Prevalent versus incident breast cancers: benefits of clinical and radiological monitoring in women with pathogenic BRCA1/2 variants.

Women with pathogenic germline BRCA1 or BRCA2 variants have a higher risk of breast cancer than in the general population. International guidelines recommend specific clinical and radiological breast follow-up. This specific breast screening program has already been shown to be of clinical benefit, but no information is available concerning the use of prognostic factors or specific survival to guide follow-up decisions. We evaluated "high-risk" screening in a retrospective single-center study of 520 women carrying pathogenic germline variants of the BRCA1 or BRCA2 gene treated for breast cancer between January 2000 and December 2016. We compared two groups of women: the incidental breast cancer group (IBCG) were followed before breast cancer diagnosis (N = 103), whereas the prevalent breast cancer group (PBCG) (N = 417) had no specific follow-up for high risk before breast cancer diagnosis. Breast cancers were diagnosed at an earlier stage in the IBCG than in the PBCG: T0 in 64% versus 19% of tumors, (p < 0.00001), and N0 in 90% vs. 75% (p < 0.00001), respectively. Treatment differed significantly between the 2 groups: less neoadjuvant chemotherapy (7.1% vs. 28.5%, p < 0.00001), adjuvant chemotherapy (47.7% vs. 61.9%, p = 0.004) and more mastectomies (60% vs. 42% p < 0.0001) in the IBCG vs PBCG groups respectively. Overall and breast cancer-specific mortality were similar between the two groups. However, the patients in the IBCG had a significantly longer metastasis-free survival than those in the PBCG, at three years (96.9% [95% CI 93.5-100] vs. 92.30% [95% CI 89.8-94.9]; p = 0.02), suggesting a possible long-term survival advantage.

18F-FDG PET/CT in Relapsed Endometrial Cancer Treated with Preoperative PD-1 Inhibitor Dostarlimab.

Dostarlimab is an immune checkpoint inhibitor (ICI) targeting the Programmed-Death-1 (PD-1) co-receptor, recently approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) as a novel therapy for recurrent or advanced endometrial cancer. We report the case of a 64-year-old woman, experiencing vaginal recurrence with microsatellite instability high/hypermutated of a FIGO stage IA grade 2 endometrial endometrioid adenocarcinoma. She received preoperative chemotherapy with four cycles of carboplatin plus paclitaxel, with stable disease on pelvic magnetic resonance imaging (MRI) and fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT). Dostarlimab (500 mg intravenously every 3 weeks) was then introduced. The subsequent evaluation after three perfusions demonstrated a complete metabolic response on 18F-FDG PET/CT according to immunotherapy-modified PET response criteria in solid tumors (imPERCIST) criteria, then confirmed by MRI according to immune response evaluation criteria in solid tumors (iRECIST). This clinical description suggests that 18F-FDG PET/CT might take place among available tools for guiding the preoperative management for recurrent endometrial cancer patients receiving dostarlimab immunotherapy that should be further explored through clinical trials.

Primary ectocervical epithelial cells display lower permissivity to Chlamydia trachomatis than HeLa cells and a globally higher pro-inflammatory profile.

The tumoral origin and extensive passaging of HeLa cells, a most commonly used cervical epithelial cell line, raise concerns on their suitability to study the cell responses to infection. The present study was designed to isolate primary epithelial cells from human ectocervix explants and characterize their susceptibility to C. trachomatis infection. We achieved a high purity of isolation, assessed by the expression of E-cadherin and cytokeratin 14. The infectious progeny in these primary epithelial cells was lower than in HeLa cells. We showed that the difference in culture medium, and the addition of serum in HeLa cultures, accounted for a large part of these differences. However, all things considered the primary ectocervical epithelial cells remained less permissive than HeLa cells to C. trachomatis serovar L2 or D development. Finally, the basal level of transcription of genes coding for pro-inflammatory cytokines was globally higher in primary epithelial cells than in HeLa cells. Transcription of several pro-inflammatory genes was further induced by infection with C. trachomatis serovar L2 or serovar D. In conclusion, primary epithelial cells have a strong capacity to mount an inflammatory response to Chlamydia infection. Our simplified purification protocol from human explants should facilitate future studies to understand the contribution of this response to limiting the spread of the pathogen to the upper female genital tract.

Screening for domestic violence during pregnancy follow-up: evaluation of an intervention in an antenatal service.

To assess the impact of a brief training for obstetricians and midwives about screening for domestic violence during pregnancy follow-up and to identify barriers to a routine enquiry. A monocentric quasi-experimental study was performed in an obstetrics department in Paris, France. We asked patients during their pregnancy follow-up to complete a survey describing their demographic characteristics. They were also asked if a health professional had screened them for domestic violence during the current pregnancy. Exclusion criteria were refusal and inability to complete the survey alone. Health professionals attended a brief training about domestic violence. The intervention provided general information about domestic violence to alert health professionals (prevalence, risk factors, consequences on women's health, pregnancy, and children) and guidelines on screening and how to deal with women disclosing domestic violence. They also had to complete a survey about their knowledge and practice concerning domestic violence. Two months later, patients consulting for their pregnancy follow-up completed the same survey. Health professionals were not aware of the study's aim throughout its course. The primary outcome was the rate of patients screened for domestic violence during pregnancy follow-up. The secondary outcome was the identification of barriers to a routine enquiry. Four hundred ninety-five patients completed the first survey (control group): 21 patients (4.8%) had been screened for domestic violence. Twenty-one health professionals attended the intervention. Eight (38.1%) stated that they never screened for domestic violence, and 3 (14.3%) stated that they always did. Three hundred ninety-five patients completed the second survey (experimental group): 17 patients (4.3% vs 4.8%, p = 0.53) stated that they had been screened for domestic violence. The main barriers to screening mentioned by health professionals were the presence of the partner, the lack of awareness of the need to screen, uncomfortable feelings, and the difficulty to identify victims. There was no increased screening for domestic violence during pregnancy follow-up after a brief training of obstetricians and midwives. An early training during medical studies or more extensive training for professionals could be more efficient.

Plasma thymidine kinase 1 activity and outcome of ER+ HER2- metastatic breast cancer patients treated with palbociclib and endocrine therapy.

PURPOSE: Previous cohort studies have reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). In this prospective study, we report here the prognostic impact of pTKa in ER+/HER2- MBC patients treated with endocrine therapy and CDK4/6 inhibitor. EXPERIMENTAL DESIGN: Patients were included into the prospective, ethics committee-approved ALCINA study (NCT02866149). Eligibility criteria were patients with ER+/HER2- MBC treated at Institut Curie with endocrine therapy and palbociclib. Plasma samples were obtained at baseline and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden). RESULTS: From May 2016 to August 2018, 103 patients treated with endocrine therapy and palbociclib were included. Patients had received a median of two prior systemic therapies for MBC (range 0-14). Median follow-up was 13.8 months (range 6-31), with median PFS and OS of 9.6 months (95%CI [7.0-11.3]) and 28 months (95%CI [23-not reached]), respectively. Median baseline pTKa was 292 Du/L (range 20-27,312 Du/L, IQR [89-853]). After adjusting for other prognostic factors, baseline pTKa remained an independent prognostic factor for both PFS (HR = 1.3 95%CI [1.1-1.4], p = 0.0005) and OS (HR = 1.3 95%CI [1.2-1.6], p < 0.0001), and 4-week pTKa was associated with OS (HR = 1.6 95%CI [1.3-2], p < 0.0001). That survival prediction was significantly improved by the addition of baseline pTKa to clinicopathological characteristics. Adding pTKa changes at 4 weeks to baseline pTKa did not further increase survival prediction. CONCLUSION: This study demonstrates the clinical validity of pTKa as a new circulating prognostic marker in ER+/HER2- MBC patients treated with endocrine therapy and palbociclib.

The role of neoadjuvant chemotherapy in ovarian cancer.

INTRODUCTION: Ovarian cancer is mostly diagnosed at advanced stage. Better survival is achieved through complete debulking surgery and chemotherapy. Historically, neoadjuvant chemotherapy (NAC) has been introduced for unresectable disease to decrease tumor load and perform a unique complete surgery. Four randomized control trials have compared primary debulking surgery to NAC, but there is still controversy about the use of neoadjuvant chemotherapy and questions about its modalities. Areas covered: We made a review of knowledge on benefits of NAC compared to primary debulking chemotherapy, in terms of survival and morbidity, methods of administration, new drugs in early and late phase trials, the selection of patients. Similar survival was observed after NAC and interval debulking surgery or primary debulking surgery. Morbidity of surgery was decreased after interval debulking compared primary debulking surgery. Conventional drugs are carboplatin and paclitaxel. Safety of bevacizumab was evaluated in phase 2 trials associated with conventional drugs. Immunotherapy trials are enrolling patients in phase 1 study. Expert commentary: NAC followed by debulking surgery is the best treatment for patients with advanced ovarian cancer.

Costs associated with Eribulin treatment for patients with metastatic breast cancer in a comprehensive cancer center in France.

BACKGROUND: There is no standard recommendation for metastatic breast cancer treatment (MBC) after two chemotherapy regimens. Eribulin (Halaven®) has shown a significant improvement in overall survival (OS) in this setting. Its use may however be hampered by its cost, which is up to three times the cost of other standard drugs. We report the clinical outcomes and health care costs of a large series of consecutive MBC patients treated with Eribulin. METHODS: A monocentric retrospective study was conducted at Institut Curie over 1 year (August 2012 to August 2013). Data from patient's medical records were extracted to estimate treatment and outcome patterns, and direct medical costs until the end of treatment were measured. Factors affecting cost variability were identified by multiple linear regressions and factors linked to OS by a multivariate Cox model. RESULTS: We included 87 MBC patients. The median OS was 10.7 months (95%CI = 8.0-13.3). By multivariate Cox analysis, independent factors of poor prognosis were an Eastern Cooperative Oncology Group (ECOG) performance status of 3, a number of metastatic sites ≥ 4 and the need for hospitalization. Per-patient costs during whole treatment were €18,694 [CI 95%: 16,028-21,360], and €2581 [CI 95%: 2226-3038] per month. Eribulin administration contributed to 79% of per-patient costs. CONCLUSIONS: Innovative and expensive drugs often appear to be the main cost drivers in cancer treatment, particularly for MBC. There is an urgent need to assess clinical practice benefits.

[New options in adjuvant endocrine therapy in breast cancer]. / Nouvelles options en hormonothérapie adjuvante des cancers du sein.

Endocrine therapy is a compulsory step in the adjuvant management of early breast cancer expressing the estrogen receptor, by reducing as much as possible serum and tissue levels of estrogens. Tamoxifen is the standard therapy for non-menopausal women. Ovarian function suppression, in addition to exemestane or tamoxifen, could be an alternative option for young women at high risk of recurrence and non menopausal after adjuvant or neo-adjuvant chemotherapy. Recent studies show a trend for improvement of overall survival and disease-free-survival with aromatase inhibitors among postmenopausal women. However, safety of aromatase inhibitors is controversial and adverse events may lead to switch for tamoxifen with no loss of efficacy. Extension therapy by tamoxifen or aromatase inhibitor after five years of tamoxifen and for a total duration of ten years significantly improves overall survival. There is to date no data supporting the extension therapy after five years of aromatase inhibitor.

Identification of the chemokine CX3CL1 as a new regulator of malignant cell proliferation in epithelial ovarian cancer.

BACKGROUND: Little is known about the molecules that contribute to the growth of epithelial ovarian carcinomas (EOC), which remain the most lethal gynecological cancer in women. The chemokine Fractalkine/CX(3)CL1 has been widely reported to play a biologically relevant role in tumor growth and spread. We report here the first investigation of the expression and role of CX(3)CL1 in EOC. RESULTS: Epithelial cells from the surface of the ovary and the Fallopian tubes and from benign, borderline and malignant tumors all stained positive for CX(3)CL1. In tumor specimens from 54 women who underwent surgical treatment for EOC diagnosis, CX(3)CL1 immunoreactivity was unevenly distributed in epithelial tumor cells, and ranged from strong (33%) to absent (17%). This uneven distribution of CX(3)CL1 did not reflect the morphological heterogeneity of EOC. It was positively correlated with the proliferation index Ki-67 and with GILZ (glucocorticoid-induced leucine zipper), previously identified as an activator of the proliferation of malignant EOC cells. Hierarchical clustering analysis, including age at diagnosis, tumor grade, FIGO stage, Ki-67 index, CX(3)CL1, SDF-1/CXCL12 and GILZ immunostaining scores, distinguished two major clusters corresponding to low and high levels of proliferation and differing in terms of GILZ and CX(3)CL1 expression. GILZ overexpression in the carcinoma-derived BG1 cell line resulted in parallel changes in CX(3)CL1 products. Conversely, CX(3)CL1 promoted through its binding to CX(3)CR1 AKT activation and proliferation in BG1 cells. In a mouse subcutaneous xenograft model, the overexpression of GILZ was associated with higher expression of CX(3)CL1 and faster tumor growth. CONCLUSION: Our findings highlight the previously unappreciated constitutive expression of CX(3)CL1 preceding tumorigenesis in ovarian epithelial cells. Together with GILZ, this chemokine emerges as a regulator of cell proliferation, which may be of potential clinical relevance for the selection of the most appropriate treatment for EOC patients.

Obstetrical Complications and Outcome in Two Families with Hereditary Angioedema due to Mutation in the F12 Gene.

Backgroud. Hereditary angioedema (HAE) is characterized by recurrent swelling of the skin, the abdomen (causing severe acute pain), and the airways. A recently discovered type caused by mutations in the factor XII gene (designated as HAE type III) occurs mainly in women. Estrogens may play an important role, but few obstetrical complications have been reported. Case. We report the symptoms and obstetrical complications of women in two families with HAE attributable to the p. Thr328Lys mutation in the F12 gene. Clinical manifestations included acute and severe maternal abdominal pain, with transient ascites, laryngeal edema, and fetal and neonatal deaths. Patients had normal C4 levels and a normal C1 inhibitor gene. Administration of C1-inhibitor concentration twice monthly decreased the attack rate in one mother, and its predelivery administration (1000 U) led to the delivery of healthy girls. Conclusions. Obstetricians and anesthesiologists should be aware of this rare cause of unexplained maternal ascites and in utero or fetal death associated with edema.

The role of Essure sterilization performed simultaneously with endometrial ablation.

PURPOSE OF REVIEW: To review operative procedures, specific risks, complications and evaluation of efficacy of Essure tubal sterilization performed simultaneously with endometrial ablation. RECENT FINDINGS: Dysfunctional uterine bleeding is a significant health problem in premenopausal women. Endometrial ablation is an effective therapeutic option for the management of menorrhagia and an alternative to hysterectomy. Most women undergoing endometrial ablation are of reproductive age, and, because pregnancy after endometrial ablation could be complicated, many of these women require permanent birth control. Since the introduction of Essure tubal sterilization, this permanent contraception method has been widely used and offers an hysteroscopic approach similar to endometrial ablation techniques. Combining these two procedures offers the advantage of performing the two procedures simultaneously, but inherent rules and technical procedures must be followed to avoid any kind of injury such as heat conduction, material injuries, specific complications and specific follow-up. SUMMARY: The combination of safety and efficacy of endometrial ablation and hysteroscopic sterilization makes a compelling argument for their concomitant use.

Long-term results of tension-free vaginal tape for female urinary incontinence: follow up over 6 years.

OBJECTIVE: To describe the long-term outcome of using tension-free vaginal tape (TVT) with and without associated procedures. METHODS: A questionnaire was mailed to a population of 61 women who had undergone TVT surgery more than 6 years ago. Of this population, 41 (80%) had suffered from stress urinary incontinence (SUI). The questionnaire included questions about urinary symptoms, satisfaction and quality of life. The questionnaire was answered by 51 of the 61 women. RESULTS: Mean follow up was 83 months. The women with SUI had a persistent cure rate of 80% with a satisfaction rate of 97%. The cure rate after 6 years was 37% in women with mixed incontinence. Concomitant hysterectomy (relative risks = 0.87) and body mass index (BMI) do not alter the long-term results of TVT procedure. Peroperative bladder injury is not associated with an increased risk of long-term lower urinary tract symptoms (LUTS) or with a decreased satisfaction rate (relative risks = 0.85). CONCLUSIONS: Concomitant hysterectomy, increased BMI and bladder injury do not alter good long-term results of TVT.

Unusual fast-growing ovarian cystic teratoma during pregnancy presenting with intracystic fat "floating balls" appearance.

A large ovarian cyst was diagnosed at 22 weeks' of gestation in a 32-year-old woman. The ultrasonographic appearance of the ovarian cyst was unusual with multiple mobile, spherical echogenic structures floating in the cystic mass, called intracystic "fat balls." Right adnexectomy was performed by laparotomy at 28 weeks' of gestation, because of rapid growth and overall size exceeding 20 cm. Pathological examination confirmed ovarian cystic teratoma. Usually, dermoid cysts are slow-growing, even in premenopausal women. The exact mechanism related to the fast growth during pregnancy is unknown. It could be related to an unusual pattern of estrogen (E)/P receptors expression in the cystic teratoma. This case shows that a fast-growing, mature ovarian cystic teratoma may occur during pregnancy.

Use of organ culture to study the human fetal testis development: effect of retinoic acid.

CONTEXT: In human, the chronology of the testicular development has been extensively studied, but the factors implicated in the onset and the regulation of gametogenesis and steroidogenesis remain hardly known. OBJECTIVES: To identify these factors, we developed an organ culture system for human fetal testes recovered during the first trimester (6-12 wk) of gestation. We first aimed at investigating the characteristics of this system by comparing the in vivo and in vitro gametogenesis and steroidogenesis. Second, we used organ culture to investigate the effect on the human testicular functions of retinoic acid (RA), previously described as a regulator of gonadal development in rodents. RESULTS: Organ culture proved to be an efficient tool for studying the early development of the testicular functions. Indeed, this system was able to maintain satisfactory development of the germ cells and Leydig cells in the absence of any added factor. For older fetuses, the number of germ cells decreased in culture and the LH was necessary to maintain the steroidogenic activity. The addition of 10(-6) m RA decreased the total number of germ cells in the fetal testis at all studied stages. This resulted from an increase in apoptosis, which slightly exceeded the increase of proliferation. However, RA had a stimulatory effect on the steroidogenic function for the youngest fetuses over a short period of time by increasing the expression of P450 cholesterol side-chain cleavage, 17 alpha-hydroxylase/C17-20 lyase, and steroidogenic acute regulatory protein. CONCLUSIONS: Thus, RA appears as a potential regulator of both gametogenesis and steroidogenesis in human fetal testis. Our organ culture is an interesting tool for studying the effects of various factors on the development of human fetal testis, in particular the effect of hormone-disrupting chemicals.