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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., Competing Interests: LC: travel support from Pharmamar and GSK. IR-C declares Honoraria self from Agenus, Blueprint, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Macrogenics, Tesaro, and Clovis; Honoraria institution from GSK, MSD, Roche, and BMS; advisory/consulting fees from Abbvie, Agenus, Advaxis, BMS, ESAÏ, Daichi, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis; research grant/funding self from MSD, Roche, and BMS; research grant/funding institution from MSD, Roche, BMS, Novartis, Astra Zeneca, and Merck Sereno; travel support from Roche, MSD, AstraZeneca and GSK. OL: receipt of grants/research support by AstraZeneca and receipt of honoraria or consultation fees by GSK, MSD, and Clovis oncology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Collet, Hanvic, Turinetto, Treilleux, Chopin, Le Saux and Ray-Coquard.)

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., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

G protein–coupled 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 β-arrestin–dependent 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 β-arrestin–biased agonist, we provided insight into the molecular mechanism triggered by 5-HT7R and revealed its therapeutic potential in the modulation of pain response.

Background: We determined the prognostic impact of lymphovascular invasion (LVI) in a large, national, multicenter, retrospective cohort of patients with early breast cancer (BC) according to numerous factors., Patients and Methods: We collected data on 17 322 early BC patients treated in 13 French cancer centers from 1991 to 2013. Survival functions were calculated using the Kaplan-Meier method and multivariate survival analyses were carried out using the Cox proportional hazards regression model adjusted for significant variables associated with LVI or not. Two propensity score-based matching approaches were used to balance differences in known prognostic variables associated with LVI status and to assess the impact of adjuvant chemotherapy (AC) in LVI-positive luminal A-like patients., Results: LVI was present in 24.3% (4205) of patients. LVI was significantly and independently associated with all clinical and pathological characteristics analyzed in the entire population and according to endocrine receptor (ER) status except for the time period in binary logistic regression. According to multivariate analyses including ER status, AC, grade, and tumor subtypes, the presence of LVI was significantly associated with a negative prognostic impact on overall (OS), disease-free (DFS), and metastasis-free survival (MFS) in all patients [hazard ratio (HR) = 1.345, HR = 1.312, and HR = 1.415, respectively; P < 0.0001], which was also observed in the propensity score-based analysis in addition to the association of AC with a significant increase in both OS and DFS in LVI-positive luminal A-like patients. LVI did not have a significant impact in either patients with ER-positive grade 3 tumors or those with AC-treated luminal A-like tumors., Conclusion: The presence of LVI has an independent negative prognostic impact on OS, DFS, and MFS in early BC patients, except in ER-positive grade 3 tumors and in those with luminal A-like tumors treated with AC. Therefore, LVI may indicate the existence of a subset of luminal A-like patients who may still benefit from adjuvant therapy., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of competing interest Authors have nothing to declare in relation with the study., (Copyright © 2021. Published by Elsevier Ltd.)

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.

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 (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.

Background: Prognostic impact of lymph node micro-metastases (pN1mi) has been discordantly reported in the literature. The need to clarify this point for decision-making regarding adjuvant therapy, particularly for patients with endocrine receptor (ER)-positive status and HER2-negative tumors, is further reinforced by the generalization of gene expression signatures using pN status in their recommendation algorithm., Patients and Methods: We retrospectively analyzed 13 773 patients treated for ER-positive breast cancer in 13 French cancer centers from 1999 to 2014. Five categories of axillary lymph node (LN) status were defined: negative LN (pN0i-), isolated tumor cells [pN0(i+)], pN1mi, and pN1 divided into single (pN1 = 1) and multiple (pN1 > 1) macro-metastases (>2 mm). The effect of LN micro-metastases on outcomes was investigated both in the entire cohort of patients and in clinically relevant subgroups according to tumor subtypes. Propensity-score-based matching was used to balance differences in known prognostic variables associated with pN status., Results: As determined by sentinel LN biopsy, 9427 patients were pN0 (68.4%), 546 pN0(i+) (4.0%), 1446 pN1mi (10.5%) and 2354 pN1 with macro-metastases (17.1%). With a median follow-up of 61.25 months, pN1 status, but not pN1mi, significantly impacted overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), and breast-cancer-specific survival. In the subgroup of patients with known tumor subtype, pN1 = 1, as pN1 > 1, but not pN1mi, had a significant prognostic impact on OS. DFS and MFS were only impacted by pN1 > 1. Similar results were observed in the subgroup of patients with luminal A-like tumors (n = 7101). In the matched population analysis, pN1macro, but not pN1mi, had a statistically significant negative impact on MFS and OS., Conclusion: LN micro-metastases have no detectable prognostic impact and should not be considered as a determining factor in indicating adjuvant chemotherapy. The evaluation of the risk of recurrence using second-generation signatures should be calculated considering micro-metastases as pN0., Competing Interests: Disclosure The authors have declared no conflicts of interest. Data sharing The data sets generated and/or analyzed during the current study are not publicly available, as the study has used clinical databases of 13 different comprehensive cancer centers in France (ClinicalTrials.govNCT02869607)., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

The production of CD73-derived adenosine (Ado) by Tregs has been proposed as a resistance mechanism to anti-PD-1 therapy in murine tumor models. We reported that human Tregs express the ectonucleotidase CD39, which generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4 + T cells (Teffs) enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6, and MDR1, and production of IL17A/IFNγ/IL22/GM-CSF. CD39 + Tregs selectively targeted CD73 + Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73 + Teffs to secrete IL17A. CD73 + Teffs infiltrating breast and ovarian tumors were functionally blunted by Tregs expressing upregulated levels of CD39 and ATPase activity. Moreover, tumor-infiltrating CD73 + Teffs failed to express inhibitory immune checkpoints, suggesting that CD73 might be selected under pressure from immune checkpoint blockade therapy and thus may represent a nonredundant target for restoring antitumor immunity. Significance: Polyfunctional CD73 + T-cell effectors lacking other immune checkpoints are selectively targeted by CD39 overexpressing Tregs that dominate the breast tumor environment. Cancer Res; 78(13); 3604-18. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene affects the clinical outcome of ovarian cancer patients. Experimental Design: A study cohort of 353 women with ovarian cancer who underwent genetic germline testing for BRCA1 and BRCA2 genes was identified. Progression-free survival (PFS), platinum-free interval (PFI), and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of ovarian cancer ( n = 316) was used as a validation cohort. Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2 After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS [58%; adjusted HR, 0.36; 95% confidence interval (CI), 0.20-0.64; P = 0.001] and prolonged PFI (29.7 vs. 15.5 months, P = 0.011), compared with noncarriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42-1.07; P = 0.094) or PFI (19 vs. 15.5 months, P = 0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13-0.68; P = 0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02-0.38; P = 0.001). Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged PFS, PFI, and OS. Clin Cancer Res; 24(2); 326-33. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Breast cancer (BC) patients with comparable prognostic features have heterogeneous outcomes, party related to a possible radiotherapy resistance leading to local-regional recurrences (LRR). The objective of the present study was to identify predictive molecular biomarkers of LRR of BC., Patients and Methods: Genetic profile of 146 BC patients' tumours included in the ProfiLER clinical trial (NC01774409) between 2013 and 2016 were analysed using next-generation-sequencing and comparative-genomic-hybridization tests. Patients and tumour characteristics were retrospectively collected and analysed for association with genomic rearrangements (mutations, amplification, deletions). Only gene alterations observed in >3% of the tumours were selected., Results: A total of 193 genomic rearrangements were identified, and 16 were observed in >3% of tumours. One was statistically correlated to the risk of local relapse. A median loco-regional progression-free survival (LRPFS) of 23.6 years was reported for PIK3CA mutation carriers (n = 31, 21.2%) versus 9.9 years for PIK3CA wild-type patients (HR 0.27, 95% CI 0.12-0.65, P = 0.002 in univariate analysis). PIK3CA mutation was identified as an independent protective factor on LRR using multivariate analysis (HR 0.29, 95% CI 0.09-0.99, P = 0.047). All other mutations, amplifications or deletions were not found associated with LRPFS., Conclusion: PIK3CA mutation was associated with a lower risk of local relapse in this population of BCs. This is consistent with recent studies suggesting PIK3CA to be part of biological pathways impacting the radiosensitivity., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The Transforming growth factor β (TGFβ) signaling has a paradoxical role in cancer development and outcome. Besides, the prognostic significance of the TGFβ1, SMAD4 in breast cancer patients is an area of many contradictions. The transcriptional intermediary factor 1γ (TIF1γ) is thought to interact with the TGFβ/SMAD signaling through different mechanisms. Our study aims to define the prognostic significance of TGFβ1, SMAD4 and TIF1γ expression in breast cancer patients and to detect possible interactions among those markers that might affect the outcome., Methods: Immunohistochemistry was performed on tissue microarray (TMA) blocks prepared from samples of 248 operable breast cancer patients who presented at Centre Léon Bérard (CLB) between 1998 and 2001. The intensity and the percentage of stained tumor cells were integrated into a single score (0-6) and a cutoff was defined for high or low expression for each marker. Correlation was done between TGFβ1, SMAD4 and TIF1γ expression with the clinico-pathologic parameters using Pearson's chi-square test. Kaplan-Meier method was used to estimate distant metastasis free survival (DMFS), disease free survival (DFS) and overall survival (OS) and the difference between the groups was evaluated with log-rank test., Results: 223 cases were assessable for TIF1γ, 204 for TGFβ1 and 173 for SMAD4. Median age at diagnosis was 55.8 years (range: 27 to 89 years). Tumors were larger than 20 mm in 49.2% and 45.2% had axillary lymph node (LN) metastasis (N1a to N3). 19.4% of the patients had SBR grade I tumors, 46.8% grade II tumors and 33.9% grade III tumors. ER was positive in 85.4%, PR in 75.5% and Her2-neu was over-expressed in 10% of the cases. Nuclear TIF1γ, cytoplasmic TGFβ1, nuclear and cytoplasmic SMAD4 stainings were high in 35.9%, 30.4%, 27.7% and 52.6% respectively. TIF1γ expression was associated with younger age (p=0.006), higher SBR grade (p<0.001), more ER negativity (p=0.035), and tumors larger than 2 cm (p=0.081), while TGFβ1 was not associated with any of the traditional prognostic factors. TGFβ1 expression in tumor cells was a marker of poor prognosis regarding DMFS (HR=2.28; 95% CI: 1.4 to 3.8; p=0.002), DFS (HR=2.00; 95% CI: 1.25 to 3.5; p=0.005) and OS (HR=1.89; 95 % CI: 1.04 to 3.43; p=0.037). TIF1γ expression carried a tendency towards poorer DMFS (p=0.091), DFS (p=0.143) and OS (p=0.091). In the multivariate analysis TGFβ1 remained an independent predictor of shorter DMFS, DFS and OS. Moreover, the prognostic significance of TGFβ1 was more obvious in the TIF1γ high patient subgroup than in the patients with TIF1γ low expression. The subgroup expressing both markers had the worst DMFS (HR=3.2; 95% CI: 1.7 to 5.9; p<0.0001), DFS (HR=3.02; 95 % CI: 1.6 to 5.6; p<0.0001) and OS (HR=2.7; 95 % CI: 1.4 to 5.4; p=0.005)., Conclusion: There is a crosstalk between the TIF1γ and the TGFβ1/SMAD4 signaling that deteriorates the outcome of operable breast cancer patients and when combined together they can serve as an effective prognostic tool for those patients.

GY785 is an exopolysaccharide produced by a mesophilic bacterial strain Alteromonas infernus discovered in the deep-sea hydrothermal vents. GY785 highly sulfated derivative (GY785 DRS) was previously demonstrated to be a promising molecule driving the efficient mesenchymal stem cell chondrogenesis for cartilage repair. This glycosaminoglycan- (GAG-) like compound was modified in a classical solvent (N,N'-dimethylformamide). However, the use of classical solvents limits the polysaccharide solubility and causes the backbone degradation. In the present study, a one-step efficient sulfation process devoid of side effects (e.g., polysaccharide depolymerization and/or degradation) was developed to produce GAG-like derivatives. The sulfation of GY785 derivative (GY785 DR) was carried out using ionic liquid as a reaction medium. The successful sulfation of this anionic and highly branched heteropolysaccharide performed in ionic liquid would facilitate the production of new molecules of high specificity for biological targets such as tissue engineering or regenerative medicine.

Globotriaosylceramide (Gb3), a glycosphingolipid found in the plasma membrane of animal cells, is the endocytic receptor of the bacterial Shiga toxin. Using x-ray reflectivity (XR) and grazing incidence x-ray diffraction (GIXD), lipid monolayers containing Gb3 were investigated at the air-water interface. XR probed Gb3 carbohydrate conformation normal to the interface, whereas GIXD precisely characterized Gb3's influence on acyl chain in-plane packing and area per molecule (APM). Two phospholipids, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), were used to study Gb3 packing in different lipid environments. Furthermore, the impact on monolayer structure of a naturally extracted Gb3 mixture was compared to synthetic Gb3 species with uniquely defined acyl chain structures. XR results showed that lipid environment and Gb3 acyl chain structure impact carbohydrate conformation with greater solvent accessibility observed for smaller phospholipid headgroups and long Gb3 acyl chains. In general, GIXD showed that Gb3 condensed phospholipid packing resulting in smaller APM than predicted by ideal mixing. Gb3's capacity to condense APM was larger for DSPC monolayers and exhibited different dependencies on acyl chain structure depending on the lipid environment. The interplay between Gb3-induced changes in lipid packing and the lipid environment's impact on carbohydrate conformation has broad implications for glycosphingolipid macromolecule recognition and ligand binding., (Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Objective: To review 5 years of assisted reproductive treatments (ART) provided to couples affected by human immunodeficiency virus (HIV)., Design: Age-matched cohort study., Setting: University-based tertiary center., Patient(s): Couples in whom the male (n = 87), female (n = 57), or both (n = 17) partners were HIV infected. The first ART cycle was compared with three sets of age-matched control subjects (3-to-1) which included 261, 171, and 51 couples, respectively., Intervention(s): ART in HIV-infected couples and age-matched controls., Main Outcome Measure(s): Infertility duration and ART outcome., Result(s): When initiating ART, all three HIV-infected groups had longer infertility histories, computed from when conception was attempted or infertility diagnosed, compared with noninfected age-matched control subjects. Outcome, however, was not different when only the male or female partner was infected, though with a trend toward higher cancellation and lower pregnancy rates. When both partners were HIV infected, cancellation were higher and pregnancy rates lower (12% versus 41.2%), than in age-matched control subjects., Conclusion(s): Our data showed longer infertility histories in all HIV-infected couples when undertaking their first ART. Outcome, however, was not altered when only one partner--male or female--was HIV infected. Efforts should therefore aim at assuring that HIV-infected couples access ART as promptly as their noninfected counterparts., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the rate of intrinsic ureteral endometriosis in patients presenting with severe ureteral endometriosis., Design: Observational study between June 1992 and December 2007., Setting: University tertiary referral center., Patient(s): Twenty-nine patients presenting deeply infiltrating endometriosis (DIE) with severe ureteral endometriosis. Severe ureteral endometriosis was defined as DIE lesions causing significant obstruction to the urinary flow with ureteral stenosis., Intervention(s): Complete surgical exeresis of DIE lesions., Main Outcome Measure(s): Pre- and peroperative evaluation associated with histologic analysis. Intrinsic ureteral endometriosis was defined as presence of DIE lesions infiltrating the ureteral muscularis., Result(s): In a series of 627 patients with histologic proved DIE, we observed 29 (4.6%) patients with severe ureteral endometriosis. Ureteral lesions (n = 34) were right sided in 7 (24.1%) patients, left sided in 17 (58.6%) patients, and bilateral in 5 (17.3%) patients. Eleven (37.9%) patients presented intrinsic lesions. Out of the 34 ureteral lesions 13 (38.2%) were intrinsic. In cases of radical ureteral surgery (n = 21 patients; n = 24 ureteral lesions) intrinsic ureteral DIE was observed in 52.4% (11 cases) of the patients and in 54.2% (13 cases) of the ureteral lesions., Conclusion(s): The prevalence of intrinsic ureteral endometriosis is underestimated. This result must be taken into account when specifying the surgical modalities for patients presenting with severe ureteral endometriosis., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Deep infiltrating endometriosis (DIE) is presented as a disease with high recurrence risk. Bladder DIE is the most frequent location in cases of urinary endometriosis. Surgical removal has been recommended for bladder DIE but long-term outcomes remains unevaluated. The objectives of this study are to evaluate the rate of recurrence after partial cystectomy for patients presenting with bladder DIE and to outline the surgical modalities for handling associated posterior DIE nodules., Methods: Seventy-five consecutive patients with histologically proved bladder DIE were enrolled at a single tertiary academic center between June 1992 and December 2007. A partial cystectomy was performed for each patient. Complete surgical exeresis of all associated symptomatic DIE lesions was carried out during the same surgical procedure. Bladder DIE patients were classified into three groups: patients with isolated bladder DIE (Group A); patients with associated symptomatic posterior DIE (Group B); patients with associated asymptomatic posterior DIE (Group C). Bladder DIE recurrence was defined as a clinical reappearance of the disease or radiological evidence that mandated a new surgical procedure. We assessed pelvic pain symptoms pre- and post-operatively using a 10-cm visual analogue scale., Results: In a series of 627 patients with DIE, we observed 75 patients (12%) with bladder DIE. With a 50.9 +/- 44.6 months mean follow-up after partial cystectomy no patient presented evidence of bladder DIE recurrence. Post-operatively, we observed a significant improvement with respect to pain symptoms, with only two patients (2.7%) developing major complications during follow-up. Among patients with non-operated associated asymptomatic posterior DIE lesions (n = 15), a second surgical procedure indicated for pain symptoms was necessary in only one patient (6.7%)., Conclusions: For patients presenting with bladder DIE, no patients required further surgery for bladder recurrence after radical surgery consisting in partial cystectomy. Exeresis of associated posterior DIE nodules is indicated only when they are symptomatic.

Background: This study was designed to investigate the intra-operative characteristics and the risk of intra- and post-operative complications in cases of total laparoscopic hysterectomy (TLH) in overweight, obese and non-obese patients., Methods: This cohort study includes all patients undergoing TLH for benign pathologies between January 1993 and June 2007 in Cochin university hospital (Paris). Demographic and surgical data were analysed. A comparison between overweight and obese patients versus non-obese patients and multivariate analyses were performed., Results: Of 1460 patients undergoing TLH, 101 patients (6.9%) had a BMI of 30 or higher and 338 (23.2%) were overweight. After adjustment with respect to the patients' characteristics and past history (age, parity, past history of laparotomies, previous Cesarean section, menopausal status), no significant difference was found whether in terms of intra-operative (haemorrhage, transfusion, thrombosis, ureter, bladder or bowel injuries) or post-operative complications (hyperthermia, infections, fistula). Concerning the intra- and post-operative characteristics of these patients, only a significantly longer operating time was noted in the case of obesity (RR = 1.80; CI 95%: 1.16-2.81)., Conclusions: In our experience, provided that the operating technique is meticulous, the intra- and post-operative complications are not increased in the case of obesity, although the operating time is longer.

Objective: To investigate whether an associated ovarian endometrioma is a marker for severity of deep infiltrating endometriosis (DIE)., Design: Observational study between June 1992 and December 2005., Setting: University tertiary referral center., Patient(s): Five hundred patients with histologically assessed DIE., Intervention(s): Complete surgical exeresis of deep endometriotic lesions., Main Outcome Measure(s): Severity of the disease was quantified according to the mean number of DIE lesions and the type of main lesion., Result(s): In patients with associated ovarian endometrioma, the number of single isolated DIE lesions was statistically significantly lower (41.9% vs. 61.1%). The mean number of DIE lesions was statistically significantly higher in patients presenting with an associated ovarian endometrioma (2.51 +/- 1.72 vs. 1.64 +/- 1.0). For patients with associated ovarian endometrioma DIE lesions were more severe with an increased rate of vaginal, intestinal, and ureteral lesions., Conclusion(s): Associated ovarian endometrioma is a marker for the severity of the DIE. In a clinical context suggestive of DIE, when there is an ovarian endometrioma, the practitioner should investigate the extent of the disease to check for severe and multifocal DIE lesions.

Background: Laparoscopic hysterectomy is indicated as an alternative to laparotomy when the vaginal route is potentially difficult because of an immobile uterus and a poor vaginal accessibility. The aim of this study was to evaluate the rate, the risk factors for bladder injuries in a series of 1501 laparoscopic hysterectomies indicated for benign uterine pathologies., Methods: This study was conducted retrospectively from January 1993 to 2000 and prospectively from 2001 to July 2007.The indications, patients' characteristics and complications were recorded. The overall rate of bladder injuries, the comparison of means (t test) and percentages (exact chi(2) test) between the cases and the population with no injury, the odd ratios (OR) and multivariate analysis were performed using the statistical package for the social sciences software., Results: The rate of bladder injuries was 1% (15 patients). Risks factors were previous Caesarian section [OR: 4.33, 95% confidence interval (CI): 1.53-12.30] and previous laparotomy (OR: 4.69, 95% CI: 1.59-13.8). The rate of injury decreases with the surgeons' experience and reaches a plateau of 0.4% after 100 hysterectomies performed., Conclusions: The rate of bladder injury during total laparoscopic hysterectomy is low and decreases with the surgeon's experience. Bladder injury is not linked to an increase of post-operative morbidity when recognized and repaired during the same laparoscopic procedure. The comparison with other routes of hysterectomies should take into account these risk factors.

Background: Transvaginal ultrasonography (TVUS) has important advantages compared with transrectal ultrasonography (TRUS): it is less invasive, is cost-effective, is a familiar and well-accepted approach, and anesthesia is not required. We compared the accuracy of TVUS and TRUS for diagnosing rectal wall involvement in patients presenting with histologically proved deeply infiltrating endometriosis (DIE)., Methods: Prospective study of 134 patients with histologically proved DIE underwent preoperative investigations using both TVUS and TRUS. The radiologist (TVUS) and sonographer (TRUS) were unaware of the clinical findings but knew that DIE was suspected., Results: DIE was confirmed histologically for all the patients. A rectal wall involvement was histologically proved for 75 patients (56%). For the diagnosis of infiltration of the intestinal wall, TVUS and TRUS, respectively, had a sensitivity of 90.7% and 96.0%, a specificity of 96.5% and 100.0%, a positive predictive value of 97.1% and 100.0% and a negative predictive value of 88.9% and 95.2%., Conclusions: TVUS and TRUS have similar degrees of accuracy for predicting intestinal involvement. TVUS must be the first-line imaging process to perform for patients presenting with clinically suspected DIE. The question for the coming years is to define if it is necessary for TRUS to be carried out systematically in cases of clinically suspected DIE.

Dearomatization of electron-poor benzofurans is possible through involvement of the aromatic 2,3-carbon-carbon double bond as dienophile in normal electron demand [4 + 2] cycloadditions. The tricyclic heterocycles thereby produced bear a quaternary center at the cis ring junction, a feature of many alkaloids such as morphine, galanthamine, or lunaridine. The products arising from the reaction have been shown to depend on different factors among which the type of the electron-withdrawing substituent of the benzofuran, the nature of the reacting diene, and the method of activation. In the presence of all-carbon dienes, the reaction yields the expected Diels-Alder adducts. When thermal activation is insufficient, a biactivation associating zinc chloride catalysis and high pressure is required to generate the cycloadducts in good yields and high stereoselectivities, for instance, when cyclohexadiene is involved in the process. The use of more functionalized dienes, such as those bearing alkoxy or silyloxy substituents, also shows the limits of the thermal activation, and hyperbaric conditions are, in this case, well-suited. The involvement of Danishefsky's diene induces a competition in the site of reactivity. The aromatic 2,3-carbon-carbon double bond is unambiguously the most reactive dienophile, and the 3-carbonyl unit becomes a competitive site of reactivity with benzofurans bearing substituents prone to heterocyloaddition, in particular under Lewis acid activation. The sequential involvement of both the aromatic double bond and the carbonyl moiety as dienophiles is then possible by using an excess of diene under high-pressure activation. In line with the experimental results, DFT computations suggest that the Diels-Alder process involving the aromatic double bond is preferred over the hetero-Diels-Alder route through an asynchronous concerted transition state. However, Lewis acid catalysis appears to favor the heterocycloaddition pathway through a stepwise mechanism in some cases.

Background: The aim of this study was to evaluate the risk of ureteral injuries and to discuss how to avoid their occurence after laparoscopic hysterectomy indicated for benign uterine pathologies., Methods: This observational study covers the period from January 1993 to December 2005 (retrospective study from 1993 to 2000 and prospective from 2001). We reviewed incidence, methods of diagnosis and management of ureteral injuries., Results: The rate of ureteral injuries was 0.3% (four patients). Three patients presented a ureteral fistula diagnosed secondarily some time after the operation. The fourth patient presented a ureteral injury that was diagnosed peroperatively. Three out of four of the lesions were observed on the right side. In every case, there were preoperative risk factors connected with a past history of surgery, or the lateral location of uterine myomas. All four patients needed ureterovesical reimplantation. The outcome was good in all four cases., Conclusions: The rate of ureter complications after laparoscopic hysterectomy is low and comparable to that observed after hysterectomy by laparotomy. The risk should not prevent laparoscopic hysterectomy being used more widely. Prevention depends on training in the technique and the surgeon's experience.

Objective: It has been hypothesized that bladder endometriotic nodules are an independent form of endometriosis that should be considered a distinct clinical entity. If this is true, the frequency of nonvesical endometriotic lesions in affected patients should be similar to the prevalence of the disease in the general population (about 10%). The aim of the study was to evaluate the presence of other forms of endometriosis in patients with bladder endometriotic nodules., Design: Case series., Setting: Two gynecologic surgical units., Patient(s): Fifty-eight women with large bladder endometriotic nodules., Intervention(s): To evaluate the concomitant presence of other forms of endometriosis., Main Outcome Measure(s): Presence of superficial peritoneal implants, ovarian endometriomas, adhesions, and extravesical deep peritoneal endometriosis., Result(s): The presence of superficial peritoneal implants, ovarian endometriomas, adhesions, and extravesical deep peritoneal endometriosis was observed in 58.6% (95% confidence interval [CI]: 45.2-71.2), 44.8% (95% CI: 32.2-58.2), 81.0% (95% CI: 68.4-89.6), and 27.6% (95% CI: 16.7-40.8) of cases, respectively. The presence of at least one of them was documented in 87.9% of cases (95% CI: 76.7-94.3)., Conclusion(s): Endometriotic nodules of the bladder are frequently associated with other forms of pelvic endometriosis. This result does not support the vision that bladder endometriotic nodules should be considered an independent form of the disease.

Background: To investigate whether knowledge of the anatomical distribution of histologically proven deeply infiltrating endometriosis (DIE) lesions contributes to understanding the pathogenesis., Methods: Observational study between June 1992 and December 2004 (retrospective study between 1992 and 2000; prospective study between 2001 and 2004). Continuous series of 426 patients suffering from pelvic pain who underwent complete surgical exeresis of DIE. DIE lesions were classified according to four different possibilities: (i) Firstly, DIE lesions were classified as located in the anterior or posterior pelvic compartment. (ii) Secondly, DIE were classified as left, median and right. (iii) Thirdly, DIE lesions were classified as pelvic or abdominal. (iv) Fourthly, DIE lesions that could present in a right and/or left location were classified as unilateral or bilateral., Results: These 426 patients presented 759 histologically proven DIE lesions: bladder (48 lesions; 6.3%); uterosacral (USL) (400 lesions; 52.7%); vagina (123 lesions; 16.2%); ureter (16 lesions; 2.1%) and intestine (172, 22.7%). DIE lesions are significantly more often located in the pelvis (n=730 lesions) than in the abdomen (n=29 lesions) (P<0.0001). Pelvic DIE lesions are significantly more often located in the posterior compartment of the pelvis [682 DIE lesions (93.4%) versus 48 DIE lesions (6.6%); P<0.0001]. Pelvic DIE lesions are significantly more frequently located on the left side. For patients with unilateral pelvic DIE lesions, the anatomical distribution is significantly different in the three groups: left (172 lesions; 32.0%), median (284 lesions; 52.8%) and right (82 lesions; 15.2%) (P<0.0001). For patients with lateral lesions, left DIE lesions (172 lesions; 67.8%) were found significantly more frequently than right DIE lesions (82 lesions; 32.2%) (P<0.0001). A similar predisposition was observed when we included patients with bilateral pelvic DIE lesions (P=0.0031). The same significantly asymmetric distribution is observed for total (pelvic and abdominal) DIE lesions., Conclusions: Our results demonstrate that distribution of DIE lesions is asymmetric. It is possible that this is related to the anatomical difference between the left and right hemipelvis and to the flow of peritoneal fluid. These findings support the hypothesis that retrograde menstruation of regurgitated endometrial cells is implicated in the pathogenesis of DIE.

Objective: To compare the accuracy of rectal endoscopic ultrasonography (REU) and magnetic resonance imaging (MRI) for predicting rectal wall involvement in patients presenting histologically proven deeply infiltrating endometriosis (DIE)., Methods: This was a retrospective study of a continuous series of 81 patients presenting histologically proven DIE who underwent preoperative investigations using both REU and MRI. The sonographer and the radiologist, who were unaware of the clinical findings and patient history, but knew that DIE was suspected, were asked whether there was involvement of the digestive wall., Results: Rectal DIE was confirmed histologically in 34 of the 81 (42%) patients. For the diagnosis of rectal involvement, sensitivity, specificity and positive and negative predictive value for REU were 97.1%, 89.4%, 86.8% and 97.7% and for MRI they were 76.5%, 97.9%, 96.3% and 85.2%., Conclusion: The sensitivity and negative predictive value of REU were higher than those of MRI suggesting that REU performs better than MRI in the diagnosis of rectal involvement for patients presenting with DIE. Prospective studies with a large number of patients are needed in order to validate these preliminary results., (Copyright 2004 ISUOG)