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Patients with a Klinefelter syndrome (KS), defined by a 47 XXY karyotype, were long considered infertile. Testicular sperm extraction (TESE) now allows them to access fatherhood. We will present the data of studies since first experiment of TESE. Several factors influencing TESE outcome were proposed in these different studies. Among them, clinical and hormonal parameters have reported by few studies, age has been one of the most discussed prognostic factor of positive sperm retrieval rate. Data seems to show that TESE carried out before an age greater than 30 has a poorer prognosis for positive sperm retrieval. In few studies performed in younger patient, before 20 years, SRR was closed to result for 20 to 30 year old patients. Offering a TESE before 16 years old does not improve positive sperm extraction rate. In fact, the few studies carried out before the age of 16 were of poorer prognosis, most often linked to insufficient maturation of the residual gametes. In addition, androgen therapy, frequently prescribed in case of Klinefelter syndrome, did not seem to show any effect on sperm retrieval but only few studies were interested in the possible impact of this treatment. In conclusion, further studies are necessary to determine the interest of new markers to predict the chance of sperm retrieval, taking into account age, hormonal therapy.

BACKGROUND Testicular tissue freezing is proposed for fertility preservation to (pre)pubertal boys with cancer before highly gonadotoxic treatment. Studies accurately comparing human (pre)pubertal testicular tissue quality before freezing and after thawing are exceptional. No study has reported this approach in a systematic manner and routine care. OBJECTIVES To assess the impact of a control slow freezing protocol on testicular tissue architecture and integrity of (pre)pubertal boys after thawing. MATERIALS AND METHODS (Pre)pubertal boys (n = 87) with cancer from 8 Reproductive Biology Laboratories of the French CECOS network benefited from testicular tissue freezing before hematopoietic stem cell transplantation. Seminiferous tubule cryodamage was determined histologically by scoring morphological alterations and by quantifying intratubular spermatogonia and the expression of DNA replication and repair marker in frozen-thawed testicular fragments. RESULTS A significant increase in nuclear and epithelial score alterations was observed after thawing (p

International audience; Abstract Aim: To provide practice guidelines about fertility preservation (FP) in oncology. 93Methods: We selected 400 articles after a PubMed review of the literature (1987e2019). Recommendations: Any child, adolescent and adult of reproductive age should be informed about the risk of treatment gonadotoxicity. In women, systematically proposed FP counselling between 15 and 38 years of age in case of treatment including bifunctional alkylating agents, above 6 g/m2 cyclophosphamide equivalent dose (CED), and for radiation doses on the ovaries 3 Gy. For postmenarchal patients, oocyte cryopreservation after ovarian stimulation is the firstline FP technique. Ovarian tissue cryopreservation should be discussed as a first-line approach in case of treatment with a high gonadotoxic risk, when chemotherapy has already started and in urgent cases. Ovarian transposition is to be discussed prior to pelvic radiotherapy involving a high risk of premature ovarian failure. For prepubertal girls, ovarian tissue cryopreservation should be proposed in the case of treatment with a high gonadotoxic risk. In pubertal males, sperm cryopreservation must be systematically offered to any male who isto undergo cancer treatment, regardless of toxicity. Testicular tissue cryopreservation must be proposed in males unable to cryopreserve sperm who are to undergo a treatment with intermediate or severe risk of gonadotoxicity. In prepubertal boys, testicular tissue preservation is: - recommended for chemotherapy with a CED 7500 mg/m2 or radiotherapy 3 Gy on both testicles. - proposed for chemotherapy with a CED 5.000 mg/m2 or radiotherapy 2 Gy. If several possible strategies, the ultimate choice is made by the patient.

ObjectiveTesticular germ cell tumours (TGCT) are the most common cancer in men of working age and its incidence has increased notably over the past 40 years. Several occupations have been identified as potentially associated with TGCT risk. The aim of this study was to further explore the relationship between occupations, industries and TGCT risk in men aged 18–45 years.MethodsThe TESTIS study is a multicenter case–control study conducted between January 2015 and April 2018 in 20 of 23 university hospital centers in metropolitan France. A total of 454 TGCT cases and 670 controls were included. Full job histories were collected. Occupations were coded according to the International Standard Classification of Occupation 1968 version (ISCO-1968) and industry according to the 1999 version of Nomenclature d’Activités Française (NAF-1999). For each job held, ORs and 95% CIs were estimated using conditional logistic regression.ResultsA positive association was observed between TGCT and occupation as agricultural, animal husbandry worker (ISCO: 6–2; OR 1.71; 95% CI (1.02 to 2.82)), as well as salesman (ISCO: 4–51; OR 1.84; 95% CI (1.20 to 2.82)). An increased risk was further observed among electrical fitters and related, electrical and electronics workers employed for 2 years or more (ISCO: 8–5; OR≥2 years1.83; 95% CI (1.01 to 3.32)). Analyses by industry supported these findings.ConclusionsOur findings suggest that agricultural, electrical and electronics workers, and salesmen workers experience an increased risk of TGCT. Further research is needed to identify the agents or chemicals in these high-risk occupations which are relevant in the TGCT development.Trial registration numberNCT02109926.

STUDY QUESTION Should testicular sperm extraction (TESE) in non-mosaic 47,XXY Klinefelter syndrome (KS) patients be performed soon after puberty or could it be delayed until adulthood? SUMMARY ANSWER The difference in sperm retrieval rate (SRR) in TESE was not significant between the ‘Young’ (15–22 years old) cohort and the ‘Adult’ (23–43 years old) cohort of non-mosaic KS patients recruited prospectively in parallel. WHAT IS KNOWN ALREADY Several studies have tried to define predictive factors for TESE outcome in non-mosaic KS patients, with very heterogeneous results. Some authors have found that age was a pejorative factor and recommended performing TESE soon after puberty. To date, no predictive factors have been unanimously recognized to guide clinicians in deciding to perform TESE in azoospermic KS patients. STUDY DESIGN, SIZE, DURATION Two cohorts (Young: 15–22 years old; Adult: 23–43 years old) were included prospectively in parallel. A total of 157 non-mosaic 47,XXY KS patients were included between 2010 and 2020 in the reproductive medicine department of the University Hospital of Lyon, France. However 31 patients gave up before TESE, four had cryptozoospermia and three did not have a valid hormone assessment; these were excluded from this study. PARTICIPANTS/MATERIALS, SETTING, METHODS Data for 119 patients (61 Young and 58 Adult) were analyzed. All of these patients had clinical, hormonal and seminal evaluation before conventional TESE (c-TESE). MAIN RESULTS AND THE ROLE OF CHANCE The global SRR was 45.4%. SRRs were not significantly different between the two age groups: Young SRR=49.2%, Adult SRR = 41.4%; P = 0.393. Anti-Müllerian hormone (AMH) and inhibin B were significantly higher in the Young group (AMH: P = 0.001, Inhibin B: P LIMITATIONS, REASONS FOR CAUTION c-TESE was performed in the whole study; we cannot rule out the possibility of different results if microsurgical TESE had been performed. Because of the limited sensitivity of inhibin B and AMH assays, a large number of patients had values lower than the quantification limits, preventing the definition a threshold below which negative TESE can be predicted. WIDER IMPLICATIONS OF THE FINDINGS In contrast to some studies, age did not appear as a pejorative factor when comparing patients 15–22 and 23–44 years of age. Improved accuracy of inhibin B and AMH assays in the future might still allow discrimination of patients with persistent foci of spermatogenesis and guide clinician decision-making and patient information. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by a grant from the French Ministry of Health D50621 (Programme Hospitalier de Recherche Clinical Régional 2008). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER NCT01918280.

The purpose of this work was to construct shallow neural networks (SNN) using time-lapse technology (TLT) from morphokinetic parameters coupled to assisted reproductive technology (ART) parameters in order to assist the choice of embryo(s) to be transferred with the highest probability of achieving a live birth (LB).A retrospective observational single-center study was performed, 654 cycles were included. Three SNN: multilayers perceptron (MLP), simple recurrent neuronal network (simple RNN) and long short term memory RNN (LSTM-RNN) were trained with K-fold cross-validation to avoid sampling bias. The predictive power of SNNs was measured using performance scores as AUC (area under curve), accuracy, precision, Recall and F1 scoreIn the training data group, MLP and simple RNN provide the best performance scores; however, all AUCs were above 0.8. In the validating data group, all networks were equivalent with no performance scores difference and all AUC values were above 0.8.Coupling morphokinetic parameters with ART parameters allows to SNNs to predict the probability of LB, and all SNNs seems to be efficient according to the performance scores. An automatic time recognition system coupled to one of these SNNs could allow a complete automation to choose the blastocyst(s) to be transferred.

International audience; The aim of this work was to construct a score issued from a machine learning system with self-improvement capacity able to predict the fate of an ART embryo incubated in a time lapse monitoring (TLM) system. A retrospective study was performed. For the training data group, 110 couples were included and, 891 embryos were cultured. For the global setting data group, 201 couples were included, and 1186 embryos were cultured. No image analysis was used; morphokinetic parameters from the first three days of embryo culture were used to perform a logistic regression between the cell number and time. A score named DynScore was constructed, the prediction power of the DynScore on blastocyst formation and the baby delivery were tested via the area under the curve (AUC) obtained from the receiver operating characteristic (ROC). In the training data group, the DynScore allowed the blastocyst formation prediction (AUC = 0.634, p < 0.001), this approach was the higher among the set of the tested scores. Similar results were found with the global setting data group (AUC = 0.638, p < 0.001) and it was possible to increase the AUC of the DynScore with a regular update of the prediction system by reinforcement, with an AUC able to reach a value above 0.9. As only the best blastocysts were transferred, none of the tested scores was able to predict delivery. In conclusion, the DynScore seems to be able to predict the fate of an embryo. The reinforcement of the prediction system allows maintaining the predictive capacity of DynScore irrespective of the various events that may occur during the ART process. The DynScore could be implemented in any TLM system and adapted by itself to the data of any ART center.

Due to high cure rate in childhood and adolescent cancer, fertility preservation is a major concern. Chemotherapy, radiotherapy and surgery may alter gonadal function, and uterine cavity in women. In women, combined toxicity affecting both endocrine function and ovulation are observed leading to premature ovarian insufficiency. In men, spermatogenesis is frequently affected whereas endocrine function is almost always preserved. The current article focuses on investigations concerning gonadal function after treatment for a cancer during childhood or adolescence and treatment of subsequent infertility or hypogonadism. Nevertheless, those therapeutic are still limited and pretherapeutic preservation of fertility is preferred when possible.

International audience

The increased incidence of tumors in children and adolescents (Lacour, 2010), as well as therapeutic advances in recent decades, have led to an increase of fertility disorders in young adult cancer survivors. In pubescent boys, the use of cryopreserved sperm and assisted reproductive technology (ART) is a validated preventive option. Currently, there is no consensus on the age at which the semen cryoconservation has to be proposed. There is a wide disparity of care among centers in France. Based on the observation of Nathan,11 years old, in whom semen cryopreservation was performed at his request, we analyze local practices and discuss the indications for cryopreservation of sperm in young teenagers with cancer treated by potentially sterilizing treatment.

Due to high cure rate in childhood and adolescent cancer, fertility preservation is a major concern. Chemotherapy, radiotherapy and surgery may alter gonadal function, and uterine cavity in women. In women, combined toxicity affecting both endocrine function and ovulation are observed leading to premature ovarian insufficiency. In men, spermatogenesis is frequently affected whereas endocrine function is almost always preserved. The current article focuses on investigations concerning gonadal function after treatment for a cancer during childhood or adolescence and treatment of subsequent infertility or hypogonadism. Nevertheless, those therapeutic are still limited and pretherapeutic preservation of fertility is preferred when possible.

Testicular sperm extraction (TESE) in adult patients with nonmosaic 47,XXY provides a sperm retrieval rate (SRR) of approximately 50%. Age is the only significant prognostic factor. Whether TESE should be performed in adolescent patients for sperm cryopreservation remains to be determined.The objective of the study was to compare SRR between young (15-23 y) and adult (23 y) patients with 47,XXY, and to determine whether previous androgenic treatment had a deleterious effect.We designed a prospective comparative study between two groups enrolled in parallel from September 2010 onward.University hospital.Forty one patients with nonmosaic 47,XXY karyotype and azoospermia were included. Twenty five patients from 15-22 years of age were assigned to the "Young" group, and 16 patients age 23 years or more, to the "Adult" group.A bilateral testicular open biopsy was performed by a single surgeon. The reproductive biologist who performed TESE was blind to the patient's age. Principal Outcome Measure: The main outcome measure was the SRR. The TESE procedure was considered positive if at least 20 sperm cells could be cryopreserved for intracytoplasmic sperm injection.SRR was 13/25 = 52% in the Young group and 10/16 = 62.5% in the Adult group, the difference being nonsignificant (P = .73). Ages were 24.3 ± 7.4 years in the 23 cases of positive TESE, and 23.7 ± 7.4 in the 18 cases of negative TESE, the difference being nonsignificant (P = .42). SRR was 9/17 = 52.9% for patients with and 14/24 = 59.1% for patients without previous testosterone (T) treatment, the difference being nonsignificant (P = .98).According to the present results, performing TESE at a younger age (15-23 y) in patients with azoospermic nonmosaic 47,XXY Klinefelter did not increase SRR relative to adult patients (25-39 y). Previous replacement treatment with moderate doses of T did not seem to be deleterious for the recovery of sperm cells by TESE.

The quantification of BRCA1 messenger RNA molecules by a quantitative competitive one-step reverse transcriptase polymerase chain reaction method indicates that BRCA1 is upregulated both in human male and female germ cells and in preimplantation embryos. Because BRCA1 is involved in several pathways that participate in preserving intact chromosome and genome integrity, these data suggest that BRCA1 dysfunction might alter human embryogenesis or fertility.

Objective To determine the feasibility of fertility preservation in adolescent males with cancer. Design Large multicenter retrospective study of male patients ≤20 years from 23 centers of a national network of sperm banks over a 34-year period. Setting Sperm banks. Patient(s) A total of 4,345 boys and young men aged 11 to 20 years. Intervention(s) Age, cancer diagnosis, feasibility of sperm banking, and sperm parameters. Main Outcome Measure(s) Description of patients, and success of their fertility preservation. Result(s) We observed a mean yearly increase in referred patients of 9.5% (95% confidence interval, 9.1%–9.8%) between 1973 and 2007. Over the study period, the percentage of younger cancer patients who banked their sperm increased, especially in the 11–14 year age group, rising from 1% in 1986 to 9% in 2006. We found that 4,314 patients attempted to produce a semen sample, 4,004 succeeded, and sperm was banked for 3,616. The mean total sperm count was 61.75 × 10 6 for the 11–14 year age group, and 138.81 × 10 6 for the 18–20 year age group. It was noteworthy that intercenter variations in practices involving young patients seeking to preserve their fertility before cancer therapy were observed within this national network. Conclusion(s) Our results emphasize the need for decisive changes in public health policy to facilitate the access to reproductive health-care for young cancer patients.

Objective: To compare two blastocyst culture systems: culture on Vero cells and sequential media in the same time period. Design: Retrospective study. Setting: Institutional practice assisted reproductive technology center. Patient(s): Ninety-nine selected patients undergoing IVF with blastocyst culture. Intervention(s): In vitro fertilization and transfer of at least one expanded blastocyst after culture using either Vero cells or sequential media (S 2 medium). Main Outcome Measure(s): Blastocyst, pregnancy, and implantation rates. Result(s): The blastocyst formation rate (41.6% vs. 31.6%) is significantly increased with sequential media compared with the coculture system, but there is no statistically significant difference in the pregnancy and implantation rates (39.5% vs. 38.6% and 23.7% vs. 15.1%, respectively). Conclusion(s): Blastocyst culture on sequential media offers a better dynamic of embryo development (22% vs. 13.6% blastocyst at day 5). There was no statistically significant difference between the two groups in the take-home baby rate (18 vs. 12).

The increased incidence of tumors in children and adolescents (Lacour, 2010), as well as therapeutic advances in recent decades, have led to an increase of fertility disorders in young adult cancer survivors. In pubescent boys, the use of cryopreserved sperm and assisted reproductive technology (ART) is a validated preventive option. Currently, there is no consensus on the age at which the semen cryoconservation has to be proposed. There is a wide disparity of care among centers in France. Based on the observation of Nathan,11 years old, in whom semen cryopreservation was performed at his request, we analyze local practices and discuss the indications for cryopreservation of sperm in young teenagers with cancer treated by potentially sterilizing treatment.

Objective Sperm cryopreservation can be offered to men with spinal cord injury, as only 10% of spinal cord injured men (SCI) can have a child without assistive reproductive technologies (ART). Very few studies are dedicated to the outcomes of these cryopreservations. Our study aims to analyze the outcomes of these cryopreservation, namely their use or not for an ART, and to evaluate the success rate in case of ART. Material/patients and methods In May 2015, we retrospectively identified all people with stable spinal cord injury sent to the CECOS ( Centre d’etudes de la conservation des œufs et du sperme : Egg, Sperm Embryo banking) by the department of neuroperineology based in the hospital Henry Gabrielle, for the first time between 1st January 2009 and 31st December 2013, to undergo a sperm cryopreservation of spermatozoa. Results In June 2015, among the 65 men surveyed, 22 had a medical consultation as a couple for an AMP. Among these 22 couples, 11 have engaged in a program of medically assisted procreation. Thirty-two trials of medically assisted procreation were realized: 5 intrauterine inseminations (IUI), 16 in vitro fecondation (IVF) with intracytoplasmic sperm injection (ICSI) and 11 frozen embryo transfers (FET). Eleven clinical pregnancies were obtained. Six pregnancies were completed and7 children were born healthy. Six of 11 couples had at least one child. We also analyse the spermatic parameters of the cohort of 65 men with spinal cord injury, which are similar to those usually seen in the literature (numeration conserved, but decreased spermatic volume, altered morphologies and mobilities of sperm). Discussion–conclusion Our study helps to assess the results of this very specific and multidisciplinary ART care, which remains largely uninvestigated, in order to optimize its effectiveness.

International audience; Until now, complete ex vivo spermatogenesis has been reported only in the mouse. In this species, the duration of spermatogenesis is 35 days, whereas it is 54 days in the rat and 74 days in humans. We performed long-term (until 60 days) cultures of fresh or frozen rat or human seminiferous tubule segments in a bioreactor made of a hollow cylinder of chitosan hydrogel. Testicular tissues were obtained from 8- or 20-day-old male rats or from adult human subjects who had undergone hormone treatments leading to a nearly complete regression of their spermatogenesis before bilateral orchiectomy for gender reassignment. The progression of spermatogenesis was assessed by cytological analyses of the cultures; it was related to a dramatic increase in the levels of the mRNAs specifically expressed by round spermatids, Transition protein 1, Transition protein 2, and Protamine 3 in rat cultures. From 2% to 3.8% of cells were found to be haploid cells by fluorescence in situ hybridization analysis of human cultures. In this bioreactor, long-term cultures of seminiferous tubule segments from prepubertal rats or from adult men allowed completion of the spermatogenic process leading to morphologically mature spermatozoa. Further studies will need to address the way of optimizing the yield of every step of spermatogenesis by adjusting the composition of the culture medium, the geometry, and the material properties of the chitosan hydrogel bioreactors. Another essential requirement is to assess the quality of the gametes produced ex vivo by showing their ability to produce normal offspring (rat) or their biochemical normality (human).

In the vertebrate genome, methylation of deoxycytosine residues of CpGs dinucleotide has been associated with transcriptional silencing of genes, parental imprinting, X-inactivation and chromatin remodelling. In human somatic tissues, the 5' end of the BRCA1 CpG island is methylated, whereas this region is unmethylated in mature germ cells and early embryos. In gametes, as in somatic tissues, the CpG sites in the coding region are methylated. We took advantage of this bimodal distribution as a model to analyse the epigenetic reprogramming of coding regions during early human embryogenesis using the bisulphite-based genomic sequencing method. During preimplantation divisions, exon 11 of BRCA1 was slowly demethylated and retained approximately 30% of its methylated residues at the blastocyst stage. Moreover, the change in the distribution of methylated residues was not restricted to the BRCA1 gene, since for another gene, p53, a relatively high level of methylation (50%) of exon 4 was observed in blastocysts. Taken together, these data suggest that a significant part of the methylated residues of coding sequences might be conserved during preimplantation development.

Abstract 1669 Most epidemiologic studies performed in chronic myelogenous leukemia (CML) relate that the disease occurs preferentially in males with a sex ratio of ∼1.2. In addition, CML can be diagnosed in young adults and masculine fertility is a matter of concern, particularly because tyrosine kinase inhibitors (TKI) may impact on spermatogenesis by a selective inhibition of Src kinases, PDGF-R and c-kit. Sperm cryopreservation is recommended by some authors at diagnosis in males that would expect to have children later on. In a retrospective analysis we have analysed the spermograms of 62 chronic phase (CP) and 2 onset blast crisis (BC) CML males referred to our 3 centres between 2001 and 2012, collected at diagnosis before TKI treatment, and we have compared the results obtained to those of 15 healthy volunteer donors from the cryopreservation bank database, after informed consent. In 10 patients we could collect some data for patients being on imatinib mesylate (IM). CML patients had a median age of 31 (16–48) years, significantly younger than that in the control group of healthy donors: 37 (34–45) years (p=0.001). Sokal scores were 24% high, 27% intermediate and 49% low for evaluable patients (13 patients unknown or not available). The median BCR-ABLIS value at diagnosis was 77.65%. Patients had a median duration of 26 (0–38) days of hydroxyurea prior to commencing any TKI and 65% of evaluable patients had HU before TKI. None of the patients got interferon prior to TKI. The semen cryopreservation was performed within a median of 10 (2–102) days after CML diagnosis and after a median abstinence of 5 (0.5–30) days. The median volume of semen obtained in CML patients was 2.95 (0.5–14.9) ml and 3 (1.4–5.3) ml for normal donors (p=0.3). Williams test showed 72 (0–87)% of necrospermia in patients versus 18 (4–32)% in donors (p=0.00003). The median number of spermatozoa obtained was not different in patients [46 (0.03–200) 106/ml] than that in donors [74 (19.2–253) 106/ml] (p=0.24), as well as the number of spermatozoa per ejaculate observed (p=0.49). The motility of spermatozoa at 30 minutes after collection was not different between patients (median = 47.5%) and donors (median = 50%) (p=0.12), however higher numbers of atypical spermatozoa were observed in patients [median = 77.5 (16–100)%] rather than in donors [median = 45% (22–89)%], p=0.008, and the multiple abnormalities index (MAI) was significantly higher in patients [median = 1.99 (1.14–2.7)] than that in donors [median = 1.33 (1.09–1.55)], p=0.00006. There was no correlation between age at diagnosis, Sokal index and the number of spermatozoa per ml obtained (p=0.7 and 0.21 respectively). Ten CP CML patients had spermograms after a median of 1440 (9–1456) days of IM treatment and the results obtained were compared to i) the results of each individual patient at CP diagnosis and ii) to the results of healthy comparators. In comparison to the characteristics observed at diagnosis, the semen volume (median = 3.1 ml), Williams test (median = 65%), the motility at 30 minutes (median = 37.5%) and the MAI (median = 1.71) were not different (p=ns for all), however, the numbers of spermatozoa (median = 14.9 106/ml and = 37.05 ml per ejaculate) collected on IM were significantly lower (p=0.014 and p=0.045 respectively). The different parameters evaluated on IM were compared to those of normal controls and showed significant alterations. The semen volume was not different (p=0.94), neither the motility of spermatozoa (p=0.24), but the Williams test was highly perturbed on IM [median 65 (24–79)% versus 18 (4–32)% in donors] p=0.00003, as well as the numbers of spermatozoa as 106 per ml, collected on IM [median 14.9 (0.67–179)) versus normal [74 (19.2–253)], p=0.0036 or as 106 per ejaculate collected on IM [median 37.5 (2.68–572.8)) versus normal [149 (30–535.3)], p=0.026. Atypical forms were significantly more abundant on IM [median = 80 (68–90)%] versus healthy controls [median = 45% (22–89)], p=0.0058. Finally, the MAI was severely altered on IM [median = 1.71 (1.61–1.98)] versus normal individuals [median = 1.33 (1.09–1.55)], p=0.00013. In conclusion, this work demonstrates the existence of significant sperm alterations in young males with CML at diagnosis of undetermined origin, prior to any treatment. These alterations persist on IM treatment and little is know about the impact of second generation TKI. Thus the most appropriate approach remains a matter of debate in thus setting. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huguet:Novartis, BMS: Speakers Bureau. Michallet:Novartis, Pfizer, Teva, Genzyme, Janssen Cilag, BMS, Merck, Pfizer, Gilead, Alexion: Consultancy, Speakers Bureau. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy.