BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges.

BRCA1/2 genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of BRCA1/2 genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) have revolutionized the therapeutic landscape of BRCA1/2-mutated tumors, especially of BRCA1/2 high-grade serous ovarian cancer (HGSC), taking advantage of HR deficiency through the synthetic lethality concept. However, PARPi efficiency differs among patients, and most of them will develop resistance, particularly in the relapse setting. In the current proposal, we aim to review primary and secondary resistance to PARPi in HGSC owing to BRCA1/2 alterations. Of note, as several mechanisms of primary or secondary resistance to PARPi have been described, BRCA1/2 reversion mutations that restore HR pathways are by far the most reported. First, the type and location of the BRCA1/2 primary mutation have been associated with PARPi and platinum-salt sensitivity and impact the probability of the occurrence and the type of secondary reversion mutation. Furthermore, the presence of multiple reversion mutations and the variation of allelic frequency under treatment underline the role of intratumor heterogeneity (ITH) in treatment resistance. Of note, circulating tumor DNA might help us to detect and characterize reversion mutations and ITH to finally refine the treatment strategy. Importantly, forthcoming therapeutic strategies, including combination with antiangiogenics or with targeted therapies, may help us delay and overcome PARPi resistance secondary to BRCA1/2 reversion mutations. Also, progression despite PARPi therapy does not preclude PARPi rechallenge in selected patients.

Gynecological carcinosarcomas: Overview and future perspectives.

Gynecologic carcinosarcoma (CS) are rare and aggressive tumors composed of high-grade carcinoma and sarcoma. Carcinosarcoma account for less than 5% of uterine and ovarian carcinoma and patients have poor outcome with a 5-year overall survival of less than 30%. In early-stage setting, the treatment mainstay is surgery and adjuvant chemoradiotherapy or adjuvant chemotherapy in uterine (UCS) and ovarian CS (OCS), respectively. In metastatic or advanced stage disease, chemotherapy is the rule with a lower response rate and poorer prognosis compared to other high-grade carcinomas. Although very few treatment options are available, CS are often excluded from the clinical trials precluding therapeutic improvement. However, recent molecular advances are paving the way for new therapeutic strategies. In the current proposal, we extensively review the uterine and ovarian carcinosarcomas including epidemiology, pathology, genomic landscape, as well as current therapies and future perspectives.

Recommandations pour la pratique clinique Nice/Saint-Paul-de-Vence 2022­2023 : prise en charge du cancer de l'endomètre localisé.

Recommendations for clinical practice, Nice/Saint-Paul-de-Vence 2022-2023: Management of localized endometrial cancer Endometrial cancer is the most frequent gynecological cancers in industrialized countries and its incidence increases. The newmolecularclassification allows determination of the risk of recurrence and helps orienting therapeutic management. Surgery remains the cornerstone of treatment. Minimally invasive approach must be preferred for stages I and II. Surgery includes hysterectomy with bilateral adnexectomy, sentinel lymph node biopsy even in high risk diseases and omentectomy for non-endometrioid tumors (except in case of clear cells tumors). Fertility preservation can be proposed in low grade, stage I tumors without myometrial involvement. In stage III/IV disease, lymph node debulking without totallymphadenectomy is indicated. In case of peritoneal carcinomatosis, first-line cytoreductive surgery is recommended if complete resection can be achieved. Adjuvant therapy is not recommended in low risk tumors. In intermediate risk tumors, curietherapy is indicated. In tumors with high-intermediate risk, curietherapy and external radiotherapy are indicated according to prognostic factors (stage II, lymphovascular invasion); adjuvant chemotherapy can be considered on a case-by-case basis. In high risk tumors, chemotherapy and external radiotherapy are recommended using a concomitant or sequential approach.

Do surgeons overestimate diaphragmatic peritoneal disease in interval debulking surgery of ovarian cancer?

INTRODUCTION: Cytoreductive surgery is a key point in ovarian cancer treatment. Substantial morbidity may be consecutive to this major radical surgery. However, the objective of no residual tumor (CC-0) had demonstrated its clear improvement of prognosis. Could macroscopically-driven interval debulking surgery (IDS) overestimate active cancer cells and be unnecessarily morbid? MATERIALS AND METHODS: This retrospective cohort study was conducted in Center Leon Berard Cancer Center between 2000 and 2018. We included women with advanced epithelial ovarian cancer who received neoadjuvant chemotherapy and underwent an IDS including resection of peritoneal metastases on the diaphragmatic domes. The primary endpoint was the pathological outcome of peritoneal resections of diaphragmatic domes. RESULTS: Peritoneal resections of diaphragmatic domes consisted of 117 patients. 75 patients required resection of nodules from the right cupola only, 2 patients from the left cupola only, and 40 patients bilaterally. Pathological analysis of the diaphragmatic domes found that 84.6% of samples demonstrated the presence of malignant cells, and only 12.8% found no tumor involvement. Pathology analysis could not be performed for 3 patients (2.6%) (vaporization). CONCLUSION: Surgical evaluation after neoadjuvant chemotherapy in ovarian cancer does not often overestimate peritoneal involvement by active carcinomatosis. Potential surgical morbidity due to peritoneal resection in IDS is admissible.

[Treatments for rare ovarian tumors: What's new?] / Avancées thérapeutiques dans la prise en charge des tumeurs rares malignes ovariennes.

Even if each rare ovarian tumor (ROT) has a low incidence, the sum of all these entities represents almost the half of all ovarian neoplasms. Thus, development of dedicated clinical trial emerged as a prerequisite to improve their managements. Owing to the spreading of dedicated institutional networks and (supra)national collaborations, the number of clinical trials has increased the past few years, with different types of trials; while some focused on specific molecular features, others assessed innovative molecules. Furthermore, relevant randomized clinical trials were designed as a mean to position new treatment options. Currently, innovative molecular-driven trials, based on master protocol trials are emerging and may shed light towards the improvement of personalized medicine regarding ROT.

Splenectomy in epithelial ovarian cancer surgery.

OBJECTIVE: Splenectomy is performed in 4-32% of cytoreductive surgeries for ovarian cancer. The objective of our study was to assess splenectomy and evaluate its impact on overall and disease-free survival. METHODS: We conducted a retrospective single-center study between January 2000 and December 2016. Patients who underwent a cytoreduction for epithelial ovarian cancer, regardless of stage and surgical approach, were eligible for the study. Patients deemed not operable were excluded from the study. Patients were stratified into two groups, splenectomy or no splenectomy. A univariate analysis followed by a multivariate analysis was conducted to evaluate the postoperative complications after splenectomy and the overall and disease-free survival. RESULTS: This cohort included 464 patients. Disease stages, peritoneal carcinomatosis scores, and the rate of radical surgery (Pomel classification) were significantly higher in the splenectomy group, p=0.04, p<0.0001, and p<0.001, respectively. However, no significant difference was found in the rate of complete cytoreduction between the two groups (p=0.26) after multivariate analysis. In univariate analysis, splenectomy was significantly associated with extensive surgical procedures. In multivariate analysis, the two more prevalent complications in the splenectomy group were the risk of abdominopelvic lymphocele (overall response (OR) =4.2; p=0.01) and blood transfusion (OR=2.4; p=0.008). The average length of hospital stay was significantly longer in the splenectomy group, 17.4 vs 14.6 days (p<0.0001). The delay in adjuvant chemotherapy was longer in the splenectomy group (p=0.001). There was no significant difference in overall and disease-free survival (p=0.09) and (p=0.79), respectively. CONCLUSION: Splenectomy may be considered an acceptable and safe procedure; however, with no impact on overall or disease-free survival. In addition, it is associated with longer hospital stay and longer time to chemotherapy.

The need to tailor the omission of axillary lymph node dissection to patients with good prognosis and sentinel node micro-metastases.

BACKGROUND: Results of IBCSG-23-01-trial which included breast cancer patients with involved sentinel nodes (SN) by isolated-tumor-cells or micro-metastases supported the non-inferiority of completion axillary-lymph-node-dissection (cALND) omission. However, current data are considered insufficient to avoid cALND for all patients with SN-micro-metastases. METHODS: To investigate the impact of cALND omission on disease-free-survival (DFS) and overall survival (OS), we analyzed a cohort of 1421 patients <75 years old with SN-micro-metastases who underwent breast conservative surgery (BCS). We used inverse probability of treatment weighting (IPTW) to obtain adjusted Kaplan-Meier estimators representing the experience in the analysis cohort, based on whether all or none had been subject to cALND omission. RESULTS: Weighted log-rank tests comparing adjusted Kaplan-Meier survival curves showed significant differences in OS (p-value = 0.002) and borderline significant differences in DFS (p-value = 0.090) between cALND omission versus cALND. Cox's regression using stabilized IPTW evidenced an average increase in the risk of death associated with cALND omission (HR = 2.77, CI95% = 1.36-5.66). Subgroup analyses suggest that the rates of recurrence and death associated with cALND omission increase substantially after a large period of time in the half sample of women less likely to miss cALND. CONCLUSIONS: Using IPTW to estimate the causal treatment effect of cALND in a large retrospective cohort, we concluded cALND omission is associated with an increased risk of recurrence and death in women of <75 years old treated by BCS in the absence of a large consensus in favor of omitting cALND. These results are particularly contributive for patients treated by BCS where cALND omission rates increase over time.

Evaluation of ferrocenyl-containing γ-hydroxy-γ-lactam-derived tetramates as potential antiplasmodials.

A series of ferrocenyl-containing γ-hydroxy-γ-lactam tetramates were prepared in 2-3 steps through ring opening-ring closure (RORC) process of γ-ylidene-tetronate derivatives in the presence of ferrocenyl alkylamines. The compounds were screened in vitro for their antiplasmodial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) clones of P. falciparum, displaying activity in the range of 0.12-100 µM, with generally good resistance index. The most active ferrocene in these series exhibited IC50 equal to 0.09 µM (3D7) and 0.12 µM (W2). The low cytotoxicity of the ferrocenyl-containing γ-hydroxy-γ-lactam tetramates against Human Umbilical Vein Endothelial (HUVEC) cell line demonstrated selective antiparasitic activity. The redox properties of these ferrocene-derived tetramates were studied and physico-biochemical studies evidenced that these derivatives can exert potent antimalarial activities via a mechanism distinct from ferroquine.

Clinical and Histopathological Predictors of Recurrence in Uterine Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP): A Multicenter Retrospective Cohort Study of Tertiary Centers.

BACKGROUND: The term uterine smooth muscle tumor of uncertain malignant potential (STUMP) indicates a rare, equivocal entity between benign leiomyomas and leiomyosarcomas. In the present study, we evaluated a comprehensive range of clinical, surgical, and pathological features in a large multicenter series of patients with STUMP to identify risk factors for recurrence. METHODS: This is a retrospective study performed by collecting consecutive cases diagnosed between January 2000 and December 2020 in five tertiary centers. Associations between STUMP recurrence and clinicopathological characteristics as well as surgical treatment modality were investigated. RESULTS: Eighty-seven patients affected by STUMP were considered. Of them, 18 cases (20.7%) recurred: 11 as leiomyosarcoma (LMS) and 7 as STUMP. The mean time to recurrence was 79 months. We found that fragmentation/morcellation, epithelioid features, high mitotic count, Ki-67 value > 20%, progesterone receptor (PR) < 83%, and p16 diffuse expression were associated with higher risk of recurrence and shorter recurrence-free survival (RFS). Furthermore, morcellation/fragmentation and mitotic count remained independent risk factors for recurrence and shorter RFS after multivariate analysis, while the presence of epithelioid features was an independent risk factor for recurrence only. CONCLUSIONS: Our results suggest that morcellation is associated with risk of recurrence and shorter RFS, thus it should be avoided if a STUMP is suspected preoperatively. Epithelioid features, high proliferation activity, low PR expression, and diffuse p16 expression are also unfavorable prognostic factors, so patients presenting these features should be closely followed up.

Serodolin, a ß-arrestin-biased ligand of 5-HT7 receptor, attenuates pain-related behaviors.

G protein­coupled receptors (GPCRs) are involved in regulation of manifold physiological processes through coupling to heterotrimeric G proteins upon ligand stimulation. Classical therapeutically active drugs simultaneously initiate several downstream signaling pathways, whereas biased ligands, which stabilize subsets of receptor conformations, elicit more selective signaling. This concept of functional selectivity of a ligand has emerged as an interesting property for the development of new therapeutic molecules. Biased ligands are expected to have superior efficacy and/or reduced side effects by regulating biological functions of GPCRs in a more precise way. In the last decade, 5-HT7 receptor (5-HT7R) has become a promising target for the treatment of neuropsychiatric disorders, sleep and circadian rhythm disorders, and pathological pain. In this study, we showed that Serodolin is unique among a number of agonists and antagonists tested: it behaves as an antagonist/inverse agonist on Gs signaling while inducing ERK activation through a ß-arrestin­dependent signaling mechanism that requires c-SRC activation. Moreover, we showed that Serodolin clearly decreases hyperalgesia and pain sensation in response to inflammatory, thermal, and mechanical stimulation. This antinociceptive effect could not be observed in 5-HT7R knockout (KO) mice and was fully blocked by administration of SB269-970, a specific 5-HT7R antagonist, demonstrating the specificity of action of Serodolin. Physiological effects of 5-HT7R stimulation have been classically shown to result from Gs-dependent adenylyl cyclase activation. In this study, using a ß-arrestin­biased agonist, we provided insight into the molecular mechanism triggered by 5-HT7R and revealed its therapeutic potential in the modulation of pain response.

Uptake of Recommendations for Posttreatment Cancer-Related Fatigue Among Breast Cancer Survivors.

BACKGROUND: Physical activity (PA) and psychosocial interventions are recommended management strategies for cancer-related fatigue (CRF). Randomized trials support the use of mind-body techniques, whereas no data show benefit for homeopathy or naturopathy. METHODS: We used data from CANTO (ClinicalTrials.gov identifier: NCT01993498), a multicenter, prospective study of stage I-III breast cancer (BC). CRF, evaluated after primary treatment completion using the EORTC QLQ-C30 (global CRF) and QLQ-FA12 (physical, emotional, and cognitive dimensions), served as the independent variable (severe [score of ≥40/100] vs nonsevere). Outcomes of interest were adherence to PA recommendations (≥10 metabolic equivalent of task [MET] h/week [GPAQ-16]) and participation in consultations with a psychologist, psychiatrist, acupuncturist, or other complementary and alternative medicine (CAM) practitioner (homeopath and/or naturopath) after CRF assessment. Multivariable logistic regression examined associations between CRF and outcomes, adjusting for sociodemographic, psychologic, tumor, and treatment characteristics. RESULTS: Among 7,902 women diagnosed from 2012 through 2017, 36.4% reported severe global CRF, and 35.8%, 22.6%, and 14.1% reported severe physical, emotional, and cognitive CRF, respectively. Patients reporting severe global CRF were less likely to adhere to PA recommendations (60.4% vs 66.7%; adjusted odds ratio [aOR], 0.82; 95% CI, 0.71-0.94; P=.004), and slightly more likely to see a psychologist (13.8% vs 7.5%; aOR, 1.29; 95% CI, 1.05-1.58; P=.014), psychiatrist (10.4% vs 5.0%; aOR, 1.39; 95% CI, 1.10-1.76; P=.0064), acupuncturist (9.8% vs 6.5%; aOR, 1.46; 95% CI, 1.17-1.82; P=.0008), or CAM practitioner (12.5% vs 8.2%; aOR, 1.49; 95% CI, 1.23-1.82; P<.0001). There were differences in recommendation uptake by CRF dimension, including that severe physical CRF was associated with lower adherence to PA (aOR, 0.74; 95% CI, 0.63-0.86; P=.0001) and severe emotional CRF was associated with higher likelihood of psychologic consultations (aOR, 1.37; 95% CI, 1.06-1.79; P=.017). CONCLUSIONS: Uptake of recommendations to improve CRF, including adequate PA and use of psychosocial services, seemed suboptimal among patients with early-stage BC, whereas there was a nonnegligible interest in homeopathy and naturopathy. Findings of this large study indicate the need to implement recommendations for managing CRF in clinical practice.

SLFN11 captures cancer-immunity interactions associated with platinum sensitivity in high-grade serous ovarian cancer.

Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative helicase, as the strongest predictor of sensitivity to DNA-damaging agents (DDAs), including platinum. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma (HGSOC) specimens before platinum-based chemotherapy treatment, we show, for the first time to our knowledge, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. We observed SLFN11 expression in both infiltrating innate and adaptive immune cells, and analyses in a second, independent, cohort revealed that SLFN11 was associated with immune activation in HGSOC. We found that platinum treatments activated immune-related pathways in ovarian cancer cells in an SLFN11-dependent manner, representative of tumor-immune transactivation. Moreover, SLFN11 expression was induced in activated, isolated immune cell subpopulations, hinting that SLFN11 in the immune compartment may be an indicator of immune transactivation. In summary, we propose SLFN11 is a dual biomarker capturing simultaneously interconnected immunological and cancer cell-intrinsic functional dispositions associated with sensitivity to DDA treatment.

Fast Compression of MCMC Output.

We propose cube thinning, a novel method for compressing the output of an MCMC (Markov chain Monte Carlo) algorithm when control variates are available. It allows resampling of the initial MCMC sample (according to weights derived from control variates), while imposing equality constraints on the averages of these control variates, using the cube method (an approach that originates from survey sampling). The main advantage of cube thinning is that its complexity does not depend on the size of the compressed sample. This compares favourably to previous methods, such as Stein thinning, the complexity of which is quadratic in that quantity.

Pyridazino-1,3a,6a-Triazapentalenes as Versatile Fluorescent Probes: Impact of Their Post-Functionalization and Application for Cellular Imaging.

Pyridazino-1,3a,6a-triazapentalenes (PyTAP) are compact fused 6/5/5 tricyclic scaffolds which exhibit promising fluorescent properties. Chemically stable, they can be post-functionalized using standard Pd-catalyzed cross-coupling chemistry. Several original PyTAP bearing additional unsaturated substituents in positions 2 and 8 were synthetized and their spectroscopic properties analyzed. They have been successfully tested as fluorescent probes for cellular imaging.

Anti-müllerian hormone levels and antral follicle count in women with a BRCA1 or BRCA2 germline pathogenic variant: A retrospective cohort study.

BACKGROUND: Some studies suggested a decreased ovarian reserve among BRCA1/2 pathogenic variant carriers, with conflicting results. METHODS: We conducted a retrospective single-center observational study of ovarian reserve and spontaneous fertility comparing BRCA1/2 pathogenic variant carriers to controls (women who attended consultations to discuss fertility preservation before gonadotoxic treatment). Measures of associations between plasma AMH concentration, AFC and BRCA1/2 status were modelled by nonlinear generalized additive regression models and logistic regressions adjusted for age at plasma storage, oral contraceptive use, body mass index, cigarette smoking, and the AMH assay technique. RESULTS: The whole population comprised 119 BRCA1/2 pathogenic variant carriers and 92 controls. A total of 110 women (42 carriers, among whom 30 were cancer-free, and 68 controls) underwent an ovarian reserve evaluation. Spontaneous fertility analysis included all women who previously attempted to become pregnant (134 women). We observed a tendency towards a premature decrease in ovarian reserve in BRCA1/2 pathogenic variant carriers, but no difference in mean AMH or AFC levels was found between BRCA1/2 pathogenic variant carriers and controls. An analysis of the extreme levels of AMH (≤5 pmol/l) and AFC (≤7 follicles) by logistic regression suggested a higher risk of low ovarian reserve among BRCA1/2 pathogenic variant carriers (adjusted odds ratio (OR) = 3.57, 95% CI = 1.00-12.8, p = 0.05; and adjusted OR = 4.99, 95% CI = 1.10-22.62, p = 0.04, respectively). DISCUSSION: Attention should be paid to BRCA1/2 pathogenic variant carriers' ovarian reserve, considering this potential risk of premature alteration.

Molecular Characterization of Ovarian Yolk Sac Tumor (OYST).

Most patients with malignant ovarian germ cell tumors (MOGTCs) have a very good prognosis and chemotherapy provides curative treatment; however, patients with yolk sac tumors (OYSTs) have a significantly worse prognosis. OYSTs are rare tumors and promising results are expected with the use of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens. We initiated a project in collaboration with EORTC SPECTA, to explore the molecular characteristics of OYSTs. The pilot project used retrospective samples from ten OYST relapsed and disease-free patients. Each patient had a molecular analysis performed with FoundationOne CDx describing the following variables according to the Foundation Medicine Incorporation (FMI): alteration type (SNV, deletion), actionable gene alteration, therapies approved in EU (for patient's tumor type and other tumor types), tumor mutational burden (TMB), and microsatellite instability (MSI) status. A total of 10 patients with OYST diagnosed between 2007 and 2017 had a molecular analysis. A molecular alteration was identified in four patients (40%). A subset of three patients (33.3% of all patients) harbored targetable oncogenic mutations in KRAS, KIT, ARID1A. Two patients at relapse harbored a targetable mutation. This retrospective study identifies clinically relevant molecular alterations for all relapsed patients with molecular analysis. Dedicated studies are needed to demonstrate the efficacy of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens and to explore the potential relationship of a molecular alteration and patient outcome.

Imprecise neural computations as a source of adaptive behaviour in volatile environments.

In everyday life, humans face environments that feature uncertain and volatile or changing situations. Efficient adaptive behaviour must take into account uncertainty and volatility. Previous models of adaptive behaviour involve inferences about volatility that rely on complex and often intractable computations. Because such computations are presumably implausible biologically, it is unclear how humans develop efficient adaptive behaviours in such environments. Here, we demonstrate a counterintuitive result: simple, low-level inferences confined to uncertainty can produce near-optimal adaptive behaviour, regardless of the environmental volatility, assuming imprecisions in computation that conform to the psychophysical Weber law. We further show empirically that this Weber-imprecision model explains human behaviour in volatile environments better than optimal adaptive models that rely on high-level inferences about volatility, even when considering biologically plausible approximations of such models, as well as non-inferential models like adaptive reinforcement learning.

Impact of multidisciplinary tumour board in the management of ovarian carcinoma in the first-line setting. Exhaustive analysis from the Rhone-Alpes region.

OBJECTIVE: Epithelial ovarian cancer (EOC) is a poor prognosis disease partly linked to diagnosis at an advanced stage. The quality of care management is a factor that needs to be explored, more specifically optimal organisation of first-line treatment. METHODS: A retrospective study, dealing with all patients diagnosed within the Rhone-Alpes region with initial diagnosis EOC in 2012, was performed. The aim was to describe the impact of multidisciplinary tumour boards (MTB) in the organisation of care and the consequence on the patient's outcomes. RESULTS: 271 EOC were analysed. 206 patients had an advanced EOC. Median progression-free survival (PFS) is 17.8 months (CI95%, 14.6-21.2) for AOC. 157 patients (57.9%) had a front-line surgery versus 114 patients (42.1%) interval debulking surgery. PFS for AOC patients with no residual disease is 24.3 months compared with 15.3 months for patients with residual disease (p = .01). No macroscopic residual disease is more frequent in the patients discussed before surgery in MTB compared with patients not submitted before surgery (73% vs. 56.2%, p < .001). CONCLUSION: These results highlight the heterogeneity of medical practices in terms of front-line surgery versus interval surgery, in the administration of neoadjuvant chemotherapy and in the setting of MTB discussion.