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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.

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&rsquo, 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.

Nitroreductases (NTRs), a family of flavin-containing enzymes, can be overexpressed in regions of tumor hypoxia, i.e., areas deprived of oxygen. The detection of NTR may be applied for monitoring the hypoxia level in tumors. To quantify NTR, novel sensors were designed based on the conjugation of pyridazino-1,3a,6a-triazapentalene to a para-nitrophenyl, directly or with an alkyne linker, resulting in two probes denoted as 1-NO2 and 2-NO2. Both probes had a weak fluorescence (form off), while their reduction by NTR led to the over 15-fold enhancement of fluorescence intensity (form on) regardless of the oxygen concentration in their environment. The detection limit was as low as ca. 20−30 ng/mL of NTR. Interestingly, the presence of human serum albumin significantly enhanced the observed fluorescence turned on by NTR in particular for the 2-NO2 probe. The in vitro response to both probes was evaluated on the highly metastatic human melanoma A2058 cell line, where NTR levels increased under hypoxic conditions. Their low toxicity, high photostability, and efficient uptake combined with a strong correlation between the enhancement of fluorescence and hypoxia in cells indicate the high potential of the 1-NO2 and 2-NO2 probes for the assessment of the hypoxic environment in biomedical research. The designed compounds allowed for a fast determination of the difference in NTR content of cells without the need for special sample preparation such as cell lysis. The changes can be monitored using a plate reader, flow cytometer, and fluorescence microscope, which that makes these probes a remarkably universal tool.

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.

International audience; A pyrazino-1,3a,6a-triazapentalene dye-based molecule was intercalated by direct co-precipitation method into the galleries of negatively charged layered double hydroxide (LDH) to form a new luminescent LDH filler. The materials of cation composition Zn/Al = 2 lead to well-defined organic inorganic assemblies. The structure of the hybrid materials was characterized by X-ray diffraction (XRD), Fourier-transform infrared spectra (FTIR) and UV–visible spectra. Optical properties of the materials, at both solid state and slurry state, were also recorded and absolute photoluminescent quantum yields (PLQY) were determined showing that the nanohybrid LDH slurry exhibited higher luminescence properties under UV excitation than the corresponding LDH powder. LDH fillers were used to prepare composite films by dispersion in both hydrophobic or hydrophilic polymer matrix such as poly (dimethyl siloxane) (PDMS) and poly(ethylene oxide) (PEO), respectively. Composite films were characterized by Small Angle X-ray Scattering (SAXS) and PLQY were recorded in order to compare the behaviour of the nanohybrid LDH filler in both polymer matrices. It was found that the aggregation of particles is still observed by SAXS.

International audience; 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.

A complementary to SMC framework for effective sampling in high-dimensions is that of Markov chain Monte Carlo (MCMC). In this framework there is a single target distribution but samples are drawn sequentially as a Markov chain that is invariant with respect to the target. For the purposes of this book we are primarily interested in the MCMC kernels that are used to generate the successive samples because we can use them as transition kernels in Feynman-Kac models. The combination of SMC with MCMC kernels, which we develop in subsequent chapters, creates opportunities for optimising parameters in the MCMC kernels using information about the target extracted from the particle population. This chapter lays down the fundamental notions, the most important of which for the purposes of this book being the notion of invariance, and a few typical MCMC kernels.

We introduce Markov processes using probability kernels. This allows us to define state-space models with wildly different state-spaces and dynamics in a common framework. We study two basic sets of properties of the probability distributions of such processes: the evolution of marginal distributions via recursions, and the structure of conditional distributions. In terms of the latter, we discuss the notion of conditional independence; when the Markov process consists of two components, , we study the distribution of conditional on ; we call the process whose distribution is this conditional distribution a partially observed Markov process. We show that state-space models are instances of this framework.

The sequential analysis of state-space models remains to this day the main application of Sequential Monte Carlo. The intent of this Chapter is to define informally state-space models, and discuss several typical examples of such models from different areas of Science.

In Chap. 16, we discussed PMCMC algorithms, i.e., MCMC samplers that (a) rely on particle filters to approximate the intractable likelihood; yet (b) leave invariant the exact posterior distribution of the considered (state-space) model. Potentially, PMCMC algorithms suffer from the same limitations as all MCMC samplers: they do not offer an easy way to estimate marginal likelihoods; they are too expensive for sequential scenarios; and calibrating their tuning parameters may be cumbersome (recall the numerical experiments of Sect. 16.5.2).

This chapter is an introduction to the theoretical study of particle estimates: how they converge as N → +∞, and whether their error stays stable over time. The focus is on results that are easy to prove from first principles. References to more technical results are given in the bibliography at the end of the chapter.

Another special case where the forward and backward recursions developed in Chap. 5 may be implemented exactly is when the considered state-space model is linear and Gaussian. The corresponding algorithms are commonly known as the Kalman filter and the Kalman smoother. The recursions follow immediately from the generic formulae of Chap. 5, but in this setting they become linear algebra calculations. Various alternative, mathematically equivalently but computationally different, recursions can be obtained. This chapter provides insights into these possibilities and touches upon the practical implementation of such recursions.

We have stated in the previous chapter that the main application of Sequential Monte Carlo is the sequential analysis of state-space models. However, SMC may be used in other contexts. Notably, it may be applied to any computational task that may formulated as an artificial filtering problem. We briefly review in this chapter some of these extra applications of SMC and their connection to state-space models. In particular, we discuss rare-event simulation, Bayesian sequential (and non-sequential) inference, likelihood-free inference, and more generally the problem of simulating from, and computing the normalising constant of, a given probability distribution.

We consider again the problem of estimating the parameter θ of a state-space model, this time from a Bayesian viewpoint. That is, we view θ as the realisation of a random variable Θ, with prior distribution ν(dθ), and we wish to compute the distribution of Θ conditional on data y0:T. This conditional distribution is called the posterior distribution, and represents the remaining uncertainty regarding the value of θ once data has been observed.

We have seen in Chap. 2 that most state-space models depend on some parameter θ; typically Open image in new window. In certain applications, θ is known, while in others it must be learnt from data, either in one go (from some data-set y0:T), or sequentially (as datapoints y0, y1, … arrive).

Building on the concepts of the previous chapter we introduce in this chapter Feynman-Kac models. This concept plays a central role in this book, as all SMC algorithms may be viewed as a Monte Carlo approximation of some underlying Feynman-Kac model.

This short chapter considers the special case where the state-space of the considered model is finite; \(\mathcal {X}=\{1,\ldots ,K\}\). In that case the integrals of the forward and backward recursions become sums over K terms, which can be computed exactly at a cost that is shown to be \(\mathcal {O}(TK^2)\). State-space models with a finite state-space model are usually called hidden Markov models. Applying the generic algorithm to their “bootstrap” Feynman-Kac formalisation yields an exact algorithm known as the forward-backward algorithm.

In this final chapter, we discuss a few advanced topics that were not covered in previous chapters, and some open problems that will hopefully be addressed in the near future.

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.

Resume Introduction Les tumeurs malignes rares de l’ovaire regroupent les tumeurs borderline complexes, les tumeurs germinales, les tumeurs des cordons sexuels et les tumeurs epitheliales rares. Les indications et modalites de preservation de la fertilite, la prise en charge d’une infertilite, les possibilites de contraception et de traitement hormonal de la menopause sont des questions frequentes en pratique clinique. Un groupe d’experts du reseau national dedie aux cancers gynecologiques rares (TMRG/TMRO) associe a des experts nationaux de la fertilite, des traitements hormonaux et de la contraception se sont reunis pour proposer des recommandations nationales. Methodes Un panel de 39 experts de differentes specialites a participe a l’elaboration des recommandations, en suivant la methode DELPHI (consensus formalise d’experts). Apres revue systematique de la litterature, des recommandations ont ete redigees puis soumises a deux tours successifs de cotations. Resultats Trente-cinq recommandations ont ete retenues, precisant les indications de preservation de la fertilite, les situations contre-indiquant une stimulation ovarienne (en preservation de la fertilite ou dans la prise en charge d’une infertilite), les possibilites de contraceptions (notamment hormonales) et de traitement hormonal de la menopause pour chaque type tumoral. De facon generale, une prudence a ete retenue pour les tumeurs potentiellement hormonosensibles comme les tumeurs des cordons sexuels, les adenocarcinomes sereux et endometrioides de bas grade, ainsi que pour les tumeurs borderline avec criteres histologiques pejoratifs. Discussion Dans le contexte d’une litterature pauvre, ces recommandations etablies via consensus formalise d’experts devraient constituer une aide aux cliniciens dans la prise en charge de ces patientes.

Aim: To assess the value of Post-mastectomy radiation therapy (PMRT) in breast cancer patients with no or minimal lymph nodes involvement. Materials and methods: We retrospectively analyzed a French multi-centric cohort of 4283 patients treated between 1980 and 2013, by mastectomy and axillary dissection with or without PMRT. Practices were analyzed according 3 treatment periods (1980-1999, 2000-2005; 2006-2013). The value of PMRT on loco-regional recurrence, disease-free survival, breast cancer specific survival and overall survival was assessed in pN0-1mi patients, using multivariate analyses (logistic regression and Cox model). It was subsequently assessed according to the number of clinicopathologic recurrence-risk factors, generating a prognostic index (f-PMRT index), in an attempt to isolate a pN0-1mi patients subgroup deriving benefit from PMRT. We tested the accuracy of the Cambridge-PMRT (c-PMRT) index in the discrimination of patients with significantly different outcomes, as well as the value of PMRT in each c-PMRT prognostic group. Results: PMRT was considered in more than half pN0-1mi patients of our cohort. Whereas matching pN0-1mi patients according to the number of clinicopathologic recurrence-risk factors led to isolate a higher-risk subpopulation (≥ 3 RR factors), PMRT had no significant impact on patients' outcomes, on multivariate analysis. Whereas the Cambridge-PMRT index had the potential to discriminate 3 patient populations with significantly different outcomes, its use did not help to the decision making for PMRT. Conclusion: Despite a large cohort, we failed to isolate a subgroup of early breast cancer patients suitable for PMRT, in the absence of lymph node involvement. Citation Format: Forissier V, Tallet A, Cohen M, Classe J-M, Reyal F, Chopin N, Mazouni C, Gimbergues P, Daraï E, Colombo PE, Azuar P, Lambaudie E, Houvenaeghel G. Is post mastectomy radiotherapy contributive in pN0-1mi breast cancers patients? Results of a French multi-centric cohort [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-17.

Background: Recent updated analysis of the HERA (HERceptin Adjuvant) trial indicate that tumor hormone receptor status (HR)remains a major determinant of outcome in HER2-positive (HER2+) early breast cancer (BC) patients, with higher rates of recurrence and death in women with HR-negative (HR-) disease, even after 11 years' median follow-up. Furthermore, data reported from the HERA trial suggest that the timing of recurrences is different, with an initial higher frequency of disease-free survival (DFS) events in patients with HR- disease than those with HR-positive disease (HR+). No evidence of a different trastuzumab efficacy according to the HR of the primary tumor was found. In this study, we examined the impact of HR on outcome in a large, multicenter, “real-world”, retrospective cohort of HER2+ early breast cancer patients Methods: HER2+ BC were retrospectively identified from a large cohort of 23,375 consecutive patients who underwent primary surgery at 17 French centers between Dec 1987 and Jan 2014. A multivariate Cox model was built including age, tumor size, SBR grade, lymphovascular invasion, lymph node involvement, hormonal receptors status, adjuvant chemotherapy, adjuvant hormone therapy, trastuzumab, radiotherapy and type of surgery. Results: A total of 1308 cases were identified, including 829 (63%) HR+ and 479 (47%) HR- patients. Median follow-up was 52 months (range 0 to 201). Compared with HR+, HR- patients had significantly smaller tumors (37 vs. 31% ≤ 10mm, p=0.027; information for multifocal tumors was not available), with higher SBR grade (58 vs. 40% grade 3, p Conclusions: Our results suggest that HR status remains a major determinant of outcome in HER2+ BC, including the timing of recurrence. Yet, this prognostic impact appears to be mitigated by trastuzumab-based adjuvant treatment. Citation Format: de Nonneville A, Gonçalves A, Cohen M, Reyal F, Classe JM, Giard S, Colombo PE, Muracciole X, Chopin N, Lambaudie E, Houvenaeghel G. Impact of hormone receptor status in HER2-Positive early breast cancer in the trastuzumab era: Results of a National multi-institutional study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-04.

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.

Surgery is still a essential step for breast cancer treatment. Complete tumor removal during surgery rely on surgeon's ability to differentiate tumor from normal tissue. To date, no intra operative method is available and reliable enough to help the surgeon delineate precisely tumor extension in the adjacent normal tissue. Thus, surgeons rely solely on pre operative imaging techniques to delineate tumor margins. Recent advances made in the field of non-invasive imaging and vectorized nano-size particles have revealed a remarkable potential for improved tumor-margin detection. AngiostampTM is a new fluorescent agent for intra operative imaging. This system provides strong binding on αvβ3 integrin-rich tumor neoangiogenesis. Our general hypothesis is that targeting αvβ3 integrin-rich breast carcinoma neoangiogenesis should provide improved delivery of diagnostic compounds and assist surgeons intra operatively using near-infrared imaging techniques. We conducted preclinical studies to evaluate the distribution of angiostampTM in vivo in murine breast tumor model and to determine the expression of αvβ3 integrin on human breast specimens. The capacity of AngiostampTM to target αvβ3 integrin was assessed in 4T1 breast tumor model. After tumor implantation, mices were injected with AngiostampTM or a saline solution. Detection of the tumors was performed at different timepoints (early, progressive and established tumors, N= 24 mices/timepoint) using near infrared (NIR) imaging system (FluobeamTM) to detect fluorescence in tumor tissue. In parallel, the expression of αvβ3 integrins in normal breast tissue, benign lesions (N=20) and various tumors subtypes (N=120) was assessed by immunohistochemistry. In mice injected with AngiostampTM, fluorescence was observed only within the tumors with low background. AngiostampTM labeled tumors at all timepoint. No false negative fluorescence was found as confirmed by histopathological analyses. In humans, the αvβ3 integrin are expressed in normal breast epithelial cells and benign metaplastic or proliferative epithelial lesions. However, due to the density of carcinomatous cells, the level of expression was much higher in breast cancer: 94% of invasive ductal carcinomas and 100% of invasive lobular carcinomas had a membranous staining (moderate to high intensity). Expression in breast cancer was not restricted to tumor subtypes neither hormone receptor expression nor SBR grade. Based on this preclinical demonstration, AngiostampTM could allow a better intra-operative detection of tumor bed in breast cancer, increasing the efficiency of surgical procedure especially for infraclinic disease and decreasing the rate of second surgery. Preclinical development is ongoing and the first clinical trial is expected in 2017. Citation Format: Beurrier F, Dutour A, Chen Y, Froc E, Gayet P, Guillermet S, Rizo P, Chopin N, Faure C, Dammaco MA, Klinger S, Ferraioli D, Garin G, Treilleux I. Preclinical validation of a new tumor imaging agent targeting αvβ3 to detect breast tumor using NIR-light imaging [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-08.

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.

Introduction/Background Surgery is the cornerstone of ovarian Granulosa Cell Tumor (GCT). Complete resection with adequate staging is the gold standard in 1st line setting. The aim of this study is to assess the impact of an appropriate surgery according to the guidelines. Methodology This is a nationwide five-year retrospective study, including 463 patients (of the 639 included patients) with a definitive diagnosis of GCT between 2011 and 2016. Medical and surgical practices were analyzed for conformity. Conformity to guidelines was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysteretomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsy and peritoneal cytology) according to the FIGO classification. Results 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 (51,8%), while a fertility-sparing surgery was performed in 98 cases (21,2%). A complete surgical staging was performed in only 76 cases (16,4%). 289 (62.4%) patients received an evaluation of the endometrium (hysterectomy or endometrial curettage). Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (29,6%) and not assessable in 48 cases (10,4%) respectively. A statistically significant improvement in the surgical management was observed among patients treated after 2012 compared to those treated before 2012. This Improvement included: endometrial evaluation (p=0,026), tumour rupture rate during surgery (p=0,010) and the global compliance of the surgery (p Conclusion Staging surgery provides a better assessment and an appropriate treatment of this rare tumors. According to this study, the implementation of a national network and guidelines dedicated to rare gynaecologic tumors seems to significantly improve the surgical management of the patients with GCT. Disclosure Nothing to disclose.

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

Everyday life features uncertain and ever-changing situations. In such environments, optimal adaptive behavior requires higher-order inferential capabilities to grasp the volatility of external contingencies. These capabilities however involve complex and rapidly intractable computations, so that we poorly understand how humans develop efficient adaptive behaviors in such environments. Here we demonstrate this counterintuitive result: simple, low-level inferential processes involving imprecise computations conforming to the psychophysical Weber Law actually lead to near-optimal adaptive behavior, regardless of the environment volatility. Using volatile experimental settings, we further show that such imprecise, low-level inferential processes accounted for observed human adaptive performances, unlike optimal adaptive models involving higher-order inferential capabilities, their biologically more plausible, algorithmic approximations and non-inferential adaptive models like reinforcement learning. Thus, minimal inferential capabilities may have evolved along with imprecise neural computations as contributing to near-optimal adaptive behavior in real-life environments, while leading humans to make suboptimal choices in canonical decision-making tasks.

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