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Background: Acrylamide is classified as a probable human carcinogen by the IARC but epidemiological evidence on the carcinogenicity of acrylamide from dietary sources is limited. This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort. Methods: This prospective cohort study included 80,597 French women (mean [SD] age at baseline: 40.8 [14] years) during a mean (SD) follow-up of 8.8 (2.3) years. Acrylamide intake was evaluated using repeated 24h dietary records (n= 5.5 [SD 3.0]), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal and post-menopausal) were assessed by Cox hazard models adjusted for known risk factors. Results: The mean (SD) dietary acrylamide intake was 30.1 (21.9) µg/d (main contributors: coffee, potato fries and chips, pastries and cakes, and bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between acrylamide intake and breast cancer risk overall (HRQ4 vs Q1= 1.21 [95% CI: 1.00-1.47]) and a positive association was observed with premenopausal cancer (HRQ4 vs Q1= 1.40 [95% CI: 1.04-1.88]). Restricted cubic spline analyses suggested evidence for non-linearity of these associations, with higher HR for intermediate (Q2) and high (Q4) exposures. Receptor-specific analyses revealed a positive association with estrogen receptor-positive breast cancer, which represented 86% of total cancer cases. Acrylamide intake was not associated with post-menopausal breast cancer. Conclusions: Results from this large prospective cohort study suggest the potential deleterious role of dietary acrylamide in breast cancer etiology, especially in premenopausal women, and provide new insights that should encourage further mitigation strategies to reduce the content of acrylamide in food. Citation Format: Alice Bellicha, Gaëlle Wendeu-Foyet, Xavier Coumoul, Meriem Koual, Fabrice Pierre, Françoise Guéraud, Laurent Zelek, Charlotte Debras, Bernard Srour, Laury Sellem, Emmanuelle Kesse-Guyot, Chantal Julia, Pilar Galan, Serge Hercberg, Mélanie Deschasaux-Tanguy, Mathilde Touvier. Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-06-03.

Breast cancer is a major public health issue and the role of pollutants in promoting breast cancer progression has recently been suggested. We aimed to assess if a mixture of pollutants, cigarette smoke, could favor the aggressivity of breast cancer cells. We also evaluated the impact of the tumor microenvironment, largely represented by adipocytes, in mediating this modification of cell phenotype. Breast cancer cells lines, MCF-7 were cultured using a transwell coculture model with preadipocytes hMADS cells or were cultured alone. Cells were treated with cigarette smoke extract (CSE) and the four conditions: control, treated by CSE, coculture, and coexposure (coculture and CSE) were compared. We analyzed morphological changes, cell migration, resistance to anoikis, stemness, epithelial-to-mesenchymal transition (EMT), and the presence of hormonal receptors in each condition. A complete transcriptomic analysis was carried out to highlight certain pathways. We also assessed whether the aryl hydrocarbon receptor (AhR), a receptor involved in the metabolism of xenobiotics, could mediate these modifications. Several hallmarks of metastasis were specific to the coexposure condition (cell migration, resistance to anoikis, stemness characterized by CD24/CD44 ratios and ALDH1A1 and ALDH1A3 rates) whereas others (morphological changes, EMT, loss of hormonal receptors) could be seen in the coculture condition and were aggravated by CSE (coexposure). Moreover, MCF-7 cells presented a decrease in hormonal receptors, suggesting an endocrine treatment resistance. These results were confirmed by the transcriptomic analysis. We suggest that the AhR could mediate the loss of hormonal receptor and the increase in cell migration

Acrylamide is classified as a probable human carcinogen by the International Agency for Research on Cancer but epidemiologic evidence on the carcinogenicity of acrylamide from dietary sources is limited.This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort, accounting for menopausal and hormone receptor status.This prospective cohort study included 80,597 French females (mean ± SD age at baseline: 40.8 ± 14 y) during a mean ± SD follow-up of 8.8 ± 2.3 y. Acrylamide intake was evaluated using repeated 24-h dietary records (n ± SD = 5.5 ± 3.0), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal, and postmenopausal) were assessed by Cox hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors).The mean ± SD dietary acrylamide intake was 30.1 ± 21.9 µg/d (main contributors: coffee, potato fries and chips, pastries, cakes, bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between dietary acrylamide exposure and breast cancer risk overall (HR for quartile 4 compared with 1: 1.21; 95% CI: 1.00, 1.47) and a positive association was observed with premenopausal cancer (HRQ4vs.Q1: 1.40; 95% CI: 1.04, 1.88). Restricted cubic spline analyses suggested evidence for nonlinearity of these associations, with higher HRs for intermediate (quartile 2) and high (quartile 4) exposures. Receptor-specific analyses revealed positive associations with estrogen receptor-positive breast cancer (total and premenopausal). Acrylamide intake was not associated with postmenopausal breast cancer.Results from this large prospective cohort study suggest a positive association between dietary acrylamide and breast cancer risk, especially in premenopausal females, and provide new insights that support continued mitigation strategies to reduce the content of acrylamide in food.This trial was registered at clinicaltrials.gov as NCT03335644.

During surgery for advanced epithelial ovarian cancer (EOC), the most important prognostic factor is the absence of residual tumor. Invisible microscopic peritoneal metastasis (mPM) are not removed during surgery and can be responsible of peritoneal recurrences. The aim of this current systematic review is to assess the role of fluorescence in evaluating mPM in EOC. We performed a systematic review using bibliographic citations from PubMed, Clinical Trials.gov, Embase, Cochrane Library, and Web of Science databases. MeSH terms for fluorescence, EOC and peritoneal carcinomatosis were combined and not restricted to the English language. The final search was performed on September 1rst, 2021. The primary outcome was to determine the diagnostic accuracy of fluorescence. We also reviewed the different techniques used. Eighty-seven studies were identified. Of these, 10 were included for analysis. The sensitivity and specificity of fluorescence ranged between 66.7-100% and 54.2-100%, respectively. Most importantly, the negative predictive value (NPV) ranged from 90 to 100% Due to the heterogeneity of the studies, no consensus was reached concerning the optimal use of fluorescence in terms of type of dye, type and timing of injection and imager to use. No adverse event was reported. Fluorescence can safely be used in EOC to evaluate mPM with a high NPV. However, a randomized controlled trial is needed to homogenize current practice.

International audience; Objective: To compare survival and morbidity rates between primary cytoreductive surgery (pCRS) and interval cytoreductive surgery (iCRS) for epithelial ovarian cancer (EOC), using a propensity score.Design: We conducted a propensity score-matched cohort study, using data from the FRANCOGYN cohort.Setting: Retrospective, multicentre study of data from patients followed in 15 French department specialized in the treatment of ovarian cancer.Sample: Patients included were those with International Federation of Gynaecology and Obstetrics (FIGO) stage III or IV EOC, with peritoneal carcinomatosis, having undergone CRS.Methods: The propensity score was designed using pre-therapeutic variables associated with both treatment allocation and overall survival (OS).Main outcome measures: The primary outcome was OS. Secondary outcomes included recurrence-free survival (RFS), quality of CRS and other variables related to surgical morbidity.Results: A total of 513 patients were included. Among these, 334 could be matched, forming 167 pairs. No difference in OS was found (hazard ratio, HR = 0.8, p = 0.32). There was also no difference in RFS (median = 26 months in both groups) nor in the rate of CRS leaving no macroscopic residual disease (pCRS 85%, iCRS 81.4%, p = 0.76). The rates of gastrointestinal tract resections, stoma, postoperative complications and hospital stay were significantly higher in the pCRS group.Conclusions: Analysis of groups of patients made comparable by propensity score matching showed no difference in survival, but lower postoperative morbidity in patients treated with iCRS.

International audience; Background: Despite recent advances in endometrial carcinoma (EC) molecular characterization, its prognostication remains challenging. We aimed to assess whether RNAseq could stratify EC patient prognosis beyond current classification systems.Methods: A prognostic signature was identified using a LASSO-penalized Cox model trained on TCGA (N = 543 patients). A clinically applicable polyA-RNAseq-based work-flow was developed for validation of the signature in a cohort of stage I-IV patients treated in two Hospitals [2010-2017]. Model performances were evaluated using time-dependent ROC curves (prediction of disease-specific-survival (DSS)). The additional value of the RNAseq signature was evaluated by multivariable Cox model, adjusted on high-risk prognostic group (2021 ESGO-ESTRO-ESP guidelines: non-endometrioid histology or stage III-IVA orTP53-mutated molecular subgroup).Results: Among 209 patients included in the external validation cohort, 61 (30%), 10 (5%), 52 (25%), and 82 (40%), had mismatch repair-deficient, POLE-mutated, TP53-mutated tumors, and tumors with no specific molecular profile, respectively. The 38-genes signature accurately predicted DSS (AUC = 0.80). Most disease-related deaths occurred in high-risk patients (5-years DSS = 78% (95% CI = [68%-89%]) versus 99% [97%-100%] in patients without high-risk). A composite classifier accounting for the TP53-mutated subgroup and the RNAseq signature identified three classes independently associated with DSS: RNAseq-good prognosis (reference, 5-years DSS = 99%), non-TP53 tumors but with RNAseq-poor prognosis (adjusted-hazard ratio (aHR) = 5.75, 95% CI[1.14-29.0]), and TP53-mutated subgroup (aHR = 5.64 [1.12-28.3]). The model accounting for the high-risk group and the composite classifier predicted DSS with AUC = 0.84, versus AUC = 0.76 without (p = 0.01).Conclusion: RNA-seq profiling can provide an additional prognostic information to established classification systems, and warrants validation for potential RNAseq-based therapeutic strategies in EC.

Resume De nouvelles approches therapeutiques moleculaires ont vu le jour ces dernieres annees pour les cancers gynecologiques avances parmi lesquels les inhibiteurs de poly-ADP-ribose-polymerases (PARPi). Ceux-ci ont demontre une efficacite dans les cancers sereux de haut grade ovarien chez les patientes porteuses de mutation du gene de predisposition aux cancers notamment du sein et de l’ovaire BRCA. Les donnees cliniques et pre cliniques suggerent que l’activite des inhibiteurs de PARPi ne serait pas limitee aux tumeurs mutees BRCA et mettraient en jeu la voie de recombinaison homologue. Ces donnees soulevent la question de l’efficacite des PARPi dans les cancers de l’endometre et du col de l’uterus a des stades avances pour lesquels les options therapeutiques sont aujourd’hui limitees. A l’heure actuelle, il existe peu de donnees disponibles quant a l’activite des PARPi dans les cancers de l’endometre et du col de l’uterus mais certains resultats semblent prometteurs. Nous proposons dans cette revue une synthese des etudes disponibles concernant les PARPi dans le cancer de l’endometre et le cancer du col de l’uterus.

The initial management of early-stage ovarian cancer consists of staging surgery including pelvic and para-aortic lymphadenectomy. The use of the sentinel lymph node (SLN) procedure in this setting may decrease the morbidity associated with this surgery. The objective of this review was to evaluate the feasibility of the SLN procedure in ovarian cancer diagnosed at an early stage by comparing the different techniques used and their accuracy. A systematic literature search was performed on PubMed and ClinicalTrials.gov for articles in English or French about the SLN technique in ovarian cancer. Ten studies were included in the analysis, with a total of 179 patients. The main tracers used were Technetium-99m, indocyanine green, and patent blue, and the most common site of injection was the proper ovarian and unfundibulopelvic ligaments. The overall detection rate was 87.7%. Of the small number of cases of lymph node metastasis reported, the SLN procedure had a sensitivity of 90.9% and a negative predictive value of 98.8%. The sentinel node procedure appears to be feasible and safe and could be reliable in determining the lymph node status of patients with early-stage ovarian cancer.

Background Lymphadenectomy is debated in patients with ovarian cancer. The aim of our study was to evaluate the impact of lymphadenectomy in patients with high-grade serous ovarian cancer receiving neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). Methods A retrospective, unicentric study including all patients undergoing NACT and IDS was carried out from 2005 to 2018. Patients with and without lymphadenectomy were compared in terms of recurrence free survival (RFS), overall survival (OS), and complication rates. Results We included 203 patients. Of these, 133 had a lymphadenectomy (65.5%) and 77 had involved nodes (57.9%). Patients without a lymphadenectomy were older, had a more extensive disease and less complete CRS. No differences were noted between the lymphadenectomy and no lymphadenectomy group concerning 2-year RFS (47.4% and 48.6%, p = 0.87, respectively) and 5-year OS (63.2% versus 58.6%, p = 0.41, respectively). Post-operative complications tended to be more frequent in the lymphadenectomy group (18.57% versus 31.58%, p = 0.09). In patients with a lymphadenectomy, survival was significantly altered if the nodes were involved (positive nodes: 2-year RFS 42.5% and 5-year OS 49.4%, negative nodes: 2-year RFS 60.7% and 5-year OS 82.2%, p = 0.03 and p Conclusion Lymphadenectomy during IDS does not improve survival and increases post-operative complications.

International audience; International Federation of Gynecology and Obstetrics (FIGO) staging classification for stage IV epithelial ovarian cancer (EOC) separates stages IVA (pleural effusion) and IVB (parenchymal and/or extra-abdominal lymph node metastases). We aimed to evaluate its prognostic impact and to compare survival according to the initial metastatic location. We conducted a multicenter study between 2000 and 2020, including patients with a FIGO stage IV EOC. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and recurrence rates. We included 307 patients: 98 (32%) had FIGO stage IVA and 209 (68%) had FIGO stage IVB. The median OS and PFS of stage IVA patients were significantly lower than those of stage IVB patients (31 versus 45 months (p = 0.02) and 18 versus 25 months (p = 0.01), respectively). Recurrence rate was higher in stage IVA than IVB patients (65% versus 47% (p = 0.004)). Initial pleural involvement was a poor prognostic factor with a median OS of 35 months versus 49 months for patients without initial pleural involvement (p = 0.024). Patients with FIGO stage IVA had a worse prognosis than patients with FIGO stage IVB EOC. Pleural involvement appears to be relevant for predicting survival. We suggest a modification of the current FIGO staging classification.

Introduction Advanced epithelial ovarian cancer (EOC) is associated with high mortality and often managed first with neoadjuvant chemotherapy (NACT) followed by debulking surgery. Laparoscopic surgery with or without robotic assistance (Minimally Invasive Surgery (MIS)) may represent a beneficial option for these patients. The objective of this literature review is to clarify the place of MIS in the management of advanced EOC for selected patients. Method Pubmed, Cochrane and Clinicaltrials.gov online databases were used for this review, to select English or French published articles. Results We selected 11 original articles published between 2015 and 2020, 6 of which compared MIS and laparotomy. Among these 11 studies, 8 were retrospective cohorts, 2 were phase II trials, and one was a case-control study. In total, there were 3721 patients, of which 854 (23%) were treated with MIS. The robotic assistance was used with 224 patients (26%) of those MIS patients.Looking specifically at MIS patients, the laparoconversion rate was 9.5%, the rate of complete resection (CC-0) was 83.4%. Finally, the MIS complication rate was 1% intraoperatively and 12% postoperatively. The rate of complete resection, postoperative complication, as well as overall survival (OS) were comparable between patients treated with MIS or laparotomy. One study found an improved disease-free survival (DFS) in MIS versus laparotomy (18 months versus 12 months; p=0,027). Conclusion MIS seems feasible, effective, and reliable in comparison to laparotomy for the completion of cytoreductive surgery after NACT without compromising oncological safety. Prospective randomized controlled trials are needed to confirm the role of MIS in advanced EOC.

Introduction The benefit of a systematic lymphadenectomy is still debated in patients undergoing neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in ovarian cancer (OC). The objective of this study was to evaluate the predictive value of the pre-NACT and post-NACT CT in predicting definitive histological lymph node involvement. The prognostic value of a positive node on the CT was also assessed. Materiel and methods A retrospective, unicentric cohort study was performed including all patients with ovarian cancer who underwent NACT and IDS with a lymphadenectomy between 2005 and 2018. CT were analyzed blinded to pathology, and nodes with small axis ≥ 10 mm on CT were considered positive. Sensitivity (Se), specificity (Sp), and negative (NPV) and positive predictive values (PPV) and their CI95% were calculated. The 2-year recurrence free survival (RFS) and 5-year overall survival (OS) was compared. Results 158 patients were included, among which 92 (58%) had histologically positive lymph nodes. CT had a Se, Sp, NPV and PPV of 35%, 82%, 47% and 73% before NACT and 20%, 97%, 47% and 91% after NACT, respectively. Patients with nodes considered positive had a non-significant lower 2-year RFS and 5-year OS on the pre-NACT and post-NACT CT. Patients at ‘high risk’ (nodes stayed positive on the CT or became positive after NACT) also had a non-significant lower 2-year RFS and 5-year OS. Conclusion Presence of enlarged lymph nodes on CT is a weak indicator of lymph node involvement in patients with advanced ovarian cancer undergoing NACT. However, it could be used to assess prognosis.

Resumen El cancer de vulva, que afecta en la mayoria de los casos a mujeres de edad avanzada, es un cancer infrecuente, pero grave, debido a las caracteristicas de las pacientes en las que aparece. La cirugia es la piedra angular de su tratamiento y ha experimentado una reduccion de su morbilidad perioperatoria local y ganglionar con el desarrollo de la tecnica del ganglio centinela en los ultimos anos. El estatus ganglionar es un factor pronostico principal. El tratamiento quirurgico depende del estadio TNM (tumor, ganglios [node], metastasis). Para los estadios mayores a T1a, consiste en una vulvectomia radical, parcial o total, con el objetivo de obtener unos margenes de al menos 1 cm asociados a una evaluacion ganglionar sistematica. Por ultimo, los progresos de la radioterapia asociada a las tecnicas de quimiosensibilizacion permiten ofrecer alternativas terapeuticas aceptables a los estadios TNM mas avanzados.

Resumen El cancer del cuello uterino se debe a la infeccion cronica por el virus del papiloma humano (VPH), que se transmite por via sexual, y su tratamiento quirurgico se basa en la colpohisterectomia ampliada para los estadios precoces. Esta intervencion puede realizarse por laparotomia o por laparoscopia clasica o asistida por robot. La cirugia minimamente invasiva esta ampliamente extendida en la practica corriente. Aqui se describe la tecnica quirurgica de colpohisterectomia ampliada por laparoscopia que se utiliza en el centro de los autores de este articulo. A continuacion, se describen las principales complicaciones y una revision de la literatura sobre los resultados de estas tecnicas minimamente invasivas.

The role of the environment in breast cancer (BC) progression has recently been suggested. We aimed to assess if a mixture of pollutants, cigarette smoke, could favor its aggressivity. We also evaluated the impact of the micro-environment, largely represented by adipocytes, in mediating this.BC cells lines MCF-7 were cultured using a transwell co-culture model with preadipocytes hMADS cells or were cultured alone. Cells were treated by cigarette smoke extract (CSE) and the four conditions: control, CSE, co-culture and co-exposure (co-culture and CSE) were compared. We analyzed morphological changes, cell migration, resistance to anoikis, stemness, epithelial to mesenchymal transition (EMT) and presence of hormonal receptors in each condition. A complete transcriptomic analysis was carried out to highlight certain pathways.Several hallmarks of metastasis were specific to the coexposure condition (cell migration, resistance to anoikis, stemness) whereas others (morphological changes, EMT, loss of hormonal receptors) could be seen in the coculture condition and were aggravated by CSE (coexposure). Moreover, MCF-7 cells presented a decrease in hormonal receptors, suggesting an endocrine treatment resistance. These results were confirmed by the transcriptomic analysis. Our in vitro results suggest that a common mixture of pollutants could promote BC metastasis in a co-culture model.

Fertility-sparing treatment in patients with cervical cancer should, in principle, follow identical algorithms to that in patients without future reproductive plans. In recent years, a trend towards non-radical procedures such as conization or simple trachelectomy has become apparent in medical literature, because of their associations with better pregnancy outcomes. However, the published reports included small numbers of patients and heterogenous treatment strategies to ascertain safety of such approaches.Our aims were to collect multi-institutional data regarding the oncological outcomes after fertility-sparing treatment in cervical cancer patients and to identify prognostic risk factors, including the influence of the radicality of individual cervical procedures.Patients aged 18-40 years with FIGO 2018 stage IA1 + lymphovascular space invasion or ≥IA2 cervical cancer who underwent any type of fertility-sparing procedure were eligible for this retrospective observational study, regardless of their histotype, tumor grade, and history of neoadjuvant chemotherapy. Associations between disease- and treatment-related characteristics with the risk of recurrence were analyzed.A total of 733 patients from 44 institutions across 13 countries were included in this study. Almost half of the patients had stage IB1 cervical cancer (49%), and two-thirds were nulliparous (66%). After a median follow-up of 72 months, 51 patients (7%) experienced recurrence of whom 19 (2.6%) died due to the disease. The most common sites of recurrence were the cervix (53%) and pelvic nodes (22%). The risk of recurrence was three times higher in patients with tumors2 cm in size than in patients with smaller tumors, irrespective of the treatment radicality (19.4% vs. 5.7%; hazard ratio 2.982, 95% CI 1.383-6.431, P = .005). The recurrence risk in patients with tumors ≤2 cm in size did not differ between patients who underwent radical trachelectomy or non-radical (conization and simple trachelectomy) cervical procedures (P = .957), regardless of tumor size subcategory (1 or 1-2 cm) or lymphovascular space invasion.Fertility-sparing non-radical cervical procedures were not associated with increased risk of recurrence compared with radical procedures in patients with tumors ≤2 cm in size in this large, multicenter retrospective study. The risk of recurrence after any type of fertility-sparing procedure was significantly greater in patients with tumors2 cm in size.

International audience; Introduction: Adjuvant therapeutic decisions in older endometrial carcinoma (EC) patients are challenged by a balance between more frequent aggressive EC and comorbidities. We assessed whether EC and comorbidities are competing or cumulative risks in older EC patients.Methods: All consecutive patients treated for FIGO stage I-IV EC in two University Hospitals in Paris between 2010 and 2017 were retrospectively included. Patients were categorized as: 70y without comorbidity (fit), and > 70y with a Charlson comorbidity index>3 (comorbid). Association between high-risk EC (2021-ESGO-ETRO-ESP) or comorbidity, and disease-specific-survival (DSS), was evaluated using Cox model (estimation of cause-specific hazard ratio (CSHR), and Fine-Gray model (subdistribution HR) to account for competing events (death unrelated with EC).Results: Overall, 253 patients were included (median age = 67y, IQR[59-77], median follow-up = 61.5 months, [44.4-76.8]). Among them, 109 (43%) were categorized at high-risk (proportion independent of age), including 67 (26%) who had TP53-mutated tumors. Comorbidity and high-risk group were both associated with all-cause mortality (HR = 4.09, 95%CI[2.29; 7.32] and HR = 3.21, 95%CI [1.69; 6.09], respectively). By multivariate analysis, patients with high-risk EC exhibited poorer DSS, regardless of age/comorbidity (Adjusted-CSHR = 6.62, 95%CI[2.53;17.3]; adjusted-SHR = 6.62 95%CI[2.50;17.5]). Patients>70y-comorbid with high-risk EC had 5-years cumulative incidences of EC-related and EC-unrelated death of 29% and 19%, respectively. In patients

Introduction Sentinel lymph node biopsy (SLN) helps define lymph node status, a major prognostic factor in vulvar cancer. The aim of the current systematic review was to assess the use of indocyanine green (ICG) coupled with near-infrared (NIR) fluorescence imaging in SLN mapping in vulvar cancer in terms of technique used, feasibility and accuracy. Data sources We performed a systematic review using bibliographic citations from PubMed, Clinical Trials.gov , Embase, Cochrane Library, and Web of Science databases. MeSH terms for SLN, ICG and vulvar cancer were combined and restricted to the English language. The final search was performed on May 28, 2020. The primary outcome was to determine if the use of ICG alone in detecting SLN in women with vulvar cancer is as accurate as the gold standard dual labeling technique. Results Of the 34 studies initially identified, 13 were included for analysis. The SLN detection rate with ICG and NIR fluorescence ranged from 89.7 to 100%. No studies demonstrated the superiority of other detection techniques compared to ICG and NIR imaging. Lower SLN detection rates were found in studies with the most metastatic lymph nodes. No consensus was reached concerning the optimal use of ICG in terms of: injection timing or site; concentrations or volume of ICG; or use of human serum albumin or hybrid tracer. No adverse events were reported. Conclusion ICG for SLN mapping appears to be safe in women with vulvar cancer with a detection rate similar to the current techniques. A large prospective randomized controlled study with optimization of the technique is necessary to homogenize current practice and determine the true value of ICG in vulvar cancer. PROSPERO ID CRD42020178261.

International audience; Background: Molecular alterations leading to homologous recombination deficiency (HRD) are heterogeneous. We aimed to identify a transcriptional profile shared by endometrial (UCEC), breast (BRCA) and ovarian (OV) cancers with HRD.Methods: Genes differentially expressed with HRD genomic score (continuous gHRD score) in UCEC/BRCA/OV were identified using edgeR, and used to train a RNAseq score (ridge-regression model) predictive of the gHRD score (PanCanAtlas, N = 1684 samples). The RNAseq score was applied in independent gynaecological datasets (CARPEM/CPTAC/SCAN/TCGA, N = 4038 samples). Validations used ROC curves, linear regressions and Pearson correlations. Overall survival (OS) analyses used Kaplan-Meier curves and Cox models.Results: In total, 656 genes were commonly up/downregulated with gHRD score in UCEC/BRCA/OV. Upregulated genes were enriched for nuclear/chromatin/DNA-repair processes, while downregulated genes for cytoskeleton (gene ontologies). The RNAseq score correlated with gHRD score in independent gynaecological cancers (R² = 0.4-0.7, Pearson correlation = 0.64-0.86, all P < 10-11), and was predictive of gHRD score >42 (RNAseq HRD profile; AUC = 0.95/0.92/0.78 in UCEC/BRCA/OV). RNAseq HRD profile was associated (i) with better OS in platinum-treated advanced TP53-mutated-UCEC (P < 0.001) and OV (P = 0.013), and (ii) with poorer OS (P < 0.001) and higher benefit of adjuvant chemotherapy in Stage I-III BRCA (interaction test, P < 0.001).Conclusions: UCEC/BRCA/OV with HRD-associated genomic scars share a common transcriptional profile. RNAseq signatures might be relevant for identifying HRD-gynaecological cancers, for prognostication and for therapeutic decision.

Resume Le statut ganglionnaire est le facteur pronostique le plus important chez les patientes atteintes d’un cancer du col uterin aux stades precoces. Le prelevement du ganglion sentinelle est une technique precise permettant d’evaluer le risque d’envahissement ganglionnaire en substitution aux curages pelviens systematiques. Une chirurgie ganglionnaire moins agressive permet de diminuer la morbidite induite par les curages pelviens, en particulier le risque de lymphœdeme des membres inferieurs. L’analyse histologique du ganglion sentinelle permet une ultrastadification qui identifie de faibles volumes tumoraux (cellules tumorales isolees et micrometastases). Sur le plan anatomique, la technique du ganglion sentinelle fournit des informations plus precises sur le drainage lymphatique des tumeurs du col en identifiant des nœuds lymphatiques en dehors des zones de curages classiques. La selection d’une population de patientes a faible risque d’atteinte ganglionnaire, une courbe minimale d’apprentissage et des regles simples garantissent un faible taux de faux negatifs. Plusieurs etudes ont montre que la technique du ganglion sentinelle est faisable, avec d’excellents taux de detection et de sensibilite. La technique combinee avec le technetium-99 et le bleu patente est largement utilisee mais la methode par fluorescence recemment introduite a montre de meilleurs taux de detection des ganglions sentinelles. Bien que les principales recommandations internationales recentes incitent a un prelevement du ganglion sentinelle en complement du curage pelvien, le prelevement exclusif du ganglion sentinelle n’est pas encore la reference, du au manque de donnees prospectives sur la survie sans recidive. Certains points sont encore discutes, tels que la valeur de l’examen extemporane du ganglion sentinelle et l’impact a long terme des micrometastases. L’essai prospectif randomise SENTICOL III devrait repondre a ces problematiques.

Resumen El tratamiento del cancer de endometrio esta bien codificado, en particular con las recomendaciones de la Societe Francaise d’Onco-Gynecologie-College National des Gynecologues et Obstetriciens Francais (SFOG-CNGOF) publicadas en 2017. Se recomienda la cirugia minimamente invasiva, especialmente para los estadios 1 y, si se cumplen algunas condiciones, para los estadios 2. Se debe comprobar antes de la intervencion la factibilidad tecnica, con una evaluacion preterapeutica que conste de una resonancia magnetica (RM) y de una exploracion fisica en la consulta y, despues, bajo anestesia general antes de comenzar la intervencion. Los autores de este articulo detallan las diferentes etapas de la histerectomia por laparoscopia en el tratamiento del cancer de endometrio, los procedimientos que se pueden asociar y el postoperatorio previsible.

Resume Les patientes porteuses d’une mutation du gene BReast Cancer 1 ou 2 (BRCA) ont une predisposition hereditaire aux cancers du sein et de l’ovaire. Ces mutations genetiques deleteres sont celles les plus couramment impliquees dans les cancers hereditaires du sein et de l’ovaire. La consultation d’oncogenetique joue un role cle dans l’identification des patientes a risque et la recherche et l’identification de la mutation chez la patiente et ses apparentes. La mise en evidence d’une mutation BRCA doit conduire a une surveillance rapprochee et peut justifier d’une chirurgie prophylactique mammaire et/ou annexielle dont les indications et les modalites sont detaillees par l’Institut national du cancer (INCa). Les inhibiteurs de poly-(ADN-riboses) polymerases (PARP), dont le plus connu est l’olaparib ont une efficacite majeure dans la prise en charge des cancers epitheliaux de l’ovaire chez les patientes porteuses d’une mutation BRCA et les nombreuses etudes en cours elargiront probablement les indications dans un futur proche.

Introduction/Background* Because of inter-tumor heterogeneity of endometrial carcinoma (EC), prognostication remains challenging. We aimed to develop a RNAseq signature to stratify EC patient prognosis beyond molecular subtyping. Methodology A prognostic signature was identified using a LASSO-penalized Cox regression model on TCGA (N=543 patients). A polyA-RNAseq-based method was developed for validation of the signature in a cohort of stage I-IV EC patients treated in two Paris Hospitals between 2010 and 2017. Model performances were evaluated using time-dependent ROC curves (prediction of disease-specific-survival (DSS)). The additional value of the RNAseq signature was evaluated using uni/multivariable Cox models (hazard ratio (HR) with [95% confidence interval]) and Kaplan-Meier analysis. Result(s)* Among 209 patients included in the validation cohort (median follow-up 55 months IQR [41-69]), 61 (30%), 10 (5%), 52 (25%), and 82 (40%), had mismatch repair-deficient, POLE-mutated, TP53-mutated tumors, and tumors with no specific molecular profile, respectively. The 38-genes signature accurately predicted DSS (AUC=80%). Using a composite classifier accounting for the RNAseq signature and the TP53-mutated group, three groups were identified: good prognosis tumors based on RNAseq signature and without TP53 mutation, characterized by excellent outcome (N=103 patients, 5-years DSS rates of 99%) (reference), poor prognosis tumors based on RNAseq signature and without TP53 mutation (N=49 patients, 5-years DSS rates of 81%; HR: 5.86 [1.16; 29.7]), and TP53-mutated tumors whatever the RNAseq signature (N=52 patients, 5-years DSS rates of 52%; HR: 11.14 [2.40; 51.7]) (HR adjusted on FIGO stage). In 81 (38%) patients with adverse features (2020 ESGO/ESTRO/ESP guidelines: non-endometrioid histology or stage III-IVA or TP53-mutated tumors), TP53-mutated molecular group was not significantly associated with poor prognosis (p=0.18). A The composite classifier identified three classes within this subgroup: RNAseq-good prognosis (N=24), non-TP53/RNAseq-poor prognosis (N=16), and TP53-mutated tumors (N=41), with 5-years DSS rates of 100%, 59%, and 71%, respectively (p=0.015). Transcriptome analyses suggested the underlying involvement of immune deprivation and wound healing processes in tumors with poor prognosis. Conclusion* We demonstrate that RNAseq characterization can refine prognostication in EC beyond molecular subgroups and main prognostic features, and warrants validation for potential RNAseq-based adjuvant therapeutic strategies in EC.

Introduction/Background* Recent findings have suggested that lymphadenectomy during primary cytoreductive surgery (CRS) in patients with ovarian cancer was not associated with an improve in survival, at the expense of a high morbidity. The aim of our study was to evaluate the impact of lymphadenectomy in patients with high-grade serous ovarian cancer benefitting from neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). Methodology A retrospective, unicentric study including all patients undergoing NACT and IDS was carried out from 2005-2018. Patients with and without lymphadenectomy were compared in terms of recurrence free survival (RFS), overall survival (OS), and complication rates. Survival was assessed using a Cox regression model and Kaplan Meyer curves. Result(s)* We included 203 patients. Of these, 133 had a lymphadenectomy (65.5%) and 77 had involved nodes (57.9%). Patients who did not benefit from a lymphadenectomy were older with a more extensive disease and lesser rate of complete CRS. No differences were noted between the lymphadenectomy and no lymphadenectomy group concerning 2-year RFS (47.4% and 48.6%, p=0.87, respectively) and 5-year OS (63.2% versus 58.6%, p=0.41, respectively). Post-operative complications tended to be more frequent in the group with a lymphadenectomy (18.57 versus 31.58, p=0.09). In the group of patients with lymphadenectomy, survival was significantly altered in patients with involved nodes (positive lymph nodes: 2-year RFS 42.5% and 5-year OS 49.4%, negative nodes: 2-year RFS 60.7% and 5-year OS 82.2%, p= 0.03 and p Conclusion* Lymphadenectomy during IDS does not improve survival and increases post-operative complications.

Introduction/Background* The benefit of a systematic lymphadenectomy is still debated in patients undergoing neo-adjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in ovarian cancer (OC). The objective of this study was to evaluate the predictive value of the pre-NACT and post-NACT CT in predicting definitive histological lymph node involvement. The prognostic value of a positive node on the CT was also assessed. Methodology A retrospective, unicentric cohort study was performed including all patients with ovarian cancer who underwent NACT and IDS with a lymphadenectomy between 2005-2018. CT were analyzed blinded to pathology, and nodes with small axis ≥ 10 mm on CT were considered positive. Sensitivity (Se), specificity (Sp), and negative (NPV) and positive predictive values (PPV) and their CI95% were calculated. The 2-year recurrence free survival (RFS) and 5-year overall survival (OS) was compared. Result(s)* 158 patients were included, among which 92 (58%) had histologically positive lymph nodes. CT had a Se, Sp, NPV and PPV of 35%, 82%, 47% and 73% before NACT and 20%, 97%, 47% and 91% after NACT, respectively. Patients with nodes considered positive had a non-significant lower 2-year RFS and 5-year OS on the pre-NACT and post-NACT CT. Patients at ‘high risk’ (nodes stayed positive on the CT or became positive after NACT) also had a non-significant lower 2-year RFS and 5-year OS. Conclusion* Presence of enlarged lymph nodes on CT is a weak indicator of lymph node involvement in patients with advanced ovarian cancer undergoing NACT. However, it could be used to assess prognosis.

The aryl hydrocarbon receptor (AhR) is a transcriptional factor that regulates multiple functions following its activation by a variety of ligands, including xenobiotics, natural products, microbiome metabolites, and endogenous molecules. Because of this diversity, the AhR constitutes an exposome receptor. One of its main functions is to regulate several lines of defense against chemical insults and bacterial infections. Indeed, in addition to its well-established detoxication function, it has several functions at physiological barriers, and it plays a critical role in immunomodulation. The AhR is also involved in the development of several organs and their homeostatic maintenance. Its activity depends on the type of ligand and on the time frame of the receptor activation, which can be either sustained or transient, leading in some cases to opposite modes of regulations as illustrated in the regulation of different cancer pathways. The development of selective modulators and their pharmacological characterization are important areas of research. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Background: Growing epidemiological evidence suggests that organochlorine chemicals (OCCs), including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may play a role in the pathogenesis of endometriosis. Objectives: We aimed to systematically review the experimental evidence (in vivo and in vitro) on the associations between exposure to OCCs and endometriosis-related end points. Methods: A systematic review protocol was developed following the National Toxicology Program /Office of Health Assessment and Translation (NTP/OHAT) framework and managed within a web-based interface. In vivo studies designed to evaluate the impact of OCCs on the onset or progression of endometriosis and proliferation of induced endometriotic lesions were eligible. Eligible in vitro studies included single-cell and co-culture models to evaluate the proliferation, migration, and/or invasion of endometrial cells. We applied the search strings to PubMed, Web of Science, and Scopus®. A final search was performed on 24 June 2020. Assessment of risk of bias and the level of evidence and integration of preevaluated epidemiological evidence was conducted using NTP/OHAT framework Results: Out of 812 total studies, 39 met the predetermined eligibility criteria (15 in vivo, 23 in vitro, and 1 both). Most studies (n=27) tested TCDD and other dioxin-like chemicals. In vivo evidence supported TCDD’s promotion of endometriosis onset and lesion growth. In vitro evidence supported TCDD’s promotion of cell migration and invasion, but there was insufficient evidence for cell proliferation. In vitro evidence further supported the roles of the aryl hydrocarbon receptor and matrix metalloproteinases in mediating steroidogenic disruption and inflammatory responses. Estrogen interactions were found across studies and end points. Conclusion: Based on the integration of a high level of animal evidence with a moderate level of epidemiological evidence, we concluded that TCDD was a known hazard for endometriosis in humans and the conclusion is supported by mechanistic in vitro evidence. Nonetheless, there is need for further research to fill in our gaps in understanding of the relationship between OCCs and their mixtures and endometriosis, beyond the prototypical TCDD. https://doi.org/10.1289/EHP8421

International audience; La formation à l'éthique de la recherche et à l'intégrité scientifique des doctorants au cours de leur formation, toutes spécialités confondues, est obligatoire depuis 2016. Elle est confiée aux écoles doctorales, qui sont libres d'organiser cet enseignement comme elles le souhaitent. Nous avons réalisé une étude auprès de l'ensemble des écoles doctorales de France afin de connaître les modalités de cette formation en 2018. Il apparaît que ces écoles sont bien engagées dans cet enseignement sur l'ensemble du territoire et que la tendance est à son renforcement, ce qui témoigne d'une prise de conscience générale de l'importance de ces sujets pour la recherche de demain.

New molecular therapeutic approaches have emerged in recent years for advanced gynaecological cancers, including targeted therapies such as poly-ADP-ribose polymerase inhibitors (PARPi). These have demonstrated efficacy in high-grade serous ovarian cancers in patients carrying a mutation in the BRCA gene, which predisposes them to breast and ovarian cancers. Clinical and pre-clinical data suggest that the activity of PARPi inhibitors may not be limited to BRCA mutated tumours and may involve the homologous recombination pathway. These data raise the question of the potential efficacy of PARPi in advanced endometrial and cervical cancers where treatment options are currently limited. At present, there are few data available on the activity of PARPi in endometrial and cervical cancers, but some results seem promising. In this review, we present a synthesis of the available studies concerning PARPi in endometrial and cervical cancer.

Background: Breast cancer (BC) is a major public health concern, and its prognosis is very poor once metastasis occurs. The tumor microenvironment and chemical pollution have been suggested recently to contribute, independently, to the development of metastatic cells. The BC microenvironment consists, in part, of adipocytes and preadipocytes in which persistent organic pollutants (POPs) can be stored. Objectives: We aimed to test the hypothesis that these two factors (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an extensively studied, toxic POP and the microenvironment) may interact to increase tumor aggressiveness. Methods: We used a co-culture model using BC MCF-7 cells or MDA-MB-231 cells together with hMADS preadipocytes to investigate the contribution of the microenvironment and 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD on BC cells. Global differences were characterized using a high-throughput proteomic assay. Subsequently we measured the BC stem cell–like activity, analyzed the cell morphology, and used a zebrafish larvae model to study the metastatic potential of the BC cells. Results: We found that coexposure to TCDD and preadipocytes modified BC cell properties; moreover, it induced the expression of ALDH1A3, a cancer stem cell marker, and the appearance of giant cancer cells with cell-in-cell structures (CICs), which are associated with malignant metastatic progression, that we demonstrated in vivo. Discussion: The results of our study using BC cell lines co-cultured with preadipocytes and a POP and an in vivo zebrafish model of metastasis suggest that the interactions between BC cells and their microenvironment could affect their invasive or metastatic potential. https://doi.org/10.1289/EHP7102