BACKGROUND:Bilateral salpingo-oophorectomy is the gold-standard risk-reducing surgery for women at high risk of tubo-ovarian or primary peritoneal cancer. Fimbriectomy with delayed oophorectomy has emerged as a promising alternative, potentially reducing tubo-ovarian cancer risk while minimizing the adverse effects of premature menopause. Larger cohorts and longer follow-up are required to confirm these findings. PRIMARY OBJECTIVES:To evaluate the effectiveness of the chosen care pathway in controlling the risk of advanced-stage tubo-ovarian carcinoma, and more specifically to determine whether prophylactic fimbriectomy with delayed oophorectomy is non-inferior to standard bilateral salpingo-oophorectomy in women at high risk and with germline mutations. STUDY HYPOTHESIS:Fimbriectomy with delayed oophorectomy is non-inferior to bilateral salpingo-oophorectomy in preventing oncological risk and reduces menopause-related health disorders. TRIAL DESIGN:This multi-center, non-randomized, pragmatic, preference-based controlled trial allows participants to choose their preventive surgical strategy between standard bilateral salpingo-oophorectomy (according to national guidelines) and fimbriectomy (considered from the age of 35, once childbearing is completed), followed by delayed oophorectomy at age 50 or at clinical menopause. Participants will undergo annual long-term follow-up until age 70. The association between the chosen care pathway and outcomes will be estimated using an inverse probability-weighted, cause-specific Cox model, with age as the time scale. MAJOR INCLUSION/EXCLUSION CRITERIA:This study will be proposed during oncogenetic counseling to pre-menopausal women aged 30 to 50 years with a documented pathogenic germline mutation (BRCA1, BRCA2, RAD51C, RAD51D, or PALB2). Exclusion criteria include prior bilateral oophorectomy or salpingectomy and a personal history of tubo-ovarian cancer. PRIMARY ENDPOINT:Advanced-stage tubo-ovarian or primary peritoneal carcinoma. SAMPLE SIZE:A total of 1100 patients is planned. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS:Recruitment will last 5 years (2026-2031). The first interim analysis is planned 6 to 8 years after study initiation (2032-2034). Final analysis is planned when all patients reach age 70 (around 2071). TRIAL REGISTRATION NUMBER:NCT06726330.

Complete cytoreductive surgery remains one of the strongest determinants of outcome in ovarian cancer, yet surgeons still lack rapid tissue-assessment tools that can be repeated throughout an operation. Here we evaluated whether SpiderMass ambient mass spectrometry, combined with machine-learning models, could support ex vivo ovarian tissue typing and exploratory immune microenvironment mapping. A total of 128 ovarian specimens, from 119 patients, were analyzed to train subtype-classification models from fresh-frozen and formalin-fixed paraffin-embedded (FFPE) material, and 24 independent tissues (from 16 patients) were reserved for blinded region-level testing. Initial PCA-LDA models were improved by screening 24 classifiers; Ridge models reached up to 97% 5-fold cross-validation accuracy on the combined cohort. In blinded analyses, the mixed Ridge model produced the fewest errors, although misclassification remained concentrated in underrepresented endometrioid regions. A dual-input network combining SpiderMass spectra with digitized histology improved internal performance to 99% in 5-fold cross-validation and 100% on a small, blinded image-spectrum set, outperforming the molecular-only branch. Model explanation followed by MALDI-MSI cross-checking identified 26 subtype-associated lipids. We then trained a LightGBM cell-state model from immune and epithelial cell spectra and applied it to SpiderMass imaging data. Spatial predictions were broadly concordant with multiplex MALDI-IHC and highlighted subtype-specific differences in immune-cell distribution. In an exploratory analysis of eight high-grade serous carcinoma samples obtained before chemotherapy, longer survivalappeared to be associated with higher lymphocyte scores, higher M1-like macrophage scores and a higher M1/M2 ratio, whereas shorter survival appeared to be associated with higher cancer-cell scores. These data support SpiderMass as a promising ex vivo platform for ovarian cancer typing and hypothesis-generating immunoscoring, while underscoring the need for prospective intraoperative studies, orthogonal biomarker validation, validation in larger cohorts for exploratory immunoscoring and multicenter patient-level external validation before clinical implementation.

Risk reducing salpingo-oophorectomy has long been the gold standard for preventing the development of tubo-ovarian cancers in high-risk population such as BRCA1/2 mutation carriers. Although a clear survival benefit has been demonstrated of these prophylactic procedures, important side effect from the associated surgical menopause have been described. Given that recent evidence suggests that most high-grade serous carcinomas (HGSC), the majority of all ovarian carcinomas, and especially for patients with a genetic predisposition originate in the fallopian tube, where also precursor lesions such as STIC can be found, an alternative risk reduction strategy has emerged, the prophylactic fimbriectomy with delayed oophorectomy. Multiple studies have already investigated the acceptability, side effects and safety of this procedure, with promising results. And currently multiple studies are ongoing to investigate the long-term effects on sexuality and the risk of developing subsequent tubo-ovarian carcinomas. A long-term follow-up in a large population is essential given the latency of 4-5 years between precursor lesions and HGSC. In this review, we provide an overview of the current knowledge on the origin, screening, and risk-reducing surgery for the prevention of tubo-ovarian cancers in high-risk women.

ObjectiveTreatment of high-grade serous ovarian carcinomas relies on surgery and chemotherapy, potentially followed by bevacizumab and/or poly (ADP-ribose) polymerase inhibitors (PARPi). The modeled CA-125 ELIMination rate constant K (KELIM) is a pragmatic indicator of tumor primary chemosensitivity. Although it is well established thatBRCAmutations are associated with platinum sensitivity, the relationship betweenBRCAstatus and KELIM score has yet to be elucidated. This study aimed to evaluate the interactions betweenBRCAand KELIM, and their respective prognostic values.MethodsWe retrospectively collected data from 743 patients with high-grade serous ovarian carcinomas included in a French nationwide registry (NCT03275298) treated with neoadjuvant platinum-based chemotherapy followed by surgery. We analyzed the interactions betweenBRCAand KELIM, and their impacts on progression-free survival and overall survival.ResultsBRCA-mutated(BRCAm) patients had higher standardized KELIM thanBRCA-wild type (BRCAwt) tumors (median 1.16 vs 1.06, respectively; p=0.001). The prognostic value of the KELIM score was independent ofBRCAin multivariate analyses. KELIM score andBRCAcould be combined to define three prognostic groups: (1) an unfavorable prognostic group with bothBRCAwt and unfavorable KELIM (median progression-free survival 12.0 months); (2) an intermediate prognostic group with eitherBRCAm and unfavorable KELIM, orBRCAwt and favorable KELIM (median progression-free survival of 16.0 and 18.8 months, respectively; HR 0.64 compared with the unfavorable group, p<0.001); and (3) a favorable prognostic group with bothBRCAm and favorable KELIM (median progression-free survival 28.8 months; HR 0.37 compared with the unfavorable group, p<0.001).ConclusionsThe KELIM score provides complementary prognostic information with respect toBRCA,and discriminates different prognoses withinBRCAm orBRCAwt patients. Patients with bothBRCAwt/unfavorable KELIM have a poor prognosis, underscoring the urgent need for novel therapeutic strategies.

La salpingo-ovariectomie prophylactique a longtemps été considérée comme la norme pour prévenir les cancers tubo-ovariens chez les populations à haut risque, comme les porteurs de mutations BRCA1/2. Malgré le bénéfice en termes de survie, ces procédures prophylactiques sont associées à des effets secondaires importants liés à la ménopause chirurgicale. Des études récentes suggèrent que la plupart des carcinomes séreux de haut grade, représentant la majorité des carcinomes ovariens, notamment chez les personnes génétiquement prédisposées, sont issus dans la trompe de Fallope. En conséquence, une stratégie alternative de réduction des risques a émergé : la fimbriectomie prophylactique suivie d’une ovariectomie différée. De nombreuses études ont examiné l’acceptabilité, les effets secondaires et la sécurité de cette procédure, avec des résultats prometteurs. Des recherches en cours s’intéressent aux effets à long terme sur la sexualité et le risque de carcinomes tubo-ovariens. Un suivi à long terme dans une grande population est essentiel, compte tenu de la latence de quatre à cinq ans entre les lésions précurseurs et les carcinomes séreux de haut grade. Dans cette revue, nous proposons un aperçu des connaissances actuelles sur l’origine, le dépistage et la chirurgie de réduction de risque prévention des cancers tubo-ovariens chez la femme à haut risque.

OBJECTIVE:Post-operative shoulder and subcostal pain are common after laparoscopic gynecologic surgery, often attributed to residual intraperitoneal carbon dioxide. This study aimed to evaluate whether active gas aspiration via a peritoneal drain reduces post-operative pain compared to standard manual gas evacuation. METHODS:We conducted a single-center, randomized, single-blind, phase III clinical trial at the Oscar Lambret Cancer Center (France) from January 2022 to November 2023. Women aged ≥18 years undergoing laparoscopic or robot-assisted gynecologic surgery were randomized 1:1 to receive either manual gas evacuation (control group) or active carbon dioxide aspiration using a subcostal drain connected to vacuum (experimental group). All patients underwent pulmonary recruitment maneuvers. The primary endpoint was the incidence of clinically significant shoulder/subcostal pain (Numeric Rating Scale [NRS] ≥3) within 24 hours post-operatively. Secondary endpoints included pain intensity over the first post-operative week, analgesic use, and adverse events. RESULTS:A total of 166 patients scheduled to undergo laparoscopy (82 control, 84 experimental) were enrolled in the trial. At 6 hours and 24 hours post-operatively, the proportion of patients experiencing NRS ≥3 shoulder/subcostal pain did not significantly differ between groups (6 hours: 5/82, 6.1%, vs 2/84, 2.4%; 24 hours: 8/70, 11.4%, in both arms). Maximum overall pain during the first 24 hours was also comparable (NRS ≥3: 42/82, 51.2%, vs 47/84, 56.0%, p = .54). Analgesic consumption, pain at day 30, and adverse event rates were not significantly different. No complications were attributed to the aspiration technique. CONCLUSIONS:In this randomized trial, active gas aspiration via a peritoneal drain did not significantly reduce post-operative shoulder or subcostal pain compared to standard manual gas evacuation in gynecologic laparoscopy. Given the low incidence of significant pain and the lack of added benefit, routine use of active aspiration drains is not supported in this surgical context.

AbstractUp to 40% of patients with estrogen receptor (ER)-positive breast cancer will develop resistance against the majority of current ER-directed therapies. Resistance can arise through various mechanisms such as increased expression levels of coregulators, and key mutations acquired in the receptor’s ligand binding domain rendering it constitutively active. To overcome these resistance mechanisms, we explored targeting the ER Activation Function 2 (AF2) site, which is essential for coactivator binding and activation. Using artificial intelligence and the deep docking methodology, we virtually screened > 1 billion small molecules and identified 290 potential AF2 binders that were then characterized and validated through an iterative screening pipeline of cell-based and cell-free assays. We ranked the compounds based on their ability to reduce the transcriptional activity of the estrogen receptor and the viability of ER-positive breast cancer cells. We identified a lead compound, VPC-260724, which inhibits ER activity at low micromolar range. We confirmed its direct binding to the ER-AF2 site through a PGC1α peptide displacement experiment. Using proximity ligation assays, we showed that VPC-260724 disrupts the interaction between ER-AF2 and the coactivator SRC-3 and reduces the expression of ER target genes in various breast cancer models including the tamoxifen resistant cell line TamR3. In conclusion, we developed a novel ER-AF2 binder, VPC-260724, which shows antiproliferative activity in ER-positive breast cancer models. The use of an ER-AF2 inhibitor in combination with current treatments may provide a novel complementary therapeutic approach to target treatment resistance in ER-positive breast cancer.

Introduction/Background Low grade serous ovarian cancer (LGSOC) is a rare entity which risk factors, treatment response and risk of relapse are partially understood. Currently available data suffer from small sample size and heterogeneous management, leading to limited knowledge. Mutlivariation Information-based Inductive Causation (MIIC) is a network learning method, able to analyze and exploit simultaneously and exhaustively a large number of patients data, to identify non visible correlation, without an a priori classification on the type of reconstructed network (causal or non-causal). The aim of this study was to identify new and unknown association on patients with a LGSOC using the MIIC algorithm, in order to develop new hypothesis. Methodology We conducted a multicenter retrospective study in 31 French healthcare centers between 2010 and 2017. We included all patients with a LGSOC, and collected clinical, histological, molecular, surgical and treatment data. The MIIC algorithm was applied to this database. Results 317 patients were included. Variables were selected and pre-processed as follow: Center, age, menopausal status, tabacco consumption, abdominal surgery history, BMI, previous lesion (borderline or de novo), ascitis, initialCA125 level, initial Peritoneal Carcinosis Index, sus mesocolic involvment, digestive resection, wide peritonectomy, number of nodes removed, positive nodes, Complete resection,FIGO stage, Estrogen Receptor, Progesteron Receptor, somatic BRCA mutation, BRAF mutation, KRAS mutation, MicroSatellite Instability, chemotherapy, Hyperthermic IntraPeritoneal Chemotherapy, Bevacizumab, endocrine therapy, recurrence and death status. Known or obvious associations such as age and menopausal status, ascitis, CA125, allowed us to perform quality control of the algorithm. In addition, new associations that were previously little known or unknown, and still unexplored, have been highlighted, such as relationship between menopausal status and wide peritonectomy or nodal involvement. Conclusion The use of MIIC algorithm on a large LGSOC database has enabled the identification of interesting hypothesis, and future research topics. Disclosures The authors have no conflict of interest to declare.

OBJECTIVE:The purpose of this study was to establish a consensus on the surgical technique for sentinel lymph node (SLN) dissection in cervical cancer. METHODS:A 26 question survey was emailed to international expert gynecological oncology surgeons. A two-step modified Delphi method was used to establish consensus. After a first round of online survey, the questions were amended and a second round, along with semistructured interviews was performed. Consensus was defined using a 70% cut-off for agreement. RESULTS:Twenty-five of 38 (65.8%) experts responded to the first and second rounds of the online survey. Agreement ≥70% was reached for 13 (50.0%) questions in the first round and for 15 (57.7%) in the final round. Consensus agreement identified 15 recommended, three optional, and five not recommended steps. Experts agreed on the following recommended procedures: use of indocyanine green as a tracer; superficial (with or without deep) injection at 3 and 9 o'clock; injection at the margins of uninvolved mucosa avoiding vaginal fornices; grasping the cervix with forceps only in part of the cervix is free of tumor; use of a minimally invasive approach for SLN biopsy in the case of simple trachelectomy/conization; identification of the ureter, obliterated umbilical artery, and external iliac vessels before SLN excision; commencing the dissection at the level of the uterine artery and continuing laterally; and completing dissection in one hemi-pelvis before proceeding to the contralateral side. Consensus was also reached in recommending against injection at 6 and 12 o'clock, and injection directly into the tumor in cases of the tumor completely replacing the cervix; against removal of nodes through port without protective maneuvers; absence of an ultrastaging protocol; and against modifying tracer concentration at the time of re-injection after mapping failure. CONCLUSION:Recommended, optional, and not recommended steps of SLN dissection in cervical cancer have been identified based on consensus among international experts. These represent a surgical guide that may be used by surgeons in clinical trials and for quality assurance in routine practice.

Objective: Brachytherapy of the vaginal dome is the recommended adjuvant treatment for intermediate-risk endometrial cancer. This study assessed the results of dosimetric planning of high-dose-rate brachytherapy exclusively in the first treatment session. Study design: This retrospective study included all patients who underwent hysterectomy for endometrial cancer followed by adjuvant brachytherapy of the vaginal dome between 2012 and 2015. Local recurrence rates, overall survival (OS) rates, recurrence-free survival (RFS) rates, and related acute and late toxicity rates were evaluated. Results: This analysis included 250 patients, of whom 208 were considered to be at high-intermediate risk of disease recurrence. After a median follow-up of 56 months, the cumulative incidence of local recurrence was 4.8% at 3 years [95% confidence interval (CI) 2.8-8.3] and 7.8% at 5 years (95% CI 4.8-12.6). The 5-year OS rate was 86.2% (95% CI 80.6-90.3), and the 5-year RFS rate was 77.5% (95% CI 71.1-82.7). Acute toxicity occurred in 20 (8%) patients, of which two patients had grade >= 3 toxicity. Only one patient (0.4%) presented with late grade >= 3 toxicity. Conclusion: These findings confirm the tolerability of this brachytherapy approach, indicating minimal cases of late grade >= 3 toxicity, associated with a good 5-year OS rate. With the advent of molecular prognostic factors, the current focus revolves around discerning those individuals who gain the greatest benefit from adjuvant therapy, and tailoring treatment more effectively.

Supplementary Table S1: Cloning and RT-PCR primers used in this study; Supplementary Figure S1: Luciferase and cell viability experiments with MR49C and PC3 cells; Supplementary Figure S2: ITC control experiment between AR-DBD and dsDNA; Supplementary Figure S3: ChIP-PCR analysis; Supplementary Figure S4: Quality control for ChIP experiments

PDF file, 109K, Inhibition of VPC-3022 against wild-type AR in HeLa-AR cells. HeLa-AR cells transfected with ARR3tk-luciferase reporter were treated with VPC-3022 for 24 hours in various concentrations in the presence of 0.1 nM R1881. Error bars indicate standard deviation.

5510 Background: Standard treatment for patients with first platinum-sensitive relapse of epithelial ovarian cancer (EOC) is based on surgery and second-line systemic chemotherapy (CT). The role of hyperthermic intra-peritoneal chemotherapy (HIPEC) remains uncertain. Methods: The CHIPOR multicentric randomized phase III trial (NCT01376752), conducted in 31 institutions, enrolled patients with a first platinum-sensitive relapse (platinum-free interval of ≥6 months) of EOC. Patients were treated with 6 cycles of platinum and taxane based CT ± bevacizumab, and those amenable to a complete cytoreductive surgery at the end of CT were enrolled and randomly assigned to receive HIPEC (cisplatin 75 mg/m² at 41°C for 60 min) or not. Randomization was performed during complete cytoreductive surgery, stratified by center, surgical outcome (no residual disease vs residual <0.25 cm), chemotherapy-free interval before relapse, and PARP inhibitor use (yes vs no). The primary endpoint was overall survival (OS). The target sample size was 404 evaluable patients, providing 80% power at 5% alpha after 268 deaths. Secondary endpoints included progression-free survival (PFS), peritoneal PFS, patient-reported outcomes, safety, and postoperative morbidity and mortality (≤60 days after surgery). Results: Between May 11, 2011, and May 14, 2021, 415 patients were randomized. Baseline characteristics were balanced between treatment arms. At the data cutoff (Jan 8, 2023), with a median follow-up of 6.2 years, 268 patients (65%) had died. Efficacy results are summarized below. Conclusions: HIPEC significantly improves OS and peritoneal PFS of women with first platinum-sensitive relapse of EOC treated with second-line platinum-based CT followed by secondary complete cytoreductive surgery. Ongoing analyses, including patient reported outcome, BRCA status, bevacizumab exposure, and subsequent therapy, will be presented. Clinical trial information: NCT01376752 . [Table: see text]

Ovarian cancer is the leading cause of death from gynecologic cancer worldwide. High-grade serous carcinoma (HGSC) is the most common and deadliest subtype of ovarian cancer. While the origin of ovarian tumors is still debated, it has been suggested that HGSC originates from cells in the fallopian tube epithelium (FTE), specifically the epithelial cells in the region of the tubal-peritoneal junction. Three main lesions, p53 signatures, STILs, and STICs, have been defined based on the immunohistochemistry (IHC) pattern of p53 and Ki67 markers and the architectural alterations of the cells, using the Sectioning and Extensively Examining the Fimbriated End Protocol. In this study, we performed an in-depth proteomic analysis of these pre-neoplastic epithelial lesions guided by mass spectrometry imaging and IHC. We evaluated specific markers related to each preneoplastic lesion. The study identified specific lesion markers, such as CAVIN1, Emilin2, and FBLN5. We also used SpiderMass technology to perform a lipidomic analysis and identified the specific presence of specific lipids signature including dietary Fatty acids precursors in lesions. Our study provides new insights into the molecular mechanisms underlying the progression of ovarian cancer and confirms the fimbria origin of HGSC.

Le linfoadenectomie fanno parte della stadiazione della maggior parte dei tumori ginecologici pelvici. La loro realizzazione per via laparoscopica, iniziata più di 20 anni fa, ha trasformato la loro morbilità. Nel tempo, gli approcci e i mezzi per realizzarle si sono diversificati. Le tecniche attuali sono descritte in dettaglio, sottolineando i punti critici, gli sviluppi o le opzioni e la gestione delle complicanze più comuni, al fine di consentire a qualsiasi chirurgo ginecologo-oncologo di eseguire una procedura appropriata e sicura.