph node (LN) metastasis may allow minimizing the surgical staging and omit lymphadenectomy in obese patients. To identify molecular biomarkers that could predict LN involvement in obese patients with EC we performed gene expression analysis in 549 EC patients using publicly available transcriptomic datasets. Patients were filtrated according to cancer subtype, weight (>30 kg/m 2 ) and LN status. While in the LN+ group, NEB, ANK1, AMIGO2, LZTS1, FKBP5, CHGA, USP32P1, CLIC6, CEMIP, HMCN1 and TNFRSF10C genes were highly expressed; in the LN- group CXCL14, FCN1, EPHX3, DDX11L2, TMEM254, RNF207, LTK, RPL36A, HGAL, B4GALNT4, KLRG1 genes were up-regulated. As a second step, we investigated these genes in our patient cohort of 35 patients (15 LN+ and 20 LN-) and found the same correlation with the in-silico analysis. In addition, immunohistochemical expression was confirmed in the tumor tissue. Altogether, our findings propose a novel panel of genes able to predict LN involvement in obese patients with endometrial cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 López-Ozuna, Kogan, Hachim, Matanes, Hachim, Mitric, Kiow, Lau, Salvador, Yasmeen and Gotlieb.)

Background: Due to the COVID-19 pandemic, a large portion of oncology consultations have been conducted remotely. The maladaptation or compromise of care could negatively impact oncology patients and their disease management., Objective: We aimed to describe the development and implementation process of a web-based, animated patient education tool that supports oncology patients remotely in the context of fewer in-person interactions with health care providers., Methods: The platform created presents multilingual oncology care instructions. Animations concerning cancer care and mental health during the COVID-19 pandemic as well as immunotherapy and chemotherapy guides were the major areas of focus and represented 6 final produced video guides., Results: The videos were watched 1244 times in a period of 6 months. The most watched animation was the COVID-19 & Oncology guide (viewed 565 times), followed by the video concerning general treatment orientations (viewed 249 times) and the video titled "Chemotherapy" (viewed 205 times). Although viewers were equally distributed among the age groups, most were aged 25 to 34 years (342/1244, 27.5%) and were females (745/1244, 59.9%)., Conclusions: The implementation of a patient education platform can be designed to prepare patients and their caregivers for their treatment and thus improve outcomes and satisfaction by using a methodical and collaborative approach. Multimedia tools allow a portion of a patient's care to occur in a home setting, thereby freeing them from the need for hospital resources., (©Sena Turkdogan, Gabriel Schnitman, Tianci Wang, Raphael Gotlieb, Jeffrey How, Walter Henri Gotlieb. Originally published in JMIR Cancer (https://cancer.jmir.org), 21.06.2021.)

Objective: Risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations. The aim of this meta-analysis is to evaluate the risk of endometrial cancer (EC) in BRCA1 or BRCA2 germline mutation carriers and to examine the justifiability of prophylactic hysterectomy at the time of RRSO., Data Sources: PubMed, Cochrane Central Register of Controlled Trials, BIOSIS, Medline (Ovid), Web of Science, ClinicalTrials.gov, and Google Scholar were searched. Eleven articles were selected and analyzed using the OpenMetaAnalyst 2012 software., Methods of Study Selection: Randomized controlled studies, cohort studies, and case-control studies evaluating the risk of EC and specifically uterine papillary serous carcinoma (UPSC) in germline BRCA1/2 mutation carriers were included. Articles were excluded if they did not meet the inclusion criteria, or if data were not reported and the authors did not respond to inquiries. We assessed the methodological quality of the included studies on the basis of the Newcastle-Ottawa scale. Dichotomous results from each of the studies eligible for the meta-analysis were expressed as the proportion of patients with EC or UPSC per total number of BRCA mutation carriers, with 95% confidence interval (CI). The Mantel-Haenszel statistical method was used., Tabulation, Integration, and Results: Eleven studies reported the outcome of interest and were included in the final meta-analysis. In total, 13 871 carriers of BRCA1 and BRCA2 mutations were identified. The pooled prevalence rates of EC and UPSC in BRCA1/2 mutation carriers were 82/13 827 (0.59%) and 19/11 582 (0.16%), respectively. The EC prevalence was 46/7429 (0.62%) in BRCA1 mutation carriers and 17/3546 (0.47%) in BRCA2 mutation carriers, with relative risk of 1.18 (95% CI, 0.7-2.0). For UPSC, the prevalence was 15/7429 (0.2%) and 3/3546 (0.08%) among BRCA1 and BRCA2 mutation carriers, respectively, (relative risk 1.39; 95% CI, 0.5-3.7)., Conclusion: Most studies in this meta-analysis suggest a slightly increased risk of EC in BRCA mutation carriers, mainly for BRCA1. The decision regarding concurrent hysterectomy should be tailored individually to each patient on the basis of the patient's age, type of mutation, future need for hormone replacement treatment, history of breast cancer, tamoxifen use, and personal operative risks., (Copyright © 2020 AAGL. Published by Elsevier Inc. All rights reserved.)

Guidelines for the treatment of tubo-ovarian cancer patients beyond third line are lacking. We aimed to evaluate the effect of response in each line on patient's outcome as well as identify variables that predict response for additional line of chemotherapy. A cohort study was performed including all patients with advanced high-grade ovarian cancer. Survival analysis was performed using Kaplan-Meier curves and log-rank tests. Odds ratios and hazard ratios were calculated using multilevel, mixed-effects logistic regression and Cox regression, adjusting for repeated measures within individual patients. Two-hundred thirty-eight patients were included and underwent up to 10 lines of chemotherapy. The median progression-free survival was 15.6 and overall survival (OS) was 55.6 months. Response rates dropped with each additional line and by line 5, most patients (61%) became refractory and only 16% had any type of response (complete 4% or partial 12%). By line 2, whether a patient had partial disease (PR), stable disease (SD) or progressive disease (PD) did not have an effect on the OS. From line 2, whether a patient had PR, SD or PD did not have an effect on chemotherapy-free interval. Number of previous lines and time from previous line were the only variables that significantly correlated with both outcome of patients and response to the next line. In conclusion, time interval from the previous line of chemotherapy is the major clinical factor that predicts beneficial effect of another line of treatment in patients with ovarian cancer., (© 2020 Union for International Cancer Control.)

Background: Dyspareunia affects most women after treatment for gynecologic malignancies. However, to date, evidence-based interventions remain limited and no study has examined the effects of multimodal physical therapy on psychosexual outcomes in these patients., Aim: To assess the effects of multimodal physical therapy on psychosexual outcomes including sexual distress, body image concerns, pain anxiety, pain catastrophizing, pain self-efficacy and depressive symptoms in women with dyspareunia after treatment for gynecologic malignancies., Methods: Thirty-one gynecologic cancer survivors with dyspareunia enrolled in this prospective single-arm interventional study. The participants undertook 12 weekly sessions of physical therapy incorporating education, pelvic floor muscle exercises with biofeedback, manual therapy and home exercises. Outcome measures were evaluated pre- and post-treatment. Paired t-tests were conducted to investigate the changes from pre-treatment (P-value ˂ 0.05) while effect sizes (Cohen's d) were calculated to measure the magnitude of the change., Main Outcome Measures: Sexual distress (Female Sexual Distress Scale-Revised), body image concerns (Body Image Scale), pain anxiety (Pain Anxiety Symptoms Scale), pain catastrophizing (Pain Catastrophizing Scale), pain self-efficacy (Painful Intercourse Self-Efficacy Scale) and depressive symptoms (Beck Depression Inventory-II)., Results: Significant changes were found from pre- to post-treatment for all psychosexual outcomes. Women reported reductions in sexual distress (P ˂ 0.001, d = 1.108), body image concerns (P ˂ 0.001, d = 0.829), pain anxiety (P ˂ 0.001, d = 0.980), pain catastrophizing (P ˂ 0.001, d = 0.968) and depression symptoms (P = 0.002, d = 0.636) with an increase in pain self-efficacy (P ˂ 0.001, d ≥ 0.938) following the intervention., Clinical Implications: The results suggest that multimodal physical therapy significantly improves sexual distress, body image concerns, pain anxiety, pain catastrophizing, pain self-efficacy and depressive symptoms in our sample of women with dyspareunia after treatment for gynecologic malignancies. The medium to large effect sizes obtained with the high proportion of women presenting meaningful changes according to the known minimal clinically important difference or clinical cut-off underlines the significance of these effects., Strengths & Limitations: The current study used validated questionnaires to assess the psychosexual outcomes of a well-designed physical therapy intervention using multiple modalities to address the multifaceted aspect of dyspareunia in cancer survivors. This study did not include a control group, which may limit drawing definitive conclusions., Conclusion: Findings showed that multimodal physical therapy yielded significant improvements in psychosexual outcomes in gynecologic cancer survivors with dyspareunia. A randomized controlled trial is indicated to confirm these results. Cyr M-P, Dumoulin C, Bessette P, et al. A Prospective Single-Arm Study Evaluating the Effects of a Multimodal Physical Therapy Intervention on Psychosexual Outcomes in Women With Dyspareunia After Gynecologic Cancer. J Sex Med 2021;18:946-954., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: More than one-half of gynecological cancer survivors are affected by pain during sexual intercourse, also known as dyspareunia. Oncological treatments may result in pelvic floor muscle (PFM) alterations, which are suspected to play a key role in dyspareunia. However, to our knowledge, no study has investigated PFM function and morphometry in this population. The aim of the study was to characterize and compare PFM function and morphometry between gynecological cancer survivors with dyspareunia and asymptomatic women., Methods: Twenty-four gynecological cancer survivors with dyspareunia and 32 women with a history of total hysterectomy but without pelvic pain (asymptomatic women) participated in this comparative cross-sectional study. PFM passive forces (tone), flexibility, stiffness, maximal strength, coordination, and endurance were assessed with an intra-vaginal dynamometric speculum. Bladder neck position, levator plate angle, anorectal angle, and levator hiatal dimensions were measured at rest and on maximal contraction with 3D/4D transperineal ultrasound imaging., Results: Compared with asymptomatic women, gynecological cancer survivors showed heightened PFM tone, lower flexibility, higher stiffness, and lower coordination and endurance. At rest, they had a smaller anorectal angle and smaller levator hiatal dimensions, indicating heightened PFM tone. They also presented fewer changes from rest to maximal contraction for anorectal angle and levator hiatal dimensions, suggesting an elevated tone or altered contractile properties., Conclusions: Gynecological cancer survivors with dyspareunia present with altered PFM function and morphometry. This research therefore provides a better understanding of the underlying mechanisms of dyspareunia in cancer survivors., Impact: Our study confirms alterations in PFM function and morphometry in gynecological cancer survivors with dyspareunia. These findings support the rationale for developing and assessing the efficacy of physical therapy targeting PFM alterations in this population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cancer metastasis involves dissemination of malignant cells from the primary tumor, via local lymphatic vessels to gain access to systemic circulation, while evading the destruction by immune cells, followed by successful extravasation and initiation of malignant growth in the distant organ. Despite the obvious contribution of the lymphatic system to the metastatic spread of cancer, basic research regarding the mechanisms leading to tumor dissemination via lymphatic vessels has been limited for years. Recent identification of molecular growth factors of lymphangiogenesis have led to new advances in our understanding of the underlying mechanisms of tumor metastasis. These growth factors have enabled scientists to better identify peritumoral lymphatics and to visualize precisely the ingrowth of tumor cells into the lumen of lymphatic capillaries. Moreover, it has been shown that these molecular markers secreted from a primary tumor can induce lymphangiogenesis in close regional lymph nodes, even prior to tumor cells arrival, which may facilitate metastasis spread. Comprehensive research of the multiplex interactions between tumor cells, lymphatics and the immune system will be crucial to further enhance the development of therapeutic and prognostic approaches to cancer. This review presents the ontogeny and anatomy of the lymphatic vasculature, discuss the immunological, molecular and physiological control of lymphatic vessel function, and explore the contribution of the lymphatic system to the development of metastases.

Introduction: We compared oncologic and clinical outcomes in patients with advanced ovarian cancer who received dose-dense weekly paclitaxel with 3-weekly carboplatin with those who received standard 3-weekly chemotherapy., Material and Methods: Comparison of all consecutive patients with advanced (International Federation of Gynecology and Obstetrics stages III-IV) ovarian cancer who received a dose-dense protocol between 2010 and 2016 with an immediate historical cohort of consecutive patients who received standard chemotherapy. Patients who received less than three cycles of treatment were excluded., Results: In all, 246 patients were included in the study, of whom 128 received the dose-dense protocol and 118 were treated with the standard Q3-week protocol. Patients in the dose-dense group had significantly better progression-free survival than those receiving the standard protocol (median progression-free survival 22 vs 15 months; log rank = 0.026). The overall survival of patients in the dose-dense group was also better than that of the patients in the standard protocol group; however, this difference was not statistically significant (median overall survival 66 vs 54 months; log rank = 0.185). The dose-dense protocol remained significantly associated with favorable survival outcome in multivariable analysis adjusted for stage, histologic type, cytoreductive results and neoadjuvant chemotherapy. The use of the dose-dense protocol was associated with higher rates of gastrointestinal, dermatologic, neurologic and hematologic side effects., Conclusion: Despite the limitations associated with the comparison to a historical cohort, a dose-dense chemotherapy protocol resulted in a significantly improved progression-free survival and the overall survival tended to be better, but this difference did not reach statistical significance compared with the standard chemotherapy protocol, and may be considered as a treatment alternative, albeit with some increased side effects., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology.)

The nuclease MRE11A is often included in genetic test panels for hereditary breast and ovarian cancer (HBOC) due to its BRCA1-related molecular function in the DNA repair pathway. However, whether MRE11A is a true predisposition gene for HBOC is still questionable. We determined to investigate this notion by dissecting the molecular genetics of the c.1516G > T;p.E506* truncating MRE11A variant, that we pinpointed in two unrelated French-Canadian (FC) HBOC patients. We performed a case-control study for the variant in ~ 2500 breast, ovarian, and endometrial cancer patients from the founder FC population of Quebec. Furthermore, we looked for the presence of second somatic alterations in the MRE11A gene in the tumors of the carriers. In summary, these investigations suggested that the identified variant is not associated with an increased risk of developing breast or ovarian cancer. We finally performed a systematic review for all the previously reported MRE11A variants in breast and ovarian cancer. We found that MRE11A germline variants annotated as pathogenic on ClinVar often lacked evidence for such classification, hence misleading the clinical management for affected patients. In summary, our report suggests the lack of clinical utility of MRE11A testing in HBOC, at least in the White/Caucasian populations.

There is limited knowledge on non-invasive lymphedema risk-reduction strategies for women with gynecological cancer. Understanding factors influencing the feasibility of randomized controlled trials (RCTs) can guide future research. Our objectives are to report on the design and feasibility of a pilot RCT examining a tailored multidimensional intervention in women treated for gynecological cancer at risk of lymphedema and to explore the preliminary effectiveness of the intervention on lymphedema incidence at 12 months. In this pilot single-blinded, parallel-group, multi-centre RCT, women with newly diagnosed gynecological cancer were randomized to receive post-operative compression stockings and individualized exercise education (intervention group: IG) or education on lymphedema risk-reduction alone (control group: CG). Rates of recruitment, retention and assessment completion were recorded. Intervention safety and feasibility were tracked by monitoring adverse events and adherence. Clinical outcomes were evaluated over 12 months: presence of lymphedema, circumferential and volume measures, body composition and quality of life. Fifty-one women were recruited and 36 received the assigned intervention. Rates of recruitment and 12-month retention were 47% and 78%, respectively. Two participants experienced post-operative cellulitis, prior to intervention delivery. At three and six months post-operatively, 67% and 63% of the IG used compression ≥42 h/week, while 56% engaged in ≥150 weekly minutes of moderate-vigorous exercise. The cumulative incidence of lymphedema at 12 months was 31% in the CG and 31.9% in the IG ( p = 0.88). In affected participants, lymphedema developed after a median time of 3.2 months (range, 2.7-5.9) in the CG vs. 8.8 months (range, 2.9-11.8) in the IG. Conducting research trials exploring lymphedema risk-reduction strategies in gynecological cancer is feasible but challenging. A tailored intervention of compression and exercise is safe and feasible in this population and may delay the onset of lymphedema. Further research is warranted to establish the role of these strategies in reducing the risk of lymphedema for the gynecological cancer population.

Objectives: Painful sexual intercourse (dyspareunia) is a distressing condition affecting a large proportion of gynecological cancer survivors, yet treatments remain limited and poorly studied. This multicenter prospective interventional study examined the feasibility, acceptability and effects of multimodal pelvic floor physical therapy in gynecological cancer survivors with dyspareunia., Methods: Thirty-one endometrial and cervical cancer survivors with dyspareunia participated in 12 weekly 60-min physical therapy sessions combining education, manual therapy, pelvic floor muscle exercises using biofeedback and home exercises, which included the use of a dilator. The adherence rate to home exercises (≥80%), the attendance rate at physical therapy sessions (≥80% of participants attending ≥10 sessions) and the dropout rate (˂15%) served as feasibility and acceptability outcomes and benchmarks. Pain intensity, pain quality, sexual function, pelvic floor dysfunction symptoms and quality of life were measured at baseline and post-treatment. Treatment satisfaction and participants' perceived improvement were also assessed., Results: The adherence rate was 88% (SD 10), 29/31 (94%) women attended ≥10 treatment sessions, and the dropout rate was 3%. Moreover, women experienced significant improvements in all outcomes after the intervention (p ≤ 0.044). They also reported being highly satisfied with the treatment (9.3/10 (SD 1.2)), and 90% of them were very much or much improved., Conclusions: Our findings support the feasibility and acceptability of multimodal pelvic floor physical therapy for gynecological cancer survivors with dyspareunia. The intervention also led to significant improvements in pain, sexual function, pelvic floor dysfunction symptoms and quality of life. A randomized controlled trial is needed to confirm these results., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)