David Cibula

Optimizing prehabilitation in gynecologic malignancies: Improving acceptance, overcoming barriers, and managing program complexity

Prehabilitation aims to improve patients' physical condition before a stressful event, such as surgery, and enhance recovery. Despite its potential benefits, many emerging prehabilitation programs face challenges in enrolling or retaining patients. In our prehabilitation study PHOCUS, which aims to prepare ovarian cancer patients for surgery, we have also encountered lower acceptance and retention rates. Particularly the most vulnerable patients, who are old and frail, and may benefit the most from the prehabilitation, decline participation due to the complexity of the proposed program. In our review we discussed obstacles and barriers that prevent patients' participation based on both literature and our experience. Among the main reasons are patient's low motivation, high intensity of the program and a lack of social support. To overcome these challenges, we suggest increasing the program's flexibility, adapting the program according to individual patient's needs and enhancing patients' education about the benefits of prehabilitation.

A Simple Cervicovaginal Epigenetic Test for Screening and Rapid Triage of Women With Suspected Endometrial Cancer: Validation in Several Cohort and Case/Control Sets

PURPOSE Endometrial cancer (EC) incidence has been rising over the past 10 years. Delays in diagnosis reduce survival and necessitate more aggressive treatment. We aimed to develop and validate a simple, noninvasive, and reliable triage test for EC to reduce the number of invasive diagnostic procedures and improve patient survival. METHODS We developed a test to screen and triage women with suspected EC using 726 cervical smear samples from women with and without EC, and validated the test in 562 cervicovaginal samples using three different collection methods (cervical smear: n = 248; vaginal swab: n = 63; and self-collection: n = 251) and four different settings (case/control: n = 388; cohort of women presenting with postmenopausal bleeding: n = 63; a cohort of high-risk women with Lynch syndrome: n = 25; and a nested case/control setting from a screening cohort and samples taken up to 3 years before EC diagnosis: n = 86). RESULTS We describe the Women's cancer risk IDentification – quantitative polymerase chain reaction test for Endometrial Cancer (WID-qEC), a three-marker test that evaluates DNA methylation in gene regions of GYPC and ZSCAN12. In cervical, self-collected, and vaginal swab samples derived from symptomatic patients, it detected EC with sensitivities of 97.2% (95% CI, 90.2 to 99.7), 90.1% (83.6 to 94.6), and 100% (63.1 to 100), respectively, and specificities of 75.8% (63.6 to 85.5), 86.7% (79.3 to 92.2), and 89.1% (77.8 to 95.9), respectively. The WID-qEC identified 90.9% (95% CI, 70.8 to 98.9) of EC cases in samples predating diagnosis up to 1 year. Test performance was similar across menopausal status, age, stage, grade, ethnicity, and histology. CONCLUSION The WID-qEC is a noninvasive reliable test for triage of women with symptoms suggestive of ECs. Because of the potential for self-collection, it could improve early diagnosis and reduce the reliance for in-person visits.

Ultrasound examiners' ability to describe ovarian cancer spread using preacquired ultrasound videoclips from a selected patient sample with high prevalence of cancer spread

ABSTRACTObjectivesTo assess the ability, as well as factors affecting the ability, of ultrasound examiners with different levels of ultrasound experience to detect correctly infiltration of ovarian cancer in predefined anatomical locations, and to evaluate the inter‐rater agreement regarding the presence or absence of cancer infiltration, using preacquired ultrasound videoclips obtained in a selected patient sample with a high prevalence of cancer spread.MethodsThis study forms part of the Imaging Study in Advanced ovArian Cancer multicenter observational study (NCT03808792). Ultrasound videoclips showing assessment of infiltration of ovarian cancer were obtained by the principal investigator (an ultrasound expert, who did not participate in rating) at 19 predefined anatomical sites in the abdomen and pelvis, including five sites that, if infiltrated, would indicate tumor non‐resectability. For each site, there were 10 videoclips showing cancer infiltration and 10 showing no cancer infiltration. The reference standard was either findings at surgery with histological confirmation or response to chemotherapy. For statistical analysis, the 19 sites were grouped into four anatomical regions: pelvis, middle abdomen, upper abdomen and lymph nodes. The videoclips were assessed by raters comprising both senior gynecologists (mainly self‐trained expert ultrasound examiners who perform preoperative ultrasound assessment of ovarian cancer spread almost daily) and gynecologists who had undergone a minimum of 6 months' supervised training in the preoperative ultrasound assessment of ovarian cancer spread in a gynecological oncology center. The raters were classified as highly experienced or less experienced based on annual individual caseload and the number of years that they had been performing ultrasound evaluation of ovarian cancer spread. Raters were aware that for each site there would be 10 videoclips with and 10 without cancer infiltration. Each rater independently classified every videoclip as showing or not showing cancer infiltration and rated the image quality (on a scale from 0 to 10) and their diagnostic confidence (on a scale from 0 to 10). A generalized linear mixed model with random effects was used to estimate which factors (including level of experience, image quality, diagnostic confidence and anatomical region) affected the likelihood of a correct classification of cancer infiltration. We assessed the observed percentage of videoclips classified correctly, the expected percentage of videoclips classified correctly based on the generalized linear mixed model and inter‐rater agreement (reliability) in classifying anatomical sites as being infiltrated by cancer.ResultsTwenty‐five raters participated in the study, of whom 13 were highly experienced and 12 were less experienced. The observed percentage of correct classification of cancer infiltration ranged from 70% to 100% depending on rater and anatomical site, and the median percentage of correct classification for the 25 raters ranged from 90% to 100%. The probability of correct classification of all 380 videoclips ranged from 0.956 to 0.975 and was not affected by the rater's level of ultrasound experience. The likelihood of correct classification increased with increased image quality and diagnostic confidence and was affected by anatomical region. It was highest for sites in the pelvis, second highest for those in the middle abdomen, third highest for lymph nodes and lowest for sites in the upper abdomen. The inter‐rater agreement of all 25 raters regarding the presence of cancer infiltration ranged from substantial (Fleiss kappa, 0.68 (95% CI, 0.66–0.71)) to very good (Fleiss kappa, 0.99 (95% CI, 0.97–1.00)) depending on the anatomical site. It was lowest for sites in the upper abdomen (Fleiss kappa, 0.68 (95% CI, 0.66–0.71) to 0.97 (95% CI, 0.94–0.99)) and highest for sites in the pelvis (Fleiss kappa, 0.94 (95% CI, 0.92–0.97) to 0.99 (95% CI, 0.97–1.00)).ConclusionsUltrasound examiners with different levels of ultrasound experience can classify correctly predefined anatomical sites as being infiltrated or not infiltrated by ovarian cancer based on video recordings obtained by an experienced ultrasound examiner, and the inter‐rater agreement is substantial. The likelihood of correct classification as well as the inter‐rater agreement is highest for sites in the pelvis and lowest for sites in the upper abdomen. However, owing to the study design, our results regarding diagnostic accuracy and inter‐rater agreement are likely to be overoptimistic. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Overall survival with maintenance olaparib in platinum-sensitive relapsed ovarian cancer by somatic or germline BRCA and homologous recombination repair mutation status

Abstract Background The open-label, single-arm, multicentre ORZORA trial (NCT02476968) evaluated maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) with a germline (g) or somatic (s) BRCA1 and/or BRCA2 mutation (BRCAm) or a non-BRCA homologous recombination repair mutation (non-BRCA HRRm). Methods Patients were in response to platinum-based chemotherapy after ≥2 prior lines of treatment and underwent prospective central screening for tumour BRCA status, then central gBRCAm testing to determine sBRCAm or gBRCAm status. An exploratory cohort evaluated non-BRCA HRRm in 13 predefined genes. Patients received olaparib 400 mg (capsules) twice daily until investigator-assessed disease progression. Secondary endpoints included overall survival (OS) and safety. Results 177 patients received olaparib. At the final data cutoff (25 June 2021), median OS from study enrolment was 46.8 (95% confidence interval [CI] 37.9–54.4), 43.2 (31.7–NC [not calculated]), 47.4 (37.9–NC) and 44.9 (28.9–NC) months in the BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts, respectively. No new safety signals were identified. Conclusion Maintenance olaparib showed consistent clinical activity in the BRCAm and sBRCAm cohorts; exploratory analysis suggested similar activity in the non-BRCA HRRm cohort. These findings highlight that patients with PSR OC, beyond those with gBRCAm, may benefit from maintenance olaparib.

Magnetic resonance imaging and ultrasound examination in preoperative pelvic staging of early‐stage cervical cancer: post‐hoc analysis of SENTIX study

ABSTRACTObjectivesSENTIX was a prospective, single‐arm, international multicenter study that evaluated sentinel lymph node biopsy without pelvic lymph node dissection in patients with early‐stage cervical cancer. We aimed to evaluate the concordance between preoperative imaging modalities (magnetic resonance imaging (MRI) and ultrasound) and final pathology in the clinical staging of early‐stage cervical cancer by post‐hoc analysis of the SENTIX study data.MethodsIn total, 47 sites across 18 countries participated in the SENTIX study. Patients with Stage IA1/lymphovascular space invasion‐positive to IB2 (International Federation of Gynecology and Obstetrics (FIGO) classification (2018)) cervical cancer, with usual histological types and no suspicious lymph nodes on imaging, were prospectively enrolled between May 2016 and October 2020. Preoperative pelvic clinical staging on either pelvic MRI or ultrasound examination was mandatory. Tumor size discrepancy (< 10 mm vs ≥ 10 mm) between imaging and pathology, as well as the negative predictive value (NPV) of MRI and ultrasound for parametrial involvement and lymph node macrometastasis, were analyzed.ResultsAmong 690 eligible prospectively enrolled patients, MRI and ultrasound were used as the staging imaging modality in 322 (46.7%) and 298 (43.2%) patients, respectively. A discrepancy of tumor size ≥ 10 mm was reported between ultrasound and final pathology in 39/298 (13.1%) patients and between MRI and pathology in 53/322 (16.5%), with no significant difference in the accuracy of tumor measurement between the two imaging modalities. The NPV of ultrasound in assessing parametrial infiltration and lymph node involvement was 97.0% (95% CI, 0.95–0.99%) and 94.0% (95% CI, 0.91–0.97%), respectively, and that of MRI was 95.3% (95% CI, 0.93–0.98%) and 94.1% (95% CI, 0.92–0.97%), respectively, with no significant differences between the parameters. Ultrasound and MRI were comparable regarding the tumor size measurement (P = 0.452), failure to detect parametrial involvement (P = 0.624) and failure to detect macrometastases in sentinel lymph node (P = 0.876).ConclusionsPelvic ultrasound examination and MRI had similar concordance with histology in the assessment of tumor size and of parametrial and lymph node invasion in early‐stage cervical cancer. Ultrasound examination should be considered part of preoperative pelvic clinical staging in early‐stage cervical cancer, especially in limited‐resource regions where MRI is unavailable. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Epithelial ovarian cancer (EOC) is among the top five causes of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant cells to the peritoneum. Despite improvements in medical therapies, particularly with the implementation of novel drugs targeting homologous recombination deficiency, the survival rates of patients with EOC remain low. Unlike other neoplasms, EOC remains relatively insensitive to immune checkpoint inhibitors, which is correlated with a tumor microenvironment (TME) characterized by poor infiltration by immune cells and active immunosuppression dominated by immune components with tumor-promoting properties, especially tumor-associated macrophages (TAMs). In recent years, TAMs have attracted interest as potential therapeutic targets by seeking to reverse the immunosuppression in the TME and enhance the clinical efficacy of immunotherapy. Here, we review the key biological features of TAMs that affect tumor progression and their relevance as potential targets for treating EOC. We especially focus on the therapies that might modulate the recruitment, polarization, survival, and functional properties of TAMs in the TME of EOC that can be harnessed to develop superior combinatorial regimens with immunotherapy for the clinical care of patients with EOC.

Immunological configuration of ovarian carcinoma: features and impact on disease outcome

Epithelial ovarian carcinoma (EOC) is a relatively rare malignancy but is the fifth-leading cause of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant disease to the peritoneum. At odds with other neoplasms, EOC is virtually insensitive to immune checkpoint inhibitors, correlating with a tumor microenvironment that exhibits poor infiltration by immune cells and active immunosuppression. Here, we comparatively summarize the humoral and cellular features of primary and metastatic EOC, comparatively analyze their impact on disease outcome, and propose measures to alter them in support of treatment sensitivity and superior patient survival.

ESGO/ISUOG/IOTA/ESGE Consensus Statement on pre-operative diagnosis of ovarian tumors

The European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis (IOTA) group, and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence-based statements on the pre-operative diagnosis of ovarian tumors, including imaging techniques, biomarkers, and prediction models. ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group, including expert practising clinicians and researchers who have demonstrated leadership and expertise in the pre-operative diagnosis of ovarian tumors and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence-based, the current literature was reviewed and critically appraised. Preliminary statements were drafted based on the review of the relevant literature. During a conference call, the whole group discussed each preliminary statement and a first round of voting was carried out. Statements were removed when a consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. The statements were then revised accordingly. Another round of voting was carried out according to the same rules to allow the whole group to evaluate the revised version of the statements. The group achieved consensus on 18 statements. This Consensus Statement presents these ESGO/ISUOG/IOTA/ESGE statements on the pre-operative diagnosis of ovarian tumors and the assessment of carcinomatosis, together with a summary of the evidence supporting each statement.

ESGO/ISUOG/IOTA/ESGE Consensus Statement on preoperative diagnosis of ovarian tumors

ABSTRACTThe European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis (IOTA) group and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence‐based statements on the preoperative diagnosis of ovarian tumors, including imaging techniques, biomarkers and prediction models.ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group, including expert practising clinicians and researchers who have demonstrated leadership and expertise in the preoperative diagnosis of ovarian tumors and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence‐based, the current literature was reviewed and critically appraised.Preliminary statements were drafted based on the review of the relevant literature. During a conference call, the whole group discussed each preliminary statement and a first round of voting was carried out. Statements were removed when consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. The statements were then revised accordingly. Another round of voting was carried out according to the same rules to allow the whole group to evaluate the revised version of the statements. The group achieved consensus on 18 statements.This Consensus Statement presents these ESGO/ISUOG/IOTA/ESGE statements on the preoperative diagnosis of ovarian tumors and the assessment of carcinomatosis, together with a summary of the evidence supporting each statement.

Preoperative staging of ovarian cancer: comparison between ultrasound, CT and whole‐body diffusion‐weighted MRI (ISAAC study)

AbstractObjectivesTo compare the performance of transvaginal and transabdominal ultrasound with that of the first‐line staging method (contrast‐enhanced computed tomography (CT)) and a novel technique, whole‐body magnetic resonance imaging with diffusion‐weighted sequence (WB‐DWI/MRI), in the assessment of peritoneal involvement (carcinomatosis), lymph‐node staging and prediction of non‐resectability in patients with suspected ovarian cancer.MethodsBetween March 2016 and October 2017, all consecutive patients with suspicion of ovarian cancer and surgery planned at a gynecological oncology center underwent preoperative staging and prediction of non‐resectability with ultrasound, CT and WB‐DWI/MRI. The evaluation followed a single, predefined protocol, assessing peritoneal spread at 19 sites and lymph‐node metastasis at eight sites. The prediction of non‐resectability was based on abdominal markers. Findings were compared to the reference standard (surgical findings and outcome and histopathological evaluation).ResultsSixty‐seven patients with confirmed ovarian cancer were analyzed. Among them, 51 (76%) had advanced‐stage and 16 (24%) had early‐stage ovarian cancer. Diagnostic laparoscopy only was performed in 16% (11/67) of the cases and laparotomy in 84% (56/67), with no residual disease at the end of surgery in 68% (38/56), residual disease ≤ 1 cm in 16% (9/56) and residual disease > 1 cm in 16% (9/56). Ultrasound and WB‐DWI/MRI performed better than did CT in the assessment of overall peritoneal carcinomatosis (area under the receiver‐operating‐characteristics curve (AUC), 0.87, 0.86 and 0.77, respectively). Ultrasound was not inferior to CT (P = 0.002). For assessment of retroperitoneal lymph‐node staging (AUC, 0.72–0.76) and prediction of non‐resectability in the abdomen (AUC, 0.74–0.80), all three methods performed similarly. In general, ultrasound had higher or identical specificity to WB‐DWI/MRI and CT at each of the 19 peritoneal sites evaluated, but lower or equal sensitivity in the abdomen. Compared with WB‐DWI/MRI and CT, transvaginal ultrasound had higher accuracy (94% vs 91% and 85%, respectively) and sensitivity (94% vs 91% and 89%, respectively) in the detection of carcinomatosis in the pelvis. Better accuracy and sensitivity of ultrasound (93% and 100%) than WB‐DWI/MRI (83% and 75%) and CT (84% and 88%) in the evaluation of deep rectosigmoid wall infiltration, in particular, supports the potential role of ultrasound in planning rectosigmoid resection. In contrast, for the bowel serosal and mesenterial assessment, abdominal ultrasound had the lowest accuracy (70%, 78% and 79%, respectively) and sensitivity (42%, 65% and 65%, respectively).ConclusionsThis is the first prospective study to document that, in experienced hands, ultrasound may be an alternative to WB‐DWI/MRI and CT in ovarian cancer staging, including peritoneal and lymph‐node evaluation and prediction of non‐resectability based on abdominal markers of non‐resectability. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Tumour-free distance: a novel prognostic marker in patients with early-stage cervical cancer treated by primary surgery

Abstract Background Models predicting recurrence risk (RR) of cervical cancer are used to tailor adjuvant treatment after radical surgery. The goal of our study was to compare available prognostic factors and to develop a prognostic model that would be easy to standardise and use in routine clinical practice. Methods All consecutive patients with early-stage cervical cancer treated by primary surgery in a single referral centre (01/2007–12/2016) were eligible if assessed by standardised protocols for pre-operative imaging and pathology. Fifteen prognostic markers were evaluated in 379 patients, out of which 320 lymph node (LN)-negative. Results The best predictive model for the whole cohort entailed a combination of tumour-free distance (TFD) ≤ 3.5 mm and LN positivity, which separated two subgroups with a substantially distinct RR 36% and 6.5%, respectively. In LN-negative patients, a combination of TFD ≤ 3.5 mm and adenosquamous tumour type separated a group of nine patients with RR 33% from the rest of the group with 6% RR. Conclusions A newly identified prognostic marker, TFD, surpassed all traditional tumour-related markers in the RR assessment. Predictive models combining TFD, which can be easily accessed on pre-operative imaging, with LN status or tumour type can be used in daily practice and can help to identify patients with the highest RR.

Sentinel lymph node mapping and intraoperative assessment in a prospective, international, multicentre, observational trial of patients with cervical cancer: The SENTIX trial

SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multicentre, prospective observational trial evaluating sentinel lymph node (SLN) biopsy without pelvic lymph node dissection in patients with early-stage cervical cancer. We report the final preplanned analysis of the secondary end-points: SLN mapping and outcomes of intraoperative SLN pathology. Forty-seven sites (18 countries) with experience of SLN biopsy participated in SENTIX. We preregistered patients with stage IA1/lymphovascular space invasion-positive to IB2 (4 cm or smaller or 2 cm or smaller for fertility-sparing treatment) cervical cancer without suspicious lymph nodes on imaging before surgery. SLN frozen section assessment and pathological ultrastaging were mandatory. Patients were registered postoperatively if SLN were bilaterally detected in the pelvis, and frozen sections were negative. ClinicalTrials.gov (NCT02494063). We analysed data for 395 preregistered patients. Bilateral detection was achieved in 91% (355/395), and it was unaffected by tumour size, tumour stage or body mass index, but it was lower in older patients, in patients who underwent open surgery, and in sites with fewer cases. No SLN were found outside the seven anatomical pelvic regions. Most SLN and positive SLN were localised below the common iliac artery bifurcation. Single positive SLN above the iliac bifurcation were found in 2% of cases. Frozen sections failed to detect 54% of positive lymph nodes (pN1), including 28% of cases with macrometastases and 90% with micrometastases. SLN biopsy can achieve high bilateral SLN detection in patients with tumours of 4 cm or smaller. At experienced centres, all SLN were found in the pelvis, and most were located below the iliac vessel bifurcation. SLN frozen section assessment is an unreliable tool for intraoperative triage because it only detects about half of N1 cases.

Management of patients with intermediate-risk early stage cervical cancer

Tisotumab Vedotin in Combination With Carboplatin, Pembrolizumab, or Bevacizumab in Recurrent or Metastatic Cervical Cancer: Results From the innovaTV 205/GOG-3024/ENGOT-cx8 Study

PURPOSE Tissue factor is highly expressed in cervical carcinoma and can be targeted by tisotumab vedotin (TV), an antibody-drug conjugate. This phase Ib/II study evaluated TV in combination with bevacizumab, pembrolizumab, or carboplatin for recurrent or metastatic cervical cancer (r/mCC). METHODS This open-label, multicenter study (ClinicalTrials.gov identifier: NCT03786081 ) included dose-escalation arms that assessed dose-limiting toxicities (DLTs) and identified the recommended phase II dose (RP2D) of TV in combination with bevacizumab (arm A), pembrolizumab (arm B), or carboplatin (arm C). The dose-expansion arms evaluated TV antitumor activity and safety at RP2D in combination with carboplatin as first-line (1L) treatment (arm D) or with pembrolizumab as 1L (arm E) or second-/third-line (2L/3L) treatment (arm F). The primary end point of dose expansion was objective response rate (ORR). RESULTS A total of 142 patients were enrolled. In dose escalation (n = 41), no DLTs were observed; the RP2D was TV 2 mg/kg plus bevacizumab 15 mg/kg on day 1 once every 3 weeks, pembrolizumab 200 mg on day 1 once every 3 weeks, or carboplatin AUC 5 on day 1 once every 3 weeks. In dose expansion (n = 101), the ORR was 54.5% (n/N, 18/33; 95% CI, 36.4 to 71.9) with 1L TV + carboplatin (arm D), 40.6% (n/N, 13/32; 95% CI, 23.7 to 59.4) with 1L TV + pembrolizumab (arm E), and 35.3% (12/34; 19.7 to 53.5) with 2L/3L TV + pembrolizumab (arm F). The median duration of response was 8.6 months, not reached, and 14.1 months, in arms D, E, and F, respectively. Grade ≥3 adverse events (≥15%) were anemia, diarrhea, nausea, and thrombocytopenia in arm D and anemia in arm F (none ≥15%, arm E). CONCLUSION TV in combination with bevacizumab, carboplatin, or pembrolizumab demonstrated manageable safety and encouraging antitumor activity in treatment-naive and previously treated r/mCC.

Tumor Treating Fields therapy in platinum-resistant ovarian cancer: Results of the ENGOT-ov50/GOG-3029/INNOVATE-3 pivotal phase 3 randomized study

Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression. The pivotal, phase 3 ENGOT-ov50/GOG-3029/INNOVATE-3 study evaluated efficacy and safety of TTFields therapy with paclitaxel (PTX) vs PTX in patients with platinum-resistant ovarian cancer (PROC). Adult patients with PROC with ≤ 5 total prior lines of therapy (LOT), including ≤ 2 prior LOT for platinum-resistant disease, and ECOG PS of 0-1 were randomized 1:1 to receive TTFields (200 kHz; ≥ 18 h/day) + PTX (80 mg/m Between March 2019 and November 2021, 558 patients (ECOG PS 0, 60.2 %; median [range] age, 62 [22-91] years) were assigned TTFields+PTX (n = 280) or PTX (n = 278). 24.4 % had 4 + prior LOT. Median OS was 12.2 months with TTFields+PTX vs 11.9 months with PTX (HR, 1.01; 95 % CI, 0.83-1.24; p = 0.89). Grade ≥ 3 adverse events (AEs) were similar between treatment groups. Grade 1/2 device-related skin AEs occurred in 83.6 % of patients receiving TTFields therapy. In exploratory post-hoc analysis in PLD-naive patients, median OS was 16 months with TTFields+PTX (n = 113) vs 11.7 months with PTX (n = 88; nominal HR, 0.67; 95 % CI, 0.49-0.94; p = 0.03). No new safety signals were identified. TTFields+PTX did not significantly improve OS compared with PTX in the intent-to-treat population. An exploratory post-hoc analysis suggests a potentially favorable benefit-risk profile for TTFields therapy in PLD-naive patients.

Sentinel lymph node biopsy without systematic pelvic lymphadenectomy in females with early-stage cervical cancer: final outcome of the SENTIX prospective, single-arm, noninferiority, international trial

Sentinel lymph node (SLN) biopsy with ultrastaging is standard in endometrial and vulvar cancers, whereas systematic pelvic lymphadenectomy (PLND) remains recommended in cervical cancer. The SENTIX trial prospectively evaluated the safety of SLN biopsy without PLND in early-stage cervical cancer. Female patients, International Federation of Gynaecology and Obstetrics 2018 stage IA1/LVSI+ to IB2 disease, were enrolled between 2016 and 2020 across 47 sites in 18 countries. All underwent SLN biopsy followed by hysterectomy/trachelectomy. Patients with undetected, unilateral or intraoperatively metastatic SLNs were excluded from the intention-to-treat cohort. SLNs were assessed by pathological ultrastaging. Of 731 patients enrolled, 594 formed the intention-to-treat cohort. SLN metastases were identified in 82 patients (12%), 56.1% intraoperatively and 43.9% by ultrastaging. At 2 years, the recurrence rate was 6.1% (one-sided 95% CI 7.9%), confirming noninferiority to the 7% reference rate. Two-year disease-free and overall survival rates were 93.3% (95% CI 94.9-91.6) and 97.9% (95% CI 98.9-97.0), respectively. Here we show that SLN biopsy without systematic PLND did not increase the risk of recurrence in patients with early-stage cervical cancer. Pathological ultrastaging of SLNs detected about 44% of N1 cases, which would be missed by a standard lymph node assessment. Trial registration: ClinicalTrials.gov ( NCT02494063 ).

Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer

Abstract Purpose: We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). Patients and Methods: Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The Kaplan–Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1.1. Results: MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22 to 79, from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or physician's choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n = 11, 8.1%), BRAF V600E (n = 8, 5.9%), RAF1 (n = 2, 1.5%), and NF1 (n = 7, 5.2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared with those without, MAPK pathway alterations treated with binimetinib [HR, 0.5; 95% confidence interval (CI) 0.31–0.79]. There was a nonsignificant trend toward PFS improvement in PCC-treated patients with MAPK pathway alterations compared with those without (HR, 0.82; 95% CI, 0.43–1.59). Conclusions: Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with low-grade serous ovarian cancer (LGSOC) treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and used as a future stratification factor.

Pelvic exenteration for vulvar cancer: contemporary outcomes from a multinational cohort study

Women with vulvar cancer are considerably older than those with other gynaecological malignancies, raising concerns about the tolerability of radical surgery. Yet, for locally advanced or recurrent disease, pelvic exenteration may be the only curative option. Robust evidence to guide decision-making in this population is lacking. This multicentre observational cohort study used data from the COREPEX registry including women who underwent anterior or total pelvic exenteration between 2005 and 2023 across 20 European tertiary referral centres. The primary outcome was overall survival (OS); secondary outcomes were progression-free survival (PFS) and major postoperative complications. Associations were assessed using multivariable Cox and binomial regression models adjusted for relevant covariates. Among 861 women, 79 (9.2%) had vulvar cancer. Median follow-up was 49 months for OS and 40 months for PFS. Women with vulvar cancer were older and more often overweight. Five-year OS was 32% (95% CI, 19-46) in vulvar cancer versus 29% (95% CI, 25-34) in other cancers, adjusted HR 1.05 (95% CI, 0.75-1.46). Five-year PFS was 34% versus 29%, adjusted HR 0.96 (95% CI, 0.69-1.34). Major complications occurred in 33% vs 29%, adjusted RR 1.12 (95% CI, 0.77-1.58). Lymph node metastases, positive margins, and recurrent or persistent disease independently predicted poorer survival. Despite their older age, women with vulvar cancer had survival and morbidity comparable to those with other gynaecological malignancies. These findings support pelvic exenteration as a curative option for selected women with vulvar cancer when complete resection is feasible.

European Society of Gynaecological Oncology resource-stratified guidelines for the management of patients with cervical cancer.

In 2023, the European Society of Gynaecological Oncology (ESGO), jointly with the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP), published evidence-based guidelines for the management of patients with cervical cancer. Acknowledging that limitations exist even in high-income countries, some of these established standards of care are not applicable in clinical practice in some areas of the world. Following a global ESGO survey involving 256 clinicians from 57 countries, which pointed out potential limitations, barriers, and missing guidelines, ESGO decided to develop alternative management strategies for situations when optimal resources are unavailable or limited. A multi-disciplinary international development group consisting of 22 experts, utilizing feedback from the survey conducted mostly in low- and middle-income regions, identified potential limitations to the standards of care as defined in the updated ESGO-ESTRO-ESP guidelines published in 2023 and suggested alternative approaches. New resource-stratified guidelines on the management of women living with the human immunodeficiency virus have been newly proposed. To ensure a global perspective, the guidelines were reviewed by 188 independent international practitioners from Asia, Africa, Europe, and South, Central, and North America. These resource-stratified guidelines focus on achieving the best patient outcomes, with alternative management strategies based on expert opinions in areas with limited evidence. They should be used as a guide for the next best alternatives in multi-disciplinary care settings such as diagnostics, pathology, surgery, radiotherapy, systemic therapy, palliative care, and follow-up management. Efforts should always focus on providing optimal available care. In the absence of key resources, the primary effort should be directed toward consulting and referring patients to other facilities that provide better conditions.

Comparison of ultrasound with computed tomography and whole‐body diffusion‐weighted MRI in prediction of surgical outcome using ESMO ‐ ESGO criteria in patients with tubo‐ovarian carcinoma: prospective ISAAC study

ABSTRACT Objective To test the non‐inferiority of extended abdominopelvic ultrasound examination compared with contrast‐enhanced computed tomography (CT) and whole‐body diffusion‐weighted magnetic resonance imaging (WB‐DWI/MRI) in discriminating preoperatively between resectable and non‐resectable disease based on the European Society for Medical Oncology (ESMO) and European Society of Gynecological Oncology (ESGO)‐defined criteria in patients with tubo‐ovarian carcinoma. Methods The Imaging Study on Advanced ovArian Cancer was a prospective multicenter observational study conducted in five European gynecological oncology centers. All centers had ESGO accreditation to perform advanced ovarian cancer surgery, and ultrasound examinations were performed by a European Federation of Societies for Ultrasound in Medicine and Biology level‐III examiner in a standardized manner. Included in the analysis were patients enrolled between 2020 and 2022 with suspected or histologically proven primary tubo‐ovarian (including peritoneal) carcinoma who, for the purposes of the study, underwent ultrasound and CT imaging, as well as WB‐DWI/MRI if available, prior to surgery. The index tests, which included the preoperative imaging modalities as well as intraoperative exploration at the start of surgery, supplemented by biopsy or follow‐up imaging for extra‐abdominal locations, evaluated the presence of disease at eight anatomical sites that, if infiltrated, would indicate non‐resectability of the tumor according to the ESMO‐ESGO criteria. Surgical outcome, described by the surgeons at the end of the procedure, was used as the reference standard and non‐resectability was defined as the presence of residual disease > 1 cm or when debulking surgery was not feasible. The area under the receiver‐operating‐characteristics curve (AUC) and F 1  score were used to assess the performance of the preoperative imaging methods and surgical exploration in discriminating between patients with resectable and those with non‐resectable disease, based on the ESMO‐ESGO criteria. We also calculated the percentage agreement between imaging findings and surgical exploration findings at the start of surgery, supplemented when applicable by biopsy or follow‐up imaging for extra‐abdominal locations, regarding the presence of tumor infiltration at each of the eight anatomical sites associated with non‐resectability. Results Of 279 patients enrolled during the study period, 242 were included in the final analysis. In the subgroup of 167 patients who underwent surgery and had been examined by all three imaging methods, the AUC of the three imaging modalities and surgical exploration for discriminating between resectable and non‐resectable disease based on the ESMO‐ESGO criteria was 0.835 (95% CI, 0.756–0.915) for ultrasound, for CT it was 0.754 (95% CI, 0.664–0.843), for WB‐DWI/MRI it was 0.720 (95% CI, 0.626–0.814) and for surgical exploration it was 0.952 (95% CI, 0.915–0.988). Ultrasound was not inferior to CT or WB‐DWI/MRI, based on the AUC and F 1 score, in discriminating between patients with resectable and those with non‐resectable tubo‐ovarian carcinoma. At surgical exploration, at least one non‐resectability criterion was present in 32.2% cases. The criteria observed most frequently at surgical exploration were small‐bowel involvement (23.6% of cases), diffuse deep infiltration of the root of the small‐bowel mesentery (18.2% of cases) and hepatic hilum involvement (5.4% of cases). The percentage agreement between ultrasound and surgical exploration in assessing the presence of disease in at least one of the eight anatomical sites that, if infiltrated, would indicate non‐resectability of tumor, was 83.9%, surpassing the percentage agreement with surgical exploration of both CT (77.7%) and WB‐DWI/MRI (75.8%). Conclusion When performed by an experienced examiner, ultrasound is not inferior to either CT or WB‐DWI/MRI in discriminating between resectable and non‐resectable disease in patients with tubo‐ovarian carcinoma, based on evaluation of the presence of the disease in at least one of eight anatomical sites that, if infiltrated, would indicate non‐resectability of the tumor. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Primary Analysis of EPIK-O/ENGOT-ov61: Alpelisib Plus Olaparib Versus Chemotherapy in Platinum-Resistant or Platinum-Refractory High-Grade Serous Ovarian Cancer Without BRCA Mutation

PURPOSE Patients with platinum-resistant/platinum-refractory high-grade serous ovarian cancer (HGSOC) without a BRCA mutation have poor prognosis and limited treatment options. We report efficacy and biomarker data from EPIK-O, which investigated alpelisib + olaparib versus single-agent chemotherapy in these patients. PATIENTS AND METHODS EPIK-O was an open-label, phase III trial that randomly assigned patients with platinum-resistant/platinum-refractory HGSOC with no germline or known somatic BRCA mutation 1:1 to alpelisib 200 mg once daily + olaparib 200 mg twice daily or treatment of physician's choice (TPC; paclitaxel 80 mg/m 2 once weekly or pegylated liposomal doxorubicin 40-50 mg/m 2 once every 28 days). Patients had 1-3 previous systemic therapies. Previous bevacizumab was required (unless contraindicated); previous poly(adenosine diphosphate-ribose) polymerase inhibitors were allowed. Primary end point was progression-free survival (PFS) per RECIST 1.1 (blinded independent review committee [BIRC]). Secondary efficacy end points included overall response rate (ORR; per BIRC), duration of response (per BIRC), and overall survival (OS; key secondary end point). RESULTS A total of 358 patients (alpelisib + olaparib [n = 180], TPC [n = 178]) were included. The median follow-up time was 9.3 months. At data cutoff (April 21, 2023), 33 (18.3%) and 30 (16.9%) patients remained on treatment with alpelisib + olaparib and TPC, respectively. The median PFS (BIRC) was 3.6 versus 3.9 months (hazard ratio [HR], 1.14 [95% CI, 0.88 to 1.48]; one-sided P = .84) for alpelisib + olaparib versus TPC. The ORR was 15.6% (95% CI, 10.6% to 21.7%) versus 13.5% (95% CI, 8.8% to 19.4%). The median OS was 10.0 versus 10.6 months (HR, 1.22; 95% CI, 0.87 to 1.71). The safety profile of alpelisib + olaparib was consistent with that observed for the individual agents. CONCLUSION The primary objective, PFS improvement, was not met in EPIK-O. No new or unexpected adverse events were observed. Biomarker analyses provided new insights for responders to alpelisib + olaparib.

Decoding the Molecular Landscape of 262 Uterine Sarcomas: RNA-Seq Clustering of ESS, UTROSCT, and UUS with Prognostic Insights.

Low-grade endometrial stromal sarcomas (LG-ESS), high-grade ESS (HG-ESS), undifferentiated uterine sarcomas (UUS), and uterine tumors resembling ovarian sex cord tumors are distinct non-smooth muscle cell neoplasms with varying clinical outcomes, often exhibiting overlapping characteristics. Diagnosis can be supported by identifying characteristic recurrent translocations, which may be absent in some cases, complicating the distinction of equivocal cases. Additionally, cases with overlapping features of low-grade and high-grade characteristics are recognized. To address these challenges, we analyzed RNA-seq profiles of 262 cases. Our results revealed that LG-ESS, with and without recurrent fusions, clustered into 2 partially overlapping expression profiles associated with distinct overall and relapse-free survival outcomes, with the cluster containing a majority of fusion-negative tumors demonstrating better prognoses. uterine tumors resembling ovarian sex cord tumors expression profiles closely resembled those of both LG-ESS subgroups, with NCOA3 fusion-positive cases clustering in groups with better survival outcomes. Furthermore, a distinct cluster for HG-ESS with BCOR and YWHAE fusions was identified, differentiating these tumors from HG-ESS without fusions. ONECUT3 emerged as a potential specific marker for this HG-ESS-fusion entity. A significant expression overlap was observed between monomorphic HG-ESS without fusions and pleomorphic UUS. These samples separated further into 2 mixed clusters distinguished by differences in immune activity, which significantly influenced overall survival and relapse-free survival outcomes. Unsupervised clustering of UUS revealed subgroups resembling either HG-ESS or muscle-cell-differentiated tumors, suggesting that UUS may include poorly differentiated distinct entities, such as leiomyosarcoma, and that the distinction from HG-ESS may, in some cases, be arbitrary. Our transcriptome analysis highlights several entities with distinct survival characteristics, providing a foundation for further characterization of these rare, often difficult-to-classify, tumors.

Olaparib as Treatment Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer: Phase III SOLO3 Study Final Overall Survival Results

Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020 ). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy for Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors

Mismatch repair-deficient (dMMR) endometrial cancer (EC) is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877 ) in newly diagnosed, high-risk EC after surgery with curative intent. Patients were randomly assigned to pembrolizumab 200 mg or placebo (six cycles) plus carboplatin-paclitaxel (four to six cycles) once every 3 weeks, then pembrolizumab 400 mg or placebo once every 6 weeks (six cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary end point. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis on the basis of the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

Somatic Genomic and Transcriptomic Characterization of Primary Ovarian Serous Borderline Tumors and Low-Grade Serous Carcinomas

Low-grade serous carcinoma (LGSC) may develop from serous borderline tumor (SBT) tissue, where the micropapillary type (mSBT) presents the highest risk for progression. The sensitivity of LGSC to standard chemotherapy is limited, so alternative therapeutic approaches, including targeted treatment, are needed. However, knowledge about the molecular landscape of LGSC and mSBT is limited. A sample set of 137 pathologically well-defined cases (LGSC, 97; mSBT, 40) was analyzed using capture DNA next-generation sequencing (727 genes) and RNA next-generation sequencing (147 genes) to show the landscape of somatic mutations, gene fusions, expression pattern, and prognostic and predictive relevance. Class 4/5 mutations in the main driver genes (KRAS, BRAF, NRAS, ERBB2, USP9X) were detected in 48% (14/29) of mSBT cases and 63% (47/75) of LGSC cases. The USP9X mutation was detected in only 17% of LGSC cases. RNA next-generation sequencing revealed gene fusions in 6 of 64 LGSC cases (9%) and 2 of 33 mSBT cases (9%), and a heterogeneous expression profile across LGSC and mSBT. No molecular characteristics were associated with greater survival. The somatic genomic and transcriptomic profiles of 35 mSBT and 85 LGSC cases are compared for the first time. Candidate oncogenic gene fusions involving BRAF, FGFR2, or NF1 as a fusion partner were identified. Molecular testing of LGSC may be used in clinical practice to reveal therapeutically significant targets.

Ultrasound-guided core needle biopsy: evaluating adequacy, accuracy, and safety in gynecologic oncology

Tissue biopsy is an important component of pre-surgical pathologic diagnosis of cancer for treatment planning and clinical research. Core needle biopsy, or Tru-Cut biopsy, was introduced in the 1960s and 1970s but has not yet become routine in gynecologic oncology, and few studies have examined its adequacy or accuracy in this setting. We report our experience of ultrasound-guided core needle biopsy in patients with gynecologic malignancies. We conducted a retrospective study of ultrasound-guided core needle biopsy at a single tertiary hospital in Prague, Czech Republic, using electronic medical records of cases between 2010 and 2022. We examined the adequacy of biopsy samples, accuracy relative to surgical pathology specimens, and safety. Ultrasound-guided core needle biopsy was performed using standardized procedures. A total of 690 core needle biopsy procedures were evaluated (456 in newly diagnosed cases and 234 in recurrent cases), including 16 repeat procedures, in 674 patients. The 3 most common biopsy sites were ovary (29.3%), carcinomatosis (17.4%), and indeterminate pelvic mass (10.2%). Most (85.9%) biopsies retrieved 3 tissue samples. Core needle biopsy was adequate to establish a diagnosis in 622 of 690 cases (90.1%), and repeat core needle biopsy yielded an additional 16 adequate samples (2.3%). The adequacy rate was highest for ovarian biopsies (96.6%) and lowest for uterine body biopsies (83.3%). Pathologic assessment of core needle biopsy agreed with surgical specimens in 263 of 273 patients who underwent surgery, with an accuracy rate of 96.3%. There was no clear correlation between inaccurate biopsy results and final histotypes. Complications occurred in 9 of 690 core needle biopsy procedures (1.3%), including 6 cases of intra-procedural bleeding (3 required hospitalization), 2 cases of infection, and 1 case of a psychogenic reaction (non-epileptic seizure). Ultrasound-guided core needle biopsy is an accurate, well-tolerated technique that provides reliable diagnostic tissue in gynecologic oncology and may be considered a preferred approach for initial evaluation and confirmation of disease.

Extended Versus Short Prehabilitation Programme for Patients With Advanced Ovarian Cancer Undergoing Major Surgery

Standard treatment for advanced ovarian cancer includes a combination of cytotoxic chemotherapy and citorreductive surgery. During neo-adjuvant administration of chemotherapy, many patients experience a decline in their functional capacity, leading to an increased risk of postoperative complication as a combination of potential malnutrition, decreased physical activity levels and increased anxiety. Prehabilitation programs conducted within Enhanced Rescovery After Surgery (ERAS) pathways have shown to reduce postoperative complications and length of hospital stay in a diverse group of cancer surgeries and, according to some preliminary evidence, can also increase tumour response in patients receiving neoadjuvant chemotherapy. The aim of this study is to compare two modalities of prehabilitation (extended versus estandard) on postoperative complications and response to neoadjuvant chemotherapy. A total of 225 patients will be randomized in a 2:1 ratio to extended prehabilitation (initiated at the onset of neoadjuvant therapy) or standard prehabilitation (initiated after the course of neoadjuvant therapy is completed). In both groups the prehabilitation program will be delivered in the same manner, including supervised (virtual or facility-based) exercise training, nutritional optimization and psychological support and will be supported by a digital platform.

Evaluation of DNA Methylation Markers for Endometrial Cancer Risk-stratification Using Patient-collected Urine and Vaginal Samples and Clinician-collected Cervical Samples From Women With Postmenopausal Bleeding

The goal of this observational study is to investigate the clinical utility of DNA-methylation testing in urine and vaginal samples collected by patients and cervical samples collected by clinicians, to determine the risk of endometrial cancer in symptomatic women with postmenopausal bleeding. The study aims to answer the following research questions: * What is the diagnostic accuracy of DNA methylation testing in urine, vaginal and cervical samples compared to traditional TVUS for endometrial cancer detection? * What is the 2-year risk of EC among women testing negative on TVUS and/or DNA methylation tests or those testing positive on methylation only? Researchers will compare DNA methylation testing in patient-collected urine and vaginal samples as well as in clinician-collected cervical samples, with the traditional diagnostic pathway for women with PMB, which includes TVUS evaluation, and when indicated by abnormal TVUS findings, endometrial biopsy according to clinical guidelines. Participants will * take a urine and vaginal sample * have a cervical sample collected by a clinician * undergo TVUS evaluation according to clinical guidelines * If TVUS shows thickened endometrium (≥ 5 mm) and/or irregularity, an endometrial biopsy will be collected according to clinical guidelines * fill out a questionnaire regarding acceptability and preferences of sampling methods and complete a lifestyle questionnaire.

The Clinical Utility of DNA Methylation Testing in Patient-collected Urine and Vaginal Samples to Detect Endometrial Cancer: a Case-control Study

The goal of this observational case-control study is to investigate the use of DNA-methylation testing in patient-collected urine and vaginal samples to detect endometrial cancer. The study aims to answer the following questions: * Can DNA methylation testing in vaginal and full-void urine samples distinguish endometrial cancer cases from healthy controls? Researchers will compare patient-collected urine and vaginal samples from patients with diagnosed endometrial cancer (cases) to gynaecologically and oncologically healthy controls (controls). Participants will * take a urine and vaginal sample at the hospital. * answer a questionnaire regarding acceptability and preferences of self-sampling methods. * answer a lifestyle questionnaire.

Clinical Studies of Endometrial Cytology and Cervical Methylation Assays in Endometrial Cancer Screening and Fertility-Preservation Evaluation

The current study aims to assess high-risk patients using both liquid-based cytology and cervical methylation testing. The results will be compared with the traditional hysteroscopic pathological findings to determine the sensitivity and specificity of these methods for early detection of endometrial cancer, thereby evaluating their potential application in early screening. Primary Objectives： 1. To evaluate the sensitivity, specificity, and accuracy of endometrial cytology for screening endometrial cancer. 2. To assess the sensitivity, specificity, and accuracy of methylation testing for screening endometrial cancer. 3. To perform further molecular testing on tissue samples obtained from endometrial cytology and cervical methylation tests, aiming to explore early screening-sensitive indicators. Secondary Objectives： 1. To determine the value of endometrial cytology in evaluating the efficacy of fertility-sparing treatments for endometrial cancer. 2. To assess the value of methylation testing in evaluating the efficacy of fertility-sparing treatments for endometrial cancer.

Intermediate Risk Cervical Cancer: Radical Surgery +/- Adjuvant Radiotherapy

The objective of the trial is to evaluate if adjuvant (chemo)radiation is associated with a disease-free survival benefit after radical surgery in patients with intermediate risk cervical cancer. The primary endpoint of the study is the disease-free survival from the day of randomisation. A total of 514 patients are required to achieve 80% power on 5% significance level with non-inferiority margin of 5% to test the difference between the ARMs using Cox proportional hazards model. The maximal tolerated margin for non-inferiority in 2-year DFS is 5% (including expected drop-out rate of 10%).

Imaging Study in Advanced Ovarian Cancer

The aim of the study is the assessment of tumour sites critical for the achievement of optimal cytoreduction in patients with advanced ovarian cancer using Ultrasound, CT and WB-DWI/MRI. The study uses an equivalence design with a hypothesis that cases with non-resectable disease identified by Index test (Ultrasound, CT and WB-DWI MRI) are equivalent to a portion of cases identified during surgery.

Safety and Efficacy of Tisotumab Vedotin Monotherapy & in Combination With Other Cancer Agents in Subjects With Cervical Cancer

This is an open label, multi-center trial of tisotumab vedotin monotherapy and in combination with bevacizumab, pembrolizumab, or carboplatin in subjects with recurrent or stage IVB cervical cancer. The trial consists of two-parts a dose escalation part and an expansion part. The expansion part of the trial will be initiated once the Recommended Phase 2 Dose (RP2D) of the combinations have been determined in the dose escalation part.

Sentinel Lymph Node Biopsy in Patients With Early Stages Cervical Cancer

To evaluate whether a less radical surgical approach with sentinel lymph node biopsy is non-inferior to treatment with systematic pelvic lymphadenectomy. The null hypothesis is that the recurrence rate after SLN biopsy is non-inferior to the reference recurrence rate of 7 % (at the 24th month of follow-up) in patients after systematic pelvic lymphadenectomy, but that the less radical surgery is associated with significantly lower postoperative morbidity.

A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer

The MILO Study (MEK Inhibitor in Low-grade Serous Ovarian Cancer) is a Phase 3 study during which patients with recurrent or persistent low-grade serous (LGS) carcinomas of the ovary, fallopian tube or primary peritoneum will receive either investigational study drug MEK162 or a chemotherapy chosen by the physician (liposomal doxorubicin, paclitaxel or topotecan). Patients will be followed to compare the effectiveness of the study drug to that of the selected chemotherapies. Patients may be eligible to crossover from physician's choice chemotherapy to MEK162 if they meet certain inclusion criteria including centrally confirmed disease progression. Approximately 360 patients from North America, Europe and Australia will be enrolled in this study.