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Objectives Description of fertility and prognosis of patients with borderline ovarian tumor (BOT) treated by fertility-sparing surgery through a longitudinal study from the French national cancer network. Methods All consecutive patients diagnosed with BOT from the French National Network dedicated to Ovarian Malignant Rare Tumors from 2010 and 2017 were selected. In 2018, an update was made by sending a questionnaire regarding recurrence and fertility to patients aged under 43 years at diagnosis and treated conservatively. We compared the characteristics of the patients with/without recurrence and with/without live birth. Results Fifty-two patients aged 18 to 42 years presented a desire of pregnancy. Thirty patients (58%) presented a FIGO IA tumor, and 20 patients were treated by bilateral cystectomies (38%). We observed at least one live birth for 33 patients (63%) and local recurrences in 20 patients (38%). Both recurrence and live birth in 17 patients (33%) were reported, with recurrence occurring before pregnancy, after a second fertility-sparing treatment, in half of the cases. No factors associated with recurrence or live birth in this study were identified. Moreover, in this population, both recurrence and live birth were independent of age, with a linear risk along time. Disease-free survival was worse for patients treated with bilateral cystectomy (n = 20, 38%), with no difference in terms of fertility. Conclusion Two third of the patients experienced life birth after conservation surgery. We did not highlight an age/time from surgery for which the risk of recurrence outweighs the chance of pregnancy and to radicalize surgery. Moreover, almost a quarter of the live birth occurred after recurrence, with no more further event to date in these patients. The results encourage to consider a second fertility-sparing surgery after local borderline recurrence in the case of pregnancy desire. All these decisions must be discussed in specialized multidisciplinary boards.

International audience; 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.

BackgroundThe 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.MethodsThis 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.ResultsEighty-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.ConclusionsOur 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.

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., Highlights • In a study of 17 322 early BC patients, LVI had a significant independent negative prognostic impact on survival. • LVI negatively impacted survival in almost every patient category and cancer subtype, with and without AC. • LVI did not have a negative survival impact in patients with ER+ grade 3 or with luminal A-like tumors with chemotherapy. • Results suggest a possible benefit of AC in LVI-positive luminal A-like patients.

International audience; 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 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., Highlights • A tendency towards a premature decrease in the ovarian reserve in BRCA1/2 pathogenic variant carriers was found. • BRCA1/2 pathogenic variant carriers presented a higher risk of a low ovarian reserve. • Information and education regarding reproduction is mandatory among BRCA1/2 pathogenic variant carriers.

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.

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.

Aim To assess the value of post-mastectomy radiation therapy (PMRT) to breast cancer (BC) patients with no or minimal lymph node (LN) involvement. Materials and methods We retrospectively analysed a French multi-centric cohort of 4283 patients treated by mastectomy and axillary dissection, with or without PMRT, between 1980 and 2013. Practices were analysed for three treatment periods (1980–1999, 2000–2005 and 2006–2013). The impact of PMRT on loco-regional recurrence (LRR), disease-free survival (DFS), BC-specific survival and overall survival was assessed in pN0-1mi patients using multivariate analyses (logistic regression and Cox model). It was subsequently assessed based on the number of clinicopathological recurrence-risk factors, generating a prognostic index (French-PMRT index), to isolate a pN0-1mi patients subgroup that might derive a benefit from PMRT. We tested the accuracy of the Cambridge-PMRT (c-PMRT) index to discriminate between patients with significantly different outcomes and the value of PMRT in each c-PMRT prognostic group. Results More than half of the pN0-1mi patients of our cohort underwent PMRT, which almost significantly improved LRR-free survival and DFS. Matching pN0-1mi patients based on the number of clinicopathologic recurrence-risk factors identified a higher risk subpopulation (≥3 recurrence-risk factors), but PMRT did not improve patient outcomes. Although the c-PMRT index had the potential to predict patient outcomes, its use did not help in making the decision of whether or not to use PMRT. Conclusion We failed to isolate a subgroup of early BC patients without LN involvement suitable for PMRT, despite studying a large cohort.

Introduction The aim of this study was to examine changes in therapeutic practices for early breast cancer T0-2 N0 managed by upfront surgery and SLNB. Population Between 1999 and 2012, 15.508 patients were treated. Four periods were determined: 1999–2003, 2004–2006, 2007–2009 and > 2009. Five tumor subtypes were defined according to hormonal receptors (HR) and Her2: Luminal A (HR + Her2- Grade 1–2), Her2 (Her2+ HR-), Triple-negative (HR- Her2-), Luminal B Her2- (HR + Her2- Grade 3), Luminal B Her2+ (HR + HER2+). Methods Rates of axillary lymph node dissection (ALND), adjuvant chemotherapy ± trastuzumab, endocrine treatment, mastectomy and post mastectomy radiotherapy (PMRT) were analyzed according to treatment periods with univariate and multivariate analysis. Overall and disease-free survivals were analyzed according to treatment periods adjusted for HR and then for tumor subtypes. Results Rates of ALND, adjuvant chemotherapy and endocrine treatment varied significantly according to treatment periods, for HR positive and negative tumors. ALND rate decreased for all tumor subtypes with a decrease of adjuvant chemotherapy rate for Luminal A tumors and an increase for Luminal B Her2+ and Her2-tumors. Endocrine treatment rate decreased for Luminal A and increased for Luminal B Her2+ tumors. In multivariate analysis, these modifications with time remained significant. Mastectomy and PMRT rates increased. In multivariate analysis, overall and disease-free survivals increased during successive periods. Conclusion A global therapeutic de-escalation in ALND and adjuvant systemic treatment, combined with an actual escalation in some specific subsets was demonstrated, but without negative impact on survival.

The group of rare malignant ovarian tumors includes the group of germ cell tumors, sex cords stromal ovarian tumors, small cell carcinoma, malignant Brenner tumors, rare epithelial tumors such as mucinous carcinoma, clear cell carcinoma, or low-grade serous carcinoma, as well as ovarian carcinosarcoma. Together they comprise about 10% of all ovarian tumors. Due to their low prevalence and their heterogeneity, data and treatment recommendations are limited. Even though all ovarian tumors are staged according to the FIGO staging of epithelial ovarian tumors, treatment differs especially in germ cell tumors and sex cords stromal ovarian tumors. Non-epithelial ovarian tumors can arise from a variety of ovarian precursor cells such as germ cells, granulosa cells, theca cells, or stromal fibroblasts. As can be expected already due to their divergent precursor lesions, these malignancies are substantially different but united by their rarity. This overview article gives a comprehensive summary on the pathology and clinical presentation, as well as therapy recommendations of a selection of those rare ovarian tumors, based on the latest national guidelines and related important publications.

Ovarian cancers express highly immunogenic tissue-specific antigens. The resulting immune infiltration is a major prognostic factor. There is therefore a strong biological rationale for the development of immunotherapy in ovarian cancer. However, based on Phase I and II clinical trials data, the efficacy of anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors (ICPIs) remains limited in monotherapy in heavily pre-treated patients. Currently, the identification of predictive biomarkers of response and resistance is one of the major areas of research. Identifying effective combination of anti-PD-1 or anti-PD-L1 with other anticancer agents is another clinical need. Several combinations were evaluated. The association of ICPIs with chemotherapy (anthracyclines or carboplatin+paclitaxel) is disappointing (JAVELIN studies). The association with PARP inhibitors, anti-angiogenic agents and CTLA-4 inhibitors seems promising. Other immune therapies such as cell therapies (adoptive transfer of intra-tumor lymphocytes, CAR T cells or vaccines from dendritic cells) could be the future of immunotherapy in ovarian cancer but only early phase studies clinical data is available at this time.

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.

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

The French national rare gynecological tumor network has been established to improve the quality of care through offering expertise in double reading histological diagnosis, reviewing cases and guiding management of these tumors through specialized multidisciplinary tumor boards and online clinical guidelines (www.ovaire-rare.com). The aim of this study is to evaluate the impact of the development and implementation of this network by assessing the conformity of medical practice with the guidelines concerning the granulosa cell tumors (GCTs).This is a French nationwide study, including 463 patients (out of the 639 identified patients) with a definitive diagnosis of GCT between 2011 and 2016. Surgical practices were analyzed for conformity with the current guidelines (www.ovaire-rare.org). Medical records, surgical and pathological reports were systematically analyzed. Total conformity was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysterectomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsies and peritoneal cytology) according to the FIGO stage. Partial conformity referred to a conservative or radical surgery without surgical staging and non-conformity was defined as a non-optimal surgery as recommended by the guidelines.Median age at diagnosis was 49 years old (range 10-89). The median size of tumor was 94 mm (range 5-400). Radical surgery was performed in 240 patients (52%); while a fertility-sparing surgery was performed in 98 cases (21%). A surgical staging was performed in 76 cases (16%) and an evaluation of the endometrium in 289 cases (62%). Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (30%) and not assessable in 48 cases (10%). A statistically significant difference for compliance was observed in restaging surgery (p 0,001), radical surgery (p = 0,017) and the period (before or after) of the implementation of the network (p 0,001). Survival analyses did not allow us to demonstrate a significant difference in overall survival nor in PFS although there was a trend in favor of optimal surgery compared to incomplete/non optimal surgery.Surgical management's conformity to the guidelines increases over time from 2011 to 2016. According to this study, the implementation of a national network dedicated to rare gynecologic tumors seems to significantly improve the surgical management of the patients with ovarian granulosa cell tumors.

Aim There is no consensual indication for surgical resection after diagnosis on per-cutaneous biopsy of borderline breast lesions (B3). We evaluate under-evaluation rate of per-cutaneous biopsy and predictive factors of under-evaluation. We analyze accuracy of reported decision-making tools. Methods We conduct a prospective multicentric study including, atypic-ductal hyperplasia (ADH), atypic-lobular hyperplasia (ALH), atypic-cylindro-cubic metaplasia (FEA), papilloma, radial scars (RS) and phyllod tumors. When several B3 lesions were associated, the more severe lesion was used to classify the lesion. We determined breast cancers (BC) rate and histologic type. Among 478 patients, 518 B3 lesions were studied: 15.1% (78) FEA, 48.6% (252) ADH, 16.8% (n = 87) ALH, 5.4% (n = 28) RS, 12% (n = 62) papilloma, 0.8% (n = 4) phyllod tumors and 0,8% (n = 4) with a suspicious low grade DCIS. More than 1 lesion was identified in 31.9% (165) of cases. A surgical resection was performed for 86.3% (447/518) lesions. Significant factors of surgical resection were: residual micro-calcification after biopsy (OR: 2.7) and type of B3 lesion. Results Overall BC rate was 15.3% (68/445) with 79.4% (54) in-situ carcinomas. According to B3 lesions, BC rates were 12.9% for FEA, 20% for ADH, 11.6% for ALH, 3.7% for RS, 8.8% for papilloma and 25% for suspicious in-situ carcinoma. A score has been calculated and patients were distributed in 3 groups. Patient's rates without BC were respectively: 100%, 80.4% and 80.6% (p = 0.029). Conclusion In conclusion, it could be suggested to avoided complementary surgical resection in case of good radio-pathologic concordance and low probability of BC.

Objectives: To analyze axillary lymph node involvement (ALNI) rate and survival for mucinous (MC) and tubular (TC) breast carcinomas considered being of very good prognosis and for which an axillary surgical exploration could be questioned. Methods: Our multicentric cohort consisted of 21,135 patients with clinically node-negative invasive breast cancer, without neoadjuvant therapy, between 1999 and 2013 in 10 French centers. ALNI rate and survival were analyzed according to patient and tumor characteristics. Results: Our cohort consisted of 672 TC and 245 MC. Patients were older and tumor size greater for MC and pathologic factors were more pejorative. The rate of mastectomies and adjuvant chemotherapy was higher in the MC group. Axillary lymph node status was determined by SLNB alone in 71.2% of patients. ALNI rates were 17.9% and 18% for TC and MC, respectively. ALNI rate was lesser for MC (OR 0.503, p = 0.024) and greater in case of lympho-vascular invasion (OR 5.0, p < 0.0001) and for tumors >10 mm (OR 2.17, p = 0.042). Median follow-up was 58 months. The 5- and 7-year overall survival rates were 97.1% and 95% for TC, respectively; 92.3% and 91.2% for MC ( p = 0.043); 5- and 7-year disease-free survival rates were 97.9% and 97.2% versus 95.2 and 93.6% ( p = 0.041). Lympho-vascular invasion was the only predictive factor for overall survival (hazard ratio [HR] = 2.70)’ grade 2 (HR = 10) and HR-negative (HR = 4.9) were the two predictive factors for disease-free survival. Conclusion: This study confirms the need for an axillary exploration for these tumors even for a tumor size

Introduction Rare ovarian tumours include complex borderline ovarian tumours, sex-cord tumours, germ cell tumours and rare epithelial tumours. Indications and modalities of fertility preservation (FP), infertility management, contraindications for hormonal contraception or menopause hormone therapy are frequent issues in clinical practice. A panel of experts from the French national network dedicated to rare gynaecological cancers, and experts in reproductive medicine and gynaecology have built guidelines on FP, contraception and menopause hormone therapy in women treated for ovarian rare tumours. Material and methods A panel of 35 experts from different specialties contributed to the preparation of the guidelines, following the DELPHI method (formal consensus method). Statements were drafted after a systematic literature review and then rated through two successive rounds. Results Thirty-five recommendations were identified, concerning indications for FP, contraindications for ovarian stimulation, contraceptive options and menopause hormone therapy for each tumour type. Discussion Overall, caution has been recommended in the case of potentially hormone-sensitive tumours such as sex-cord tumours, serous and endometrioid low-grade adenocarcinomas, as well as for high-risk serous borderline ovarian tumours. Conclusion In the context of a scarce literature, a formal consensus method allowed the elaboration of guidelines, which will help clinicians in the management of these patients.

International audience; BACKGROUND:Tumour features associated with isolated invasive breast cancer (BC) ipsilateral local recurrence (ILR) after breast conservative treatment (BCT) and consequences on overall survival (OS) are still debated. Our objective was to investigate these points.METHODS:Patients were retrospectively identified from a cohort of patients who underwent BCT for invasive BC in 16 cancer centres. End-points were ILR rate and OS. The impact of ILR on OS was assessed by multivariate analysis (MVA) for all patients and according to endocrine receptors (ERs) and grade or tumour subtypes.RESULTS:Of 15,570 patients, ILR rate was 3.1%. Cumulative ILR rates differed according to ERs/grade (ERs+/Grade2: HR 1.42, p = 0.010; ERs+/Grade3: HR 1.41, p = 0.067; ERs-: HR 2.14, p

International audience; An unusual class, compact in sizes, of fluorescent probes based on pyridazino-1,3a,6a-triazapentalene scaffolds exhibits highly fluorescent properties (quantum yield values up to 73%, large Stokes shifts, emission wavelengths located in the green-yellow range, excellent solubility) with very good photostability suitable for optical imaging applications. Fluorescent organic molecules are essential compounds for the detection, quantification and understanding of biological processes applied in chemical biology, biochemistry, biomedical research and diagnostics. 1 The main advantages of fluorescent organic molecules include high versatility, moderate molecular size and weight, chemical stability, and ability to exhibit switchable or activatable spectroscopic properties. This fluorogenic behavior can be initiated by a chemical or biochemical process according to four main different reaction mechanisms: pH sensitivity, complexation/decomplexation, formation or cleavage of a covalent bond and redox reactions. 2-5 Although numerous fluorophores have already been described in the literature, the diversity of the molecular frameworks of those commonly used for cell imaging probes is often limited to coumarin, xanthene (fluorescein, rhodamine, Texas), BODIPY and cyanine cores. 6,7 These dyes cannot be considered as ideal probes for optical imaging since none of them combine high fluorescence with optimal absorption and emission wavelengths, good chemical and photostability, sufficient water solubility and small molecular weight/size. Therefore, the discovery of novel fluorophore-based scaffolds remains an important challenge to offer new highly versatile platforms providing alternative and/or complementary molecular tools for novel bioimaging applications. 8-12 In this context, focusing on very low molecular weight/size fluorophores is of major interest for minimizing pharmacokinetic alterations of the targeting biomolecules to which they are linked. 13 Small dyes may also find specific interest in ligase fusion proteins. 14 Obviously, those fluorophores have to rely on (i) optimized spectroscopic properties, including high quantum yield values, large Stokes shifts and good photostability, 15,16 and (ii) biological media compatibility i.e. good chemical stability, low cytotoxicity, cell permeability and solubility, in order to be considered as suitable probes for cellular imaging. a) Namba et al. : Our work : N N N (N) Fused 1,3a,6a-triazapentalenes N N N b) Hung et al. : c)  em = 389 nm /  = 0.014 Benzotriazapentalene 1 OFF ON 1,3a,6a-triazapentalene (TAP) ON-High quantum yields-Good water solublity-Shift towards longer wavelengths:  em up to 518nm-Large Stokes shift: up to 100 nm-High chemical stability-Compact structures-Easy modulation-Photostable-Non toxic N N N  em = 397 nm /  < 0.001  em up to 518 nm /  up to 0.73 Blue emission Green emission No emission Fig 1 Summary of the state of the art in the field of triazapentalene derivatives. Photophysical properties of 1a,3a,6a-triazapentalene (a) benzotriazapentalene (b), and novel nitrogen-containing fused ring TAP derivatives (c). A few years ago, Namba's team pioneered the fluorescent properties of the 1,3a,6a-triazapentalene (TAP) derivatives (Figure 1a) 17 and showed that this highly condensed dipolar structure offers very promising spectroscopic properties and suitability for biological applications. 18,19 To study the impact of the TAP substituents on spectroscopic properties, the development of specific synthetic pathways was required. 20-26

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., Highlights • LN micro-metastases have no detectable prognostic impact. • pN1 status, but not pN1mi, significantly impacted overall survival, disease-free survival, metastasis-free 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. • LN micro-metastases should not be considered as a determining factor in indicating adjuvant chemotherapy.

Genital melanoma is a rare pathology. We present the experience of two comprehensive cancer centers in Lyon (France) in the management of genital melanoma in order to identify prognostic factors and optimal treatments. Between April 1992 and Mars 2014, 16 patients with a primary genital melanoma were referred to our department. Nine patients presented a vaginal melanoma, six vulvar melanomas and only one cervical melanoma. The median dimension of the lesion was 33.7 mm (5–100 mm). The AJCC stage ranged from IB to IIIC. 12 cases were the classic dark-blue flat melanoma and the other 4 cases were an atypical amelanotic tumor. Wide local surgery was performed in nine patients. A radical surgery was performed in six patients. In the large cervical melanoma, radiotherapy was performed as first-line treatment. In all the patients regional lymph node staging was performed. Adjuvant treatment was realized in nine patients. Two patients are alive without recurrence. Only one patient was lost to the first follow-up. The other 13 patients experienced a rapid recurrence. The median disease-free survival and the median overall survival were 11.8 months (2–49 m) and of 30.4 m (11–144 m), respectively. The disease-free survival and overall survival could be linked to a clinical presentation (Breslow thickness and morphology of lesion) associated to the early diagnosis. In our small series, the most important prognosis factor remains the tumor thickness. These rare lesions should be treated in experienced centers in order to improve their prognostic.

Phyllodes tumors (PT) are uncommon fibroepithelial breast neoplasms and there is currently no clear consensual treatment for these tumors. The aim of our study was to evaluate the surgical management and outcome of benign and borderline PT. We retrospectively assessed 76 cases of benign or borderline PT managed at the Leon Berard comprehensive cancer center in Lyon, France between July 2003 and December 2013. The mean age at diagnosis was 37.9 years and the median follow-up was 58 months. Seventy-five patients (99%), with a mean tumor size of 27 mm, underwent a breast-conserving procedure. The tumor margins were considered positive (when the tumor was present at the inked surgical section) in seven of 76 cases (9%) and negative in 65 out of 76 cases (86%). We observed the presence of small negative surgical margins

International audience; BACKGROUND:Invasive lobular carcinomas (ILCs) represent approximately 10% of all breast cancers. Despite this high frequency, benefit of adjuvant chemotherapy (CT) is still unclear.METHODS:Our objective was to investigate the impact of CT on survival in ILC. Patients were retrospectively identified from a cohort of 23,319 patients who underwent primary surgery in 15 French centers between 1990 and 2014. Only ILC, hormone-positive, human epidermal growth factor 2 (HER2)-negative patients who received adjuvant endocrine therapy (ET) were included. End-points were disease-free survival (DFS) and overall survival (OS). A propensity score for receiving CT, aiming to compensate for baseline characteristics, was used.RESULTS:Of a total of 2318 patients with ILC, 1485 patients (64%) received ET alone and 823 (36%) received ET + CT. We observed a beneficial effect of addition of CT to ET on DFS and OS in multivariate Cox model (HR = 0.61, 95% confidence interval, CI [0.41-0.90]; p = 0.01 and 0.52, 95% CI [0.31-0.87]; p = 0.01, respectively). This effect was even more pronounced when propensity score matching was used. Regarding subgroup analysis, low-risk patients without CT did not have significant differences in DFS or OS compared to low-risk patients with CT.CONCLUSION:ILC patients could derive significant DFS and OS benefits from CT, especially for high-risk patients.

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

Benefit of adjuvant trastuzumab-based chemotherapy for node-positive and/or1 cm human epidermal growth factor receptor 2-positive (HER2+) breast carcinomas has been clearly demonstrated in randomized clinical trials. Yet, evidence that adjuvant chemotherapy with or without trastuzumab is effective in pT1abN0 HER2+ tumors is still limited. The primary objective of this study was to investigate the impact of adjuvant chemotherapy ± trastuzumab on outcome in this subpopulation.A total of 356 cases of pT1abN0M0 HER2 + breast cancers were retrospectively identified from a large cohort of 22,334 patients, including 1248 HER2+ patients who underwent primary surgery at 17 French centers, between December 1994 and January 2014. The primary end point was disease-free survival (DFS). A multivariate Cox model was built, including adjuvant chemotherapy, tumor size, hormone receptor status, and Scarff Bloom Richardson (SBR) grade.A total of 138 cases (39%) were treated with trastuzumab-based chemotherapy, 29 (8%) with chemotherapy alone, and 189 (53%) received neither trastuzumab nor chemotherapy. Adjuvant chemotherapy ± trastuzumab was associated with a significant DFS benefit (3-year 99 vs. 90%, and 5-year 96 vs. 84%, Hazard ratio, HR 0.26 [0.10-0.67]; p = 0.003, logrank test) which was maintained in multivariate analysis (HR 0.19 [0.07-0.52]; p = 0.001). Metastasis-free survival was also increased (HR 0.25 [0.07-0.86]; p = 0.018, logrank test) at 3-year (99 vs. 95%) and 5-year (98 vs. 89%) censoring. Exploratory subgroup analysis found DFS benefit to be significant in hormone receptor-negative, hormone receptor-positive, and pT1b tumors, but not in pT1a tumors.Adjuvant chemotherapy ± trastuzumab is associated with a significantly reduced risk of recurrence in subcentimeter node-negative HER2+ breast cancers. Most of the benefit may be driven by pT1b tumors.

Controversy exists about the prognosis of breast cancer in young women. Our objective was to describe clinicopathological and prognostic features to improve adjuvant treatment indications.We conducted a retrospective multi centre study including fifteen French hospitals. Disease-free survival's data, clinical and pathological criteria were collected.5815 patients were included, 15.6% of them where between 35 and 40 years old and 8.7% below 35. In 94% of the cases, a palpable masse was found in patients ≤35 years old. Triple negative and HER2 tumors were predominantly found in patients ≤35 (22.2% and 22.1%, p 0.01). A young age ≤40 years (p 0.001; hazard ratio [HR]: 2.05; 95% confidence limit [CL]: 1.60-2.63) or ≤35 years (p 0.001; [HR]: 3.86; 95% [CL]: 2.69-5.53) impacted on the indication of chemotherapy. Age ≤35 (p 0.001; [HR]: 2.01; 95% [CL]: 1.36-2.95) was a significantly negative factor on disease-free survival. Chemotherapy (p 0.006; [HR]: 0.6; 95% [CL]: 0.40-0.86) and positive hormone receptor status (p 0.001; [HR]: 0.6; 95% [CL]: 0.54-0.79) appeared to be protector factors. Patients under 36, had a significantly higher rate of local recurrence and distant metastasis compared to patients35-40 (21.5 vs. 15.4% and 21.8 vs. 12.6%, p 0.01).Young women present a different distribution of molecular phenotypes with more luminal B and triple negative tumors with a higher grade and more lymph node involvement. A young age, must be taken as a pejorative prognostic factor and must play a part in indication of adjuvant therapy.

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 cancelation and lower pregnancy rates. When both partners were HIV infected, cancelation 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.

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.

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.

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 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

IntroductionThe status of regional node remains one of the most important factors to guide adjuvant therapy in endometrial cancer (EC). Pelvic recurrence occurs in up to 15% of early EC patients with negative pelvic lymph nodes (LNs). The prognostic significance of detecting micrometastases (μM) in LN is debated. This retrospective case-control study performed in the Oncological Gynecology Department in Lyon between December 1998 and June 2012 reports the incidence and the clinical significance of μM detected during ultrastaging of negative sentinel lymph node (SLN) in EC.Patients and MethodsNinety-three patients affected by type I and II EC were submitted to surgery with SLN. Dual-labeling method was used to detect SLN. All the SLNs were subjected to ultrastaging researching μM. The patients with a locoregional or distant relapse represented the case-series (CS). The patients without locoregional or distant recurrences were the case-controls (CC).They were matched (1:2 ratio) according to age, International Federation of Gynecology and Obstetrics stage, and histopathologic features.ResultsTen patients presenting a relapse represented CS. In the remaining 83 patients without recurrence, 20 CC were individualized. The detection rate of SLN per hemipelvis was of 17 (85%) of 20 hemipelvis and of 33 (82.5%) of 40 hemipelvis for CS and CC, respectively. Two SLN of CS arm were positives at frozen section. One of the 8 patients of CS arm with negative SLNs was positive for μM by immunohistochemistry analysis.ConclusionsLymph node status is one of the most important histopathologic features to determine the adjuvant treatment. The SLN technique could be proposed in selected patients affected by early EC. The μM in SLN could be researched and could help to modulate the following treatment. The multicenter study must be performed to clarify the optimal method of research of SLN in EC and the significance of μM in the LN.

The aim of the study was to determine Monarc (American Medical Systems) sling position after surgical treatment of stress urinary incontinence (SUI) through the transobturator approach. A total of 54 consecutive women with SUI were evaluated post-operatively with transvaginal ultrasound. A concomitant hysterectomy was performed in ten cases and a concomitant prolapse surgery in six cases. Ultrasound measurements include urethral length, the distance between the upper edge of the sling and the bladder neck (BN-S) and the BN-S/U ratio. The mean distance between the transobturator tape and the bladder neck was found to be 12.6 +/- 3.2 mm in the group of patients who underwent the transobturator procedure alone, 13 +/- 3.1 mm in the transobturator plus hysterectomy group and 12 +/- 2.8 mm in the transobturator plus prolapse group. The superior tape margin was at the mid-urethra in 81.5% of patients and always at a distance greater than 7 mm from the bladder neck. Eight patients did not have satisfactory results after the surgery. Only in one out of these eight patients was the transobturator sling not found to be at the mid-urethra. The superior tape margin of the Monarc sling remained at the level of mid-urethra in the majority of cases. It was never located too proximally beneath the bladder neck.

Objective: An abnormality of the optical transmission waveform obtained during measurement of the activated partial thromboplastin time (aPTT) has been described to identify a high-risk intensive care unit population consisting of patients with sepsis or with higher mortality rates than patients with normal aPTT waveforms. We investigated the abnormal aPTT biphasic waveform as a diagnostic and prognostic marker of infection. Design: Prospective, observational study investigating the predictive value of aPTT waveform analysis for the diagnosis and prognosis of sepsis. Setting: Surgical intensive care unit of a university hospital. Patients: We studied 187 consecutive patients who fulfilled at least two or more criteria of the systemic inflammatory response syndrome at admission or during intensive care stay and classified as having systemic inflammatory response syndrome, sepsis, severe sepsis, or septic shock during an 8-month period. Interventions: Laboratory analyses including aPTT waveform analysis and procalcitonin and C-reactive protein concentrations were measured at days 1–3. Measurements and Main Results: The final diagnoses were systemic inflammatory response syndrome in 49%, sepsis in 16%, severe sepsis in 12%, and septic shock in 23% of patients. On day 1, the biphasic waveform was significantly more abnormal in patients with severe sepsis or septic shock than in patients with systemic inflammatory response syndrome or sepsis. The biphasic waveform was more accurate than procalcitonin and C-reactive protein for differentiating patients with severe sepsis and septic shock, with 90% sensitivity and 92% negative predictive value. Biphasic waveform values were significantly more abnormal during days 1–3 in septic nonsurvivors than in survivors and nonseptic nonsurvivors. The biphasic waveform exhibited the best specificity (91%) and negative predictive value (98%) for the prognosis of sepsis-related mortality on day 3. Conclusions: In intensive care units, when the analyzer is available, aPTT waveform analysis is an inexpensive, rapid, effective, and readily available tool providing information for the diagnosis of severe sepsis and the prognosis of septic patients.

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.

Background. To evaluate the relationship between the severity of dysmenorrhea and endometrioma. Methods. Descriptive study with prospective design. Two hundred and thirty-nine women with histologically proved endometriomas. The severity of dysmenorrhea was assessed prospectively with a 10-cm visual analog scale. Various indicators concerning the endometrioma and the extent of deep infiltrating endometriosis were recorded during surgery in 239 patients. Correlations were sought with a multiple regression logistic model. Results. According to univariate analysis, the following variables were related to more severe dysmenorrhea: subperitoneal infiltration (uterosacral ligament and rectal infiltration) and R-AFS score of implants. None of the specific characteristics of endometriomas were associated with severe dysmenorrhea. After multiple regression analysis, rectal infiltration and R-AFS score of implants were the only factors that remained related to dysmenorrhea severity. Conclusions. When there is an endometrioma, severe dysmenorrhea is not directly related with the characteristics specific to these ovarian cysts. The associated deep infiltrating endometriotic lesions and in particular rectal infiltration could explain these symptoms.

Study objective To identify the preoperative factors affecting the risk of conversion to laparotomy during total laparoscopic hysterectomy (TLH) indicated for benign conditions (surgery performed in cases of genital prolapse and/or urinary stress incontinence was excluded). Design Retrospective comparative study (Canadian Task Force classification II-2). Setting University tertiary referral center for gynecologic endoscopic surgery. Patients Four hundred sixteen consecutive patients who underwent TLH during the first 5 years of our experience performing TLH. Intervention Total laparoscopic hysterectomy. Measurements and main results The rate of conversion to laparotomy was 7% (29 patients). Factors that were found to be independently related to the risk of conversion to laparotomy are the following: body mass index (adjusted OR 1.09; 95% CI 1.01–1.18); uterine width on transvaginal ultrasonography (US) between 8 and 10 cm (adjusted OR 4.01; 95% CI 1.54–10.45); uterine width on US greater than 10 cm (adjusted OR 9.17; 95% CI 2.74–30.63); lateral myoma measuring greater than 5 cm on US (adjusted OR 3.57; 95% CI 0.97–13.17); history of adhesion-causing abdominopelvic surgery (adjusted OR 2.92; 95% CI 1.23–6.94). Conclusion Transvaginal US evaluation is essential before performing TLH. Awareness of the risk factors for conversion to laparotomy is essential for proper patient information and better selection of patients.

Systematic metastasis staging in early breast cancer is no longer recommended. However, it is still performed before adjuvant chemotherapy.We assessed metastasis screening of asymptomatic women with a local breast cancer without lymph node involvement when adjuvant chemotherapy was indicated. The screening result was classified in 3 groups: "non-metastatic", "metastatic" and "suspect". For suspect screening, we analyzed the checking period and the consequences on cares.Out of 1545 patients with possible indication of chemotherapy, 690 indications of chemotherapy were validated by multidisciplinary meeting. Six hundred and thirty-nine metastasis screening were done. Five hundred and fifty-five screenings (86.9 %) were "non-metastatic", 3 screenings (0.5 %) were "metastatic" and 81 screenings (12.7 %) were "suspect". Out of this 81 suspect screening, only 47 screening have been checked, using 61 further investigations. No breast cancer metastasis was finally identified.Low rate of metastasis suggest reassessing metastasis screening before adjuvant chemotherapy for patients without lymph node involvement.

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.

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.

Deeply infiltrating endometriosis (DIE) manifests itself mainly in the form of pain, predominantly deep dyspareunia, and painful functional symptoms that are aggravated monthly during menstruation, with the semiology being directly correlated with the location of the lesions (bladder, rectum). A workup to assess the extent of the disease is necessary to establish an accurate map of the DIE lesions, which is the essential condition to perform complete exeresis. The treatment of first intention is surgical, because medical treatments are only palliative in the majority of cases. Successful treatment depends on achieving radical surgical exeresis. Analysis of the anatomical distribution of the DIE lesions allows a "surgical classification" to be proposed to standardize the modalities of surgical treatment. Further studies are needed to specify the place and modalities of medical treatments preoperatively and postoperatively.

Study objective To assess the results of complete surgical excision for patients with painful functional symptoms in a context of histologically proven deeply infiltrating endometriosis (DIE). Design Retrospective analysis (Canadian Task Force classification II-2). Setting University-affiliated hospital. Patients One hundred thirty-two patients with pelvic pain symptoms and histologically proved DIE. The DIE lesions were classified according to surgical classification: uterosacral ligaments (USL), vagina, bladder, or intestine. Intervention Complete surgical excision of DIE lesions. Measurements and main results A retrospective analysis was made of medical, operative, and pathologic reports as well as of questionnaires mailed to patients. Efficiency of surgical excision was assessed according to two methods: objective evaluation (numerical rating scale) and subjective evaluation (patients were asked to classify the improvement after surgery with one of the following: excellent, satisfactory, slight, or no improvement). For each symptom, the mean scores according to the numerical rating scale were significantly lower postoperatively. The difference between the preoperative and postoperative scores was 5.2 points ± 3.6 for dysmenorrhea, 4.6 points ± 3.1 for deep dyspareunia, 4.4 points ± 3.7 for painful defecation during menstruation, 4.9 ± 3.2 for lower urinary tract symptoms during menses, and 4.6 points ± 3.4 for noncyclic chronic pelvic pain. Comparable results were observed for patients in each group according to the surgical classification of their DIE lesions: USL (n = 78 patients); vagina (n = 25 patients); bladder (n = 13 patients); and intestine (n = 16 patients). Subjective evaluation showed that the improvement was considered to be excellent in 40.2% of women (53 patients), satisfactory in 42.4% (56 patients), slight in 14.4% (19 patients), and nonexistent in 3.0% (4 patients). The patients’ characteristics (i.e., age, gravidity, parity, body mass index, preoperative medical treatment, follow-up after surgery, number and location of DIE lesions, revised American Fertility Society stage, associated endometrioma) did not differ significantly according to whether the improvement was considered to be excellent (Group A: 53 patients) or not (Group B: 79 patients). Among the infertile patients (n = 78; 59.1%), there was no difference in pain improvement if the patient was pregnant or not in the 42 women who achieved pregnancy after the surgery. Conclusion Complete surgical excision of DIE lesions results in a statistically significant reduction in painful functional symptoms. These results are observed whatever the main location of DIE lesions. The patients’ preoperative characteristics have no significant influence on the result.