Exploring uterine involvement in hysterectomy samples following conization for adenocarcinoma in situ of the uterine cervix: Insights from a multicenter study by the FRANCOGYN group.

BACKGROUND: Adenocarcinoma in situ (AIS) of the cervix can progress to invasive adenocarcinoma. While hysterectomy is standard, conservative management may be considered for women desiring future pregnancies. This study aimed to determine the prevalence of residual disease in hysterectomy specimens following excisional therapy with clear margins for AIS. METHODS: A retrospective FRANCOGYN cohort study was conducted on patients who underwent a hysterectomy after conization with clear margins for AIS between 2008 and 2021. The primary goal was to assess the prevalence of residual disease in the hysterectomy specimens. Secondary objectives included identifying preoperative predictors of residual disease and comparing recurrence rates between patients with and without residual disease. RESULTS: Of 53 hysterectomies performed after conization with negative margins for AIS, 20.8% (11/53) showed residual disease in the final histology. None of the patients had invasive cancer. In the residual disease group, 18% (2/11) had persistent CIN 3, and 82% (9/11) had persistent AIS. These patients tended to have higher BMI (27.5 kg/m² vs. 23.6 kg/m², p=0.04) and shorter endocervical margins (2mm vs. 5mm, p=0.01). No recurrences were observed during follow-up. CONCLUSION: Despite clear margins on the initial conization for AIS, 20% of patients had residual disease in their hysterectomy samples, though no invasive cancer was found. A hysterectomy should be considered after completing childbearing, even if initial margins are clear.

Margin status after loop electrosurgical excision procedure (LEEP) and laser excision in patients with high-grade cervical neoplasia.

INTRODUCTION: Early management of high-grade cervical intraepithelial neoplasia is one of the key steps in cervical cancer prevention after vaccination and screening. It relies on lesion removal by surgical excision, and the French National Cancer Institute (INCa) in 2016 recommend using a loop electro excision procedure (LEEP). However, the laser excision method seems to be as effective with similar rates of negative excision margins and postoperative clearance of HPV. OBJECTIVE: The main objective of our study was to compare the laser excision method to LEEP by evaluating the quality of the surgical margins. We also studied factors associated with the status of the margins and the depth of cones. METHODS: We conducted a retrospective unicentric study between 2009 and 2017. RESULTS: Two hundred and thirty-one patients were included: 154 laser excisions and 77 LEEP. Negative surgical margin was achieved in 69.5 % of laser excisions and 72.7 % of LEEP (p = 0.649). Concerning factors predicting margin status, only a greater cone depth was associated with negative margins (OR: 0.91 (95 %CI: 0.84, 0.89); p = 0.02). The surgical technique was not found to be associated with the status of the margins (OR: 0.85 (95 %CI: 0.46,1.56); p = 0.61). Concerning factors predicting cone depth, only the LEEP was associated with a shorter cone depth (OR: 0.24 (95 %CI: 0.08, 0.69); p 0.008). Significant results are based on univariate analysis. CONCLUSION: No difference was found between the two technics concerning the rate of negative margins. However, LEEP seems to be associated with shorter cone depth in this study.

Clinical use of Indocyanine green fluorescence method for sentinel lymph node biopsy in breast cancer in France in 2021.

INTRODUCTION: Indocyanine green (ICG) for axillary sentinel lymph node (SLN) detection in early breast cancer is at least equivalent to radioisotopic and/or colorimetric techniques. This procedure has not yet been recommended by learned societies in France. Following the recent drug approval of Infracyanin ® in this indication, we wished to study the use of ICG in France. METHODS: We conducted a web-based survey among members of multiple French breast cancer societies throughout November 2021. The survey assessed the profile of the respondent, the use or not of ICG for the detection of SLN in breast cancer, the technique used and the opinion of non-users and their expectations on the subject. RESULTS: Seventy-five surgeons participated. More than a third (37 %) have been using ICG for the detection of SLN in breast cancer for 2 to 3 years. Technique was highly variable. According to 82.1 % of the respondents, less than 20 procedures are necessary to master the use of ICG. The main advantage reported for this method is the reduction of organizational constraints. The obstacles to the use of the ICG are the near infra-red camera equipment, but also the lack of validation by the French guidelines. Among non-users, 83 % would like to develop this technique in their center and 72.3 % are interested in training on this subject. CONCLUSION: This work highlights the need for French learned societies to take a stand on this issue but also the need to carry out studies on the technical aspects in order to standardise practices.

What is the most pertinent definition of malnutrition in epithelial ovarian cancer to assess morbidity and mortality?

INTRODUCTION: Malnutrition is common in ovarian cancer and is a major cause of morbidity and mortality. We aimed to define the most pertinent way to assess malnutrition in patients with epithelial ovarian cancer (EOC) in order to study its impact on morbidity (intra and post-operative complications) and survival (OS, overall survival and RFS, recurrence-free survival). METHODS: We retrospectively included all patients with EOC from 2003 to 2020. Nutritional status was assessed using the weight loss at diagnosis (more or <5%), albuminemia, the Nutritional Risk Index (NRI), and the Malnutrition Universal Screening Tool (MUST). RESULTS: Six hundred and fifteen patients were included. Among them, 34% declared having lost >5% of their usual weight, 58% had an albuminemia <35 g/L, 86% presented an abnormal NRI and 29% an abnormal MUST score. After univariate analysis, weight loss>5% appeared to be significantly associated with RFS. An abnormal NRI or MUST score were significantly associated with a decrease in OS in univariate analysis. None of the markers of malnutrition studied were correlated with morbidity. CONCLUSION: We were not able to reach a consensus concerning the most accurate definition to define malnutrition and predict morbidity and mortality in EOC. However, this modifiable prognosis factor must be systematically assessed and managed accordingly.

Environmental health in medical schools in France: A call from medical students.

OBJECTIVE: Environmental factors contribute to more than 25% of all global disease but as medical student, we consider that environmental health is insufficiently taught. We are not armed for facing patient's questions, prevent diseases linked to environmental exposure and adapt care in susceptible population. MATERIAL AND METHODS: We conducted a national French survey, using a web-based questionnaire from October to November 2021. All medical students were interrogated to assess their knowledge on environmental health and their desire to obtain a specific curriculum on this topic. RESULTS: Two hundred and thirty-two students responded to the survey and most (62.7%) had never had any teaching on environmental health during their medical studies. The majority claimed to have no knowledge on environmental health (63.6%), and most had never been read or seen media content about it (59.2%). Those who had knowledge on environmental health, had been informed through social media, questioning the reliability of this content. Most (87.3%) were ready to take a specific course on environmental health issues during their medical studies in order to better inform their patients with evidence-based medicine and identify at risk population. CONCLUSION: Through a survey, we identified the need and the emergency of implanting a curriculum on environmental medicine in our medical education.

The Role of the Kynurenine/AhR Pathway in Diseases Related to Metabolism and Cancer.

The Aryl hydrocarbon receptor (AhR) is a xenobiotic and endobiotic receptor, which regulates many cellular processes from contaminant metabolism to immunomodulation. Consequently, it is also involved in pathophysiological pathways and now represents a potential therapeutical target. In this review, we will highlight the ancestral function of the protein together with an illustration of its ligand's battery, emphasizing the different responses triggered by these high diverse molecules. Among them, several members of the kynurenine pathway (one key process of tryptophan catabolism) are AhR agonists and are subsequently involved in regulatory functions. We will finally display the interplay between Tryptophan (Trp) catabolism and dysregulation in metabolic pathways drawing hypothesis on the involvement of the AhR pathway in these cancer-related processes.

Patterns of recurrence in surgically treated women for TP53-mutated endometrial carcinomas.

OBJECTIVE: To describe the patterns of recurrence and the prognosis of patients with a recurrent TP53 mutated endometrial carcinoma treated initially by surgery. METHODS: All patients with endometrial carcinoma, treated at hospital European Georges Pompidou between 2001 and 2021 were retrospectively included. Patients were separated into two groups: TP53-mutated and not TP53-mutated (POLE/ultramutated-like (POLEmut), dMMR (mismatch repair-deficient) and NSMP (No specific molecular profile)). We estimated survival using recurrence free survival, overall survival and overall survival from recurrence. The risk of recurrence according to TP53 status and the type of recurrence (locoregional recurrence, peritoneal recurrence, and metastasis) were also compared between the two groups. RESULTS: Two hundred and ninety-one patients with endometrial carcinoma were included. Of these, 57 were TP53-mutated and 234 patients were not TP53-mutated. TP53 mutated patients had the worst recurrence free survival and overall survival (p < 0.001 for each). The hazard rate of recurrence was higher during the first three years for TP53 mutated endometrial carcinoma then tend to join the one of no TP53 mutated. There was a statistical difference between the two groups in terms of cumulative incidence of peritoneal recurrence (p = 0.002). There was, however, no statistical difference in overall survival from recurrence. CONCLUSIONS: TP53-mutated endometrial carcinoma were more likely to experience a recurrence during the first three years and most often peritoneal recurrence compared to not TP53-mutated. TP53 status in endometrial carcinoma could be useful to define follow-up. Further prospective studies are required to assess the predictive impact of TP53 mutation on chemotherapy benefit.

Prognostic impact of cytoreductive surgery conducted with primary intent, versus cytoreductive surgery after neoadjuvant chemotherapy, in the management of patients with advanced epithelial ovarian cancers: a multicentre, propensity score-matched study from the FRANCOGYN group.

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.

Could uterine conservation be an option in presumed early-stage epithelial ovarian cancer?

PURPOSE: In early-stage epithelial ovarian cancer (EOC), patients usually undergo a hysterectomy. However, in fertility sparing surgery (FSS), carefully selected patients could conserve their uterus. The aim of our study was to evaluate the incidence and epidemiologic characteristics associated with uterine involvement in patients with early-stage EOC, outside of FSS. METHODS: We conducted a retrospective, monocentric, study from 2003 to 2019 and included all patients with a presumed early-stage EOC (FIGO I) who underwent a hysterectomy. The incidence of uterine involvement, predictive factors of uterine involvement, and the impact of uterine involvement on survival (recurrence-free survival and overall survival) were analyzed. RESULTS: Eighty-five patients had an early-stage EOC. Of these, six had an uterine involvement (7%). The populations of patients with or without uterine involvement did not differ except for CA 125 at diagnosis (136 ± 138 versus 356 ± 723, p = 0.04, respectively). No patient or tumor characteristics were predictive of uterine involvement. Uterine involvement was not associated with recurrence-free survival (HR = 1.26, IC95% 0.36-4.4, p = 0.72) or overall survival (HR = 0.7, IC95% 0.1-6.1, p = 0.77). CONCLUSION: Due to the small size of our sample, no conclusion can be drawn, yet it could be hypothesized that, for selected patients, a systematic hysterectomy could be discussed, notably in restaging surgery.

Cigarette smoke and tumor microenvironment copromote aggressiveness of human breast cancer cells.

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.

A Suggested Modification to FIGO Stage IV Epithelial Ovarian Cancer.

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.

Analysis of risk factors for recurrence in cervical cancer patients after fertility-sparing treatment: The FERTIlity Sparing Surgery retrospective multicenter study.

BACKGROUND: 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 toward nonradical 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 the safety of such approaches. OBJECTIVE: This study aimed to collect multi-institutional data regarding the oncological outcomes after fertility-sparing treatment in patients with cervical cancer and to identify prognostic risk factors, including the influence of the radicality of individual cervical procedures. STUDY DESIGN: Patients aged 18 to 40 years with International Federation of Gynecology and Obstetrics 2018 stage IA1 with positive 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. RESULTS: 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 of patients were nulliparous (66%). After a median follow-up of 72 months, 51 patients (7%) experienced recurrence, of whom 19 (2.6%) died because of the disease. The most common sites of recurrence were the cervix (53%) and pelvic nodes (22%). The risk of recurrence was 3 times higher in patients with tumors >2 cm in size than in patients with smaller tumors, irrespective of the treatment radicality (19.4% vs 5.7%; hazard ratio, 2.982; 95% confidence interval, 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 and patients who underwent nonradical (conization and simple trachelectomy) cervical procedures (P=.957), regardless of tumor size subcategory (<1 or 1-2 cm) or lymphovascular space invasion. CONCLUSION: Nonradical fertility-sparing cervical procedures were not associated with an 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 tumors >2 cm in size.

Impact of mixtures of persistent organic pollutants on breast cancer aggressiveness.

INTRODUCTION: Breast cancer (BC) is frequent with a poor prognosis in case of metastasis. The role of the environment has been poorly evaluated in its progression. We searched to assess whether a mixture of pollutants could be responsible of BC aggressiveness. METHODS: Patients undergoing surgery for their BC were prospectively included in the METAPOP cohort. Forty-two POPs were extracted, among them 17 dioxins (PCDD/F), 16 polychlorobiphenyls (PCB), 8 polybromodiphenylethers (PBDE) and 2,2',4,4',5,5'-hexabromobiphenyl (PBB153) were measured in the adipose tissue surrounding the tumor. BC aggressiveness was defined using tumor size and metastasis (distant or lymph nodes). Two complementary models were used to evaluate the impact of the mixture of pollutants: the BKMR (Bayesian Kernel machine regression) and WQS (weighted quantile sum regression) models. The WQS estimates the weight (positive or negative) of a certain chemical based on its quantile and the BKMR model applies a kernel-based approach to estimate posterior inclusion probabilities. The sub-group of patients with a body mass index (BMI) > 22 kg/ m2 was also analyzed. RESULTS: Ninety-one patients were included. Of these, 38 patients presented a metastasis, and the mean tumor size was 25.4 mm. The mean BMI was 24.5 kg/m2 (+/- 4.1). No statistical association was found in the general population. However, in patients with a BMI > 22 kg/ m2, our mixture was positively associated with tumor size (OR: 9.73 95 %CI: 1.30-18.15) and metastasis (OR = 3.98 95 %CI = 1.09-17.53) using the WQS model. Moreover, using the BKMR model on chemical families, dioxin like chemicals and PCDD were associated with a higher risk of metastasis. DISCUSSION: These novel findings identified a mixture associated with breast cancer aggressiveness in patients with a BMI > 22 kg/ m2.

Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.