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FGFR1 amplification could mediate resistance to endocrine therapy and FGFR1 inhibition reverses this resistance. This phase Ib seeks to evaluate whether the combination of lucitanib, a potent FGFR/VEGFR/PDFGR inhibitor, in combination with fulvestrant, an endocrine agent, reverses resistance to fulvestrant. Eligible patients for this study were postmenopausal with ER+/HER2- mBC and have relapsed during or after treatment with fulvestrant. There were 2 parts in the study: a dose allocation to assess the tolerability of the combination in terms of DLTs and MTD using a modified Continual Reassessment Method (mCRM) [part I] and a dose expansion, with patients assigned to 2 different cohorts based on FGFR amplification, to further evaluate the tolerability of the combination and to identify the recommended phase II dose (RP2D) [part II]. Surrogate target hitting biomarkers were also dosed at baseline and on-treatment. The sponsor decided to halt the clinical development in mBC indication and the study was prematurely terminated after 18 patients (15 in part I and 3 in part II). The presentation will focus on these 18 patients. Patients had ECOG PS 0 or 1 and median number of previous treatments in metastatic setting was 3. Two doses of lucitanib (10mg daily n=9 and 12.5mg daily n=6) in combination with 500 mg/month of fulvestrant were tested in part I. At the 10mg dose level, one patient experienced a DLT (grade 3 hypertension). Based on global lucitanib development program data, it was decided to start Part II with lucitanib 10mg daily. The most common related grade ≥3 toxicities occurring in more than 10% of patients were hypertension (78%) and asthenia (22%). All patients required at least one dose interruption mainly for toxicities, while 13 patients (72%) required at least a dose reduction for toxicities. Thirteen patients (72%) withdrew from the study for disease progression, 3 (17%) for adverse events (at 10mg) and 2 (11%) for non-medical reasons. Three patients achieved a confirmed partial response (as per RECIST v1.1), one at 10mg and two at 12.5mg. About 55% of the patients experienced clinical benefit with a median duration of the benefit of 39.6 weeks and a maximun duration of the benefit of 79.1 weeks for 1 patient (PR at Cycle 4). Biomarker modulations were consistent with lucitanib mode of action; targeting VEGFRs (significant increase of VEGFA, IL8, PlGF) and FGFR1 (significant increase of FGF23). The combination is feasible but requires close patient monitoring and intensive management of adverse events. Those are in line with the anti-angiogenic activity of lucitanib. 10mg (N=12)12.5mg (N=6)All (N=18)Objective Response Rate (ORR)n(%) 11 (8.3)2 (33.3)3 (16.7) 95% CI 3[1.5;35.4][9.7;70.0][5.8;39.2]Clinical Benefit Rate (CBR)n(%) 24 (33.3)6 (100.0)10 (55.6) 95% CI 3[13.8;61.0][61.0;100.0][33.7;75.4]Duration of Clinical Benefitmedian (weeks)28.171.339.6 95% CI 3[27.9; 32.7][29.1; 79.1][27.9; 79.1]1: CR or PR 2: CR or PR or stabilization (SD or NonCR/NonPD) >24 weeks or at end of cycle 6 3: 95% Wilson method of Confidence interval of the estimate Citation Format: Campone M, Bachelot T, Penault-Llorca F, Pallis A, Agrapart V, Pierrat M-J, Poirot C, Paux G, Dubois F, Xuereb L, Robert R, Andre F. A phase Ib study of oral administration of lucitanib in combination with fulvestrant in patients with HR+ metastatic breast cancer (mBC) [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 P1-09-11.

Purpose: The FGFR1 gene is amplified in 14% of patients with HR+/HER2− breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed. Patients and Methods: Patients with HR+/HER2− metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) FGFR1 amplified, (ii) FGFR1 nonamplified, 11q13 amplified, and (iii) FGFR1 and 11q13 nonamplified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. FGFR1 copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC. Results: Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%–35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%–18%) and 15% (95% CI, 6%–34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high FGFR1 amplification (≥4 CNV) than those without high amplification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers. Conclusions: Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR+/HER2− MBC. Although based on small sample sizes, exploratory biomarker analyses suggested that patients with high FGFR1 amplification or expression might derive greater benefit.

During the last 10 years, the concept of "biased agonism" also called "functional selectivity" swamped the pharmacology of 7 transmembrane receptors and paved the way for developing signaling pathway-selective drugs with increased efficacy and less adverse effects. Initially thought to select the activation of only a subset of the signaling pathways by the reference agonist, bias ligands revealed higher complexity as they have been shown to stabilize variable receptor conformations that associate with distinct signaling events from the reference. Today, one major challenge relies on the in vitro determination of the bias and classification of these ligands, as a prerequisite for future in vivo and clinical translation. In this review, current experimental considerations for the bias evaluation related to choice of the cellular model, of the signaling pathway as well as of the assays are presented and discussed.

International audience; Dendrogenin A (DDA) is a mammalian metabolite that displays anticancer and chemopreventive properties in mice. At the cancer cell level, DDA induces differentiation and death. We investigated herein the nature of DDA cytoxicity in cancer cells. We showed that DDA triggers biochemical and cellular features of macroautophagy/autophagy and that autophagy is cytotoxic. DDA induces both the accumulation of pro-lysosomal sterols and stimulates the expression of regulators of autophagy such as NR4A, LC3 and TFEB through binding to the liver X receptor (LXR), a ligand-dependent transcription factor consisting of 2 isoforms, NR1H2 and NR1H3. These effects are not observed with canonical LXR agonists such as the oxysterol 22(R)-hydroxycholesterol or the synthetic molecules T0901317 and GW3965. DDA effects were measured on melanoma and acute myeloid leukemia cells including patient-derived leukemia cells in vitro and in vivo. Importantly the induction of lethal autophagy kills cells independently of their cytogenetic subgroups and does not differentiate bulk cancer cells from cancer cell progenitors. Together these data show that DDA drives LXR to induce the expression of autophagic genes leading to cancer cells death. This opens up new perspectives for cancer treatment.

Background: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors α/β (PDGFRα/β). FGF aberrancy, as defined by amplification of either FGFR1, or 11q (containing FGF ligands 3, 4, CCND1, and 19), or both, is a hallmark genomic alteration that can be observed in up to 25% of patients with breast cancer. In a phase I clinical trial of lucitanib at daily doses of 5 to 20 mg, heavily pretreated patients with advanced breast cancer patients and FGF aberrancy experienced an objective response rate (ORR) of 50% and a median progression-free survival (PFS) over 9 months (Soria et al, 2014). This compelling clinical activity has led to the initiation of a global clinical development program for lucitanib in breast cancer. Trial design: this is a phase II trial testing the efficacy of lucitanib at the dose of 15 mg daily in patients with ER+/HER2- metastatic breast cancer who have received at least one first-line systemic anticancer therapy in the metastatic setting. After informed consent, metastatic tissue (fresh biopsy or archival) is centrally evaluated by FISH for FGFR1- and/or 11q- amplification. Based on FISH results, patients are allocated to cohort 1 (FGFR1-amp), cohort 2 (11q-amp) or cohort 3 (neither). Patients with dual amplification are allocated to cohort 1. The primary objective is to evaluate the ORR of single agent lucitanib in the three cohorts. Secondary objectives include clinical benefit rate, PFS, safety and pharmacokinetics in addition to exploratory biomarker analyses. A Simon two-stage design will be used for each of the cohorts to test the null hypothesis that the ORR is 5% or less versus 20% using a one-sided test with 5% level of significance and 90% power. In each cohort separately, an initial 21 patients with measurable disease at baseline will be assessed at the end of stage 1. If at least 2 patients respond per the pre-specified criteria, this cohort will accrue additional 20 patients. The null hypothesis will be rejected if there are at least 5 responders among all 41 patients. Eligibility Criteria: ER+/HER2- metastatic breast cancer who have received at least a first line of systemic anticancer therapy and no more than 2 line of chemotherapy with or without targeted therapy in the metastatic setting and have ECOG performance status ≤ 2. Patients with uncontrolled hypertension and at risk of developing hypertension related complications are not eligible. Conclusion: FINESSE is a phase II trial testing lucitanib, a multikinase inhibitor, in three selected populations in order to investigate the ORR in FGFR1 or 11q amplified or non-amplified populations and to explore the role of FGFR1 or 11q amplifications through correlative translational analyses. As of May 21st 2015, 40 patients have been enrolled, 19 of them in the FGFR1-amplified arm. Citation Format: Andre F, Daly F, Azim Jr HA, Agrapart V, Fumagalli D, Gingras I, Guitart M, Lange A, Turner NC, Pierrat M-J, Loibl S, Poirot C, Curigliano G, Loi S, Pallis A, Piccart M, Cortes J. FINESSE - An open, 3-cohort, phase II trial testing oral administration of lucitanib in patients with FGFR1-amplified or non-amplIfied oestrogeN rEceptor poSitive metaStatic breast cancEr. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-03.

We reviewed the studies about fertility-sparing in young patient presenting a benign ovarian tumor. It appears that more than the histologic nature of the ovarian cysts, it is the surgical treatment of the cyst which may decrease fertility. Some good practice of surgical procedures must be kept in mind when one manages a benign ovarian tumor in a young patient wishing to preserve her fertility: surgery should be avoided as much as possible; kystectomy is better than oophorectomy; no radical surgery should be done without pathological certitudes; electrocoagulation must be avoided on the cyst walls. In some situations, fertility is specially endangered: bilateral ovarian cysts, recurrence or strong probability of recurrence (endometriomas), poor ovarian reserve (previous chemo- or radiotherapy, age>35, premature ovarian failure). In these situations, a pre-operative assessment of the ovarian reserve could be useful. Beside the surgical 'good procedures', gamete cryopreservation procedures could be used. Cryopreservation of mature oocytes (after ovarian hyperstimulation) or in vitro mature oocytes (after antral follicle retrieval) can be proposed. Ovarian tissue cryopreservation is another option. Oocyte (or embryos) cryopreservation can be proposed before or after the surgery. The global management of benign ovarian tumors in young patients should be decided between surgeons and specialists in reproductive biology.

To determine whether ovaries can be preserved in selected young women with peritoneal pseudomyxoma (PMP).The traditional rule is to systematically perform a bilateral oophorectomy.A new policy was developed to preserve the ovaries when they are macroscopically normal in young women with PMP, strongly desiring a future pregnancy.Thirty-three women younger than 41 years were selected after undergoing complete cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for PMP. A normal ovary was preserved in 6 of them, but in 6 of the 14 women who strongly desired a future pregnancy. Subsequently, ovarian preservation was only performed in cases of grade-1 PMP. Ovarian invasion was correlated with the grade (p0.05) and with the extent of peritoneal disease (p0.01). After a median follow-up of 54 months, none of the 6 women with preserved ovaries has developed an ovarian or a peritoneal recurrence. One woman became pregnant and egg harvesting and cryopreservation were performed for 4 women with a partially normal ovary.This new policy allowed ovarian preservation in 43% of the young women desiring a future pregnancy and has already resulted in one birth. It exclusively concerned low-grade PMP. Recurrence in the preserved ovary was 0% with our selection criteria.

Temozolomide is an oral alkylating agent with proven efficacy in recurrent high-grade glioma. The antitumour activity of this molecule is attributed to the inhibition of replication through DNA methylation. However, this methylation may also perturb other DNA-dependent processes, such as spermatogenesis. The ability to father a child may be affected by having this treatment. Here we report a pregnancy and a baby born after 6 cures of temozolomide.The quality of gametes of the father has been studied through these cures and after the cessation of treatment. Sperm parameters, chromosomal content and epigenetic profiles of H19, MEST and MGMT have been analysed.Sperm counts decrease significantly and hypomethylation of the H19 locus increase with time even staying in the normal range.This is the first report of an epigenetic modification in sperm after temozolomide treatment suggesting a potential risk for the offspring. A sperm cryopreservation before the initiation of temozolomide treatment should be recommended.

Background: As a result of advances in treatment, almost 80% of children and adolescents who currently receive a diagnosis of cancer become long-term survivors. Potential adverse consequences of treatment include impaired puberty and fertility due to gonadal removal, genital tract injury or damage to germ cells from adjuvant therapy. In recent years, treatment of solid tumors and hematological malignancies has been modified in an attempt to minimize damage to the reproductive system. Simultaneously, advances in assisted reproductive technologies have led to new possibilities for the prevention and treatment of infertility. We review experimental data in animal models and clinical experience in adults and discuss strategies to preserve fertility in prepubertal children. Conclusions: Fertility preservation should now be considered in children facing cancer treatment that has a high risk of gonadal toxicity including high-dose chemotherapy and bilateral irradiation of the gonads at toxic doses.

Resume Depuis plusieurs annees, les equipes d’AMP sont regulierement sollicitees par des couples desirant un enfant, mais dont l’un des partenaires ou bien les deux sont infectes par le VIH et/ou le virus de l’Hepatite C et ces demandes sont en augmentation constante. Le 10 mai 2001 parait un arrete qui fixe les conditions particulieres de la prise en charge. Il s’agit la de dispositions contraignantes qui maintiennent le couple sous le sceau d’une sexualite codifiee par la quantification normee des constantes biologiques retrouvees dans les fluides vitaux et sexuels. Ici, l’intimite des conduites et du corps desirant se traduit par une objectivation biologique, prelude a la naissance d’un corps calibre et filtre.

Le risque d’infertilite, par le biais de la gonadotoxicitedes chimiotherapies, estunedes sequelles a long terme majeures chez les enfants, lesadolescentset lesjeunes adultes. Ce risque differe selon l’âge et lesexedespatientsaumomentdu traitement, leschematherapeutique et les associations de medicaments cytotoxiques utilisees. Les alkylants sont lesmedicaments les plus gonadotoxiques, avec une sterilite definitive quand ils sont utilises dans des schemas d’intensification therapeutique. L’evaluationdes « degâts » de la chimiotherapie sur les gonades faitpartiedusuividespatients, qu’ils aient ete traites dans l’enfance, l’adolescence ou a l’âge adulte en âge de procreer, et est particulie rement difficile chez les femmes. Les deuxseules techniques de preservation de la fertilite eprouvees sont, chez l’homme pubere, la cryoconservation de sperme et, chez la femme pubere, la cryoconservation d’embryons obtenus par fecondation in vitro; les autres techniques etant en cours d’evaluation.

Ovarian tissue cryopreservation (OTCP) is a new procedure of medically assisted procreation, still at the experimental stage, whose primary aim is to store female gametes as sperm cryopreservation permits to do for male gametes. Ovarian tissue is removed very simply by laparoscopy. It survives well to freezing if the medium contains a cryoprotective agent and the rate of freezing is slow. In contrast, thawing must be rapid. There are three processes for the utilization of ovarian tissue after thawing. In vitro maturation and xenografting remain impossible for technical and ethical reasons. Autologous transplantation (orthotopic or heterotopic) of the tissue is therefore the only foreseeable method over the short term. Indications for OTCP must remain rare as long as no pregnancy has been obtained in human. At the present time, only female patients who would inevitably suffer the loss of their fertility should be able to take advantage of OTCP. Basically, this would mean women subjected to castrating anticancer therapy. It would seem reasonable to set the age limit at 35-years for carrying out OTCP. Lastly, female patients should be clearly informed that the method is still at the research stage, and in France samples must be taken in accordance with the laws governing clinical research.

Background: Because cigarette smoke is a powerful ROS producer, we hypothesized that the spermatozoa of smokers would be more at risk of having increased DNA fragmentation than spermatozoa of non-smoking men. Methods: A Cross-Sectional Study was performed on consenting smokers and non-smokers, consulting in an infertility clinic for routine sperm analysis. The application of a novel TUNEL assay coupled to a vitality marker, LIVE/DEAD®, allowed both DNA fragmentation and viability measurement within spermatozoa of participants to be analyzed by flow cytometry. Results: The coupled vitality-DNA fragmentation analysis revealed that non-smokers and smokers respectively presented medians of 3.6% [0.6-36.8] and 3.3% [0.9-9.6] DNA fragmented spermatozoa among the living spermatozoa population (p>0.05). Conclusion: No deleterious effect of smoking on spermatozoa was found in our study. More studies concerning potential mutagenic capacities of cigarette smoke on spermatozoa are necessary. In addition, the coupled vitality-DNA fragmentation analysis may orient Assisted Reproductive Technologies teams when confronted with patients having a high percentage of DNA-fragmented living spermatozoa. © 2014 Clinical Cytometry Society.

Summary Human herpesvirus-6 (HHV-6) is a betaherpesvirus whose genome may integrate into human chromosomes. Chromosomally integrated HHV-6 (ciHHV-6) may be transmitted vertically from parents to children. HHV-6 DNA has been detected in semen, but its integrated or extrachromosomal status has not yet been characterised. The aim of this study was to determine the prevalence of HHV-6 DNA and to search for ciHHV-6 forms in spermatozoa purified from semen obtained from subjects explored for low fertility. A total of 184 sperm samples were purified using PureSperm®. HHV-6 viral load and species identification were performed by real-time polymerase chain reaction. Of 179 sperm specimens analysed, three were positive for HHV-6 (1.7%). Two samples (1.1%) had viral loads of 680 232 and 2 834 075 copies per million spermatozoa, compatible with loads expected for a ciHHV-6 form. The viral load of the third positive sample (73 684 copies per million spermatozoa) was lower than would be expected for ciHHV-6 infection, implying that the HHV-6 DNA detected in spermatozoa corresponds mainly to ciHHV-6. However, viral DNA may also be detected at a low level that is not in favour of the presence of ciHHV-6. Further studies are necessary to determine the origin of detected viral genomes.

Resume De nombreux progres ont ete faits ces dernieres annees dans le domaine de l'assistance medicale a la procreation et notamment dans la prise en charge des hypofertilites masculines. Sur le plan feminin, des techniques prometteuses, bien qu'encore experimentales, commencent a voir le jour. Parmi celles-ci, la congelation de fragments ovariens et la maturation ovocytaire in vitro paraissent particulierement interessantes. Actuellement, la congelation de fragments ovariens permet d'essayer de preserver un potentiel de fertilite a des patientes devant subir un traitement sterilisant. Lorsque le developpement in vitro des follicules ovariens sera au point avec obtention d'ovocytes en metaphase 2 apres maturation ovocytaire in vitro , on pourra congeler de facon plus large le tissu ovarien et le considerer comme une source d'ovocytes utilisable a la demande. Par exemple, on pourrait pour toutes les patientes rentrant dans un protocole d'assistance medicale a la procreation, au debut de leur prise en charge, prelever des fragments d'ovaire, les congeler et les decongeler un par un en vue d'une culture folliculaire suivie d'une maturation ovocytaire in vitro et d'une fecondation in vitro , evitant ainsi toute stimulation ovarienne. Les perspectives de ces techniques sont larges et pourraient bien un jour changer, de facon radicale, nos facons de penser et de pratiquer.

We reviewed the studies about fertility-sparing in young patient presenting a benign ovarian tumor. It appears that more than the histologic nature of the ovarian cysts, it is the surgical treatment of the cyst which may decrease fertility. Some good practice of surgical procedures must be kept in mind when one manages a benign ovarian tumor in a young patient wishing to preserve her fertility: surgery should be avoided as much as possible; kystectomy is better than oophorectomy; no radical surgery should be done without pathological certitudes; electrocoagulation must be avoided on the cyst walls. In some situations, fertility is specially endangered: bilateral ovarian cysts, recurrence or strong probability of recurrence (endometriomas), poor ovarian reserve (previous chemo- or radiotherapy, age35, premature ovarian failure). In these situations, a pre-operative assessment of the ovarian reserve could be useful. Beside the surgical 'good procedures', gamete cryopreservation procedures could be used. Cryopreservation of mature oocytes (after ovarian hyperstimulation) or in vitro mature oocytes (after antral follicle retrieval) can be proposed. Ovarian tissue cryopreservation is another option. Oocyte (or embryos) cryopreservation can be proposed before or after the surgery. The global management of benign ovarian tumors in young patients should be decided between surgeons and specialists in reproductive biology.

In the last decade, fertility preservation has risen as a major field of interest, creating new interactions between oncologists and gynecologists. Various options, such as cryopreservation of ovarian tissue, have been developed and are currently routinely proposed in many centers. However, many of the options remain experimental and should be offered to patients only after adequate counseling. This paper addresses the efficiency and the potential of the different fertility preservation approaches.

L’amelioration de la survie apres traitement anticancereux des enfants, adolescentes et adultes jeunes, doit faire prendre en compte les effets a long terme de ces therapeutiques et notamment ceux sur la fonction ovarienne. Depuis le milieu des annees 1990, la question de la preservation de la fertilite feminine avant la mise en route d’un traitement potentiellement sterilisant est devenue incontournable. Ainsi, la congelation ovocytaire est de plus en plus proposee aux patientes devant subir de tels traitements. L’ovocyte peut etre congele soit au stade d’ovocyte mature, bloque en metaphase II, soit au stade de vesicule germinative, notamment au sein du cortex ovarien.

To evaluate the effect of Temozolomide on female fertility and the relevance of our coverage in preservation of fertility.From 2005 to 2009, 24 patients treated with Temozolomide for a low-grade glioma were included in the study (12 women who underwent a fertility preservation consultation and 12 women who did not). A retrospective study of their medical records and sending a questionnaire were undertaken to assess their fertility after treatment.Of the 24 patients, 15 patients had no fertility preservation and the remaining nine had a cryopreservation of embryos with or without an oocyte cryopreservation. Four patients are or have been pregnant (delivery, spontaneous miscarriage, pregnancy being in the group of preserving fertility and a current pregnancy in the group where no fertility preservation has been achieved).First study on the effect of Temozolomide on female fertility.Temozolomide is not totally gonadotoxic.

Comparison of in vitro development, survival and oocyte maturation rates of mice preantral follicles frozen by various methods.Cryopreservation of the germinal cells using the slow freezing method for entire ovary (Ova Cong) or isolated preantral follicles (Iso Cong) and vitrification in a closed system of isolated preantral follicles (Iso Vitr). Non-freezing follicles were considered as the control group. The four groups were simultaneous cultured for 12 days in a microdrop system. At each day of the culture, mean diameter was measured and at the end of the culture, follicular survival and mature oocyte rates were compared.Iso Cong and Ova Cong follicles achieved a smaller diameter (423.0 ± 47.1 μm et 450.3 ± 15.7 μm, respectively) than control group (680.7 ± 12.3 μm) at the 12th day of culture. At the end of the culture 6.21 % of Iso Cong follicles, 53.41 % of Ova Cong follicles and 83,77 % of Control follicles were alive. Mature oocyte rates were similar for the cryopreserved groups, 44.4 % for Iso Cong group and 44.7 % for Ova Cong group, but smaller than the Control group with 90 % of mature oocytes. Only 1/171 of the Iso Vitr follicles survived to the culture.This study shows that mice's ovarian follicles can grow in vitro after cryopreservation but their diameter, survival and oocytes maturation rates are smaller than in the control group.

Le syndrome de Turner est caracterise par une dysgenesie gonadosomatique, consequence d’une monosomie totale ou partielle ou d’une anomalie de structure de l’un des deux chromosomes X dans tout ou partie variable des cellules constitutives de l’organisme.

Background: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1-3 (FGFR1-3), vascular endothelial growth factor receptors 1-3 (VEGFR1-3) and platelet-derived growth factor receptors α/β (PDGFRα/β). FGF aberrancy, as defined as FGFR1-or 11q- amplification, is a hallmark genomic alteration in breast cancer, observed at a frequency of up to 25% of patients and is strongly associated with luminal B type. Breast cancer patients with measurable disease and FGF aberrancy treated in the ongoing Phase 1/2 clinical trial of lucitanib monotherapy experienced an overall response rate of 50% (6 out of 12 patients). FGFR1-knock down was shown to decrease cell proliferation and reverse resistance to endocrine therapy in a FGFR1-amplified breast cancer cell line, hence supporting the idea of combining lucitanib with an endocrine agent such as fulvestrant, at the time of resistance. This has led to this Phase Ib study of lucitanib in combination with fulvestrant in metastatic breast cancer. Trial design: INES is a multicenter, open-label, 2 -part study to assess the tolerability of lucitanib in terms of Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicities (DLTs) when administered with fulvestrant. A Continual Reassessment Method (CRM) will be used for the 1st part. A minimum of 3 patients will be enrolled at the initial dose level of 10 mg daily in combination with fulvestrant. Additional doses of 12.5 mg and 15 mg of lucitanib will be tested with the option of deescalating to 7.5 mg in case of DLTs. A minimum of 9 patients will be included at the MTD. In the 2nd part, 2 cohorts will be opened: fourteen FGF+ patients (FGFR1-or 11q- amplification), and fourteen non-amplified patients. All patients will receive fulvestrant 500 mg monthly and lucitanib at the recommended dose (RD) until unacceptable toxicity according to the investigator, disease progression or patient withdrawal. The main objective is to identify the Phase II RD when lucitanib is combined with fulvestrant. Secondary objectives include determination the Pharmacokinetic (PK) profile of lucitanib and metabolites; Measurement of tumour response; Description of the pharmacodynamic (PD) profile of lucitanib and investigation of any potential exposure dose-response relationships for safety, efficacy and PD. Eligibility Criteria: Patients with estrogen receptor-positive, HER2 negative, breast cancer after progression or recurrence on prior therapy including fulvestrant. Patients should have ECOG performance status 0 or 1. Patients with uncontrolled hypertension are not eligible. For part 2, the presence of a metastatic site for biopsy to assess the presence of FGFR1- and/or 11q- amplification, which will be analysed centrally using FISH, is required. Conclusion: INES is a phase Ib trial testing lucitanib in combination with fulvestrant in order to select the RD for phase II and seek preliminary efficacy signal in FGFR1- or 11q- amplified or non- amplified patients. As of June 2014, 3 patients have been enrolled in the 10 mg dose escalation cohort. Citation Format: Mario Campone, Thomas Bachelot, Fabrice André, Chadi Saba, Valérie Agrapart, Marie-Jeanne Pierrat, Frédéric Dubois, Thibault Chesnel, Camille Poirot. Phase Ib dose allocation study of oral administration of lucitanib given in combination with fulvestrant in patients with estrogen receptor-positive and FGFR1-amplified or non-amplified metastatic breast cancer (INES) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-03.

Comparison of oocyte development within the follicle in vitro and in vivo has a major impact on research into ovarian physiology and clinical practice. Despite major differences in ovarian physiology between rodents and humans, mice provide a useful model for studies of the endocrine and paracrine mechanisms controlling follicular development. In this study, early preantral follicles were isolated from 12-day-old mice and cultured individually in microdrops under oil during 6, 9 or 12 days. Taking into account previous observations, several oocyte criteria (diameter, chromatin configuration, transcriptional activity, intracytoplasmic calcium signalling and ability to undergo meiosis) were assessed to check that the development pattern of oocytes during follicle growth in vitro was similar to that already observed for oocytes developing in vivo, and that they reached the fertilizable oocyte stage. Results indicate that, during the 12-day-culture period, the oocytes grew until 74.3 +/- 4.2 microm, they became transcriptionally quiescent with a surrounded nucleolus (SN) chromatin organization, 50% of them exhibited regular calcium signals and 73.4% of them resumed meiosis. These data demonstrate that the protocol used generates oocytes with characteristics similar to oocytes allowed to mature fully in vivo and that it could be useful to set up the experimental culture of human ovarian follicles.

Survival improvement of children, adolescents and young women with cancer has led to consider with more cautiousness the long time iatrogenic side effects of treatments. Among those, premature ovarian failure has been described even for children. The aim of the study was to evaluate the indications and the feasibility of ovarian tissue cryopreservation for prepubertal girls.From September 2000 to December 2004, 47 prepubertal girls were referred by oncologists for ovarian tissue cryopreservation. After informed consent, the ovarian tissue was collected and frozen by a slow cooling protocol until the temperature of liquid nitrogen. A histological analysis and a follicular account were performed.The harvest of ovarian tissue was performed for 45 patients. No surgical side effect occurred. The younger girls had a follicular density higher than the older. No metastatic ovarian tumour was found.Numerous arguments as the follicular density in the ovary, the age of the patient, no surgical side effect, no metastatic ovarian tumour and recent progress in term of birth after ovarian tissue autografting allowed to think it is very important and ethical to propose an ovarian tissue cryopreservation even for children before sterilising treatment.

Mature oocytes are rare and highly specialized cells. In vitro maturation of human oocytes is an emerging assisted reproductive technology allowing to produce more mature oocytes without ovarian stimulation. Whereas in vitro maturation is technically more demanding than conventional in vitro fertilization for the laboratory, it carries many potential advantages, for example, in terms of lower treatment heaviness and removal of risk of severe ovarian hyperstimulation syndrome for the patients. Although the technology is still experimental, oocytes in vitro maturation has been successfully used and pregnancies and live births have been reported. Despite these successes, the overall efficiency of in vitro maturation remains low and this procedure must still be improved. The different steps of in vitro maturation process are shown and discussed as well as results in terms of pregnancy and live birth rates.

Longer survival after anticancer treatment has lead to concern about the long-term adverse effects. Altered fertility is of particular importance. Before sterilizing treatment, three non-exclusive methods can be proposed to preserve female fertility: in vitro fertilization followed by cryopreservation of embryos, cryopreservation of mature ovocytes, cryopreservation of ovarian tissue. The method or methods chosen will depend on the age of the patient, here marital status, the urgency of the treatment, and the type of disease. Embryo cryopreservation is a routine practice in medically assisted reproduction centers, while cryopreservation of mature ovocytes and ovarian tissue is still in the experimental phase. It is known however that mature ovocytes can be used after cryopreservation. Cyropreservation of ovarian tissue is a more difficult problem. To date, there have not been any pregnancies or births after freezing-thawing of human ovarian tissue. This tissue could be used in two ways: autograft and in vitro folliculo-ovocyte maturation. Despite the uncertainty concerning use, women cryopreservation of ovarian tissue quite well.

Journal Article, FLWIN, info:eu-repo/semantics/published

Ovarian tissue cryopreservation (OTCP) is a new procedure of medically assisted procreation, still at the experimental stage, whose primary aim is to store female gametes as sperm cryopreservation permits to do for male gametes. Ovarian tissue is removed very simply by laparoscopy. It survives well to freezing if the medium contains a cryoprotective agent and the rate of freezing is slow. In contrast, thawing must be rapid. There are three processes for the utilization of ovarian tissue after thawing. In vitro maturation and xenografting remain impossible for technical and ethical reasons. Autologous transplantation (orthotopic or heterotopic) of the tissue is therefore the only foreseeable method over the short term. Indications for OTCP must remain rare as long as no pregnancy has been obtained in human. At the present time, only female patients who would inevitably suffer the loss of their fertility should be able to take advantage of OTCP. Basically, this would mean women subjected to castrating anticancer therapy. It would seem reasonable to set the age limit at 35-years for carrying out OTCP. Lastly, female patients should be clearly informed that the method is still at the research stage, and in France samples must be taken in accordance with the laws governing clinical research.

THP-1 monocytoid cells, either not infected or chronically infected with human immunodeficiency virus type 1 (HIV-1), were challenged with Toxoplasma gondii. Parasitic growth, as assessed by trophozoite counting and measurement of supernatant p30 membrane antigen, was similar in HIV-infected and noninfected THP-1 cells. Also, T. gondii did not affect HIV replication. These experiments therefore failed to demonstrate any interaction between HIV-1 and T. gondii replication in concurrently infected monocytoid cells.

Dendrogenin A (DDA) is a steroidal alkaloid that we recently discovered in mammalian tissues and normal cells. We did not detect DDA in a panel of melanoma and breast cancer cells, while DDA was present in normal Human Mammary Epithelial Cells and normal Human Epidermal Melanocytes suggesting that a deregulation of DDA metabolism may occur during carcinogenesis. We established that DDA triggered melanoma and breast cancer cells re-differentiation and death in vitro and in vivo, demonstrating its anticancer potency. In the present study, we investigated the molecular mechanisms involved in the cytotoxicity of DDA in melanoma cells. We found that DDA induced a time- and concentration-dependent cytotoxicity with the characteristics of apoptosis in human (SKMEL-28) and mouse (B16F10) melanoma cell lines. DDA induced the impairment of mitochondrial functions and activated the executioner caspase 3. However, caspase inhibitors failed to inhibit cytotoxicity suggesting that other mechanisms were involved. DDA triggered autophagy in melanoma cells and induced an autophagic flux. Genetic and pharmacological inhibition of autophagy inhibited DDA cytotoxicity showing that autophagy was involved in the cytotoxicity, which contrasts with the classical involvement of autophagy in tumor cell survival. In the search for cytotoxic effectors, we found that DDA stimulated the re-expression and re-localization of Nur77 (NR4A1) to the mitochondria, and the re-expression of Nor1 (NR4A3) in melanoma cells. We showed that pharmacological inhibition of the nucleo-cytoplasmic shuttling of Nur77, and the knock-down of Nur77 and Nor1, led to the inhibition of the cytotoxic autophagy. This establishes that Nur77 and Nor1 are involved in the induction of cytotoxic autophagy by DDA. Using a combination of molecular modeling, binding, luciferase gene reporter and transcriptional assays in tumor cells, we showed that DDA was a ligand of LXRα (NR1H3) and LXRβ (NR1H2) and a selective modulator of LXR-dependent gene expression. Interestingly, DDA displayed a specific transcriptional fingerprint compared to prototypical LXR modulators. Finally, we found that LXRβ was required for the stimulation of Nur77 and Nor1 expression by DDA and the induction of a cytotoxic autophagy. Altogether, these data established that the newly identified mammalian steroidal alkaloid DDA is a ligand of LXR that induced cytotoxic autophagy through an LXRβ-,Nur77- and Nor1-dependent mechanism in melanoma cells. Thus, DDA constitutes a promising drug candidate for melanoma treatment through an original mechanism of action. Since Nur77 and Nor1 expression has been found to be repressed in a number of aggressive tumors, DDA may represent an interesting option for the treatment of cancers expressing LXRβ. Citation Format: Gregory Segala, Mathias C. Poirot, Philippe de Medina, Michael Paillasse, Jean-Marc Lobaccaro, Sandrine Silvente-Poirot, Marc Poirot. Dendrogenin A is a newly identified mammalian steroidal alkaloid that induced autophagic cell death in melanoma cells through an LXRbeta-, Nur77- and Nor1-dependent way. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1662. doi:10.1158/1538-7445.AM2013-1662

Summary. The determination of total fibrinolytic activity of ejaculates was realized by fibrin plate method. For the same seminal samples, tissue plasminogen activator (t-PA), urinary plasminogen activator (uPA) antigens and uPA activity were specifically quantified. The seminal values were fifty times higher than in the blood for t-PA and fifteen times for uPA. There was no correlation between the both levels but from split ejaculates measurements a higher concentration was observed in all first fractions. By zymography assays, it was shown that seminal plasminogen activators are under active forms. The lack of proUrokinase in semen was also demonstrated.

To obtain good quality superconducting thin films on conventional sapphire and silicon substrates we have investigated the deposition of buffer layers of lanthanum aluminate. The depositions were performed using rf-magnetron sputtering with a lanthanum aluminate target and a heated or rotating substrate holder. Energy-dispersive x-ray spectroscopy analysis showed that the stoichiometry of the films is correct and scanning electron microscopy analysis indicated good film morphology. X-ray diffraction analysis was used to determine the phase, purity, and degree of crystallinity of the buffer films both before and after annealing. We have been able to produce smooth amorphous and crystalline films of lanthanum aluminate with the correct stoichiometry on both sapphire and silicon and are currently working toward single crystal buffer layers with particular orientations.